Hemophilia: Landscape & Forecast

Landscape & Forecast
Hemophilia
Disease Landscape & Forecast
Published November 2016
Written by Kerri Brown, M Pharm

Hemophilia | Landscape & Forecast www.DecisionResourcesGroup.com
Table of Contents
. . . . . . . . . . Landscape
Disease . . . . . . . . . . . . . .&
. . Forecast
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
..................
. . . . . . . . . . . .Summary
Executive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. . . . . . . . . . . . . . . . . .
Introduction
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .Outlook
Commercial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
...................
. . . . . . . Outlook
Market . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
...................
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
..................
. . . . . . . Overview
Market . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10
..................
. . . . . . . Drivers
Market . . . . . . . and
. . . . Constraints
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
...................
. . . . . .Factors
What . . . . . . . Are
. . . .Driving
. . . . . . .the
. . . Market
. . . . . . . for
. . . Hemophilia?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
..................
. . . . . .Factors
What . . . . . . . Are
. . . .Constraining
. . . . . . . . . . . .the
. . . .Market
. . . . . . .for
. . .Hemophilia?
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14
..................
. . . . . . . . . . . . . . . . . Trends
Segment-Specific . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
...................
. . . . . . . . . . . .A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Hemophilia ..................
. . . . . . . . . . . .B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Hemophilia ..................
. . . . . . . . . . . .with
Hemophilia . . . . Inhibitors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
..................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
Forecast ...................
. . . . . . . . . . and
Etiology . . . . . Pathophysiology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
...................
. . . . . . . . .and
Etiology . . . .Pathophysiology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
...................
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
..................
. . . . . . . .Overview
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26
..................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Etiology ...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Pathophysiology ...................
. . . . Pathways
Key . . . . . . . . . .and
. . . .Drug
. . . . .Targets
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
...................
. . . . . . . . . . . . . . . . .Overview
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Introduction ...................
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .31
..................
. . . . . . .Insights
Expert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
..................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Overview ...................
. . . . . . . . . . . . . .Populations
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
...................
. . . . . . . . . . .Prevalent
Diagnosed . . . . . . . . . Cases
. . . . . .of
. . Hemophilia
. . . . . . . . . . . .A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
...................
. . . . . . . . . . .Prevalent
. . . . . .of
. . Hemophilia
. . . . . . . . . . . .B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
...................
© 2018 DR/Decision Resources, LLC. All rights reserved. 2

. . . . . . . . . . .Prevalent
. . . . . .of
. . Severe
. . . . . . . Hemophilia
. . . . . . . . . . . with
. . . . .Inhibitors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
...................
. . . . . . . . . . . . . Prevalent
Drug-Treated . . . . . . . . . .Cases
. . . . . .of. .Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
...................
. . . . . . . . . .Treatment
Current . . . . . . . . . . . . Overview
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Introduction ...................
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
..................
. . . . . . . . . . .Overview
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45
..................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Diagnosis ...................
. . . . . . . . . . .Criteria
Diagnostic . . . . . . . and
. . . . Diagnostic
. . . . . . . . . . .Tests
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
...................
. . . . . . . . . . .Providers
Treatment . . . . . . . . .and
. . . .Referral
. . . . . . . .Patterns
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47
..................
. . . . . . .Insight
Expert . . . . . . .on
. . .Diagnosis
. . . . . . . . . of
. . Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47
..................
. . . . . . . . . . .Goals
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
...................
. . . . . . . . Zero
Achieve . . . . .Annual
. . . . . . .Joint
. . . . . Bleeds
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50
..................
. . . . . .Optimization
Allow . . . . . . . . . . . . .of
. .Patients'
. . . . . . . . .Physical
. . . . . . . .Activity
. . . . . . . Levels
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50
..................
. . . . . . . . . .Adherence
Maximize . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51
..................
. . . . . . . . . injection
Minimize . . . . . . . . .burden
. . . . . . . (by
. . . .reducing
. . . . . . . . frequency
. . . . . . . . . .of
. . administration)
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51
..................
. . . . Physician
Key . . . . . . . . . .Insights
. . . . . . . .on
. . Clinical
. . . . . . . .End
. . . .Points
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51
..................
. . . . Current
Key . . . . . . . .Therapies
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53
Overview ..................
. . . . . . . . . . . . . .Hemophilia
Recombinant . . . . . . . . . . .A. Treatments
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
...................
. . . . . . . . . . . . . .Hemophilia
Recombinant . . . . . . . . . . .B. .Treatments
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
...................
. . . . . . . .Agents
Bypass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
...................
. . . . . . . . Practice
Medical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
...................
. . . . . . . . . . . .A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63
Hemophilia ..................
. . . . . . . . . . . .B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64
Hemophilia ..................
. . . . . . . . . . . .with
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65
..................
. . . . . . . . . . . . vs.
On-Demand . . . Prophylaxis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .66
..................
. . . . . . . . . . . . . . . . .Tailoring
Pharmacokinetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67
..................
. . . . . . . Patients
Outlier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .67
..................
. . . . . . . . . . .Guidelines
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
...................
. . . . . . . . . . . . . . . Treatment
Region-Specific . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
...................
. . . . . . . . . . . . . . . . . . . . . . . .Treatment
Country/Region-Specific . . . . . . . . . .Practices
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69
..................
. . . . . . . . .Need
Unmet . . . . . . Overview
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70
...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Introduction ...................
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70
..................

. . . . . . .Insight
Expert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71
..................
. . . . . . . . . . . of
Attainment . . .Unmet
. . . . . . .Needs
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
...................
. . . . . . . .Attainment
Current . . . . . . . . . . .of
. . Unmet
. . . . . . . Needs
. . . . . . in
. . .Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72
..................
. . . . . . .Attainment
Future . . . . . . . . . . .of
. . Unmet
. . . . . . . Needs
. . . . . . in
. . .Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72
..................
. . . . . . . . . . . .Therapies
Emerging . . . . . . . . . . . .Overview
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .74
...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Introduction ...................
. . . . Findings
Key . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .74
..................
. . . . . . . . .Overview:
Pipeline . . . . . . . . . Hemophilia
. . . . . . . . . . . .A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .75
..................
. . . . . . . . .Overview:
. . . . . . . . . . . .B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
..................
. . . . . . . . .Overview:
. . . . . . . . . . . .with
. . . .Inhibitors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78
..................
. . . . . . . . . . . Pipeline
Late-Phase . . . . . . . . Analysis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
...................
. . . . . . . . Developments
Notable . . . . . . . . . . . . . . in
. . .the
. . .Late-Phase
. . . . . . . . . . .Pipeline
. . . . . . . .for
. . .Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .80
..................
. . . . . . . . . . . . . Designation
Orphan-Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
...................
. . . . . . . . . . . . . Provisions:
Orphan-Drug . . . . . . . . . . .United
. . . . . . .States
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
...................
. . . . . . . . . . . . . Provisions:
Orphan-Drug . . . . . . . . . . .Europe
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
...................
. . . . . . . .Registries
Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
...................
. . . . . . . . . . . .Patient
Hemophilia . . . . . . .Registries
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
...................
. . . . . . Hemophilia
Other . . . . . . . . . . . .Registries
. . . . . . . . . and
. . . . Databases
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
...................
. . . . Emerging
Key . . . . . . . . . .Therapies
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
...................
. . . . . . . . . . . .A. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Hemophilia ...................
. . . . .94-9027
BAY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87
..................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92
N8-GP ..................
. . . . .910
ACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97
..................
. . . . . . . . . . . .B. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Hemophilia ....................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103
N9-GP ...................
. . . . . . . . . . . .with
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
....................
. . . . .817
BAX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107
...................
. . . . 689
CSL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109
...................
. . . . .910
ACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113
...................
. . . . . . . . . . . .Pipeline
Early-Phase . . . . . . . .Analysis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
....................
. . . . . . . . Developments
Notable . . . . . . . . . . . . . . in
. . .the
. . .Early-Phase
. . . . . . . . . . . .Pipeline
. . . . . . . .for
. . .Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .118
...................
. . . . . . . . .and
Access . . . . .Reimbursement
. . . . . . . . . . . . . . . . . . .Overview
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
.....................
. . . . . . . . . . . . . . . Reimbursement
Region-Specific . . . . . . . . . . . . . . . .Practices
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
....................
. . . . . . . States
United . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
....................

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
EU5 ....................
. . . . . . . . . . . . . . .Specific
Considerations . . . . . . . .to
. . Hemophilia
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
....................
. . . . . .Value
Payer . . . . . .Drivers
. . . . . . .and
. . . .Outcomes
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .124
...................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Procurement ....................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Methodology .....................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Methodology ....................
. . . . . . . . . . . Market
Bottom-Up . . . . . . . Forecasting
. . . . . . . . . . . .Overview
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130
...................
. . . . . . . .Share
Patient . . . . . and
. . . . Sales
. . . . . .Calculations
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
...................
. . . . . . . . . . . . . . . .Rate
Drug-Treatment . . . . .Assumptions
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
....................
. . . . . . . .Share
Patient . . . . . Assumptions
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
....................
. . . . . . . . Sources
General . . . . . . . .of
. . Data
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
....................
. . . . . . . .Days
Dosing, . . . . .of
. . Therapy,
. . . . . . . . .and
. . . .Compliance
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
....................
. . . . . .per
Price . . . Treated
. . . . . . . .Patient,
. . . . . . . 2025
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
....................
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Appendix .....................
. . . . . . . .Interviewed
Experts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
....................
. . . . . . . . . . . .Bibliography
Hemophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
....................

Disease Landscape & Forecast

Executive Summary
Introduction
Key Findings
The hemophilia A market will experience strong growth over the 2015-2025 forecast period. Hemophilia A is
more commercially attractive than hemophilia B; hemophilia A has a larger patient population and a greater
unmet need. This opportunity positively influences product R&D and disease visibility and is reflected in a larger
and more diverse number of candidates launching for hemophilia A through 2025 compared with hemophilia B.
Of those products forecast to launch, the non-rFVIII products will have the most significant impact on the
hemophilia A market. Failure of rFVIII EHLs to significantly reduce dosing burden (dosing frequency and route
of administration) over rFVIII SHLs will drive uptake of the non-rFVIII products; the non- rFVIII products will offer
once a month and/or subcutaneously dosing, in contrast with the SHL and EHL products that require
intravenous administration two to three times per week. Advate was the market leader in 2015, and held a 22%
market share in the U.S., but will experience declining use among rFVIII products due to the launch of several
other SHLs and EHLs, including Advate’s follow-on molecule, BAX 826. We forecast non- rFVIII products,
including gene therapies, for hemophilia A will generate sales of over $2 billion in 2025 (among adults 20+ years
old, severe hemophilia A only).
The hemophilia B market will also experience growth over the 2015-2025 forecast period. Interviewed
physicians comment that hemophilia B is often described as a “neglected disease,” and this notion is reflected
by a smaller and slightly less diverse number of candidates launching for hemophilia B through 2025 compared
with hemophilia A. EHL FIX products will have the most significant impact on the hemophilia B market. In
contrast to the EHL FVIIIs for hemophilia A, EHL FIX products have achieved meaningful increases in half-life
extension. This increase in half-life offers marked improvements in the clinical outcomes achievable, which
translates to cost offsets. As such, the bar is set high for further product launches, such as hemophilia B gene
therapies and non-rFIX products like fitusiran. Benefix was the market leader in 2015, and held a 54% market
share in the U.S., but will experience sizeable decreases primarily due to the U.S. launch of Idelvion in 2016 and,
to a lesser extent, the availability of Alprolix. We forecast the EHL rFIX products for hemophilia B will generate
sales of around $1 billion in 2025 (adults 20+ years old, severe hemophilia B only), with gene therapies capturing
very low patient shares relative to EHL rFIX patient shares.
The hemophilia with inhibitors market will experience growth over the 2015-2025 forecast period. Development
of inhibitors and the treatment of these patients remain one of the biggest challenges in hemophilia,
particularly in hemophilia A. Non-rFVIIa products will have the most significant impact on the inhibitors market,
due to their ability to treat inhibitors directly and provide the option of prophylactic bypass therapy to inhibitor
patients subcutaneously, unlike either of the current market leaders, Feiba and NovoSeven. Feiba and
NovoSeven collectively held 100% of the bypass agent market in 2015, but they will experience marked
decreases in patient share, primarily due to the launch of the non-rFVIIa products and, to a lesser degree, the

EHL-FVIIa products. We forecast the non- FVIIa bypass agents will generate sales of around $38 million in
2025 (adults 20+ years old, severe hemophilia A and B only).
Hemophilia Market Parameters and Forecast
Drug Treatment Rate Drug-Treated Cases

(%) (males 20+ years old) Drug Patient Share (%) Sales ($MM)
U.S./EU5 U.S./EU5 U.S./EU5 U.S./EU5
Top drugs by patient share—2015
Severe hemophilia A 100/100 7052/6433 Advate 22% (US), 525-575 (US), 350-450
26% (EU5) (EU5)
Eloctate 18% (US), 400-500 (US),

0% (EU5) 0 (EU5)
Kogenate 17% (US), 400-450 (US), 250-300

18% (EU5) (EU5)
Severe hemophilia B 100/100 1217/1107 Benefix 54% (US), 200-250 (US),

79% (EU5) 200-250 (EU5)
Alprolix 31% (US), 200-250 (US),

0% (EU5) 0 (EU5)
Rixubis 8% (US), 40-50 (US),

16% (EU5) 40-50 (EU5)
Severe hemophilia A 100/100 21/19 Feiba 50% (US), 5-6 (US),

and B with inhibitors 50% (EU5) 2-3 (EU5)
NovoSeven 50% (US), 10-12 (US),

50% (EU5) 4-6 (EU5)
Top drugs by patient share—2025
Severe hemophilia A 100/100 8085/7015 ACE 910 17% (US), 600-700 (US),
15% (EU5) 300-400 (EU5)
Advate 12% (US), 350-450 (US),

10% (EU5) 175-225 (EU5)
Eloctate 9% (US), 250-300 (US),

9% (EU5) 125-175 (EU5)
Severe hemophilia B 100/100 1517/1300 Idelvion 33% (US), 300-350 (US),

35% (EU5) 200-250 (EU5)
Benefix 21% (US), 75-125 (US),

21% (EU5 175-225 (EU5)
Alprolix 19% (US), 150-200 (US),

17% (EU5) 75-125 (EU5)
Severe hemophilia A 100/100 25/22 ACE 910 23% (US), 15-20 (US)
and B with inhibitors 23% (EU5) 10-15 (EU5)
CSL 689 15% (US), 10-15 (US)

15% EU5) 5-10 (EU5)
Fitusiran 15% (US), 5-10 (US),

15% (EU5) 5-10 (EU5)
Notes: Drug-treated cases in the inhibitor population includes only adults 20+ years old with severe hemophilia A or B; the low number is a reflection of the
inhibitor incidence rate in PTPs. Patient shares in hemophilia with inhibitors include both prophylactic and on-demand regimens. All numbers of drug-treated
cases of hemophilia A and B have been adjusted to reflect the number of patients who are not receiving a bypass therapy.
Source: Decision Resources Group

Hemophilia SWOT Analysis
Source: Decision Resources Group.

Actionable Recommendations in Hemophilia
Actionable Recommendation Supporting Expert Insight
Consider investigating more closely the 10% of severe phenotype patients “FVIII is not the only thing that modulates bleeding. Maybe if you
who bleed less than their “severe” peers. It may be possible to identify a investigated those patients that don’t bleed, in a lot more detail, looking for
genetic mutation that increases clotting, such as factor V Leiden, and exploit other associated proteins, you might find they have variations.”
the pathway to convert a severe phenotype to a moderate or mild phenotype. —Hematologist, United States
Make inhibitor formation with drug X more predictable by identifying factors “The way to generate cost offsets and get priority is if they can somehow
within current treatment protocols and within patients that increase the risk of show you that their drug or their treatment is less immunogenic than all
inhibitor generation. the others, or the way they’re using the drug [protocol] is causing less
inhibitors – it’s like you’re proactively managing inhibitors out of the
‘system’ before the riot begins”
—Payer, United States
Drive ABR to zero by demonstrating how the developer’s own brand “The majority of patients with severe hemophilia need prophylaxis. Even
improves clinical outcomes via improved adherence. Do this by those on prophylaxis do not adhere; therefore only about 30% of ‘severe
characterizing the heterogeneity of the hemophilia population, identifying hemophiliacs’ are optimally treated.”
factors contributing to poor adherence, and examine the impact of type of —Hematologist, United Kingdom
non-adherence. Then, show the link between adherence and clinical “There’s so much more to [adherence] than just fewer shots each week, I
outcomes. wish it were so simple. Some patients just don't infuse on time and it’s
counterintuitive. It’s definitely worth exploring that area further, you know,
the reasons why some patients adhere and others do not, predictive
analytics.”
—Payer, United States
Make dosing and/or efficacy more predictable when using drug X. Elucidate “We don’t know exactly how to use any of these products and you ask
the drivers underlying factor consumption and variance in use. Model some questions about when do you switch and how do you switch, well,
elasticity of trough levels in achieving zero annual bleeds. nobody really knows and even PK doesn’t always tell you how it affects
bleeding.”
—Hematologist, United States
If developing a gene therapy or gene editing therapy, consider identifying ultra “I think gene therapy uptake will be very tiny. There’s a big difference
high-dose utilization patients or other subpopulations who are “undertreated,” between people who are excited about it and willing to try it, who are
then demonstrate a link between their undertreatment and poor outcomes. altruistic. And those people who are going to be on Alprolix for a couple of
On this basis, it may be possible to negate physician, patient and payer years, will they be willing to do it? If you’re lucky, you find that 5% might be
uncertainties around the use of the gene therapy by demonstrating how it willing to try it.”
can bridge this gap. —Hematologist, United States
Investigate biomarkers of acute bleeds and joint disease. “What’s really important for us, ideally, is to have markers reflecting the
joint status; the progression of joint disease. The annualized bleeding rate
(ABR) doesn’t always correlate with progression of joint disease joint
status.”
—Hematologist, Italy
Use chromogenic assays in the R&D of new agents, specifically for potency “I expect to see chromogenic use increasing when the pegylated FIX
labeling and treatment monitoring. Work toward standardization of reagents comes out.”
used. —Hematologist, United Kingdom
“I’m not exactly sure how long-acting factor concentrates will affect the
current assay systems; with the new pegylated products, aPTT appears
to be pushed up proportionally.”

Commercial Outlook
Market Outlook
Key Findings
While the drug-treated severe hemophilia population is expected to remain static at 100%, launch of numerous
novel agents will drive growth of the hemophilia A, B, and inhibitors market during the forecast period.
Non-rFVIII products will have the most significant impact on the hemophilia A market through 2025. Failure of
rFVIII EHLs to significantly reduce dosing burden (dosing frequency and route of administration) over rFVIII
SHLs will drive uptake of the non-rFVIII products in hemophilia A. The latter will offer once-weekly to once-
monthly and/or subcutaneously dosing, in contrast with the SHL and EHL products, which require intravenous
administration at least two to three times per week.
EHL rFIX products will dominate the hemophilia B market through 2025. In contrast to the EHL FVIIIs for
hemophilia A, EHL FIX products have achieved meaningful increases in half-life extension. This increase in half-
life offers marked improvements in the clinical outcomes achievable, which translates to cost offsets. As such,
the bar is set high for further product launches, such as hemophilia B gene therapies and non-rFIX products like
fitusiran.
Development of inhibitors and the treatment of these patients remain one of the biggest challenges in
hemophilia, particularly in hemophilia A. Non-rFVIIa products will have the most significant impact on the
inhibitors market, due to their ability to provide the option of BAP therapy to inhibitor patients subcutaneously,
unlike either of the current market leaders, Feiba and NovoSeven.
Market Overview
Hemophilia A: Hemophilia A is regarded as a more commercially attractive market than hemophilia B; it has a larger
patient population and there is a greater unmet need.
The hemophilia A treatment landscape will look dramatically different circa 2021, after the launch of ACE 910
and fitusiran. Standard half-life agents like Advate, Kogenate, and Refacto/Xyntha will continue to hold some
market share. However, if the clinical objective is to have zero bleeds per annum in severe phenotypes to avoid
joint arthropathy, current products for hemophilia A have failed to address this goal sufficiently.
As such, we have seen a surge in development, most recently the launch of PEGylated agents, but soon to follow
will be the novel agents ACE 910 and ALN-AT3, which could address a large unmet need, with ACE 910 taking a
substantial market share. We anticipate BAX 826 and will launch in 2021 but do not see it taking substantial
patient share. Gene therapy for hemophilia A will have launched by 2025, and we expect it to have a better
uptake compared with gene therapy for hemophilia B, as the bar for what gene therapy needs to accomplish in
hemophilia A is not so high. We see the PEGylated agents Adynovate, BAY 94-9027 and N8-GP achieving a
relatively poor patient share in the EU5 and the United States. This uptake relates to physician concerns about
long-term use of IV PEGylated products, particularly in children.

New agents have been unable to show additional medical benefit; therefore, in the EU5, they will have difficulty
commanding a price premium over existing agents and instead may opt for price parity with the SoC and aim to
increase their market share. This is different in the United States, where the manufacturer is free to set its own
price.
Hemophilia B: Extended half-life FIX products are here to stay and will hold majority market share in 2025.
Advancement of products for treatment of hemophilia B in the last 50 years has not come far, with the exception of
the development of recombinant FIX, which entered the market quite late compared with recombinant FVIII.
We expect Idelvion to be the market leader in 2025 but still see a place for Alprolix and Benefix. We also expect,
as in the United States, that Idelvion and Alprolix will command a price premium in the EU5. Gene therapy will
have launched by 2025, but we expect relatively poor uptake, since there are good effective and safe treatments
for hemophilia B, and thus, the bar for what gene therapy needs to accomplish is raised quite high.
Hemophilia with Inhibitors: Through 2025, new bypass agents will minimize the clinical impact and physical
consequences of bleeds in inhibitor patients. But, they will introduce a layer of complexity with regard to variances
in dosing ranges and treatment protocols between and within patients. We believe the current treatments
NovoSeven and Feiba will remain in use but will have lost a sizeable market share by 2025 and will be reserved for on-
demand treatment and for use in surgical procedures.
NovoSeven and Feiba will continue to dominate the inhibitor market until the launch of ACE 910, which will be a
game-changer for inhibitor patients (hemophilia A only). BAX 817 will be seen as a “me too” to NovoSeven. CSL
689 will be the first EHL rFVIIa to market. We expect CSL 689 to take some market share from NovoSeven and
Feiba, but its uptake will be limited by the market impact of ACE 910, fitusiran, and the ATFPI products when
they launch. We expect CSL 689 to face some head winds regarding physician-voiced concerns on its clinical
efficacy and/or safety.
We expect continued use of plasma-derived agents, particularly in the context of ITI.
Launching in 2019, ACE 910 will be the first non- rFVIII to reach the market in our forecast window. The launch of
ACE 910 will mark the start of a very different-looking inhibitors market through 2025, in terms of available
products. We expect ACE 910 to be a game-changer for hemophilia A patients with inhibitors. ACE 910 launches
in the United States in 2019 and the EU in 2020, with potentially huge advantages versus NovoSeven, Feiba, and
also potentially CSL 689. We expect that novel agents like ACE 910 will take some market share from NovoSeven
and Feiba but may be relegated to second-line treatment in some patients, if NovoSeven and/or Feiba has not
worked.
We see a place for gene therapies as a potential alternative to bypass agents, given that they may be able to
tolerize someone through continuous expression of factor VIII or factor IX.
Hemophilia Market Landscape

2025 Number of Drug-Treated

Drug Name Launch Year (U.S./EU5) (U.S./EU5) 2025 Patient Share (U.S./EU5)
Hemophilia A
Advate 2003/2004 970/702 12%/10%
Kogenate FS 1993/2000 485/281 6%/4%
Kovaltry/Iblias 2016/2017 243/351 3%/5%
ReFacto/Xyntha 2001/1999 404/351 5%/5%
NovoEight 2015/2014 242/210 3%/3%
Nuwiq 2016/2014 404/420 5%/6%
Helixate 1993/2000 404/351 5%/5%
Afstyla 2016/2017 323/281 4%/4%
Adynovate 2015/2016 243/210 3%/3%
Eloctate 2014/2016 728/631 9%/9%
BAY 94-9027 2017/2018 323/281 4%/4%
N8-GP 2018/2019 243/210 3%/3%
BAX 826 2021/2022 404/351 5%/5%
ACE 910 2019/2019 1374/1052 17%/15%
Fitusiran 2020/2020 647/491 8%/7%
BMN 270 2021/2022 162/210 2%/3%
BAX 888 2023/2024 81/140 1%/2%
Hemophilia B
Benefix 1997/1997 319/273 21%/ 21%
Rixubis 2013/2015 76/52 5%/4%
Ixinity 2015/ ---- 46/0 3%/0%
Alprolix 2014/2016 288/221 19%/17%
Idelvion 2016/2017 501/455 33%/35%
N9-GP 2017/2017 76/104 5%/8%
SPK-FIX 2021/2022 15/13 1%/1%
AMT-060 2021/2022 15/13 1%/1%
DTX101 2021/2022 15/13 1%/1%
Fitusiran 2020/2020 61/65 4%/5%
Hemophilia with inhibitors
Feiba 1986/1986 4/3 15%/15%
NovoSeven 1999/1996 5/4 18%/18%
BAX 817 2017/2017 2/1 6%/6%
CSL 689 2019/2019 4/3 15%/15%
ACE 910 2019/2019 6/5 23%/23%
Fitusiran 2020/2020 4/3 15%/15%
MOD-5014 2021/2021 2/2 8%/8%
Notes: Percentage totals in hemophilia A and B do not include “other recombinant drugs” or “plasma-derived drugs”, and does not consider the use of drugs in
ITI protocols. Drug-treated cases in the inhibitor population includes only adults 20+ years old with severe hemophilia A or B; the low number is a reflection of
the inhibitor incidence rate in PTPs. Patient share in hemophilia with inhibitors includes both prophylactic and on-demand regimens where appropriate. All
numbers of drug-treated cases of hemophilia A and B have been adjusted to reflect the number of patients who are not receiving a bypass therapy.

Market Drivers and Constraints
What Factors Are Driving the Market for Hemophilia?
Chronic treatment with high-cost agents: It is expensive to treat hemophilia, especially for patients with the
severe phenotype and particularly for those who develop inhibitors to the injected clotting factor treatment.
Prophylaxis protocols, where patients receive regular infusions of clotting factor throughout their lives, can lead
to superior clinical outcomes and enhanced quality of life. Life expectancy of hemophilia patients now
approaches that of the background population, in part due to health systems being able to afford more
prophylactic treatment for more people. These prophylactic protocols cost substantially more than on-demand
protocols, where patients are treated only when a bleed occurs. Through 2025, we believe that increasing
numbers of patients will be using prophylactic protocols. In addition, more patients will want to switch to
the non-rFVIII novel treatments, some of which will be priced at a premium to the SoC as they have been able to
demonstrate an additional medical benefit.
Inability of current FVIII and FIX treatments and protocols to achieve zero bleeds per year: Even in
countries like Sweden, with 100% access to prophylactic treatment protocols, patients do not always achieve
their clinical goals. Additionally, high-dose prophylaxis patients have a life expectancy approaching that of the
background population, yet even in countries like France, with no cost-containment policies, patients are still
undertreated. In addition, heterogeneity of the hemophilia population decreases predictability of treatment
dosing regimens. Latent variables underlying these observations are not well understood, and it is this gap in
knowledge that is intensely driving the hemophilia A and B market and, to some extent, the inhibitor market.
The higher prevalence of hemophilia A: Hemophilia A is more commercially attractive than hemophilia B;
hemophilia A has a larger patient population and a greater unmet need in terms of ability to achieve zero bleeds
per year. This opportunity positively influences product R&D and disease visibility and is reflected in a larger
and more diverse number of candidates launching for hemophilia A through 2025 compared with hemophilia B.
The high prevalence of hemophilia A patients with inhibitors: Development of inhibitors (particularly
inhibitors to injected factor VIII) is a serious complication of hemophilia and makes management of bleeds
extremely challenging. In severe hemophilia with no inhibitors, primary prophylaxis is the standard of care in
many countries, but the same is not true in severe hemophilia with inhibitors, mainly due to the short half-lives
of current bypass agents and spiraling treatment costs.
The overall hemophilia population is increasing in size and age: The expected median survival time of
hemophilia patients in at least some developed countries is approaching background life expectancy. The
result will be an increasing and aging hemophilia population. As well as increased treatment numbers and
overall treatment duration, older patient populations have an increased frequency of major surgeries, for which
hemophilia patients may require continuous infusions of factor.

What Factors Are Constraining the Market for Hemophilia?
Most severe hemophiliac populations, the ones most likely to require factor concentrate, have already
been identified, and genetic mutation rate is not likely to increase. Most cases of severe hemophilia are
diagnosed within the first two years of life; thus, the vast majority of diagnoses of this phenotype have already
been captured. Moderate phenotypes may be diagnosed later in life, when patients visit the dentist or play
contact sports for the first time. Mild phenotypes may only be diagnosed if the patient experiences severe
trauma or undergoes a surgical procedure.
In increasingly cost-constrained health systems, hemophilia treatment must be provided in a cost-

effective way. Opportunities for premium pricing will be limited in the EU5 going forward. We believe more and
more EU countries will follow Germany’s model, having a preference for RCTs in hemophilia and demanding to
see a new hemophilia drug’s ability to demonstrate an additional medical benefit against a comparator drug or
the SoC. Or, failing this, developers should demonstrate comparative effectiveness in another way. In the
United States, interviewed payers are considering how to leverage the competitive hemophilia landscape post-
2019, given how many products are on the market now and will be after 2019. There is a future prospect of U.S.
health plan providers covering a smaller number of products, contracted, and raising the minimum prior
authorization criteria. The purpose of this strategy is primarily to drive down price, given that, in the United
States, the pharmaceutical company sets its own price.
The advent of “curative” treatments such as gene therapies. There are over ten gene therapies in the early-
stage pipeline for hemophilia A and B, combined. Assuming that developers are able to demonstrate sustained
FVIII/FIX expression in at least some patients, we believe the advent of gene therapies and other “curative”
treatments will constrain the market considerably. Assuming that gene therapy is not able to provide a “cure,”
gene therapy could, in effect, convert a severe phenotype into a moderate or mild phenotype. These patients
would utilize considerably less factor concentrate, if any.

Segment-Specific Trends
Hemophilia A
The hemophilia A market will experience growth over the 2015-2025 forecast period, with sales in severe adult
patients 20+ years old increasing from $2.6 billion in 2015 to $3.4 billion in 2025. Hemophilia A is more
commercially attractive than hemophilia B; hemophilia A has a larger patient population and a greater unmet
need. This positively influences product R&D and disease visibility and is reflected in a larger and more diverse
number of candidates launching for hemophilia A through 2025 compared with hemophilia B.
The hemophilia A treatment landscape will start to look dramatically different from 2019 onward with the
launch of ACE 910. SHLs such as Advate, Kogenate, and Refacto/Xyntha will continue to hold some market
share. But if the clinical objective is to have zero bleeds per annum in severe phenotypes to avoid joint
arthropathy, current products for hemophilia A have failed to meet this objective sufficiently. This helps to
explain the surge in development through the forecast period, most recently the launch of PEGylated agents,
but soon to follow will be the novel agents ACE 910 and fitusiran. These agents will address a large unmet need,
and we see ACE 910 taking a substantial market share from rFVIIIs by 2025 but with Advate retaining the largest
patient share of all remaining SHL rFVIIIs in 2025.
We anticipate BAX 826, an EHL, to have launched by 2021 but do not see it taking substantial patient share, as
some patients will have switched to BAX 826 from Advate or Adynovate
Gene therapy for hemophilia A will have launched by 2025, and we expect it to have a better uptake relative to
gene therapy for hemophilia B.
By 2025, we see the PEGylated agents Adynovate, BAY 94-9027 and N8-GP having achieved a relatively poor
patient share in both EU5 and the United States. This low share relates to physician concerns about long-term
IV PEGylated products, particularly in children. This sentiment also applies to Adynovate.
Hemophilia B
The hemophilia B market will experience growth over the 2015-2025 forecast period, with sales in severe adult
patients 20+ years old increasing from $628.4 million in 2015 to $1.1 billion in 2025. Hemophilia B is sometimes
described as a “neglected disease,” and this notion is reflected by a smaller number of candidates launching for
hemophilia B through 2025 compared with hemophilia A.
Pipeline agents will face tough competition through 2025, as efficacious, “safe” options already exist in the form
of the factor IX EHLs. Unlike factor VIII EHLs, the former have achieved meaningful increases in half-life extension
and thereby offer marked improvements in clinical outcomes achievable, which translates to cost offsets. As
such, the bar is set high for further product launches, such as hemophilia B gene therapies and non-rFIX
products like fitusiran.
We expect Idelvion to be the market leader in 2025 but still see a place for Alprolix and Benefix. Several gene
therapies will have launched by 2025, but we expect relatively poor uptake, initially.

Hemophilia with Inhibitors
The hemophilia with inhibitors market will experience growth over the 2015-2025 forecast period. The main
driver behind this growth is that development of inhibitors (particularly inhibitors to injected factor VIII) is one
of the most serious complications of hemophilia and makes management of bleeds and surgical procedures
extremely challenging.
Through 2025, new bypass agents—ACE 910, fitusiran, CSL 689, and the ATFPI class—will minimize the clinical
impact and physical consequences of bleeds in inhibitor patients. They will do so by making prophylaxis a
reality for patients with inhibitors (ACE 910 will treat inhibitors to FVIII only) and with the added convenience of
potential once-weekly to once-monthly dosing. But, they will introduce a layer of complexity with regard to
variances in dosing ranges and treatment protocols between and within patients.
We believe the current treatments NovoSeven and Feiba will remain in use primarily in surgery and as on-
demand treatment options, with ACE 910 holding the largest overall patient share (prophylaxis only) in 2025.
Toward 2025, we see a place for gene therapies as a potential alternative to bypass agents because they may be
able to tolerize patients through continuous expression of factor VIII or factor IX.

Forecast
Forecast Sales of Key Therapies in Hemophilia
2015 Estimated Major- 2025 Estimated Total

Market Total Sales 2025 Estimated Total Sales in 2025 Total Major-
Agent Patient Population ($MM) Sales in the U.S. ($MM) the EU5 ($MM) Market Sales ($MM)
Hemophilia A
Advate Severe hemophilia A, 750-1250 300-500 150-250 500-700

adults 20+ years old
Kogenate FS Severe hemophilia 500-1000 100-200 75-125 200-300

A, adults 20+ years old
Kovaltry/Iblias Severe hemophilia N.A. 50-150 25-75 100-200

ReFacto/Xyntha Severe hemophilia 250-750 100-200 50-100 200-250

NovoEight Severe hemophilia 175-225 50-150 25-75 100-200

Nuwiq Severe hemophilia 175-225 100-200 50-100 200-250

Helixate Severe hemophilia 450-500 100-200 50-100 200-250

Afstyla Severe hemophilia N.A. 100-200 50-100 200-250

Adynovate Severe hemophilia 25-75 50-100 25-75 100-150

Eloctate Severe hemophilia 400-500 200-300 100-200 350-450

BAY 94-9027 Severe hemophilia N.A. 50-150 50-100 150-200

N8-GP Severe hemophilia N.A. 50-100 25-75 100-150

BAX 826 Severe hemophilia N.A. 100-200 75-125 200-300

ACE 910 Severe hemophilia N.A. 600-700 300-400 800-1200

fitusiran Severe hemophilia N.A. 200-300 100-200 350-450

BMN 270 Severe hemophilia N.A. 100-200 200-300 350-450

BAX 888 Severe hemophilia N.A. 50-100 100-200 200-250

Hemophilia B
Benefix Severe hemophilia 350-450 75-125 60-70 100-200

B, adults 20+ years old
Rixubis Severe hemophilia B, 50-100 25-50 10-20 25-75

Ixinity Severe hemophilia B, 10-20 10-20 N.A. 10-20

Alprolix Severe hemophilia B, 200-250 150-200 75-125 250-300

Idelvion Severe hemophilia B, N.A. 325-375 200-250 550-650


N9-GP Severe hemophilia B, N.A. 25-50 25-50 50-100

SPK-FIX Severe hemophilia B, N.A. 10-20 10-20 25-50

AMT-060 Severe hemophilia B, N.A. 10-20 10-20 25-50

DTX 101 Severe hemophilia B, N.A. 10-20 10-20 25-50

fitusiran Severe hemophilia B, N.A. 30-40 20-40 50-75

Feiba Hemophilia A and B with 5-10 5-10 2-5 5-15

inhibitors, adults 20+
years old, severe
NovoSeven Hemophilia A and B with 10-20 5-15 2-5 10-20

years old, severe
BAX 817 Hemophilia A and B with 5-10 0-5 5-10

inhibitors, adults 20+ N.A.
years old, severe
CSL 689 Hemophilia A and B with N.A. 5-15 5-10 15-20

years old, severe
ACE 910 Hemophilia A with N.A. 15-20 10-15 25-35

years old, severe
fitusiran Hemophilia A and B with N.A. 5-15 5-10 15-20

years old, severe
MOD-5014 Hemophilia A and B with N.A. 0-5 0-5 5-10

years old, severe

U.S. Hemophilia A Drug Sales, 2015 and 2025, Severe, Adults 20+

U.S. Hemophilia B Drug Sales, 2015 and 2025, Severe, Adults 20+

U.S. Hemophilia with Inhibitors Drug Sales, 2015 and 2025, Severe, Adults 20+

EU5 Hemophilia A Drug Sales, 2015 and 2025, Severe, Adults 20+

EU5 Hemophilia B Drug Sales, 2015 and 2025, Severe, Adults 20+

EU5 Hemophilia with Inhibitors Drug Sales, 2015 and 2025, Severe, Adults 20+

Etiology and Pathophysiology
Etiology and Pathophysiology
Key Findings
Hemophilia is an X-linked heritable coagulopathy in which a deficiency or absence of procoagulant factor VIII or
factor IX results in a disrupted clotting cascade. Blood is unable to coagulate normally, leading to uncontrolled
bleeding episodes.
Clinical severity of hemophilia A and B is classified according to the level of residual clotting factor present in
plasma; severe (<1% or normal), moderate (1-5% of normal), or mild (>5% to <40% of normal). Hemophilia
is monogenic, meaning that correcting one gene potentially makes a big impact on the disease. One does not
need to accomplish 100% correction to change the bleeding picture.
The primary symptom in the severe forms of hemophilia is hemorrhaging into the joints (e.g., knees, ankles,
elbows) and muscles. Over time, complications from recurrent hemarthrosis and soft-tissue hematomas can
result in severe arthropathy, joint contractures, and pseudotumors, leading to chronic pain, disability, and
impairment of health-related quality of life.
Arthropathy as a consequence of hemophilia represents the single largest cause of morbidity in patients with
hemophilia, and as such, prevention of this condition is one of the main aims of treatment.
Prevention (using prophylactic regimens) is not 100% effective, least so in severe hemophilia A patients, who
may still experience an ABR above zero. Further, ABR does not always correlate with progression of joint disease
status. Thus, detectable biomarkers reflecting the joint status would be helpful.

Disease Overview
Hemophilia is an X-linked heritable coagulopathy in which a deficiency or absence of procoagulant factor VIII or
factor IX results in a disrupted clotting cascade, leading to uncontrolled bleeding episodes. Clinical severity of
hemophilia A and B is classified according to the level of residual clotting factor present in plasma; severe (<1%
of normal), moderate (1-5% of normal), or mild (>5% to <40% of normal).
The primary symptom in severe phenotypes is hemorrhaging into the joints (e.g., knees, ankles, elbows) and
muscles. Unchecked, the result is progressive arthropathy and crippling disability. Intracranial hemorrhage or
bleeding into the viscera can be life-threatening.
Inhibitor (antibody) development can be a major side effect of treatment with replacement factor. Inhibitors
bind and interfere with the function of injected factor, often rendering it useless. Therefore, inhibitor patients
tend to have very bad joint disease and higher mortality than the general hemophilia population. Risk of
developing inhibitors is a complex interplay between genetics (e.g., type of mutation, ethnicity, polymorphisms
in immunoregulatory genes and in HLA class II genes) and environment (type of product used [plasma-derived
vs. recombinant], high-dose vs. low-dose factor).
Inhibitors develop in around 17% of patients with severe hemophilia A and in 1-2% of patients with severe
hemophilia B. Inhibitors can be type I (second-order kinetics and strong binding) or type II (slower kinetics and
more rapid dissociation). Type I inhibitors are more common in severe hemophilia. Factor IX inhibitors are
associated with a higher rate of anaphylactic reactions and nephrosis during ITI.
Etiology
Congenital hemophilia is a monogenic bleeding disorder, inherited in an X-linked recessive pattern and
therefore occurring primarily in males. As carriers, females can still experience bleeding problems, e.g., during
dental extractions. Rare cases of females with hemophilia have been observed, such as those caused by
lyonization or Turner’s syndrome. Around one-third of patients with congenital hemophilia have no family
history; spontaneous mutations during spermatogenesis have been implicated.
Acquired hemophilia is a rarer condition, resulting from the development of auto-antibodies to coagulation
factors, most commonly FVIII. The cause for the development of acquired hemophilia is currently unknown.

Genetics of Hemophilia
Type Gene affected Normal function of gene Number of mutations Nature of mutations
Hemophilia A F8 (produces factor VIII), Factor VIII is a cofactor for Currently 2,015 known Point (66%) and deletion
which is located on the long factor Ixa, which, in the unique variants (24%) mutations are by far
arm of the X chromosome presence of Ca2+ and (mutations).c the most common types of
at position 28. phospholipids, converts variant.c Almost half of all
factor X to the activated severe hemophilia A cases
form Xa. The F8 gene are caused by inversions
produces two alternatively between genes in intron 22
spliced transcripts; isoform and sequences outside the
A circulates in plasma and gene. Arg is the most
associates with von mutated amino acid in the
Willebrand factor in a F8 protein.
noncovalent complex.
Isoform B consists primarily
of the phospholipid binding
domain of factor VIIIc. This
binding domain is essential
for coagulant activity.
Defects in F8 result in
hemophilia A.a
Hemophilia B F9 (produces factor IX), Factor IX exists in the Currently 1,095 known Complete gene deletions
which is located on the long circulation as an inactive unique variants are a strong predictor of
arm of the X chromosome zymogen. It is converted to (mutations).d inhibitor development. Point
between positions 27.1 and its active form by factor XIa. (73%) and deletion (16%)
27.2. The role of activated factor mutations are by far the
IX in the blood coagulation most common types of
cascade is to activate factor variant.d
X to its active form through
interactions with Ca2+ ions,
membrane phospholipids,
and factor VIII. Defects in
F9 result in hemophilia B. b
a. http://www.ncbi.nlm.nih.gov/gene/2157
b. http://www.ncbi.nlm.nih.gov/gene/2158
c. http://www.factorviii-db.org/
d. http://www.factorix.org/

Pathophysiology
Intra-articular and intramuscular bleeding is a major clinical manifestation of hemophilia. Bleeding most
commonly occurs in the knees, elbows, and ankles, and is often evident from early childhood.
The pathogenesis of hemophilic arthropathy is multifactorial, with changes occurring in the synovium, bone,
cartilage, and blood vessels. Recurrent joint bleeding causes synovial proliferation and inflammation
(hemophilic synovitis) that contribute to end-stage degeneration (hemophilic arthropathy), with pain and
limitation of motion severely affecting patients’ quality of life.
The marked inflammation and synovial hypertrophy seen in hemophilic arthropathy bear resemblance to the
pathological mechanisms seen in rheumatoid arthritis, while progressive degeneration of the hyaline cartilage
mimics that observed in osteoarthritis. These processes occurring in parallel result in a degenerative arthritis
that progresses until the joint is completely destroyed.
Generally speaking, individuals with “severe” disease display clinical symptoms more frequently and are
considered at higher risk of hemorrhagic events and musculoskeletal problems.

Key Pathways and Drug Targets
Replacement of clotting factors represents an effective method of treatment for patients with hemophilia. The
mechanism of action of injected clotting factors is the temporary replacement of the missing or diminished
activity of clotting factors that are needed for effective hemostasis in hemophilia patients, based on the intrinsic
pathway of coagulation feedback cascade.
Extending the half-life of these replacement factors is seen as an approach to offer better treatment options and
a lower injection burden. While interviewed physicians note marked improvements to the half-life extensions
for the treatment of hemophilia B, efforts to extend the half-life of factor VIII treatments for hemophilia A are
less impressive.
Currently, patients who have developed inhibitors to injected FVIII or FIX must inject frequently with products
that possess relatively short half-lives.
rFVIIa’s apparent mechanism of action is activation of the final common pathway of the coagulation
cascade independent of the presence of factor VIII and factor IX. rFVIIa forms a complex with tissue factor,
which in the presence of calcium and phospholipids activates coagulation factor X, which then initiates the
conversion of prothrombin into thrombin.
Feiba’s apparent mechanism of action is induction and facilitation of thrombin generation, a process for
which factor V is crucial.
Extending the half-life of treatments for hemophilia with inhibitors may make prophylaxis a possibility for
inhibitor patients.

Most Active Areas of Research in Hemophilia A
Technology Mechanism of Action
Bispecific antibody Normally, FVIII takes on cofactor activity when activated at the site of a
coagulation reaction. An activated form of FVIII simultaneously binds
factor IXa and factor X to promote factor IXa-mediated factor X activation
and the consequent blood coagulation reaction.
The bispecific antibody also simultaneously binds factor IXa and factor X,
exerting FVIII-mimetic function to promote the blood coagulation
reaction, regardless of the presence of inhibitors against FVIII.
Gene silencing Small interfering RNA (siRNA) interferes with or blocks the gene for the
protein antithrombin, thereby reducing its production. In the body,
antithrombin blocks thrombin, one of the substances involved in blood
clotting. By reducing the production of antithrombin, the medicine is
expected to increase the clotting capacity of the blood in patients with
hemophilia A.
Tissue factor pathway inhibitor Monoclonal antibody recognizes and attaches to tissue-factor-pathway
inhibitor (TFPI). TFPI blocks the production of factor Xa, a protein central
to the clotting process. The production of factor Xa is controlled by two
separate pathways, one involving factor VIII, the other involving TFPI. By
attaching to TFPI, its action is blocked, resulting in a prolonged
production of factor Xa. This is expected to increase the ability of the
blood to clot and help control the bleeding disorder, bypassing the need
for factor VIII.
Gene therapy The liver is a natural site of production of FIX. An AAV carries the FIX gene
and uncoats and delivers the FIX gene in the nucleus of a liver cell. The
protein is then expressed into the circulation, eliminating the need for chronic
infusions of recombinant clotting factor.
Gene editing therapy Zinc finger nuclease technology targets and integrates a functional copy of
the FVIII or FIX gene into a safe-harbor site, the albumin gene or locus, in
liver cells. An albumin promoter produces and secretes continuous
therapeutic levels of clotting factors VIII and IX for hemophilia A and B,
respectively, and eliminates the need for chronic infusions of recombinant
clotting factor.

Epidemiology Overview
Introduction
Key Findings
The total number of prevalent cases of hemophilia A across the countries under study will increase by 9% from
43,000 in 2015 to 47,000 in 2025.
The total number of prevalent cases of hemophilia B across the countries under study will increase by 14% from
almost 9,300 in 2015 to over 10,600 in 2025.
Approximately 82% of all prevalent cases of hemophilia are type A, and over 99% of cases of hemophilia are
male.
We expect the diagnosed prevalence of severe hemophilia A to remain at approximately 100% through the
forecast period because almost all severe phenotype patients are usually identified easily by physicians and are
usually diagnosed between birth and age two years.
We expect the severe hemophilia drug-treated population to remain at approximately 100% through the
forecast period because almost all bleeds that a person with severe hemophilia experiences do not resolve on
their own, and they almost always require treatment.

Expert Insights
“I don’t expect diagnosis of severe hemophilia A or B to increase in the future. I do expect an increase in the
diagnosis of milder forms, when the patient is diagnosed later in life because of surgery and other pathology
that comes into play.”
– Hematologist, United Kingdom
“5-10% of all hemophiliacs [A and B] remain undiagnosed in Italy, but these are very mild cases of hemophilia. It
is almost normal to have them undiagnosed until adult age.”
– Hematologist, Italy
“As treatment gets better, people who are at risk of having kids with hemophilia are more likely to have kids, as
they face a lower risk. This will contribute to an increased diagnosed prevalence.”
–Hematologist, Unites States
“Along with life expectancy of hemophilia patients rising, plus more hemophilia patients or hemophilia carriers
deciding to have children - hemophilia is now deemed ‘treatable’ - this may account for the increases in
diagnosed prevalence we see in the future.”
– Hematologist, Germany
Overview
Prevalence of Hemophilia A per 100,000 Among People of All Ages in 2015 and
2025
The prevalence of hemophilia A varies somewhat between the countries under study, ranging from 5 per 100,000 in
Italy to 7.5 per 100,000 in the United Kingdom in 2015.

Prevalence of Hemophilia B per 100,000 Among People of All Ages in 2015 and
2025
There is some variation in the prevalence of hemophilia B among the countries under study, ranging from 1.1 per
100,000 in Italy to 1.6 per 100,000 in the United Kingdom in 2015.

Relative Sizes of the Contributing Factors to the Trend in Prevalent Cases of

Hemophilia A Over the Next Ten Years
The number of prevalent cases of hemophilia A will evolve over time as a function of changing levels of exposure to
risk factors and demographic trends.


Hemophilia B Over the Next Ten Years
The number of prevalent cases of hemophilia B will evolve over time as a function of changing levels of exposure to
risk factors and demographic trends.


Hemophilia B Over the Next Ten Years
Analysis of the Prevalent Cases of Hemophilia A in 2015 by Severity
45% of prevalent cases of hemophilia A across the countries under study were classified as severe in 2015, compared
with only 13% classified as moderate.
Analysis of the Prevalent Cases of Hemophilia A in 2015 by Severity

Analysis of the Prevalent Cases of Hemophilia B in 2015 by Severity
40% of prevalent cases of hemophilia B across the countries under study were classified as severe in 2015, compared
with only 22% classified as moderate.
Analysis of the Prevalent Cases of Hemophilia B in 2015 by Severity
Epidemiology Populations
Diagnosed Prevalent Cases of Hemophilia A
Disease Definition
We define hemophilia A as having a low level of factor VIII blood coagulation factor in blood samples. Based on these
measured concentrations of coagulation factors, mild, moderate, and severe forms of the disease can be defined, as
follows:
Mild: 0.05-0.4 IU/mL.
Moderate: 0.01-0.05 IU/mL.
Severe: <0.01 IU/mL.
Additionally, the presence of inhibitors to either factor VIII or factor IX can also be measured in the blood. The
presence of inhibitors is an important consideration in managing the disease due to their inhibiting effect on
therapeutic or prophylactic administration of blood coagulation factors.
Methods
Country-specific studies that report age- and gender-specific results were preferred. When country-specific studies
were unavailable, we extrapolated results from studies based in comparable populations. When gender-specific
results were not available, we used gender-specific results from other studies after making any appropriate

adjustments to reflect differences in age-adjusted risk.
In this section, we outline how we estimated the diagnosed prevalence of hemophilia A in those countries for which
we required extrapolations from or modification to a reported prevalence. For countries where estimates are
derived from a single country-specific study and no further extrapolations were required, see the "Sources Used"
table for the studies used.
To estimate the diagnosed prevalence of hemophilia A in the United States, we used Canadian data (Stonebreaker
JS, 2010).
To estimate the diagnosed prevalence of hemophilia A in France, Germany, and the United Kingdom, we used the
age- and gender-specific estimates from the United Kingdom (Stonebreaker JS, 2010).
To estimate the diagnosed prevalence of hemophilia A in Italy and Spain, we used the estimates from a registry-
based Italian survey (Iorio A, 2010).
We found two studies reporting contemporary, reliable, and detailed survival data for HIV-negative hemophiliacs,
one based in Italy (Tagliaferri A, 2010) and the other in the United Kingdom. We used the survival estimates from the
U.K. study in our model because it reported survival for the same age-groups as used by the Italian study we used to
estimate prevalence (Iorio A, 2008) and reported the survival numerically whereas the Italian survival study reported
estimates only graphically.
To forecast the prevalence for an age-group, G, at time t+1, we assume that the prevalence Gt+1 will equal the
prevalence at an earlier time point, Gt minus the mortality over the period t to t+1, denoted by Mt,t+1, and adding
any incident cases that would have occurred over the same period, denoted by It,t+1. In equation form:
Gt+1 = Gt - Mt,t+1 + It,t+1
Regarding the estimation of any incident cases that would have occurred in the elapsed interval, data from the
Italian registry show very few cases being diagnosed in age-groups older than 25 years. The maximum recorded age
at diagnosis in the Italian registry was 39.5 years. We therefore made a conservative assumption that the number of
incident cases diagnosed among those older than 25 would be negligible. This assumption allowed us to use the
simplified equation for age-groups 25 or older:
Gt+1 = Gt - Mt,t+1
Applying this equation using the prevalence data from the Italian registry (Iorio A, 2008) and the U.K. HIV-negative
cohort (Darby SC, 2007) therefore allowed us to forecast forward, using reasonable and conservative assumptions,
the prevalence of hemophilia as the non-HIV-infected cohorts age. Because the prevalence estimates reported in
younger age-groups in recent studies already reflect the decreased risk of HIV among hemophiliacs, we made no
adjustment in the prevalence of those age-groups over time.
We stratify by subtype by using the subtype-specific prevalence estimates reported by the Italian registry-based

study (Iorio A, 2008). The resulting proportion of the patient population in each country considered in this report is in
the region of 80-85% hemophilia A, which is a figure consistent with other studies reporting the percentage within
each subtype (Brettler DB, 1990; Kulkarni R, 2005; Plug I, 2004; Plug I, 2006).
To calculate the number of diagnosed prevalent cases of hemophilia A in each country, we multiplied the age- and
gender-specific diagnosed prevalence estimated from these studies by United Nations’ age- and gender-specific
population estimates (United Nations, 2016) for each forecast year.
We performed a review of the published epidemiological literature to identify historical trends in the diagnosed
prevalence of hemophilia A and any risk factors for hemophilia A that may be expected to change over the course of
our forecast period and therefore affect the diagnosed prevalence within any specific age-group or gender group.
From our review, we found no reliable studies depicting any risk factor that can be incorporated into our forecast
model in any quantitative way to modify diagnosed prevalence over our forecast period. Therefore, in the absence of
any supporting and quantifiable evidence for a changing risk of hemophilia A over the ten-year forecast period, we
held diagnosed prevalence constant in each group. Thus, changes in the number of diagnosed prevalent cases over
the forecast period are due to changes in the size and composition of the overall population.
Sources Used for Diagnosed Prevalence of Hemophilia A
Country Source
United States , France, Germany, United Kingdom Stonebreaker JS, 2010
Italy, Spain Iorio A, 2010
Note: Full source citations appear in "Bibliography."
Number of Diagnosed Prevalent Cases of Hemophilia A in the Major

Pharmaceutical Markets, 2015-2025
2015 2020 2025 Growth (%/yr)
United States 23,151 24,433 25,722 1.1
Europe 20,006 20,673 21,329 0.6
France 4,715 4,918 5,116 0.8
Germany 5,076 5,177 5,255 0.3
Italy 2,968 3,024 3,102 0.4
Spain 2,401 2,418 2,453 0.2
United Kingdom 4,846 5,136 5,403 1.1
Major-market total 43,157 45,106 47,051 0.9
Notes: Numbers reflect rounding. Estimates include males and females of all ages.

Diagnosed Prevalent Cases of Hemophilia B
Disease Definition
We define hemophilia B as having a low level of factor IX blood coagulation factor in blood samples. Based on these
measured concentrations of coagulation factors, mild, moderate, and severe forms of the disease can be defined, as
follows:
Mild: 0.05-0.4 IU/mL.
Moderate: 0.01-0.05 IU/mL.
Severe: <0.01 IU/mL.
Additionally, the presence of inhibitors to either factor VIII or factor IX can also be measured in the blood. The
presence of inhibitors is an important consideration in managing the disease due to their inhibiting effect on
therapeutic or prophylactic administration of blood coagulation factors.
Methods
Country-specific studies that report age- and gender-specific results were preferred. When country-specific studies
were unavailable, we extrapolated results from studies based in comparable populations. When gender-specific
results were not available, we used gender-specific results from other studies after making any appropriate
adjustments to reflect differences in age-adjusted risk.
In this section, we outline how we estimated the diagnosed prevalence of hemophilia B in those countries for which
we required extrapolations from or modification to a reported prevalence. For countries where estimates are
derived from a single country-specific study and no further extrapolations were required, see the "Sources Used"
table for the studies used.
To estimate the diagnosed prevalence of hemophilia B in the United States, we used Canadian data (Stonebreaker
JS, 2012).
To estimate the diagnosed prevalence of hemophilia B in France, Germany, and the United Kingdom, we used the
age -and gender-specific estimates from the United Kingdom (Stonebreaker JS, 2012).
To estimate the diagnosed prevalence of hemophilia B in Italy and Spain, we used the estimates from a registry-
based Italian survey (Iorio A, 2010).
We found two studies reporting contemporary, reliable, and detailed survival data for HIV-negative hemophiliacs,
one based in Italy (Tagliaferri A, 2010) and the other in the United Kingdom. We used the survival estimates from the
U.K. study in our model because it reported survival for the same age-groups as used by the Italian study we used to
estimate prevalence (Iorio A, 2008) and reported the survival numerically whereas the Italian survival study reported

estimates only graphically.
To forecast the prevalence for an age-group, G, at time t+1, we assume that the prevalence Gt+1 will equal the
prevalence at an earlier time point, Gt minus the mortality over the period t to t+1, denoted by Mt,t+1, and adding
any incident cases that would have occurred over the same period, denoted by It,t+1. In equation form:
Gt+1 = Gt - Mt,t+1 + It,t+1
Regarding the estimation of any incident cases that would have occurred in the elapsed interval, data from the
Italian registry shows very few cases being diagnosed in age-groups older than 25 years. The maximum recorded age
at diagnosis in the Italian registry was 39.5 years. We therefore made a conservative assumption that the number of
incident cases diagnosed among those older than 25 would be negligible. This assumption allowed us to use the
simplified equation for age-groups 25 or older:
Gt+1 = Gt - Mt,t+1
Applying this equation using the prevalence data from the Italian registry (Iorio A, 2008) and the U.K. HIV-negative
cohort (Darby SC, 2007) therefore allowed us to forecast forward, using reasonable and conservative assumptions,
the prevalence of hemophilia as the non-HIV-infected cohorts age. Because the prevalence estimates reported in
younger age-groups in recent studies already reflect the decreased risk of HIV among hemophiliacs, we made no
adjustment in the prevalence of those age-groups over time.
We stratify by subtype by using the subtype-specific prevalence estimates reported by the Italian registry-based
study (Iorio A, 2008). The resulting proportion of the patient population in each country considered in this report is in
the region of 15-20% hemophilia B, which is a figure consistent with other studies reporting the percentage within
each subtype (Brettler DB, 1990; Kulkarni R, 2005; Plug I, 2004; Plug I, 2006).
To calculate the number of diagnosed prevalent cases of hemophilia B in each country, we multiplied the age- and
gender-specific diagnosed prevalence estimated from these studies by United Nations’ age- and gender-specific
population estimates (United Nations, 2016) for each forecast year.
We performed a review of the published epidemiological literature to identify historical trends in the diagnosed
prevalence of hemophilia B and any risk factors for hemophilia B that may be expected to change over the course of
our forecast period and therefore affect the diagnosed prevalence within any specific age-group or gender group.
From our review, we found no reliable studies depicting any risk factor that can be incorporated into our forecast
model in any quantitative way to modify diagnosed prevalence over our forecast period. Therefore, in the absence of
any supporting and quantifiable evidence for a changing risk of hemophilia B over the ten-year forecast period, we
held diagnosed prevalence constant in each group. Thus, changes in the number of diagnosed prevalent cases over
the forecast period are due to changes in the size and composition of the overall population.

Sources Used for Diagnosed Prevalence of Hemophilia B
Country Source
United States , France, Germany, United Kingdom Stonebreaker JS, 2012
Italy, Spain Iorio A, 2010
Number of Diagnosed Prevalent Cases of Hemophilia B in the Major

2015 2020 2025 Growth (%/yr)
United States 5,003 5,402 5,845 1.6
Europe 4,273 4,525 4,762 1.1
France 1,019 1,088 1,155 1.3
Germany 1,072 1,125 1,167 0.9
Italy 627 652 683 0.9
Spain 505 527 542 0.7
United Kingdom 1,050 1,133 1,215 1.5
Diagnosed Prevalent Cases of Severe Hemophilia with Inhibitors
Disease Definition
We base our estimates of the inhibitor status of diagnosed prevalent cases of severe hemophilia on population-
based studies. We define inhibitors as the presence of alloantibodies that inhibit the procoagulant function of FVIII.
Methods
In this section, we outline how we estimated the inhibitor status of severe hemophilia in those markets for which we
required extrapolations from or modification to a reported inhibitor status. When a market's estimate is derived
from a single country-specific study, please refer to the "Sources Used" table.
To estimate the inhibitor status of severe hemophiliacs for the markets under study, we used subtype- and severity-
specific prevalence estimates from an Italian study (Iorio A, 2008).

Sources Used for Inhibitor Status of Severe Hemophilia
Country Source
All countries Iorio A, 2008
Number of Diagnosed Prevalent Cases of Severe Hemophilia with Inhibitors in the

Major Pharmaceutical Markets by Type, 2015-2025
2015 2020 2025 Growth (%/year)
United States 2,028 2,104 2,208 0.9
Hemophilia A 1,993 2,069 2,173 0.9
Hemophilia B 35 35 35 0.0
Europe 1,275 1,309 1,332 0.4
Hemophilia A 1,256 1,290 1,312 0.4
France 299 309 318 0.6
Hemophilia A 295 305 314 0.6
Germany 294 297 298 0.1
Hemophilia A 290 293 294 0.1
Italy 242 242 243 0.0
Hemophilia A 238 238 239 0.0
Spain 141 145 141 0.0
Hemophilia A 138 142 139 0.1
Hemophilia B 3 3 2 (4.0)
United Kingdom 299 316 332 1.1
Hemophilia A 295 312 326 1.0
Hemophilia A 3,249 3,359 3,485 0.7

Drug-Treated Prevalent Cases of Hemophilia
We used the following sources to estimate the percentage of prevalent cases in the diagnosed population that are
drug-treated:
Opinions of thought leaders. We conducted in-depth interviews with several hemophilia experts throughout the
major markets who shared with us their insights into population proportion diagnosed, treatment patterns,
and medical practices.
Decision Resources Group market model. Our estimates of the percentage of prevalent cases that are
diagnosed and drug-treated are used in our patient-based market model for hemophilia and cross-checked
against published sales data provided by company annual reports, SEC filings, government health authorities,
and private vendors (e.g., Symphony Health Solutions’ Pharmaceutical Audit Suite [PHAST]) in the first year of
the study period. When a drug is used to treat several diseases, we apply a “diagnosis value” (obtained from
Encuity Research’s TreatmentAnswers or physician survey data) to the total sales of the drug to obtain only
those sales that are attributable to the disease under study (i.e., sales are calculated for the diagnosis under
study). We reconcile our patient-based market model with our prescription-based market model by adjusting
variables (e.g., number of diagnosed or drug-treated patients, percentage treated with a particular drug,
compliant days of therapy), as appropriate, to yield a validated base-year market model. On that basis, we
forecast sales over a ten-year period.
Sources Used for Drug-Treated Prevalence of Hemophilia
Country Source
All countries Decision Resources Group primary research
Number of Drug-Treated Prevalent Cases of Severe Hemophilia in the Major

2015 2020 2025 Growth (%/yr)
United States 13,820 14,555 15,268 1.0
Europe 9,015 9,302 9,608 0.6
France 2,061 2,125 2,239 0.8
Germany 2,118 2,174 2,226 0.5
Italy 1,714 1,739 1,746 0.2
Spain 1,018 1,037 1,043 0.2
United Kingdom 2,104 2,227 2,354 1.1

Current Treatment Overview
Introduction
Key Findings
Administration of clotting factors represents an effective treatment for patients with hemophilia. The clotting
factors can be either plasma-derived or recombinant and, if recombinant, are described as SHL or EHL in
nature. Use of recombinant and plasma-derived varies between and within countries and depends upon patient
preference, risk of inhibitor formation, local clinical protocols, and presence of inhibitors during ITI, among
other factors.
Many more treatment options exist for hemophilia A compared with hemophilia B. This inconsistency is a
reflection of the higher commercial interest in hemophilia A, which is driven by a greater unmet need and a
larger patient population.
Terminal half-lives of SHL and EHL hemophilia A treatments remain unimpressive. These half-lives contrast
with those of hemophilia B treatments whose terminal half-lives have been extended substantially and offer
significant improvements in clinical outcomes.
We note particularly negative sentiment around the use of PEGylated EHLs in children, from both physicians
and payers, owing to safety concerns.
Dependent upon inhibitor titer levels, inhibitor patients can be effectively treated using plasma-derived or
recombinant factor VIII/factor IX in an ITI protocol. Most inhibitor patients cannot use factor VIII or factor IX for
prophylaxis because the half-life is too short, instead using bypass agents. The short half-lives of current bypass
agents often make for laborious dosing regimens.
Treatment Overview
Hemophilia is an X-linked recessive bleeding disorder that can be effectively treated by replacing the missing
clotting factor.
Treatments are plasma-derived or recombinant factor VIII or factor IX and are further classified as either SHL or
EHL. Terminal half-lives of hemophilia A agents are relatively short, with patients infusing factor at least two to
three times per week. Terminal half-lives of hemophilia B agents are relatively long, with patients able to infuse
around twice weekly using SHLs and one to two times every two weeks using EHLs.
Treatment protocols for hemophilia with inhibitors depend upon individual inhibitor titer level, phenotype
(severe, moderate, mild), and genotype (hemophilia A or B). Severe hemophilia A patients prescribed an ITI
protocol use high levels of plasma-derived or recombinant factor VIII to saturate the inhibitor, whereas mild
hemophilia A patients are shown to have worse outcomes on this protocol. Severe hemophilia B patients tend
not to be prescribed an ITI protocol, with many progressing to bypass agents. Where ITI fails, patients can use a
bypass agent either on-demand or prophylactically.

Diagnosis
Severe hemophilia (A or B) is usually diagnosed in the first two years of life.
Approximately two-thirds of patients have a family history of hemophilia and are therefore diagnosed at birth or
prenatally.
Approximately one-third of patients present as a result of new mutations. Therefore, most are diagnosed when
they start walking or get frenulum bleeds when bottle feeding. These patients typically present first to a general
practitioner/primary care physician.
Moderate severity cases can remain undetected for many years—for example, patients may not present until
after a tooth extraction. Mild severity cases can remain undetected until much later in life, when a patient
undergoes surgery or experiences major trauma.
Hemophilia Severity Level and The % Normal Factor Activity In The Blood
% Normal Factor Activity in the

Level Blood IU/mL of Whole Blood Typical Time of Diagnosis
Normal range 50-150% 0.50-1.50 IU N.A.
Mild hemophilia 5-40% 0.05-0.40 IU Often not until later life
Moderate hemophilia 1-5% 0.01-0.05 IU 0-6 years
Severe hemophilia Less than 1% Less than 0.01 IU 0-2 years
Note: Based on information from the World Federation of Hemophilia
Diagnostic Criteria and Diagnostic Tests
Generalized Assay Algorithm for Diagnosing Hemophilia

Specific Diagnostic Tests
If further investigation is warranted beyond the generalized assays, specific factor VIII and factor IX assays
(chromogenic or one-stage) measure the functional activity of each respective factor.
One-stage assays are based on the aPTT test except the sample is diluted in FVIII-deficient plasma.
Chromogenic assays are more sensitive to deviations in FVIII activity (even small changes) and more
specific than the aPTT-based one-stage assay. Additionally, a high dilution factor of the sample means less
influence of external factors on results. Chromogenic assays are typically used when assigning potencies of
FVIII.
Hallmark signs of an inhibitor can include sudden, severe bleeds in a patient being treated
prophylactically. Neutralizing anti-FVIII or anti-FIX antibodies (inhibitors) are classically recognized by
a prolonged aPTT and normal PT with persistently prolonged aPTT following mixing of the patient sample with
an equal volume of normal plasma.
The Bethesda assay is a commonly used test for inhibitors, and a modified version also exists: the Nijmegen
version. 1 BU = the amount/activity of inhibitor needed to neutralize half of the factor (VIII or IX) activity in 1 mL
of normal plasma. Inhibitors can respond in one of two ways when challenged with factor VIII or IX:
Low-responding inhibitors “produce” less than or equal to 5 BU.
High-responding inhibitors “produce” more than 5 BU.
Treatment Providers and Referral Patterns
Management of hemophilia patients primarily takes place in a specialist clinic, also known as a comprehensive
care center. CCCs support and promote optimal management of hemophilia using a multidisciplinary
healthcare team (e.g., physicians, nurses, physiotherapists, genetic counselors). There are no regional
differences in this management approach throughout the markets studied here. Patients are usually referred to
the CCC by their community physician.
Management trends could shift toward the community over the next five to ten years because many hemophilia
patients do not need the resources of a hospital anymore. Hemophilia may become a community-based
specialty with fewer centers in the next ten years and more outreach services (for example, telehealth services).
Expert Insight on Diagnosis of Hemophilia
“Assay types and their interpretation present several important challenges. Assays are influenced by local
procedures and experience of each laboratory, giving rise to interlab variability. Calibration material, aPTT
reagents, deficient plasma – all of these dictate the result. There is so much variation.”
“Big reference centers usually have an internal lab; a routine lab and a research lab. So if we need to set up a
new method, we can do it. Smaller centers rely on the general lab of the hospital. They usually do not use the

chromogenic assays and are reluctant to set up new methods solely for the hemophilia population.”
“Our hospital labs usually run a calibration curve once monthly. It’s not ideal, but they don’t have a spare hour
every day.”
“Initial phlebotomy (blood collection) techniques can be a significant source of error. Even at the very
beginning of the entire process when the blood is collected, if the lab’s techniques aren’t up to scratch, it can
affect the factor. FVIII is particularly sensitive – I’ve seen ‘false’ results before it even reaches the specific
assays.”
”aPTT assays may miss mild hemophilia A or B. Used as a general screening assay, aPTT is a global plasma
assay that depends on the sum effect of ten different coagulation factors; this is important because, under
certain conditions, low FVIII or FIX levels (mild hemophilia A or B) may be masked by increases of one or several
of the other factors resulting in a “false normal” aPTT. I think we need to standardize the aPTT reagents we are
using in our labs. Not all are sensitive enough to detect mild through to severe hemophilia A.”
“Laboratories using a one-stage assay in isolation may fail to detect some mild hemophilia A phenotypes. A
perfect diagnosis in mild Hem A should be done using both the one-stage assay and chromogenic. This is what
we do at our reference center in Italy. It’s not something that is done everywhere.”
“Using one particular assay to assign potency to a factor replacement product, a different assay to diagnose
factor levels, and yet another assay to monitor that same product in a patient gives rise to significant
differences. We should all be doing chromogenic assays. The reality is, though, that diagnostic assays might
always be one-stage assays because in diagnosis we are looking at a different set of problems than factor
recovery [monitoring of factor levels].”
— Hematologist, United States
“For certain patients, clear discrepancies exist between one-stage and chromogenic assays – we never know
which assay is more accurate. I think it is enough to do a one-stage assay in the monitoring of treatment. This is
reasonable. The future? Because of the newer agents, the chromogenic assay may be a requirement for
treatment monitoring.”

“The chromogenic assays for hemophilia B are quite new and are not used widely across the board yet. It will
probably have the same advantages as for hemophilia A. But we know less about the discrepancies between
the one stage and chromogenic. I expect to see chromogenic use increasing when the pegylated FIX comes
out.”
“So many products on the market will give us so many variables; I can see many arguments for using the
chromogenic assay across the entire board, in the future.”
—Hematologist, France
“One-stage assays tend to dominate, but they have a wider coefficient of variation than chromogenic assays;
you may miss things like lupus anticoagulants or instant acting inhibitors.”
“Even when using the same assay, different factor types produce different results. The variation is too much.
Plasma-derived products are ok but for full length recombinant, we are underestimating true values in that
patient by about 15%. With B-Domain Deleted (BDD) products, that jumps to about 40-50%. Treaters are often
giving more concentrate to a patient than they need. The risk of overtreating is very much a reality.”
—Hematologist, Germany
“The advent of long-acting factor concentrates will add a further layer of complexity to the assay procedures. At
this point, we’re at a loss regarding understanding how these new extended half-life products can be accurately
measured.”
—Hematologist, United Kingdom
“I’m not exactly sure how long-acting factor concentrates will affect the current assay systems; with the new
pegylated products, APTT appears to be pushed up proportionally. Different reagents behave very differently
with the new, longer-acting products.”
Treatment Goals
Physicians in all regions examined consistently report four main goals of hemophilia treatment, despite some
regional differences in guidelines.

Achieve Zero Annual Joint Bleeds
Increasing a patient’s factor level can help to achieve prevention of bleeds.
“In hemophilia A, we know that for each 1% incremental increase above a baseline 1% factor VIII level, there is
about an 18% decrease in the incidence of annual joint bleeds. When patients are expressing FVIII in the range
of 12-15%, the joint ABR approaches zero. And In hemophilia B, a baseline factor IX activity of 10% in boys under
10 years old should be associated with a joint ABR of about 0.1. So if you extrapolate that, a baseline factor IX
activity of 10% means teenagers should experience a joint ABR of about 0.8.”
-Hematologist, United States
Managing trough level (level of the lowest concentration) is important to avoid spontaneous bleeds, but it is
not 100% of patient management. There is an apparent ‘preoccupation’ with trying to increase the trough only,
with target joints and trough levels for different activities somewhat neglected. Regarding target joints, a higher
trough may be required for the ankle joints with a lower trough required for the knee joints.
The role and importance of the “magic threshold” or trough level (lowest optimal concentration of factor to
avoid spontaneous bleeds) is well documented, but not all patients need the same trough level. In addition,
some patients experience subclinical bleeds (non-obvious bleeds). We note contrasts in physician-reported
patients maintaining a 2% trough with no bleeds and no apparent joint disease and physician-reported patients
who are able to maintain a trough level of 10% but still suffering advanced joint disease. Physicians estimate
some patients may need factor levels approaching 50% to prevent joint disease, with one physician quoting an
ideal trough target of 50%, if concentrate were “free.”
Peaks (the levels of highest concentration) can also have important clinical effects, including the risk of
thrombotic events. They are most applicable in patients with a high level of physical activity. Our KOLs suggest
patients need a peak of 30-50% to avoid traumatic bleeding completely. But, physicians expect that not all
patients need the same peak levels, similar to the troughs. In addition, they do not know the target value for
different sporting activities. Twelve hours postinfusion, a patient’s levels could be anywhere between 20% and
50%. This level is important to know when physicians are recommending that a patient can participate in a
high-risk, impact sport.
Allow Optimization of Patients' Physical Activity Levels
Hemophilia patients are a heterogeneous cohort because tendency to bleed is highly individual. Treatment
regimens are tailored to patients’ lifestyles, in an attempt to minimize the impact of the disease balanced with
the patient’s wish to minimize the burden of treatment. We note that physicians are more inclined to tailor the
treatment to that individual patient than tailor treatment to the factor concentrate. Patients’ risk of bleeding is
dependent on many interacting variables including age, factor level, joint health, lifestyle and other
“unknowns.”
The population affected by hemophilia is primarily males, who are more likely to engage in impact sports.
Physicians note the importance of peaks to avoid traumatic bleeds during sports and will tailor treatment based
on clinical outcome to avoid bleeds and based on sports activities.

Maximize Adherence
Poor outcomes and higher costs can be attributed to low adherence rates. Patients are at higher risk of bleeds
when they miss or delay an infusion. One of the biggest limitations of prophylaxis is lifelong adherence to
treatment regimens. The majority of patients with severe hemophilia need prophylaxis, yet physicians report
that only about 30% of “severes” are optimally treated.
We note physician concerns around real-world use of the EHLs, particularly how their use might differ outside of
a controlled trial environment. One physician compares the ease of remembering to inject once every two days,
versus once every other Saturday, and implies that injecting once every other Saturday has the potential of
“doing more harm than good”.
Minimize injection burden (by reducing frequency of administration)
CVA lines increase risk of thrombosis and infection, and access is often difficult to establish in young children. In
addition, long-term use of CVA lines can cause collateral formations in the venous system. A physician-reported
alternative is to administer factor via peripheral veins; however, evidence suggesting an induction of an
immune response if the factor is repeatedly administered via peripheral veins was found. We also note
physician sentiment that a smaller volume with a longer interval may make prophylaxis easier for younger
boys.
Key End Points Used in Clinical Trials for Hemophilia
Safety End Points Description of Potential Parameters
SAEs Number of patients with at least one SAE, nature of SAE
AEs Total number of AEs, number of patients with greater than 1 AE, most common AEs
Immunological events of specific interest: Number of patients developing inhibitors in time frame X, clinically significant vs. transient inhibitor formation,
inhibitor development, immunogenicity, inhibitors to heat-shock protein/host cell proteins
hypersensitivity
Hemostasis-related events: thrombogenicity Delta plasma levels of antithrombin and thrombin generation, thromboelastography parameters (r-time, MTG,
alpha angle, and maximum amplitude)
Clinical Efficacy Description of Potential Parameters

End Points
Number and location of all bleeds, with ABR (absolute number), spontaneous ABR, delta ABR, ABR % reduction, bleed type (spontaneous,
special reference to joints, muscle and CNS traumatic), bleed location (joint, muscle, CNS), new bleeds vs. rebleeds, target joint vs. nontarget joint,
joint bleed % reduction, target joint bleed % reduction, clinical observation vs. confirmatory imaging
Doses, additional doses, and frequency of Plasma %, weekly dose and IU/kg (mean and median), dosing interval during last X months on study,
clotting factor concentrates (CFC) used elimination half-life, incremental recovery, clearance, AUC
Degree of resolution of clinical symptoms Subjects experiencing no bleeds, joint preservation scores
Other Description of Potential Parameters
Quality of life SF-36 v2, Hemo-QoL-A, EQ-5D
Key Physician Insights on Clinical End Points
“The main problem in all hemophilia studies is; ‘what is a bleed?’ It’s always patient reported outcomes, which

depends of course, on the selection of patients you’re looking at. A patient-reported bleed is not always a bleed.
They don’t come to the hospital and show the bleed. Lots of my patients with existing joint disease will report a
bleed, saying ‘I’ve got pain in the joint’ and equate that pain to a bleed. But what if it’s pain of arthropathy? Look
at some of the studies coming out of Eastern European countries; even with a trough of 30%, patients will still
report a bleed, because they experience pain in a joint. There is no good solution.”
“Nowadays, most trials are focused on ABR; at the moment, the best parameter to compare with is the ABR.”
“In the short term, you’re probably looking at ABR as a major outcome comparator. This is despite it being a
crude number.”
“ABR is just a surrogate marker used to compare efficacy. As such I regard it with some caution, as there is much
more we need to take into account.”
—Hematologist, France
“A low ABR is fine and well, but how do you know they’re not having sub-clinical bleeds? How can you have a
trial without serial MRI scans to be certain?”
– Hematologist, United States
“The annual bleeding rate does not always correlate with the progression of joint disease, or with the joint
status.”
– Hematologist, Italy
“Define a new bleed? Even better, define a re-bleed into a joint? I’ve seen plenty of variations of this definition.”
–Hematologist, United States
“I worry that some definitions are based too heavily on clinical observation alone and not enough confirmatory
analysis is being done. I’m thinking of target joints here.”
– Hematologist, France
“Some severe patients are not clear cut by definition; despite being labeled so in trials. They’re classified as
having factor levels of <1% of normal. But we suspect FVIII is not the only thing that modulates bleeding and

this probably explains the small % of severe patients who are much more controlled that their severe peers.
How do you account for this variation in trials? We’re missing part of the picture in some trials, and worse,
between trials.”
– Hematologist, United States
“With the new, novel products, we want to see large numbers of patients with long period of treatment. Due to
the nature of the disease, it’s not possible to have these large numbers initially.”
Key Current Therapies
Overview
All hemophilia treatments are branded, with the exception of some biosimilars that exist in countries such as
Russia and Iran. Only branded agents are examined in this report.
More drugs exist to treat hemophilia A than hemophilia B, which is a reflection of hemophilia A’s higher
prevalence. As such, hemophilia A attracts a higher commercial interest, visible in the greater number of new
treatments in development.
Hemophilia A is currently treated using either SHLs or EHLs, all of which are deemed safe and effective. We note
some negative sentiment around the use of PEGylated EHLs in children, from a safety perspective. Currently
available SHLs and EHLs provide relatively small improvements in terms of achievable clinical outcome
because the half-life extension cannot be sufficiently increased.
Hemophilia B is currently treated using either SHLs or EHLs. In contrast to those for hemophilia A, these agents
provide relatively large improvements in terms of achievable clinical outcome because the half-life extension
can be meaningfully increased.
Hemophilia with inhibitors is currently treated in the first instance with ITI (which utilizes high doses of factor
VIII or factor IX over a set time period). If response is not sufficient, patients may be treated using a bypass
agent. Since most inhibitor patients cannot use FVIII/FIX for prophylaxis because the half-life is too short, either
NovoSeven or Feiba can be used. The choice of product for prophylaxis is considered on an individual basis,
taking into account previous response to treatment, logistics of administration, and cost.

Mechanism of Action of Key Current Drugs or Drug Classes Used for Hemophilia
Drug Mechanism of Action
All current FVIII hemophilia A agents Temporarily replaces the missing coagulation factor VIII needed for effective hemostasis.
All current FIX hemophilia B agents Temporarily replaces the missing coagulation factor IX needed for effective hemostasis.
NovoSeven Activates factor X to produce factor Xa. Factor Xa complexes with other factors to convert prothrombin
to thrombin. Thrombin burst leads to fibrin formation and a stable hemostatic plug.
Feiba Complex mechanism of action. Restores hemostasis through multiple modes of action, including
thrombin generation on the platelet surface. Promotes thrombin generation by several mechanisms and
may differ in individual cases.
Current Treatments Used for Hemophilia
Dosing for Prophylactic Treatment Availability

Therapy (IU/kg) (launched)
Hemophilia A
Advate 20-40 US, F, G, I, S, UK
Kogenate FS 25 US, F, G, I, S, UK
Kovaltry/Iblias/Kogenate PF 20-40 US
ReFacto/Xyntha 30-50 US, F, G, I, S, UK
NovoEight 20-45 US, F, G, I, S, UK
Nuwiq 30-40 US, F, G, I, S, UK
Helixate 25 US, F, G, I, S, UK
Afstyla 20-50 US
Adynovate 40-50 US
Eloctate 25-65 US
Hemophilia B
Benefix 40 US, F, G, I, S, UK
Rixubis 60-80 US, F, G
Ixinity 50-60 US
Alprolix 50-100 US
Idelvion 25-75 US
Feiba 50-100 US, F, G, I, S, UK
NovoSeven 90 mcg/kg US, F, G, I, S, UK
US = United States; F = France; G = Germany; I = Italy; S = Spain; UK = United Kingdom.

Note: See “Appendix” for a list of brands, marketers, and generic availability of key therapies by market.

Recombinant Hemophilia A Treatments
Recombinant Factor VIII
Current treatments for hemophilia A are all recombinant FVIIIs, the first of which was Shire’s Recombinate,
launched in 1992. Hemophilia A (and B) treatments are generally considered to have either a standard half-life
or extended half-life.
SHLs for hemophilia A have a half-life of approximately 10-14 hours. Sales-leading SHLs include Advate,
Kogenate, and ReFacto/Xyntha. The most recent SHLs to launch are CSL Behring’s Afstyla and Bayer’s Kovaltry.
EHLs for hemophilia A have a half-life that approximates 20 hours, a half-life extension of about 1.5 times the
length of the SHLs. The only EHL rFVIIIs currently on the market are Adynovate and Eloctate. Eloctate was the
first EHL to market, launching mid-2014, while Adynovate followed in December 2015.
SHLs are the benchmark against which EHLs are defined; there is a large half-life difference between what is
considered an EHL for FVIII versus FIX products. Interviewed physicians and payers indicate that the half-life
extension of the so-called EHL rFVIIIs is of little clinical significance and that clinical outcomes are not
significantly improved.
Von Willebrand factor’s (vWF) half-life of 18 hours is thought to limit the extent to which the FVIII half-life can be
extended; unlike FIX, around 98% of FVIII circulates complexed with vWF. Therefore, patients with hemophilia A
may need to receive IV infusions more often or alternatively may spend less time protected against bleeds.
Half-life can be significantly shorter in pediatric patients with all brands mentioned in this report, meaning
higher doses or more frequent infusions are needed, regardless of whether the patient has hemophilia A or B.
Clinical Analysis of Recently Launched rFVIII Products for the Treatment of

Hemophilia A
Afstyla (CSL Behring): AFFINITY program: Trial 1001 was a Phase III trial that evaluated 174 subjects with severe
hemophilia A, for a total of 14,306 exposure days (EDs) and 616 spontaneous bleeding episodes (BEs) requiring
treatment (872 overall). The data from this trial confirm that the effectiveness of Afstyla are within the expectations
of a rFVIII replacement product and exceed the preset efficacy criteria. Pediatric data were reported on 84 subjects in
the pediatric trial 3002.
In trial 3002, subjects 0 to <12 years of age were treated with a total of 5,242 EDs. There were 389 BEs of which 347
required treatment with Afstyla. The data from this trial confirmed the safety and efficacy of Afstyla in the pediatric
population, confirmed the superiority of prophylactic versus on-demand treatment, and confirmed that the PK
characteristics of Afstyla are similar to other rFVIII replacement products. Of the BEs reported in the adult trial 1001,
91.9% were joint, 10.7% were muscle, and 11.2% were other. Prespecified success criteria for treatment of
BEs, routine prophylaxis, and surgical prophylaxis were all met. Success was defined as a rating score of good or
excellent, with the lower bound of 95% confidence limit for treatment success >70% for treating BEs and surgical
prophylaxis, and success for routine prophylaxis was defined as lower bound of 95% confidence limit >70% for
annualized spontaneous bleeding rate on routine prophylaxis versus on-demand treatment. Treatment of BEs with

Afstyla in the adult trial was rated as excellent or good in 92.3% of 848 treated BEs (24 BEs did not require treatment)
and 100% of 16 surgical procedures. Afstyla successfully treated 93.5% of BEs with one or two injections, and there
was no reported difference if subjects had been treated with prophylaxis or on-demand treatment when the BE
occurred. As with other FVIII preparations, both plasma-derived and recombinant, the recommended dosing of
Afstyla for on-demand treatment varies with the severity of the bleeding and on the measured blood level of FVIII
activity (FVIII:C). The treatment schedule for Afstyla (recommended starting dose for prophylaxis 20-40 IU per kg
every 2 days or 20-50 IU per kg 2 to 3 times per week) is similar to other licensed FVIII products. Routine prophylaxis
resulted in 1.14 total BEs per year and no spontaneous BEs per year. There were no BEs reported in 43% of those on
routine prophylaxis. The reported annualized rate of spontaneous BEs was decreased 92% from subjects’ prior rates
with on-demand treatment with other FVIII products. The lower limit of the 95% confidence limit for this decrement
from prior rates with on-demand treatment was 88.9%, which exceeded the prespecified success
criterion. Perioperative efficacy was evaluated in 16 major surgical procedures, defined as surgical procedure that
involved anesthesia (general, spinal, epidural, or regional block) or respiratory assistance. Results were assessed as
excellent in 94% of surgical prophylaxis cases and good in 6% (a single case). Afstyla showed a safety profile
consistent with products of the same class and within the expected background pathology for patients with
hemophilia A. No subject discontinued participation due to an AE, and no cases of FVIII inhibitor or antibody to CHO
protein formation were recorded in any subjects treated with Afstyla. There were no thromboembolic events or
deaths reported in either clinical trial. Data from the pediatric trial demonstrated adequate efficacy and safety in a
pediatric population to support use in children. Hemostatic efficacy of treatment of BEs with Afstyla was rated as
“excellent” or “good” (the defined success criterion) in 96.3% of BEs. There was no difference in subjects 0 to <6
years of age and those 6 to <12 years of age.
Kovaltry (Bayer): LEOPOLD I: All subjects had severe hemophilia A ( FVIII<1%). All were male and all had significant
exposure to FVIII products (>150 EDs in adults) at the time of entry into the trial. This study included 28 subjects in
Part A, 62 subjects in Part B (10 subjects between 12 and 17 years of age), and 7 subjects in Part C. LEOPOLD I was a
Phase I and II/III multicenter, open-label, noninferiority, partially controlled PK, crossover clinical trial in
adolescents and adults (age >12 years to <65 years). The study comprised four parts as follows: (A) assessment of PK
of Kovaltry compared with Kogenate, (B) one-year prophylaxis treatment with Kovaltry, (C) hemostatic outcome of
treatment of patients undergoing surgery, and (D) an optional one-year extension phase. Kovaltry was noninferior
compared with Kogenate after a single-dose administration and indicated a longer half-life for Kovaltry.
Prophylactic efficacy dose of 20-50 IU/kg 2-3x/week was used, and the mean and median ABR for the ITT population
was 3.8 ± 5.2 and 1 bleed/year, respectively. There were a total of 395 bleeds, and 87% were treated with less than 2
infusions and shown to be efficacious in routine prophylaxis. The hemostatic control during major and minor
surgeries was good or excellent in all cases. No immunogenicity was detectable.
LEOPOLD II: A Phase II/III study including 80 adolescent and adult PTPs (age >12 years to <65 years) with severe
hemophilia A. Ten PTPs were adolescents aged between 14 and 16 years. This study demonstrated superiority of
prophylaxis over on-demand treatment to reduce the frequency of bleeding episodes with the 2 types of potency
assignments. The median ABR was 60 bleeds per year during on-demand treatment versus 2 bleeds per year in the
prophylaxis group. Kovaltry was used in 13 major surgical cases and 46 minor surgical cases in 43 subjects to support
the indication for perioperative surgical prophylaxis. Efficacy was rated at good or excellent in 100% of both the
major and the minor cases.
LEOPOLD kids: This multicenter, open-label, single-arm Phase III trial included 51 subjects aged 1-11 years, with

severe hemophilia, >50 EDs, and no inhibitor history who received prophylactic treatment with Kovaltry. PK was
evaluated in 12 subjects. Twenty-three subjects remained bleed-free during the 6-month treatment period. The
median ABR was 1.90 bleeds per year during prophylaxis. The majority of bleeds were successfully treated with ≤2
injections. The treatment with Kovaltry was safe and well tolerated. One subject developed a low titer neutralizing
antibody to FVIII. Overall conclusion on safety: Across all trials, there were 133/193 (69%) subjects who reported at
least one AE. There was only one subject who discontinued treatment due to an AE. There were a total of 27 SAEs
reported. The most common adverse drug reactions in ≥3% in subjects were headache, pyrexia, and pruritus. There
was one report of an inhibitor in a PTP. In the ongoing PUPs study, there were 6 cases of FVIII inhibitor formation.
Adynovate (Shire): A nonrandomized open-label, two-arm treatment study evaluated efficacy, safety, and PK. A
total of 159 PTPs were enrolled in the study, and 138 subjects were used for the full analysis set (FAS) of safety and
efficacy in the treatment phase. There were a total of 17 adolescents aged 12 to less than 16 years and 121 adults
aged 16 to 65 years in the FAS. The mean number of target joints per subject was 1.60 in the prophylaxis arm and 2.18
in the on-demand arm. Of the 121 prophylaxis subjects, 21 were previously managed on an on-demand regimen
prior to the study whereas all 17 on-demand subjects had never received prophylaxis. Using a negative binomial
model to estimate ABR, the mean (median) ABR in the treatment analysis population set or safety analysis set (SAS)
population was 4.3 (1.9) in the prophylaxis arm (N=120) and 43.4 (41.9) in the on-demand arm (N=17). Thus, the use
of routine prophylaxis in the dosage and frequency prescribed was associated in this trial with a 90% reduction in
the mean ABR compared with the rate observed during on-demand therapy. This difference in the mean ABR
between treatment arms was statistically significant (P < 0.0001). The elimination half-life of Adynovate is 14.3 hours
compared with an average half-life of 8-12 hours in nonfusion protein plasma-derived or recombinant FVIII products.
The mean dose per prophylaxis infusion was 44.4 IU/kg with a median dosing interval of 3.6 days. Of the subjects
who received routine prophylaxis, 93% reduced their prestudy FVIII dosing frequency by 30% or more compared
with the on-study frequency. Additionally, 70.4% of subjects in the prophylactic arm were able to reduce the
frequency of dosing from their prestudy prophylactic treatment regimens by at least one less prophylactic infusion
per week after switching to Adynovate for prophylaxis. A total of 591 bleeds were treated during the approximately
6-month efficacy evaluation period with 361 bleeds recorded for on-demand subjects and 230 bleeds for subjects in
the prophylaxis arm. Eighty-five percent of the total bleeds required one infusion, 11% required 2 infusions, and 4%
required 3 or more infusions. Of the 120 subjects on prophylaxis, 38% experienced no bleeds. In contrast, in the on-
demand arm, 0% of subjects experienced no bleeds. For each bleeding episode, subjects were asked to rate the
efficacy of Adynovate on a 4-point scale from excellent (four points) to no response (one point). The percentage of
the bleeding episodes not rated for efficacy was 0.5%. Of rated bleeding episodes, 95.2% were rated as excellent or
good, 3% as fair, and 1.2% as no response. The adverse event profile of Adynovate was most commonly headache
(2%), nasopharyngitis (2%), upper respiratory infection (1.3%), arthralgia (1.3%), and back pain (0.7%). FVIII inhibitor
formation was not observed during the pivotal study. Seven subjects who tested negative at screening developed
transient IgG antibodies against FVIII or PEG-FVIII at 1 visit or 2 consecutive study visits after exposure to Adynovate.
Antibodies were transient and not detectable at subsequent visits or at completion of the study. None of the 137
subjects included in the SAS developed a persistent binding antibody response against FVIII, PEG-FVIII, PEG, or CHO
proteins during the study. Nine subjects showed preexisting antibodies against FVIII, PEG- FVIII, or PEG prior to first
exposure to Adynovate. A risk assessment analysis was performed by Baxalta (Shire) and demonstrated no clinically
significant adverse events, lack of therapeutic effect, or alterations in PK.

Ongoing Clinical Development
Shire is hoping to boost sales of Adynovate with a label extension for use in PUPs (NCT02615691, study
completion December 2020) and to further support the use of Adynovate in severe hemophilia A PTPs with data
from Phase IIIb continuation study (NCT01945593, study completion October 2017). Shire also hopes to enable
Adynovate to be used in personalized prophylaxis (PK tailoring) with a Phase III PK-guided dosing study
(NCT02585960 study completion November 2018).
CSL Behring hopes to further support the use of Afstyla in severe hemophilia A PTPs with data from a Phase III
extension study (NCT02172950, study completion August 2021).
Biogen is hoping to boost sales of Eloctate with a label extension for use in PUPs with severe hemophilia A
(NCT02234323, study completion September 2019).
Novo Nordisk is hoping to boost sales of NovoEight with a label extension for use in hemophilia A patients
undergoing surgery (NCT01489111, study completion December 2018) and to support use of NovoEight in
previously treated Chinese patients (NCT02938585 study completion December 2018).
Expert Insight on Recombinant FVIII Products
“Look at my type A patients on standard half-life products; the frequency of their current infusions are similar to the frequency of the infusion given
with EHL FVIII. They are too similar, in that respect.”
“With FIX, the improvement achieved with the long-acting is really impressive. But with the long-acting FVIII, the improvement in terms of clinical
outcome achievable is small.”
“I quite like the physiology behind Fc in the way that it recycles the factor VIII back into the circulation. I am more interested in the Fc fusion molecules
and that is probably because we are not sure happens with pegylated forms over many years in terms of peg accumulation.”
“For those not on prophylaxis, I think it’s questionable whether they would have any advantage on a long-acting drug. I don’t see an advantage for on-
demand patients.”
“People who are doing well on what they’re doing (standard half-life products) and have never had inhibitors, don’t want to take a risk with the newer
products, the EHLs.”

Recombinant Hemophilia B Treatments
Recombinant Factor IX
Current treatments for hemophilia B examined in this report are all recombinant FIXs. Hemophilia B (and A)
treatments are generally considered to have either a standard half-life or extended half-life.
SHLs for hemophilia B have a t0.5 of approximately 18-27 hours. SHLs include Benefix, Rixubis, and Ixinity.
EHLs for hemophilia B have a t0.5 that approximates 90 hours, a half-life extension of about 3-5 times the length
of the SHLs. The only EHL rFIXs currently on the market are Alprolix and Idelvion:
Alprolix contains the Fc region of human IgG1, which binds to the neonatal Fc receptor (FcRn). FcRn is part
of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them
back into circulation and prolonging their plasma half-life.
Idelvion’s prolonged half-life is attributed to its increased size, which decreases renal clearance, and to
prevention of digestion in lysosomes by binding to the FcRn, which normally prevents degradation of
albumin.
Patients with hemophilia A may need to receive IV infusions more often than patients with hemophilia B.
Half-life can be significantly shorter in pediatric patients with all brands mentioned in this report, meaning
higher doses or more frequent infusions are needed, regardless of whether the patient has hemophilia A or B.
SHLs are the benchmark against which EHLs are defined; there is a large half-life difference between what is
considered an EHL for FVIII versus FIX products.

Clinical Analysis of Recently Launched rFIX Products for the Treatment of

Hemophilia B
Idelvion (CSL Behring): CSL Behring performed a total of five prospective, open-label clinical studies of 111 unique
subjects with FIX deficiency/hemophilia B ( FIX <2%) to evaluate safety and efficacy. Key trials in gaining approval are
discussed below:
Study 3001 was an open-label, Phase II/III safety and efficacy study comparing on-demand treatment of Idelvion
with weekly routine prophylaxis and every 10- to 14-day routine prophylaxis and/or perioperative management
(surgery substudy) in 63 PTPs aged 12-61 years. This study achieved the agreed primary efficacy end point of greater
than 50% reduction in the annualized spontaneous bleeding rate (AsBR) of subjects managed with an on-demand
regimen, when switched to a routine prophylaxis regimen. The primary safety end point of inhibitor development
occurred in none of 63 subjects exposed to Idelvion. The adverse reactions (adverse events related to Idelvion
exposure) that did occur were rare and were not serious. The study demonstrated efficacy and safety for the
indication and routine prophylaxis of bleeding episodes in PTPs with congenital factor IX deficiency. An identified
potential safety concern was proteinuria in four subjects (4/63; 6%) enrolled in Study 3001, who had negative
urinalyses at baseline and positive urinalyses during the study.
Study 3002 was a Phase III open-label, single-arm pediatric study in 27 children <12 years of age who received
Idelvion for on-demand treatment or routine prophylaxis. The results of this study demonstrated safety in
previously treated pediatric subjects by demonstrating no inhibitor development in 25 subjects who had at least 50
EDs. In addition, there were no treatment-emergent AEs attributable to drug exposure, including the events of
special interest, thromboembolism and hypersensitivity reactions. The efficacy evaluation accomplished
determination of PK parameters for <12-year-old subjects and showed similar rates of annual total bleeding and
annual spontaneous bleeding compared with the adult subjects in Study 3001 on the routine prophylactic regimen.
Generalized safety data showed that, of the 111 subjects treated (January 9, 2015, cutoff date), two experienced
hypersensitivity reactions, with one likely to be an infusion-related reaction, rather than a hypersensitivity reaction.
No thromboembolic events, FIX inhibitors, or antibodies against Chinese hamster ovary host cell proteins were
noted.
Biogen is hoping to boost sales of Alprolix with label extension for use in PUPs (NCT02234310, Phase III, study
completion June 2019).
CSL Behring is gathering data that would support the use of Idelvion in severe hemophilia B patients with a
Phase III safety and efficacy extension study (NCT02053792, study completion March 2020).

Expert Insight on Recombinant FIX Products
“I’ll use the EHLs for prophylaxis in patients of all ages. Adults and children. If we can convince the younger patients, those who aren’t doing
prophylaxis properly because they don’t like to inject. Even if you can reduce IV infusions by 30% it will be a huge improvement over one year. But in
hemophilia A, my first targeted choice will be those patients who don’t inject regularly their prophylaxis. Hemophilia B is different, there is a higher
potential to switch more patients.”
“With FIX, the improvement achieved with the long-acting is really impressive. But with the long-acting FVIII, the improvement in terms of clinical
outcome achievable is small.”
“There are only a very small number where I’m advocating the switch from standard half-life to EHL. These are mainly in hemophilia B.”
“I think we will see the switch to long-acting products in the next 10 years, especially in hemophilia B.”
“With EHLs, I’d first target those who were a little older and who understood what was going on, but who are just having a real hassle trying to
administer factor frequently.”
Bypass Agents
NovoSeven and Feiba are currently the only marketed bypass agents for the treatment of hemophilia A or B with
inhibitors. The term “bypass agent” comes from its mechanism of directly activating Factor X, in effect
bypassing the need for FVIII or FIX in inhibitor patients. NovoSeven and Feiba are indicated in patients in
whom ITI either has failed or is contraindicated.
NovoSeven is the only recombinant activated FVII available on the market, with an adult t0.5 ~3 hours.
Feiba is an anti-inhibitor coagulant complex (contains factors II, IX, and X [inactivated] and VII [activated]).
It is made from human plasma. Its proposed mechanism of action is different from NovoSeven; it “tops up”
certain factors that are thought to contribute to a bypassing effect.
NovoSeven and Feiba differ in their terminal half-lives, and physicians can switch from one to the other if the
first is not efficacious. Choice of bypass agent used depends upon individual patients; for example, whether they
have used plasma-derived before and whether they have hemophilia A or B. Prophylaxis in inhibitor patients is
difficult to achieve. Of all identified inhibitor patients (A or B), a small number are deemed nonresponders.
These patients develop high-titer, long-term inhibitors and are expensive to treat.
Clinical Analysis of Recently Launched Bypass Products for the Treatment of

There are no recently launched bypass products for the treatment of hemophilia with inhibitors. Only two bypass
products were marketed at the time of writing: Novo Nordisk’s NovoSeven and Shire’s Feiba.
No relevant extension studies are currently ongoing, either with Feiba or with NovoSeven.

Expert Insight on Bypass Agents
“They [NovoSeven and Feiba] have about the same efficacy. It would be wonderful to have biomarkers that would predict the treatment response in
our inhibitor patients.”
“I would switch from one to the other if the first one fails. Keeping in mind that NovoSeven is more expensive than Feiba."
“If they’re PD-naïve, NovoSeven is my first choice in acute bleeds.”

“80% of my patients use NovoSeven. The rest use Feiba. We have one guy using Feiba at home, except when he comes into the clinic. Then we
switch him to NovoSeven. Not that it works any better.”
“Our bias is always toward getting rid of the inhibitor, or preventing inhibitors. Maybe you don’t need to get rid or prevent but just find a different way of
treating patients?”
-Hematologist, United States

Medical Practice
Hemophilia A
Hemophilia A is treated with recombinant or plasma-derived factor VIII concentrate. Factor can either be given
in response to bleeds (on-demand) or be given regularly to prevent bleeds (prophylaxis). The benefits of
starting prophylaxis early in children with severe hemophilia A are well documented and echoed by interviewed
physicians. A prophylactic regimen is deemed to result in fewer joint bleeds, reduced arthropathy, and
improved quality of life, compared with on-demand regimens. However, FVIII consumption, and therefore cost,
may be higher on a prophylactic regimen.
In children, prophylaxis in severe hemophilia A is often commenced by the time of the second joint bleed or
significant soft tissue bleed. Prophylactic doses are often tailored to provide maximum coverage for specific
physical activities (e.g., school, physical education lessons, sport training sessions) by administering them in
the morning. A venous access device is often inserted in children for whom venous access and/or adherence to
treatment is difficult.
In adults, the type of prophylaxis regimens used in children may not be appropriate. The dose and frequency of
infusions are usually adjusted based on bleeding phenotype. Short- or long-term secondary prophylaxis is used
in patients with advanced arthropathy if recurrent bleeds significantly interfere with work or mobility.
Desmopressin (DDAVP) has been used to control bleeds in mild and sometimes moderate hemophilia A, by
boosting plasma levels of factor VIII and VWF. Interviewed physicians report using factor concentrate in
moderate hemophilia A patients when higher factor levels are required for a prolonged period.
In both adults and children, interviewed physicians report using the SHL agents Advate, Kogenate,
Refacto/Xyntha, NovoEight, Kovaltry, Helixate, Nuwiq, and Afstyla, and they view these agents as being equal in
terms of safety and efficacy. Physicians also report using the EHLs Eloctate/Elocta and Adynovate/Adynovi, but
several express concern over using PEGylated agents like Adynovate/Adynovi in children, with some
interviewed physicians taking an even stronger stance, stating they would never use a PEGylated agent in
children or adults. We note that the likely reason for this stance is that no PEGylated drug has ever been given
intravenously as a life-long treatment (particularly in children), with one physician strongly questioning why a
manufacturer would add PEG to a native product when the long-term fate of IV PEG in the body is not fully
known.
Physicians interviewed are keen to point out that it is unusual for patients to remain on the same factor
throughout their life span. Switches between products may be made for several reasons including changes to
national tenders, patient choice, or perhaps the new product offers a lower infusion burden. Patients are often
reluctant to switch because of concerns about increasing inhibitor formation risk. Currently, there is no
evidence to suggest that switching between products significantly influences inhibitor development
(Santagostino E, 2014).

Hemophilia B
The medical practice for hemophilia B is similar to that for hemophilia A such that the condition is also treated
with plasma-derived and recombinant factor concentrate but with some notable differences.
Hemophilia B patients may have fewer bleeds and develop joint disease later and less severely than hemophilia
A patients, reflected in our observation that a higher percentage of hemophilia B patients use on-demand
therapy versus prophylaxis (than hemophilia A).
Hemophilia B has a different mutation profile than hemophilia A so has fewer genetic risk factors for the
development of inhibitors. As such, there is a lower inhibitor incidence in hemophilia B. Inhibitors occur in 1-2%
of affected individuals.
Desmopressin is not indicated in mild/moderate hemophilia B as it does not boost factor IX levels.
Interviewed physicians use recombinant SHLs like Benefix, Rixubis, or Ixinity, as well as recombinant EHLs like
Alprolix or Idelvion. Physicians specifically refer to the longer half-life of the new factor IX EHLs of up to 100
hours making a significant impact in the management of hemophilia B patients.

Inhibitor treatment involves the control and prevention of bleeds and strategies to eradicate the inhibitor.
Patients with a low-responding inhibitor may be treated with a specific factor replacement at a much higher
dose to neutralize the inhibitor and stop bleeding. Patients with a history of a high responding inhibitor but with
low titers may be treated similarly.
ITI is a method of inhibitor eradication used mostly in severe hemophilia A. ITI is normally started as soon as
possible after the inhibitor has been confirmed and when the titer is <10 BU/mL; starting titer is the most
powerful predictor of ITI success, and regimens that delay treatment until the inhibitor has fallen below 10
BU/mL show very high success rates. Physicians report that patients with mild/moderate hemophilia A who
develop an inhibitor respond less well to ITI compared with those with severe hemophilia A. Factor IX inhibitors
are associated with allergic reactions to factor IX, including life-threatening anaphylaxis, especially in those
with gene deletions. ITI in hemophilia B patients carries a relatively poor response rate and risk of anaphylaxis
and nephrotic syndrome. Addition of immunosuppressant drugs to the ITI has been associated with the highest
success rates in hemophilia B patients.
Management of bleeds depends on site and severity, knowledge of the inhibitor titer and previous response to
bypassing agents, and whether the patient is a low or high responder. Physicians report treating bleeds with
high-dose factor FVIII/factor IX in low responders but indicate they use Feiba or NovoSeven in high responders.
Mild/moderate hemophilia A patients with inhibitors may benefit from desmopressin and/or tranexamic acid.
Around 20-30% of inhibitor patients fail ITI. Most inhibitor patients cannot use factor VIII/factor IX for
prophylaxis because the half-life is too short; therefore, either NovoSeven or FEIBA is used. The choice of bypass
agent for prophylaxis is considered on an individual basis, taking into account previous response to treatment,
logistics of administration, and cost. There is wide variation in reported prophylactic regimens, in terms of both
dose and frequency of infusion. Optimal regimens for both agents remain to be established, and deciding
factors include potential ITI, the frequency of infusions, previous response to bypassing agents, and treatment
cost. The longer half-life of Feiba may make this agent a more practical option for many patients.

On-Demand vs. Prophylaxis
Hemophilia may be treated prophylactically (preventing bleeds) or on-demand (treating bleeds as they occur).
Prophylaxis decreases frequency of bleeding and may slow progression of joint disease and improve quality of
life, more so than on-demand regimens. Prophylaxis tends to carry a higher injection burden than on-demand
treatment and a higher economic cost.
Two prophylaxis protocols exist for which there are long-term data:
Malmö protocol: 25-40 IU/kg three times a week for those with hemophilia A and twice a week for those
with hemophilia B.
Utrecht protocol: 15-30 IU/kg three times a week for those with hemophilia A and twice a week for those
with hemophilia B.
Exact prophylaxis protocols vary between and within countries, and the optimal regimen is not well defined.
Prophylactic treatment rates differ between severe hemophilia A and B. A higher percentage of severe
hemophilia A patients are treated prophylactically (70-90%) than severe hemophilia B patients (50-70%), and
physicians report that this difference is related to presence of missense mutations in hemophilia B. Despite this
factor, a sizeable proportion of patients (particularly older adults) remain on-demand, as a personal preference.
Physicians treating severe hemophilia A patients are using EHLs both in on-demand patients and in those on
prophylactic regimens. One physician was able to decrease number of bleeds by half when using Eloctate once
weekly in an on-demand patient.
Factor Replacement Protocols
Protocol Details
On-demand Treatment given at the time of clinically evident bleeding
Primary prophylaxis Regular continuous treatment initiated in the absence of documented osteochondral joint disease, determined by
physical examination and/or imaging studies, and started before the second clinically evident large joint bleed and age
3 years
Secondary prophylaxis Regular continuous treatment started after 2 or more bleeds into large joints and before the onset of joint disease
documented by physical examination and imaging studies
Tertiary prophylaxis Regular continuous treatment started after the onset of joint disease documented by physical examination and plain
radiographs of the affected joints
Intermittent prophylaxis Treatment given to prevent bleeding for periods not exceeding 45 weeks in a year
Note: Based on information from the World Federation of Hemophilia

Pharmacokinetic Tailoring
Pharmacokinetic tailoring in hemophilia refers to the adjustment of dosing frequency based on an individual’s
pharmacokinetic response to the injected factor. Individual tailoring of factor infusions can minimize the impact
of individual pharmacokinetic differences when trying to achieve optimal prophylaxis regimens.
Differences in factor serum clearance exist between patients. Physicians report a half-life range of 6-25 hours in
hemophilia A, dependent on patient. Thus, for a patient in whom a factor has a half-life of 25 hours, a SHL could
potentially be administered once every 4 days. In effect, these patients are using an EHL.
These individual differences mean that some patients may be undertreated, and some may be overtreated. This
challenge has supported physicians’ use of PK tailoring or modified versions of it.
Physician opinion on PK tailoring is split, with advantages cited including an ability to save product; increase
adherence by showing patients their curve; and improve outcomes by converting a severe patient to moderate,
which is turn has a positive effect on joint bleeds and development of joint disease. Conversely, we note
physician uncertainty about whether a patient’s PK profile is stable over time and concerns that factor VIII is not
necessarily the only determinant of the bleeding phenotype, despite factor VIII being the only variable
investigated in many PK approaches. In addition, one of our physicians who was heavily involved in PK trials
observed that patients’ PK profiles were never the same year on year. PK profiling was also reported to be of no
value in patients with previous inhibitors and who have been immune tolerized.
PK tailoring can be a cumbersome process, with ISTH guidelines quoting the need for 10-11 data points and 5
data points in pediatrics. This guideline equates to a lot of blood samples needing to be drawn if relying on just
one patient. However, a PK approach may be helpful in tailoring prophylaxis and represents an alternative to
placing all patients on prophylactic regimens.
Outlier Patients
Gaps in knowledge and understanding of hemophilia pose challenges in treatment. Physicians may be
presented with a patient scenario that does not conform to typical treatment approaches; a so-called “outlier
patient”.
For example, there are patients with high factor levels who still bleed; and patients with low factor levels (below
1% for many hours) who do not bleed spontaneously. Physicians suggest a high likelihood that a number of
other factors are involved, including mutations that increase clotting (such as factor V Leiden), as diagnostic
assays are not measuring all components involved in hemostasis and factor VIII is not the only molecule that
modulates bleeding. Approximately 10% of severe patients bleed less than expected and certainly much less
than their other “severe” peers.
Physicians are keen to stress that level of physical activity plays a role. A sedentary patient will have a milder
bleeding tendency and should not be confused with an “outlier” patient as described previously.

Treatment Guidelines
Guidelines for the treatment and management of hemophilia A and B exist in all regions covered in this report. They
are open to physicians’ individual interpretations, but practice typically follows a general protocol. They are deemed
an “influencing factor” in the clinical decision-making process as opposed to a more firm and definitive directive:
This approach contrasts with the treatment of indications that strongly follow guideline recommendations,
such as type 2 diabetes.
This less-structured treatment approach has evolved due to the difficulty of applying guidelines universally to
all hemophilia cases.
Hemophilia Treatment Guidelines, by Market
Market Key Guidelines Expert Opinion Source
United States NGC, part of AHQR (Agency for Healthcare “I don’t really think that it’s necessary to have www.guideline.gov/s
Quality and Research) published guidelines because there are enough ummaries/summary/
reviews and published experience. It’s hard to find 39323
just one set of directions for factor replacement to fit
all cases.”
France None available specific to France “The guidelines are not very precise; anything you do N.A.
is ‘in the guidelines’, so to speak. We use guidelines
from the likes of the UK and Canada to inform ours
here in France.”
Germany None available specific to Germany “The guidelines in Germany, there is a lot of variety. N.A.
You have a lot of freedom to use those guidelines.
Patients often must be considered on an individual
basis.”
Italy AICE “Guidelines do exist in Italy. I am usually involved in www.aiceonline.org

writing these. But this doesn’t mean that I always /?page_id=2401
know what to do with my patients. Sometimes the
good decisions are not written in guidelines. There is
often a tendency to have your own approach.”
Spain SETH “We often have difficulties in managing the real-life /www.seth.es/index
practice of treatment of hemophilia. The guidelines .php/guias-
are not enough to be a good doctor, but they certainly clinicas/guias-
do influence our practice.” clinicas-
nacionales.html
United Kingdom UKHCDO “We have the UKHCDO (United Kingdom www.ukhcdo.org/gu
Haemophilia Centre Doctors’ Organization) idelines
guidelines. We frequently try to produce up to date
guidelines and have working parties to improve on
those guidelines and also can refer to European-
wide guidelines as well and also Scandinavian and
even other countries, America and Canada.”

Region-Specific Treatment
Country/Region-Specific Treatment Practices
United States and EU5
Geographies examined in this report show little to no differences in treatment approach, with the following
exceptions:
EU5 physicians are more likely to treat using primary prophylaxis, whereas U.S. physicians are more likely to
treat using secondary prophylaxis.
There are regional differences in the use of PD versus recombinant factor products, with U.K. physicians
generally preferring “recombinant for all,” while in France, some centers insist that all newly diagnosed patients
be treated for 50 days with plasma-derived.

Unmet Need Overview
Introduction
Key Findings
Patients with inhibitors: Development of inhibitors (particularly inhibitors to injected factor VIII) is one of the
most serious complications of hemophilia. Treatment of patients with inhibitors is only partially addressed by
current treatments. We expect pipeline therapies to close the gap substantially, but some unmet need will
remain; cost containment may limit availability of these new drugs for all patients in 2025.
Adherence: Even in countries with 100% access to prophylactic treatment protocols, patients do not always
achieve their clinical goals. This points to the role of adherence and the heterogeneity of the hemophilia patient
population. The problem of adherence is only partially addressed by current agents. Pipeline therapies may not
have substantially closed the gap by 2025 unless they can elucidate the link between adherence and clinical
outcomes.
Predictability of dosing: Treatment protocols with the new EHL agents and their associated dose ranges can
be highly variable both between patients and within patients. Current treatments do not fully address the
problem of dosing predictability. Pipeline therapies and current therapies can close the gap by 2025 if
developers are able to link percentage trough attained to a specific set of outcomes (i.e., to model the elasticity
of trough levels).
Existence of troughs (and peaks): A caveat regarding infused factor replacement is the gradual elimination of
factor from the body toward preinfusion levels. No current therapies are able to sufficiently address this unmet
need, only minimize the fluctuations in circulating factor level. By 2025, gene therapy and gene editing may be
able to fully address this unmet need; however, there are many caveats associated with their use and the
availability of gene therapies for every patient in 2025.

Expert Insight
“If I were a blue-sky thinking, I would say let’s completely cure them, which may well happen. Secondly, maybe
some oral tablets, again that’s blue-sky thinking. Otherwise, if we are going to continue with the IV drugs, ideally
you would have elongation of the half-life, such that we had to give once every two months, every month or
every two months. Inhibitors will always be the unmet need in the sense that we still don’t have appropriate
licensed treatment for them or easily manageable treatment for them.”
“One of the terrible problems we’ve had over the last 10 or 15 years, is recombinant VIIa having such a short
half-life and having to give it every two hours or every three hours in people who have big bleeds or surgeries.
So, I think an extended half-life recombinant VIIa will be a fantastic product, but I really think this ACE 910 has
the potential to blow the whole thing out of the water and everybody else having to go away.”
“Hemophilia A is OK. We can make do with existing products and optimize treatment, so long as the patients are
able to inject often enough intravenously. So, we could make it more convenient for the patient, if they have to
have less injections with a prolonged half-life product or subcutaneous injections. My personal opinion is
maybe this time we will be successful with gene therapy. At least with hemophilia B to cure the patients.”
“There are no really unmet needs because at the moment patients have a normal life expectancy if you look at
our kids or young men, you cannot differentiate them from normal people with the treatment in Germany. So, I
think it’s pretty good already and, even though patients are different because we are not able to do the real
prophylactic treatment and to reduce bleeds to zero bleeds or to less than one bleed per year, and, so, there we
need some new product and I hope we will have some soon for these patients.”
“To make factor VIII less antigenic that would be very nice because the inhibitor development is the worst side
effect of our replacement therapy at the moment.”
“The main concern with hemophilia currently is, first, the inhibitor development. This is the big trouble when
you treat for the first time a new patient, how to avoid a risk of inhibitor development. I expect that in 10 years’
time, inhibitors won’t be an issue. Perhaps the question will be the availability of the new drugs for every
patient.”
—Hematologist, Spain

Attainment of Unmet Needs
Current Attainment of Unmet Needs in Hemophilia
Patients with inhibitors: Development of inhibitors (particularly inhibitors to injected factor VIII) is one of the
most serious complications of hemophilia and makes management of bleeds and surgical procedures extremely
challenging. In severe hemophilia with no inhibitors, primary prophylaxis is the standard of care, but the same
is not true in severe hemophilia with inhibitors, with short half-lives of current bypass agents, spiraling costs,
and lack of data limiting the use of prophylaxis in patients with inhibitors. As such, current treatments do not
fully address the unmet needs of patients with inhibitors.
Adherence: Even in countries with 100% access to prophylactic treatment protocols, patients do not always
achieve their clinical goals. This issue points to the role of adherence and the heterogeneity of the hemophilia
patient population; some patients, whether ultra high-dose or low-dose utilization patients, do not adhere to
their treatment, whether it is infused one, two, or four times per week, and latent variables influencing this
adherence are not fully understood. Adherence associated with current treatments is not broadly predictable
and is partially unmet today.
Predictability of dosing: Treatment protocols with the new EHLs and their associated dose ranges can be
highly variable both between patients (individual differences existing between one patient and the next) and
within patients (when a patient is switching from one product to another). This heterogeneity of the hemophilia
population decreases predictability and may drive up factor consumption and cost. Predictability of dosing is
not fully addressed by current treatments.
Existence of troughs and peaks: A caveat regarding infused factor replacement is the gradual elimination of
factor from the body toward preinfusion levels. Patients are at an increased risk of bleeds when trough level is
low, and this risk is highest when they are between doses or if they have delayed or missed a dose. Keeping
trough levels above a certain threshold indefinitely would essentially convert severe hemophilia into moderate
or mild hemophilia. Current treatments are unable to minimize large fluctuations of factor level (peaks and
troughs), and this remains an unmet need today.
Future Attainment of Unmet Needs in Hemophilia
Patients with inhibitors: This cohort will experience much higher physical morbidity compared with that of
the general hemophilia population. Through 2025, new bypass agents will address unmet need by minimizing
the clinical impact and physical consequences of bleeds in inhibitor patients. But, they will introduce a layer of
complexity with regard to variances in dosing ranges and treatment protocols between and within patients. We
believe the current treatments will remain in use, with most pipeline therapies gaining approval. In addition, we
see a place for gene therapies as a potential alternative to bypass agents, given that they may be able to
tolerize patients through continuous expression of factor VIII or factor IX. We anticipate two key strategies
coming to the forefront in the battle to address this large unmet need through 2025. First is the development of
ACE 910, which will make prophylaxis a reality for patients with inhibitors to factor VIII and with an added
convenience of potential once-monthly dosing. Second is the prevention of inhibitor formation through
predictive analytics with data that support treatment choices (brand, dose range, intervals, duration). A

developer that can successfully identify factors within current treatment protocols and within patients that
increase the risk of inhibitor generation may be able to compete effectively with the standard of care in 2025.
Adherence: Less frequent dosing with EHLs does not always lead to improved adherence. Through 2025,
several agents will be marketed as increasing adherence through less frequent dosing, compared with SoC.
However, they may fail to demonstrate (1) the link between adherence and clinical or QOL outcomes and (2)
how adherence changes (improves) when a patient switches from a competitor’s brand to theirs. Therefore,
stakeholders may be less able to define the utilization of that developer’s agent versus a competitor’s. We
expect developers to close this gap but not completely. Thus, we see adherence and predictability of adherence
remaining as a moderately unmet need through 2025. A developer may wish to consider characterizing the
heterogeneity of the hemophilia patient population and identifying patients where adherence is a problem
(including the type of nonadherence). In addition, developing a drug that can increase adherence through less
frequent dosing, less intrusive administration and simultaneously demonstrate associated improved outcomes
will drive annual bleed rate to zero, as will identifying how adherence changes with their new drug combined
with the ability to demonstrate cost offsets with their new drug.
Predictability of dosing: With so much variance in dosing and treatment protocols between and within
patients, a clinical risk is imposed on patients and some monetary risk is shifted to payers. Predictability in
dosing is married to predictability in pricing. Through 2025 and with the launch of several early-stage pipeline
agents, including novel agents, each having highly variable dosing and treatment protocols, we see this dosing
predictability remaining as a moderately unmet need. A developer that can elucidate the drivers behind
consumption and variance in use or, more importantly, that can link percentage trough attained to a specific set
of outcomes (i.e., to model the elasticity of trough levels in achieving zero bleeds per year) will help to close this
gap.
Existence of troughs (and peaks): Through 2025, we anticipate a mixed picture for both gene therapy and
gene editing products in addressing the clinical implications of the troughs associated with regular factor IX or
factor VIII replacement, for several reasons. First is the significant variation in the factor IX or factor VIII levels
achievable in different patients and also between drug candidates (from currently available data). Second is
the lack of long-term safety data and the impact it will have on patients’ willingness to try it through 2025. There
is little interest from parents of children or adolescents with hemophilia, the patient cohorts that are most
difficult to manage effectively. Linked to this issue are the already existing “safe” and efficacious treatments for
factor IX deficiency, so the bar for what a hemophilia B gene therapy has to accomplish is raised quite high.
Third, the emphasis on outcomes and comparative effectiveness will remain. Today, high-dose prophylaxis
patients have a life expectancy approaching that of the general population, yet even in countries with no cost-
containment policies, patients are still undertreated. Therefore, developers that can link undertreatment to
poor outcomes will eliminate some uncertainties around the use of their gene therapy/gene editing products.
Future attainment of this unmet need links back to characterizing the heterogeneity of the population and
identifying ultra high-dose utilization patients or other subpopulations who are undertreated; a developer that
can show how gene therapy or gene editing can address these discrepancies between patients will close the
gap.

Emerging Therapies Overview
Introduction
Key Findings
Developers of emerging therapies for hemophilia A are primarily shifting focus away from attempts to prolong
the half-life of rFVIII replacement products and, instead, moving toward development of agents with novel
mechanisms of action. These novel agents are non-rFVIIIs. They either attempt to address the large unmet need
in hemophilia A, both with and without inhibitors (ACE 910, fitusiran, the ATFPIs), or are “curative” gene
therapies and gene editing therapies (BMN 270, SHP 654). This focus on gene therapies comes despite previous
sentiment around the apparent difficulty of developing gene therapies for hemophilia A, due to the size of the
F8 DNA construct.
The hemophilia B pipeline has two main themes. First, development of “curative” agents such as gene therapies
(e.g., SPK-FIX, AMT-060) and gene editing therapies is under way, with an apparent expectation that they will
eventually replace rFIX products in the longer term. Second, “broad-spectrum” agents are being developed
such as fitusiran and the ATFPIs, which also address inhibitor formation, although addressing this problem is
less of an unmet need in hemophilia B compared with hemophilia A. Pipeline agents will face tough
competition through 2025, given that efficacious, “safe” options already exist in the form of the factor IX EHLs.
Developers of emerging therapies for inhibitors are focusing their efforts on extending the circulating half-life of
recombinant factor VIIa (CSL 689, MOD-5014, XTENylated FVIIa) and developing novel agents that can directly
treat patients with inhibitors (ACE 910 [hemophilia A only], fitusiran, ATFPIs). It is the latter group of pipeline
agents that will help address inhibitors as one of the biggest remaining challenges in hemophilia.

Pipeline Overview: Hemophilia A
Hemophilia A is more commercially attractive than hemophilia B. Hemophilia A has a larger patient population
and a higher unmet need. These factors positively influence R&D and disease visibility, with a larger and more
diverse number of candidates in development for hemophilia A.
Key players in the current hemophilia A R&D space include Alnylam, Biomarin, Bayer, Biogen,
Casebia Therapeutics, Novo Nordisk, Roche/Chugai, Sangamo, and Shire.
Innovation within the hemophilia A pipeline has three main themes:
A shift away from attempting to prolong the half-life of factor VIII replacement products, toward developing
agents with novel mechanisms of action.
Emergence of agents with novel mechanisms of action that attempt to address the large unmet need in
hemophilia A with and without inhibitors (ACE 910, fitusiran, the ATFPIs).
Development of “curative” agents such as gene therapies and gene editing therapies (BMN 270, SHP 654).
This focus comes despite previous sentiment around the apparent difficulty of developing gene therapies
for hemophilia A, due to the size of the F8 DNA construct.
All EHL rFVIII agents do not offer significantly increased half-life, thereby limiting their ability to offer significant
improvements in clinical outcomes. We view N8-GP and BAY 9027 as “me-too” drugs to Adynovate/Adynovi,
despite differences in B-domain deletion. BAX 826 may provide an increased half-life extension beyond that of
currently marketed EHLs.

Pipeline Trends: Hemophilia A

Pipeline Overview: Hemophilia B
Hemophilia B is less commercially attractive than hemophilia A. This fact negatively influences R&D and disease
visibility and has led hemophilia B to be described as a “neglected disease.” There is a smaller and less diverse
number of candidates in development for hemophilia B.
Key players in the current hemophilia B R&D space include Novo Nordisk, Spark Therapeutics, Uniqure,
Dimension Therapeutics, Alnylam, Casebia Therapeutics, Sangamo, Shire, and Amunix/Biogen.
Innovation within the hemophilia B pipeline has two main themes:
Development of “curative” agents such as gene therapies and gene editing therapies, with an apparent
expectation that they will eventually replace rFIX products in the longer term.
Development of “broad-spectrum” agents such as fitusiran and the ATFPIs, which also address inhibitor
formation, although addressing this issue is less of an unmet need in hemophilia B than in hemophilia A.
Pipeline agents will face tough competition through 2025, given that efficacious, “safe” options already exist in
the form of the factor IX EHLs. Unlike factor VIII EHLs, the former have achieved meaningful increases in half-life
extension and thereby offer marked improvements in clinical outcomes achievable. We see N9-GP as a “me
too” to Idelvion and Alprolix except for the prolongation technology used to extend its half-life (PEGylation).
Inhibitor risk is much lower in hemophilia B, and the risk is not perceived to be as big an issue when choosing a
FIX concentrate, unlike in hemophilia A. Therefore, we see less emphasis on the development of treatments to
address inhibitors in hemophilia B.

Pipeline Trends: Hemophilia B
Pipeline Overview: Hemophilia with Inhibitors
Development of inhibitors remains one of the biggest challenges in hemophilia, and patients with inhibitors
represent an area of very large unmet need. We believe any company able to address this problem with an
appropriate and easily manageable drug will be a game-changer.
Key players in the current hemophilia with inhibitors R&D space include CSL Behring, Roche/Chugai, OPKO,
Amunix/Biogen, Alnylam, and companies developing ATFPIs (Novo Nordisk, Bayer).
Innovation within the hemophilia with inhibitors pipeline has two themes:
Efforts to extend the circulating half-life of recombinant factor VIIa (CSL 689, MOD-5014, XTENylated FVIIa).
Currently marketed bypass agents have relatively short half-lives and confer a very high cost of treatment,
so improvements here would be welcome. We see BAX 817 as a similar offering to NovoSeven, and
interviewed physicians believe it does not offer any advantages over competing products.
Development of novel agents that can directly treat patients with inhibitors (ACE 910 [hemophilia A only],
fitusiran, ATFPIs).

Pipeline Trends: Hemophilia with Inhibitors

Late-Phase Pipeline Analysis
Notable Developments in the Late-Phase Pipeline for Hemophilia
Non- rFVIII treatment for hemophilia A takes center stage . It has not been possible to extend the circulating
half-life of rFVIII beyond approximately 1.5 times that of SHL agents, making it difficult to achieve significant
improvements in clinical outcome for hemophilia A patients, some whom may have to inject every other day.
This problem helps to explain the shift away from development of EHL rFVIII toward development of non-rFVIII
agents, with novel mechanisms of action. The first of which, ACE 910, is forecast to launch in 2019, around the
same time as BAY 94-9027 and N8-GP. ACE 910 has potentially huge advantages compared with any rFVIII,
whether SHL or EHL. We note with interest that no other companies are pursuing development of PEGylated
EHL rFVIII after the launch of N8-GP and BAY 94-9027.
End of the EHL rFIX generation for hemophilia B (for now). It has been possible to extend the circulating half-
life of rFIX to three to five times that of SHL agents, meaning significant improvements in clinical outcomes are
achievable. A hemophilia B patient can now infuse factor up to once every two weeks. These “safe” and
efficacious treatments will gain traction through our forecast period, providing additional clinical benefit and
leaving less opportunity for the currently early-stage novel therapies. Following the 2016 launch of Idelvion and
the near-term launch of N9-GP, we do not anticipate the launch of any further EHL rFIX hemophilia B products
until much later in the forecast period.
Treatment options for hemophilia patients with inhibitors are set to increase . Patients with inhibitors are
the largest remaining unmet need in hemophilia, most notably so in hemophilia A. ACE 910 can treat
hemophilia A with or without inhibitors, is subcutaneously rather than intravenously administered, and
provides convenience for the patient with at least once-weekly dosing. Elsewhere in the inhibitor space, we
note emergence of the first EHL FVIIa, CSL 689, which aims to provide less frequent dosing for inhibitor patients
on BAP protocols.

Therapies in Late-Phase Development for Hemophilia
Compound Orphan-Drug Designation US/EU Status Marketing Company
Hemophilia A
ACE 910 Yes (US and EU) Phase III Roche/Chugai
BAY 94-9027 No (US), yes ( EU) Phase III Bayer
N8-GP No (US), yes ( EU) Phase III Novo Nordisk
Compound
Hemophilia B
N9-GP Yes (US and EU) Filed Novo Nordisk
Compound
ACE 910 Yes (US and EU) Phase III Roche/Chugai
BAX 817 No (US and EU) Phase III Shire
CSL 689 Yes (US and EU) Phase II/III CSL Behring
Note: Status is based on secondary research (e.g., company reports, websites, and press releases) as well as databases such as Springer’s Adis
R&D Insight.

Estimated Launch Dates of Key Emerging Therapies for the Treatment of

Hemophilia
Drug United States EU5
Hemophilia A
BAY 9027 2018 2018
N8-GP 2019 2019
ACE 910 2019 2019
Fitusiran 2020 2020
BAX 826 2021 2021
BMN 270 2021 2022
BAX 888 2023 2024
Hemophilia B
N9-GP 2017 2018
Fitusiran 2020 2020
SPK-FIX 2021 2022
AMT-060 2021 2022
DTX 101 2021 2022
ACE 910 2019 2020
Fitusiran 2020 2020
CSL 689 2020 2020
MOD-5014 2022 2022
BAX 817 2018 2019
Note: Launch dates are estimated based on an analysis of the product’s current phase of development, development timelines for the disease,
company reports and estimates, expert opinion, status of development or marketing collaborations, and analysts’ reports. Launch dates reflect entry
for the disease under study in this table and potential delays due to reimbursement in the individual markets.
Orphan-Drug Designation
Orphan-Drug Provisions: United States
In the United States, the Rare Diseases Act of 2002 defines a disease as orphan if it affects fewer than 200,000
people or if the U.S. sales of any treatment developed for the indication are unlikely to recoup development
costs (even if the indication affects more than 200,000 people).

Expanded Market Exclusivity
If the FDA designates a drug as an orphan drug, it is granted seven years of market exclusivity (as opposed to the
usual five years for an NCE), beginning from the point that the marketing application for the indication is
approved. This exclusivity protects an orphan drug from generic entry, even if the drug’s patent life has expired.
It is important to note that this exclusivity can be revoked if the drug manufacturer cannot meet patient needs.
For example, if a company is unable to manufacture enough of a drug to treat the patient population, other
companies will be granted approval to manufacture and sell the agent.
Establishing orphan-drug status can be a valuable strategy for agents that are approved for other, larger
indications and are facing the end of their patent life as well as the inevitable loss of sales resulting from generics
competition. Approval for an orphan disease can keep generic agents off the market for several years after
patent expiry.
Tax Credits
Companies that develop orphan drugs can claim up to 50% of clinical costs as a tax credit. Given that drugs
receiving orphan-drug status must still provide all the efficacy and safety data required of any new agent, this
incentive is designed to reduce the financial burden associated with clinical trials. Clinical costs that qualify
include wages, supplies, and contract costs associated with clinical trials for the orphan indication.
Additionally, companies can claim tax credits for clinical activities that occurred prior to the approval of
orphan-drug status.
Support During the Drug Approval Process
Various incentives are in place that are intended to ease the burden associated with the drug approval process.
For example, the FDA will assist the drug developer in designing protocols for clinical trials. Although this
incentive is of little value for established companies with multiple products on the market or in clinical
development, such assistance can be useful to smaller companies with limited resources. In addition, orphan
drugs that are designed to treat deadly diseases are eligible for accelerated approval, and drugs that receive
orphan-drug status can have their PDUFA fees waived. These fees include the one-time application fee (the FDA
estimated that fee at $2,169,100 in 2014), the annual per-company establishment fee ($554,600 in 2014), and
the annual product fee ($104,060 in 2014). Although these fees amount to only a small percentage of a drug’s
overall development cost, this incentive could help smaller companies with limited resources.
Grants
The Office of Rare Diseases Research at the National Institutes of Health ( NIH) awards approximately $13 million
each year in grants to fund clinical trials for orphan diseases. Each grant is designed to fund an individual trial:
the average grant for a Phase I trial is $20,000; the average grant for a Phase II or III trial is $350,000.

Orphan-Drug Provisions: Europe
The EMA defines orphan diseases as those that affect fewer than 5 individuals out of every 10,000 (< 0.05%). The
designation also includes conditions for which a treatment is unlikely to be developed without incentives in
place or for which no satisfactory method of treatment exists and a medical product would be of significant
benefit to the individuals afflicted with the condition.
The EMA’s orphan-drug incentive program is very similar to the FDA’s program; it offers market exclusivity,
clinical trial protocol assistance, and fee waivers.
Market Exclusivity
One key difference between the two programs lies in the market exclusivity incentive. The EMA’s market
exclusivity lasts for ten years from the point that the marketing authorization application is received. However,
if, after six years, a drug is determined to be profitable enough that it is likely to recoup its development costs (a
key aspect for the designation of orphan-drug status), the remaining four years of market exclusivity can be
revoked.
Fee Reductions
Several fee reductions—first established in 2007 and revised in 2013—are available for European orphan
medicinal products. All companies are eligible for a 100% reduction in the fees for preauthorization inspections.
Small and medium enterprises (SMEs) are also eligible for a 100% reduction in the fees for new applications for
market approval, all initial and follow-up protocol assistance, and postauthorization applications and annual
fees in the first year after market approval is granted. Companies that are not SMEs are eligible for a 75%
reduction in fees for initial and follow-up protocol assistance and a 10% fee reduction for initial marketing
authorization applications.

Patient Registries
Hemophilia Patient Registries
Patient registries collect information regarding patients’ genetics, disease progression, medical history, and
treatment results that could allow clinicians to gain a better understanding of etiology and pathophysiology of
hemophilia and guide clinical research. Registries can also facilitate efficient patient recruitment for clinical trials
evaluating novel therapies, and registry data could be used to examine the efficacy and safety of interventions and
to improve treatment.
In hemophilia, a patient registry is invaluable for tracking the identification and diagnosis of people with
hemophilia and provides insight on the hemophilia population within a geography.
Registries can play a role in the monitoring of patients’ health and can contribute to the long-term planning for
hemophilia organizations and their prioritization of care. Registries can also have a role in providing an
overarching view of the disease, identifying unmet needs, providing pharmacovigilance/monitoring of long-
term safety, and supporting marketing authorizations.
The number of hemophilia registries is increasing, but problems remain:
Some patients are registered in several, while others are registered in none.
Not all treatment centers are included.
Not all patients are classified using the same definitions, between registries.
Discrepancies exist in the data parameters collected, between registries.
The rarity of the disease means there are a limited number of hemophilia patients, which can limit patient data.
Scarcity of data provides a strong argument for advocating for the use of multicenter/multinational studies and
global databases—for example, the database proposed by the World Federation of Hemophilia, the World
Bleeding Disorder Registry (WBDR).
Registries serve a surveillance purpose, and this function is particularly relevant to the entry of new
concentrates to the market.
Registries have a role to play in tendering processes (the process of making an offer or bid to be the preferred
supplier of factor in a country); assessment of factor concentrate volumes is a major part of this role.

Country Registry Name Registered Diseases Start Date
Global World Bleeding Disorder Registry Not available Not available

(WBDR)
United States ATHN Registry Hemophilia A, hemophilia B, vWD Formerly HTRS Registry, started
2004
United Kingdom The National Hemophilia Database Hemophilia A, hemophilia B, vWD, 1968
(NHD) other bleeding disorders
http://www.ukhcdo.org/nhd.htm
France FranceCoag Hemophilia A, hemophilia B, vWD, 2003

www.francecoag.org other rare
inherited bleeding disorders
Germany German Haemophilia Registry Hemophilia A, hemophilia B, vWD, 2009

www.pei.de/dhr-en other rare bleeding disorders
Italy The Italian Registry for Rare 300+ rare diseases; hemophilia A, 2001
Diseases hemophilia B, vWD, other rare 1988
The National Registry of factor deﬁciencies, inherited 2003
Congenital Coagulopathies platelet disorders, hemophilia
(RNCC) carriers
The Haemophilia Database of the
Italian Association of Haemophilia
Centres
(AICE)
Spain Hemobase Hemophilia A, hemophilia B, vWD Unknown
Other Hemophilia Registries and Databases
EU Registries and Data Collections
EUHASS/EUHANET EUHASS is a pharmacovigilance program to monitor the safety of treatments for people with inherited
bleeding disorders in Europe. Hemophilia treatment centers report adverse events directly to the
EUHASS website, and regular surveillance reports are produced. The follow-up project, EUHANET,
aims to unify the treatment quality in Europe and beyond.
PedNet PedNet registry aims to include complete cohorts of all newly diagnosed patients born from January
2000 with congenital hemophilia A and B factor VIII/ IX ≤ 0.25 IU/dl and treated in one of the 31
participating centers. Detailed information on diagnosis, clinical signs, and treatment (dose, product,
bleeding, surgery) is collected. For the first 75 exposure days, every reason for treatment is
documented, including details on treatment. Inhibitor development is centrally defined according to
predefined criteria.
ABIRISK ABIRISK Project (not exclusive to hemophilia) will investigate the correlation between patient and
clinical factors and the incidence of immunogenicity. A major goal is to further elucidate the underlying
mechanisms of immunogenicity, which may result in more science-based regulatory guidelines. In turn,
this project may reduce the regulatory burden for immunogenicity testing and save time and resources in
the biopharmaceuticals development process.
Factor IX Variant Database Interactive mutation database provides insights into mechanisms of hemophilia B. Type II mutations are
deduced to disrupt predominantly those structural regions involved with functional interactions. The
interactive features of the database may assist in making judgments about patient management.

International Databases
International Registry of Rare Bleeding This registry prospectively collects clinical and laboratory data on patients with coagulation factor
Disorders deficiencies to evaluate prevalence, bleeding frequency and management, as well as consumption of
treatment products and related complications. Current studies are analyzing fibrinogen and factor XIII
deficiencies.
SIPPET Survey of Inhibitors in Plasma Product Exposed Toddlers (SIPPET) was initiated in 2006 as an
international, prospective, controlled, randomized, and open-label clinical trial on inhibitor frequency in
previously untreated patients (PUPs) and minimally blood-component-treated patients.
GEHEP Global Emerging Haemophilia Panel (GEHEP) is an international, multi-institutional consortium to

advance hemophilia care. A global protocol was developed to facilitate the sharing of aggregated data
among GEHEP members on the intra- and inter-institutional differences in patient populations,
diagnosis, and treatment.
Key Emerging Therapies
Hemophilia A
Phase III emerging therapies for hemophilia A include two PEGylated extended half-life ( EHL) agents (Bayer’s
BAY 94-9027 and Novo Nordisk’s N8-GP) and a bispecific antibody (ACE 910).
BAY 94-9027 and N8-GP are both recombinant factor VIII molecules utilizing PEGylation to extend their
circulating half-lives and intended for replacement therapy in patients with hemophilia A. The recombinant
factor VIII market is already crowded; BAY 94-9027 and N8-GP will be the third and fourth EHL, respectively, to
market.
ACE 910 is a humanized monoclonal modified IgG4 antibody that binds both factors IXa and X, replacing the
function of the missing factor VIII in patients with hemophilia A with or without inhibitors to factor VIII. ACE 910
will be the first non-rFVIII to market.
BAY 94-9027
Bayer is developing BAY 94-9027, a B-domain-deleted recombinant factor VIII with site-specific attachment of
60 kDA PEG, for the treatment of hemophilia A. The addition of PEG is to extend BAY 94-9027’s circulating half-
life. Increasing the half-life is intended to reduce the frequency of dosing, which could improve
patient convenience and lower costs if less product is used. BAY 94-9027 is in Phase III development in the
PROTECT-VIII and PROTECT-VIII KIDS trials.

BAY 94-9027 Profile
Drug class/mechanism of action B-domain-deleted recombinant factor VIII with site-specific attachment of 60 kDA polyethylene
glycol
Efficacy PROTECT VIII (NCT01580293) : 44% of patients (n=43) in the every-five-day treatment arm
experienced no bleeds, and a median ABR of 1.9 was observed in this treatment arm. 37% of
the patients (n=43) receiving infusion every seven days experienced no bleeds with a median
ABR of 3.9 (including noncompleters). 13 patients who remained in the two times per week
treatment arm because of their high bleeding rate during the assessment period reduced their
median ABR from 17.4 to 4.1. Patients who received on-demand treatment (n=20) had a median
ABR of 23. In addition, Bayer reported that a subgroup analysis of the trial demonstrated
improved bleeding protection in patients receiving BAY 94-9027 prophylaxis dosing based on
bleeding phenotype compared with prestudy levels, highlighting the importance of phenotype-
guided dosing.
PROTECT VIII Kids (NCT01775618): Every-5-days prophylaxis dosing was the most frequently
used regimen at the beginning (45% of patients) and end (53% of patients) of the study. For
patients who switched from every-7-days treatment to more frequent dosing (n=8), median
number of total bleeds improved from 2 before switching to 1 after switching; median ABR also
improved from 18.3 before switching to 2.6 after switching. For patients who remained in the
every-7-days treatment arm throughout the study (n=7), the median number of total bleeds was
2.0 and median ABR was 1.6. 129 of 140 bleeds (92%) reported during the study were
controlled with 1-2 infusions. Response to treatment of bleeds was good or excellent in 85.7% of
bleeds; responses were similar in both age-groups.
Side effects PROTECT VIII: BAY 94-9027 was generally well tolerated, but hypersensitivity reactions were
reported in two patients. One was reported as a serious adverse event. No inhibitors to
FVIII were reported.
PROTECT VIII Kids: 8 patients (aged 2-6 years) discontinued from the study because of
suspected immunologic response against PEG, which occurred within 4 exposure days to BAY
94-9027; no major safety concerns, including FVIII inhibitor development, were observed in
these patients. All of these patients safely resumed their prior FVIII treatment at the same doses
and frequencies as before the study.
Dosing frequency Potentially infusion intervals up to once every 7 days
Dosage form Intravenous infusion
Note: Based on information from www.clinicaltrials.gov
BAY 94-9027 Clinical Development
In comparing the development program of BAY 94-9027 with that of already approved agents, we perceive the
closest clinical comparators to be Adynovate and Eloctate. The table ”BAY 94-9027 Clinical Development: PROTECT-
VIII Trial Design Analysis” highlights the the pivotal trial of BAY 94-9027 and our thoughts on the clinical development
strategy.

BAY 94-9027 Clinical Development: PROTECT-VIII Trial Design Analysis
Parameter Current Trial Design DRG Opinion on Clinical Development Strategy
Patient population N=141, male patients aged 12-65, with severe hemophilia A, N.A.
previously treated with FVIII for at least 150 exposure days.
End points Primary outcomes: Annualized number of total bleeds in on- Linking adherence to outcomes will strongly support
demand treatment arm (Weeks 0-36) and prophylaxis arm uptake of BAY 94-9027. Linking joint status to quality of
(Weeks 10-36, excluding rescue bleeds). Secondary life may provide a more sophisticated method of looking at
outcomes available at NCT01580293. disease progression. It may also be useful to examine
predictors of QOL.
Comparator(s) None. There is a gap in comparative evidence. Ability to making

indirect comparisons looking at differences (changes) in (a)
annual bleeding rate and (b) clotting factor use, using (e.g., a
rVIII vs. BAY 94-9027), also defining how similar or dissimilar
the patient populations are in each cohort, will close the gap
in comparative effectiveness data.
Trial design and duration Multicenter, partially randomized, open-label trial The study demonstrates superiority of prophylaxis to an on-
investigating safety and efficacy of on-demand and demand regimen but does not show how BAY 94-9027
prophylactic treatment with BAY 94-9027 in severe benchmarks against what Bayer perceives as being the
hemophilia A. Subjects in prophylactic treatment arms will SoC in BAY 94-9027’s launch year, e.g., Eloctate or
undergo clinical evaluation at 10 weeks. Those with Adynovate. Failure to show additional medical benefit over
adequate control of bleeding will undergo randomization to the SoC may mean price parity with the SoC in some regions.
every 5 or 7 day infusion. Those with continued bleeding will Forethought is needed regarding how BAY 94-9027 will
remain in treatment arm and have an increase in dose. Part benchmark against future products like ACE 910 or fitusiran,
B, on major surgery, is an optional substudy included to although it is obviously difficult to compare at this stage.
collect information on efficacy of BAY 94-9027 in major
surgical setting. Due to rarity of surgery in this population,
enrollment to this substudy may be independent of
participation in main study.
Other evidence N.A. A dedicated surgical trial, studies in PUPs, and post-approval
studies examining treatment of patients with inhibitors will
support use of BAY 94-9027. Examining QOL data for
patients with mild hemophilia may give insights into what gene
therapy, BAY 94-9027’s future competitor, may be able to
achieve in QOL terms.

Key Ongoing Clinical Trials for BAY 94-9027
Primary Outcome Measures and Timeframe of Estimated

Study Phase Study Size Intervention(s) Assessment Completion
PROTECT-VIII II/III 141 BAY 94-9027; 3 Annualized number of total bleeds in on-demand treatment February 2017
prophylactic arm (weeks 0-36) and prophylaxis arm (weeks 10-36,
infusion arms: excluding rescue bleeds); Part A: physician's assessment of
infusions every adequacy of hemostasis in major surgery.
five days, every
seven days, and
twice a week. 1 on-
demand arm.
PROTECT-VIII III 77 BAY 94-9027: Arm Annualized number of all bleeds; pharmacokinetics profile of December 2019
KIDS 1: Open-label BAY 94-9027 based on blood concentration over the defined
treatment with time period; response of acute bleeding events to treatment
long-acting rFVIII based on a 4-point scale (poor, moderate, good, or excellent);
for approximately characterization of a potential immune response.
6 months (or
longer until 50
exposure days) on
a regular schedule
at least once every
7 days. Arm 2:
open-label
treatment with the
same drug for 12
weeks on a regular
schedule of
2x/week.
Expert Insight
KOLs find the idea of an EHL recombinant factor VIII appealing but are concerned by the uncertainties around
the variable dosing regimens between patients and switching from an SHL to an EHL or switching between
EHLs. KOLs remain unsatisfied with the relatively small half-life extension offered by the EHLs compared with
the SHLs; the dosing schedule has not been significantly improved for hemophilia A patients.
KOLs have mixed views on the long-term toxicity of intravenously administered PEGylated molecules. We note
mixed sentiment on PEGylated EHLs like BAY 94-9027 with some physicians saying they would be happy to
prescribe them, others saying they were initially worried to prescribe them but have now changed their mind,
some who would prescribe only in adults and not children, and finally the few who would not prescribe them at
all. The same sentiments also apply to Novo Nordisk’s N8-GP and Shire’s Adynovate.

Expert Insight on BAY 94-9027
Topic Quote
Value of an EHL factor VIII to patients and “The story of an EHL factor VIII is very appealing to both doctors and the patients. I think the patients
physicians like it because they can say, OK I get the same effect as before only with a longer half-life. But there’s a
lot of uncertainties around the switching and switch-backs. The last thing they want is to start bleeding
more with the new product.”
Magnitude of half-life extension “I think the current long acting VIII is worthless. I think we’re going to have to see substantially more
improvement on the factor VIII prolongation, if we’re going to call it a long acting agent, period. 1.5
extension is of little consequence.”
PEGylation “No one, as of yet, has satisfied the whole issue of PEGylation being safe long term. It’s a protein that
we don’t know much about, long term, and it’s excreted by the liver, plenty of patients have liver
abnormalities and nobody’s ever been given PEG intravenously on a chronic basis. Why would you add
something to a native product when you don’t know the outcome, long term, of what will happen to the
PEG? If I were faced with two EHL products of identical price for hemophilia A, I would always choose
the fusion protein over the PEGylated”
“I had a preference for the fusion protein because I was not sure about the safety of PEG, but I’ve seen
in new publications and new headings and so, I’m convinced that at the PEGs used in a Adynovate
have no harm or no potential harm for the patients. So, I do not prefer anything.”
“I don’t like the PEG drugs because there’s an issue about the PEG molecule in the human body for
years, so my personal point of view is that I’d rather the FC product over the PEGgylated, but I don’t
know, and the rest of my colleagues think that there is some concern about the PEG molecule. If you
have other molecules to choose from, perhaps it’s not the best one to choose.”
“What will I use? I would use Elocta, because it is not PEGylated. Because I have done the clinical trials
for many of the companies with the PEGylated products, I’m not TOO worried BUT you never know. It’s
the unknown that we don’t know. If I had to use a PEGylated product I’d be more likely to prescribe it in
an adult than a child. Also, PEGylation did not show any remarkable difference in their half-life between
Elocta and, so, I don’t understand the great big advantage I would have by putting someone at
unknown potential risk compared to what we know about Elocta.”

Expectations for Launch and Sales Opportunity of BAY 94-9027 in Hemophilia A
BAY 94-9027 will be a late hemophilia A market entrant, launching in 2018. Arriving in a congested market and
having less time to establish itself compared with earlier entrants will hamper its market share through 2025.
There is a physician-perceived class concern with PEGylated molecules that we believe will dampen the sales
outlook for BAY 94-9027. Interviewed physicians consistently express concern about the safety and long-term
toxicity of PEGylated molecules administered intravenously. Some of our KOLs say they would refuse to
prescribe any PEGylated molecule, including Adynovate or N8-GP. Others would be more willing to prescribe
PEGylated products in adults but much less so in children.
U.S. physicians act as “advisors” to patients, and there are very few formulary restrictions on hemophilia
products in the United States. The patient has a large role to play in choosing a product. We believe the same
negative physician sentiments on PEG will also be reflected in patient preferences.
We expect ACE 910 and fitusiran to be potential game-changers. We expect they will launch in the United States
in 2019 and 2020, respectively, and will offer huge advantages over BAY 94-9027 or any other rFVIII product. We
expect that these novel agents will take some market share from all recombinant factor VIII products but most
notably the late market entrants such as BAY 94-9027. The limited time Bayer will have to establish BAY 94-9027
ahead of the ACE 910 and fitusiran launches will soften uptake of the product.
We anticipate that BAY 94-9027 will not be able to command a price premium over the SoC, particularly in
the EU5, instead going for price parity or less, and will aim for increasing its market share instead.
N8-GP
Novo Nordisk is developing N8-GP, a B-domain O -glycoPEGylated factor VIII for the treatment of hemophilia A.
Use of PEG to extend N8-GP’s circulating half-life could potentially translate into cost offsets and improved
patient convenience. N8-GP is in Phase III development, with the pivotal Pathfinder 2 trial. N8-GP is currently
being investigated in several other trials.

N8-GP Profile
Drug class/mechanism of action B-domain deleted rFVIII with a branched 40 kDa PEG attached to glycan moiety in the
truncated B domain
Efficacy Pathfinder 2 (NCT01480180): 175 patients were treated with a prophylactic regimen of 50 U/kg
every fourth day and 11 patients received on-demand treatment, when bleedings occurred.
Patients were treated for up to 21 months, resulting in median annualized bleeding rates of 1.3
and 30.9 episodes for patients treated prophylactically and on-demand, respectively. The
pharmacokinetic data documented a single-dose half-life of 18.4 hours and a mean trough level
of 8%.
Pathfinder 5 (NCT01731600)
Primary efficacy end point was incidence of inhibitory antibodies against FVIII ≥0.6 BU.
Following twice-weekly N8-GP administration (50-75 IU/kg ) for ≥50 exposure days, no patient
developed an inhibitor.
Side effects Pathfinder 2

Of 186 patients in the trial, one patient who responded well to prophylactic treatment throughout
the trial developed an FVIII inhibitor.
Pathfinder 5
No significant clinical concerns were identified.
Dosing frequency Infusion up to once every 4 days (Pathfinder 2)
Dosage form IV infusion
N8-GP Clinical Development
In comparing the development program of N8-GP with that of already approved agents, we perceive the closest
clinical comparators to be Adynovate and Eloctate. The table “N8-GP Clinical Development: Pathfinder 2 Trial
Design Analysis” highlights the pivotal trial of N8-GP and our thoughts on the clinical development strategy.

N8-GP Clinical Development: Pathfinder 2 Trial Design Analysis
Patient population N=186, male patients aged 12 or older (except in Croatia, None.
France, Russia, Israel, and the Netherlands where the lower
age limit will be 18 years), with severe hemophilia A,
previously treated with FVIII for at least 150 exposure days.
End points Primary outcomes: The incidence of FVIII inhibitors greater Linking adherence to outcomes will strongly support
than or equal to 0.6 BU (Bethesda units); annualized uptake of N8-GP.
bleeding rate in the prophylaxis arm. Secondary outcomes: Linking joint status to quality of life may provide a more
available at NCT01480180. sophisticated method of looking at disease progression. It
may also be useful to examine predictors of QOL.
Comparator(s None. There is a gap in comparative evidence. Ability to make

indirect comparisons looking at changes in (a) annual
bleeding rate and (b) clotting factor use, using (e.g., a rFVIII
vs. N8-GP), also defining how similar or dissimilar the patient
populations are in each cohort, will close the gap in
comparative effectiveness data.
Trial design and duration Non-randomized, safety/efficacy study, parallel, open- This study is nonrandomized. Once the SoC comparator is
label. Primary purpose: treatment. 2 experimental arms: defined, the study should be powered to beat that
prophylaxis and on-demand. 175 patients were treated comparator, and only then will payers acknowledge the
with a prophylactic regimen of 50 U/kg every fourth day, added benefit. The absence of an RCT will require robust
and 11 patients received on-demand treatment, when justification. One way around the absence of an RCT is
bleedings occurred. Patients were treated for up to 21 obtaining real-world data on utilization post-approval.
months, resulting in median annualized bleeding rates of This study demonstrates superiority of prophylaxis to an
1.3 and 30.9 episodes for patients treated prophylactically on-demand regimen but does not show how N8-GP
and on-demand, respectively. The PK data documented a benchmarks against what Novo Nordisk perceives as
single-dose half-life of 18.4 hours and a mean trough level being the SoC in N8-GP’s launch year, e.g., Eloctate or
of 8%. End points to be analyzed after 24 and 36 months Adynovate. Failure to show additional medical benefit may
and until the end of the trial. mean price parity with Eloctate or Adynovate in some
regions. Forethought is needed regarding how N8-GP will
benchmark against future products like ACE 910 or
fitusiran, although we acknowledge it is difficult to compare
at this stage.
Other evidence N.A. Post-approval studies examining treatment of patients with

inhibitors will support uptake of N8-GP. Examining QOL data
for patients with mild hemophilia may give insights into what
gene therapy, N8-GP’s future competitor, may be able to
achieve in QOL terms.

Key Ongoing Clinical Trials for N8-GP

Pathfinder2 III 186 N8-GP, arms: The incidence of FVIII inhibitors greater than or equal to December 2018
prophylaxis (50 0.6 BU (Bethesda units); annualized bleeding rate in the
U/kg every fourth prophylaxis arm; at 24 and 36 months and until the end of
day) and on- the trial
demand
Pathfinder3 III 43 N8-GP, surgical Hemostatic effect during surgery evaluated by the four-point December 2018
experimental arm: scale (excellent, good, moderate, or none); assessed by
individually investigator/surgeon on the day of surgery
adjusted doses of
N8-GP
administered
before, during, and
after surgery
Pathfinder5 III 68 N8-GP, Incidence of inhibitory antibodies against coagulation factor May 2018
experimental arm VIII equal to or above 0.6 Bethesda units; during the main
was twice-weekly phase of the trial (0-26 weeks of treatment)
N8-GP
administration (20-
75 IU/kg)
Pathfinder6 III 125 N8-GP, 1 Incidence of inhibitory antibodies against coagulation November 2021
experimental arm, FVIII (a) when first 50 PUPs have reached at least 50
50 exposure exposure dates, (b) when first 100 PUPs have reached 100
days. Frequency exposure dates, and (c) at the end of the trial; end of trial will
and dosage (20- be up to 4 years after patient has reached 100 exposure
75 U/kg) dates (expected to reach 12-60 months)
dependent on
whether given as
treatment for
bleeding episode
or as prophylaxis
Pathfinder7 I 22 N8-GP is the Area under the FVIII activity-time curve; 0-96 hours post- April 2017
experimental and injection
active comparator;
in both treatment
arms, dose 50
IU/kg, randomized
crossover design

Expert Insight on N8-GP
Topic Quote
Value of an EHL factor VIII to patients and “The story of an EHL factor VIII is very appealing to both doctors and the patients. I think the patients
physicians like it because they can say, OK I get the same effect as before only with a longer half-life. But there’s a
lot of uncertainties around the switching and switch-backs. The last thing they want is to start bleeding
more with the new product.”
Magnitude of half-life extension “I think the current long acting FVIII is worthless. I think we’re going to have to see substantially more
improvement on the factor VIII prolongation, if we’re going to call it a long acting agent, period. 1.5
extension is of little consequence.”
PEGylation “No one, as of yet, has satisfied the whole issue of PEGylation being safe long term. It’s a protein that
we don’t know much about, long term, and it’s excreted by the liver, plenty of patients have liver
abnormalities and nobody’s ever been given PEG intravenously on a chronic basis. Why would you add
something to a native product when you don’t know the outcome, long term, of what will happen to the
PEG? If I were faced with two EHL products of identical price for hemophilia A, I would always choose
the fusion protein over the PEGylated.”
“I had a preference for the fusion protein because I was not sure about the safety of PEG, but I’ve seen
in new publications and new headings and so, I’m convinced that at the PEGs used in a Adynovate
have no harm or no potential harm for the patients. So, I do not prefer anything.”
“I don’t like the PEG drugs because there’s an issue about the PEG molecule in the human body for
years, so my personal point of view is that I’d rather the FC product over the PEGgylated, but I don’t
know, and the rest of my colleagues think that there is some concern about the PEG molecule. If you
have other molecules to choose from, perhaps it’s not the best one to choose.”
“What will I use? I would use Elocta, because it is not PEGylated. Because I have done the clinical trials
for many of the companies with the PEGylated products, I’m not TOO worried BUT you never know. It’s
the unknown that we don’t know. If I had to use a PEGylated product I’d be more likely to prescribe it in
an adult than a child. Also, PEGylation did not show any remarkable difference in their half-life between
Elocta and, so, I don’t understand the great big advantage I would have by putting someone at
unknown potential risk compared to what we know about Elocta.”
Expert Insight
KOLs find the idea of an EHL recombinant factor VIII appealing but are concerned by the uncertainties around
the variable dosing regimens between patients and switching from an SHL to an EHL or switching between
EHLs.
KOLs remain unsatisfied with the relatively small half-life extension offered by the EHLs compared with the
SHLs; the dosing schedule has not been significantly improved for hemophilia A patients.
KOLs have mixed views on the long-term toxicity of intravenously administered PEGylated molecules. We note
mixed sentiment on PEGylated EHLs such as N8-GP with some physicians saying they were initially worried to
prescribe them but have now changed their mind, some who would prescribe only in adults and not children,
and finally the few who would not prescribe them at all. The same sentiments also apply to Bayer’s 94-9027 and
Shire’s Adynovate.

Expectations for Launch and Sales Opportunity of N8-GP in Hemophilia A
N8-GP will be a late hemophilia A market entrant, launching in 2019. Arriving in a congested market and having
less time to establish itself compared with earlier entrants will hamper its market share through 2025.
There is a physician-perceived class concern with PEGylated molecules that we believe will dampen the sales
outlook for N8-GP. Interviewed physicians consistently express concern about the safety and long-term toxicity
of PEGylated molecules administered intravenously. Some of our KOLs say they would refuse to prescribe any
PEGylated molecule, including Adynovate or BAY 94-9027. Some would be more willing to prescribe PEGylated
products in adults but much less so in children.
U.S. physicians act as “advisors” to patients, and there are very few formulary restrictions on hemophilia
products in the United States. The patient has a large role to play in choosing a product. We believe the same
negative physician sentiments on PEG will also be reflected in patient preferences.
We expect ACE 910 and fitusiran to be potential game-changers. We expect they will launch in the United States
in 2019 and 2020, respectively, and will offer huge advantages over N8-GP or any other rFVIII product. We expect
that these novel agents will take some market share from all rFVIII products but most notably the late market
entrants such as N8-GP. The limited time Novo Nordisk will have to establish N8-GP ahead of the ACE 910 and
fitusiran launches will soften uptake of the product.
We anticipate that N8-GP will not be able to command a price premium over the SoC at the time of its launch,
particularly in the EU5, instead going for price parity or lower, and will aim for increasing its market share
instead.
ACE 910
ACE 910 is being co-developed by Chugai Pharmaceutical and Roche. ACE 910 is a humanized monoclonal
modified IgG4 antibody with bispecific structure targeting factors IX, IXa, X, and Xa. It is in development for the
treatment of hemophilia A with or without inhibitors. ACE 910 binds both factors IXa and X, mimicking the
function of factor VIII. By activating factor X, ACE 910 is expected to control hemophilia A because it acts directly
on factor X, independently of factor VIII.
We anticipate that ACE 910 will be a game-changer because it will be administered by subcutaneous injection at
least once a week, with Roche/Chugai investigating the possibility of once-monthly dosing in some patients.

ACE 910 Profile
Drug class/mechanism of action Humanized monoclonal modified IgG4 antibody with bispecific structure targeting factors IX,
IXa, X, and Xa
Efficacy NCT02847637 (without inhibitors): ACE 910 demonstrated a reduction in median ABR, resulting
in patients with severe hemophilia A achieving an ABR of 1.4, 0.2, and 0 for the emicizumab
0.3, 1, and 3 mg/kg/week treatment groups, respectively. This result equated to a reduction in
ABR of greater than 95% in each group.
Side effects In November 2016, Roche reported that four patients suffered SAEs in the trial examining
patients with inhibitors. Two patients suffered thromboembolic events and two suffered
thrombotic microangiopathy when they were being treated for breakthrough bleeding using ACE
910. Roche has since instigated additional monitoring measures in the study.
In the Phase I study, 150 adverse events and 2 serious adverse events were observed in 18
patients. No thromboembolic adverse events observed. Antibodies to ACE 910 developed in 3
patients.
Dosing frequency At least once weekly
Dosage form Subcutaneous injection
ACE 910 Clinical Development
In comparing the development program of ACE 910 with that of already approved agents, we perceive its closest
comparators, based upon SoC at time of ACE 910’s launch, to be Adynovate and Eloctate and possibly an SHL
such as Advate. The table “ACE 910 Clinical Development: HAVEN 3 Trial Design Analysis” highlights the pivotal
trial of ACE 910 in hemophilia A without inhibitors and our thoughts on the clinical development strategy.

ACE 910 Clinical Development: HAVEN 3 Trial Design Analysis
Patient population N=145, male and female patients aged 12 years or older, with None.
severe hemophilia A, previously treated with FVIII for at least
24 weeks.
End points Primary outcomes: number of bleeds over time (timeframe: 24 We note that Roche/Chugai has explicitly looked at
weeks). Secondary outcomes: available at NCT02847637. “change” (reduction) in three secondary outcomes
parameters over time, which will be favorable in the eyes
of payers. Linking improvements in adherence to
outcomes, especially cost offsets, will strongly support
uptake of ACE 910. Linking joint status to quality of life
may provide a more sophisticated method of looking at
disease progression. Although health-related QOL scores
are investigated as a secondary outcome, we do not know
which ones. We believe It may also be useful to examine
predictors of QOL.
Comparator(s) None. A gap in comparative evidence is present, but a big

positive is that Roche/Chugai is making indirect
comparisons looking at reductions in (a) number of bleeds,
(b) number of joint bleeds, and (c) number of target joint
bleeds over time, using patients’ rFVIII vs. ACE 910.
Investigating changes in ABR and/or clotting factor use
over time between a rFVIII vs. ACE 910 could be useful,
as could defining how similar or dissimilar the patient
populations are in each cohort. These measures will
further close the gap in comparative effectiveness data.
Trial design and duration Randomized, multicenter, open-label, Phase III clinical trial to Study attempts to demonstrate superiority of ACE 910
evaluate the efficacy, safety, and pharmacokinetics of prophylaxis to rFVIII on-demand AND prophylactic regimens,
prophylactic emicizumab versus no prophylaxis in hemophilia but it does not show how ACE 910 benchmarks against what
A patients without inhibitors. Arm 1: prior prophylaxis with Roche/Chugai perceives as being the SoC in 2019 when
FVIII moving to prophylaxis with ACE 910 (once-weekly dose ACE 910 will launch; SoC could be Eloctate, Adynovate, an
after down-titration). Arm 2: prior on-demand with FVIII SHL such as Advate, or something else, such as a twice-
moving to prophylaxis with ACE 910 (once-weekly dose after weekly regimen. We do not know which rFVIII patients had
down-titration). Arm 3: prior on-demand with FVIII moving to been previously using (SHL or EHL and, if EHL, Eloctate or
prophylaxis with ACE 910 (dose once every 2 weeks, after Adynovate). Failure to show additional medical benefit
down-titration). Arm 4: prior on-demand with FVIII stays as through lack of direct comparative effectiveness may mean
on-demand with FVIII but with option of switching to ACE 910 price parity with the SoC in some regions. Forethought is
after 24 weeks. needed regarding how ACE 910 will benchmark in the future
against products like fitusiran, although we acknowledge it is
difficult to compare at this stage.
Other evidence N.A. A dedicated surgical trial, studies in PUPs, studies examining
PK-guided dosing will support uptake of ACE 910. Examining
QOL data for patients with mild hemophilia may give insights
into what gene therapy, ACE 910’s future competitor, may be
able to achieve in QOL terms. In the real world, identifying
latent variables contributing to “good” adherence-rate
patients could limit the impact of treatment failures if ACE 910
is injected every two weeks and the patient misses or delays
a dose.

Key Ongoing Clinical Trials for ACE 910 for the Treatment of Hemophilia A Without
Inhibitors

NCT02847637 III 145 ACE 910. 4 arms: Number of bleeds over time; 24 weeks March 2018
(hemophilia A 3 experimental,
without inhibitors) where ACE 910
given
prophylactically
at 3 mg/kg/week
for 4 weeks,
followed by either
1.5 or 3
mg/kg/week.
4th arm is an
active comparator
of no prophylaxis.
Expert Insight
Here, we provide expert insight on the use of ACE 910 to treat hemophilia A without inhibitors. Expert insight on the
use of ACE 910 to treat hemophilia A with inhibitors is provided in the section “Hemophilia with Inhibitors” within
“Key Emerging Therapies”.
Interviewed KOLs are very excited by the prospect of ACE 910 and the unmet need it may be able to address in
severe hemophilia A patients without inhibitors. These patients are currently infusing factor intravenously at
least two to three times per week.
An alternative to IV infusion is highly sought after by patients and physicians. The SQ formulation that ACE 910
offers resonates strongly with physicians. ACE 910 would enable hemophilia A patients without inhibitors to
inject at least once a week and, in some patients, at potentially longer intervals. Physicians suggest that even if
ACE 910 cannot achieve once-weekly dosing in some patients, it could be given twice weekly at a lower dose.
In November 2016, Roche reported that four thrombotic SAEs were detected in its inhibitor trial in patients
treated for breakthrough bleeding. Due to the lack of information regarding these findings and the physician
confidence in the product ahead of this news, our forecasts and market assessment have not been adjusted.

Expert Insight on ACE 910
Topic Quote
ACE 910 taking market share “We’ve actually got a patient on ACE 910 as part of the Roche trial. Obviously, for inhibitor patients it’s
absolutely fantastic because there are limitations with recombinant VIIa and Feiba and it’s practically
impossible to give them prophylaxis. Preliminary data from the trial which we are a part of at the
moment, looks good. I think for patients with inhibitors it will be absolutely fantastic, and will be the first
time they’ve had good treatment. It will be an incredible advance and everybody will be on it. We’ve also
agreed to take part in the trial of patients without inhibitors; if having this subcutaneous injection once a
week in the non-inhibitor hemophilia A patients works as well, I think that could completely change the
market and it could really blow everything else out of the water. There’ll be lots of patients who would be
having the subcutaneous injection once a week.”
ACE 910 being able to demonstrate an “Although I don’t have any personal experience in the trials of ACE 910, from the data seen in its trial, it
outcome difference is really good and certainly will improve on the unmet need for the inhibitor patients. With ACE 910 (and
with fitusiran), you have a steady state unlike the injected factors with their troughs, and, therefore, I
don’t think it is just an ‘improved convenience’ thing. I think there will be an outcome difference.”
ACE 910 achieving a price premium based “It depends. I think that if the target is a small child with very difficult veins, perhaps the payers will be
on improved convenience only willing to pay for this kind of patient, but for the adult patient with good weight, I’m not sure that our
health system will pay a lot more just for the convenience of the patient. But of course, it also depends
on the pressure that the patient's association will make because in Spain, the prescription of
recombinant doses has been supported by the pressure coming from the patient association.”
ACE 910’s ability to convert severe “I’m intrigued because you can go subcutaneously. Not because they can inject once a week, but even
hemophilia to moderate hemophilia giving it maybe a couple of times a week we can keep patients above 50% and convert them to
moderate, which I think is a really intriguing idea. Also, if you can make them more like a diabetic in
terms of administration, where you don’t have to worry about getting in a vein, I think that’s potentially a
huge game changer.”
Differentiating ACE 910’’s role in “The data I looked at are very exciting and interesting but it’s just too early to know. I think it may play a
hemophilia A inhibitor and non-inhibitor role for the regular A patients, but I don’t think it will do what factor VIII needs to do for the body. There’s
patients plenty of information about what VIII is about, which this is not going to have, but I think as a bypassing
agent for inhibitors it may be terrific. Let’s see what it does in hemophilia without inhibitors.”

Expectations for Launch and Sales Opportunity of ACE 910 in Hemophilia Without
Inhibitors
Launching in 2019, ACE 910 will be the first non- rFVIII to reach the market during our forecast window. The
launch of ACE 910 will mark the start of a very different-looking hemophilia A market through 2025, in terms of
available products.
We believe that a physician-perceived class concern with PEGylated molecules will provide a window of
opportunity for strengthening ACE 910 uptake, particularly in pediatric populations; physicians willing to
prescribe PEGylated products in adults are often reluctant to do so in children, leaving a gap for ACE 910 (and
other non-PEGylated products).
Preferential uptake of ACE 910 in pediatric populations is also likely to be supported by restrictions in use to
patients with the most difficult venous access, who are often children.
We expect ACE 910 (and fitusiran) to be a potential game-changer. ACE 910 launches in the United States in 2019
and in the EU 2020, with potentially huge advantages versus all other recombinant factor VIIIs.
We expect that novel agents such as ACE 910 will take some market share from all recombinant factor VIII
products, but most notably, the late entrants (N8-GP and BAY 94-9027) will lose out because we expect many
patients who want to switch away from an SHL, or switch from one EHL to another EHL, will be happy to wait
for the launch of ACE 910, bypassing N8-GP and BAY 94-9027, both of which either launch in the same year or
several months earlier. Also, working in ACE 910’s favor is the limited uptake time that N8-GP and BAY 94-9027
will have between their launch and the launch of ACE 910.
We anticipate that ACE 910 will show clinical superiority over the SoC and will command a price premium over
the SoC in the EU5. We anticipate that ACE 910 may find a competitor in BAX 826, if BAX 826 is able to provide
prolonged higher troughs.
In November 2016, Roche reported four SAEs occurred in its inhibitor trial NCT02622321. Due to the lack of
information regarding these findings and the physician confidence in the product ahead of this news, our
forecasts and market assessment have not been adjusted. Please see “Expectations for Launch and Sales
Opportunity of ACE 910 in Hemophilia with Inhibitors,” in the “Hemophilia with Inhibitors” section within Key
Emerging Therapies for full commentary on this event.
Hemophilia B
There is only one significant emerging therapy for hemophilia B in late-stage development, Novo Nordisk’s N9-GP, a
PEGylated EHL agent that was filed for regulatory approval in the EU and United States in mid-2016.
N9-GP is a recombinant factor IX molecule utilizing PEGylation to extend its circulating half-life and is intended
for replacement therapy in patients with hemophilia B. The recombinant factor IX market is already crowded,
and N9-GP will be the third EHL to market.

N9-GP
Novo Nordisk is developing N9-GP, a glycoPEGylated recombinant factor IX for the treatment of hemophilia B. The
use of PEG to extend N9-GP’s circulating half-life could translate into cost offsets and improved patient
convenience. N9-GP is currently filed for approval in the United States and the EU. N9-GP is being investigated in
several other trials.
N9-GP Profile
Drug class/mechanism of action GlycoPEGylated recombinant factor IX
Efficacy Paradigm 2 pivotal trial

74 patients were treated for six months on-demand or 12 months by a prophylactic regimen of 40
U/kg or 10 U/kg N9-GP once weekly. Median annualized bleeding rate for patients treated on-
demand was 15.6 episodes per year. Patients on prophylaxis had a median bleeding rate of 1.0
and 2.9 episodes per year, when treated with weekly doses of 40 U/kg and 10 U/kg,
respectively.
Side effects Paradigm 2 pivotal trial

No patients developed inhibitors to the factor IX product, and no apparent differences between
the treatment groups were observed with respect to adverse events and standard safety
parameters.
Dosing frequency Potentially once weekly
N9-GP Clinical Development
In comparing the development program of N9-GP with that of already approved agents, we perceive the closest
clinical comparators to be Alprolix and Idelvion, but we do not rule out Benefix either. The table “N9-GP Clinical
Development: Paradigm 2 Trial Design Analysis” highlights the pivotal trial of N9-GP and our thoughts on the
clinical development strategy.

N9-GP Clinical Development: Paradigm 2 Trial Design Analysis
Patient population N=74, male patients aged 13-70, with moderately severe or None.
severe hemophilia B (FIX levels less than 2%), previously
treated with FIX for at least 150 exposure days.
End points Primary: development of FIX inhibitors defined as titer equal Looking at “change” in parameters over time versus a
to or above 0.6 BU; measured 28 weeks after treatment start comparator would have been favorable in the eyes of payers.
on on-demand treatment and 52 weeks after treatment start Linking improvements in adherence to outcomes, especially
for patients on prophylaxis. Secondary: not shown but cost offsets, will strongly support uptake of N9-GP. Linking
available on www.clinicaltrials.gov. joint status to QOL may provide a more sophisticated method
of looking at disease progression. It may also be useful to
examine predictors of QOL.
Comparator(s) None. Gap in comparative evidence is present. Making indirect

comparisons looking at changes in (a) annual bleeding
rate and (b) clotting factor use, using, for example, a
recombinant factor IX vs. N9-GP could have been useful,
also outlining how similar or dissimilar the patient
populations are in each. These measures would have
closed the gap in comparative effectiveness data.
Trial design and duration Allocation: randomized; end point classification: Study attempts to demonstrate superiority of prophylaxis
safety/efficacy study; intervention model: parallel (low and high dose) to an on-demand regimen, but it does
assignment; masking: single blind (subject); primary not show how N9-GP benchmarks against what Novo
purpose: treatment. Patients received prophylaxis for 52 Nordisk perceives as being the SoC in 2017: Alprolix,
weeks, randomized to either 10 IU/kg or 40 IU/kg once Idelvion, an SHL such as Benefix, or something else such
weekly or to on-demand treatment of 28 weeks. as a once-weekly regimen. And we do not know if all
patients had been using the same FIX product when they
entered the trial. Failure to show additional medical benefit
against a reasonable comparator may mean price parity
with the above, or showing inferiority against the above
may mean a lower price point in some regions.
Forethought is needed regarding how N9-GP will
benchmark against products such as the ATFPi molecules
and gene therapies, although it is difficult to compare at
this stage.
Other evidence N.A. Examining QOL data for patients with mild hemophilia B may
give insights into what gene therapy, N9-GP’s future
competitor, may be able to achieve in QOL terms. In the real
world, identifying latent variables contributing to “good”
adherence-rate patients could limit the impact of treatment
failures if N9-GP is injected once weekly and the patient
misses or delays a dose.

Key Ongoing Clinical Trials for N9-GP
Timeframe of Estimated
Study Phase Study Size Intervention(s) Primary End Point Assessment Completion
Paradigm 5 III 25 N9-GP used in one Incidence of From 0 to 52 weeks October 2018
experimental arm inhibitory antibodies and from week 52
where a single dose against coagulation until the last patient
of 40 U/kg is factor IX (FIX) has completed the
administered IV defined as titer trial.
once weekly. above or equal to
0.6 BU.
Paradigm 6 III 50 N9-GP used in one Incidence of inhibitory (a) When the first 20 October 2022
experimental arm antibodies against PUPs have reached
studied over duration coagulation factor IX at least 50 EDs, (b)
of 50 exposure days. within 3 timeframes. when the first 40
A single IV dose of 40 PUPs have reached
U/kg, unless the 100 EDs, (c) expected
bleeding episode is to reach 24-72
severe in which case months.
it should be treated
with 80 U/kg.
Expert Insight
KOLs are enthusiastic about the EHL FIX products because they give patients the opportunity to achieve
significant improvements in clinical outcomes, but experts have some questions and concerns around the
practicalities of switching between SHL and EHL FIX or between EHL FIX products.
With N9-GP, some physicians voice concern about the long-term toxicity of IV PEGylated FIX, with some refusing
to treat children with it, and some refusing to prescribe it at all, when there is an alternative available without
the “fear” of PEG attached. One KOL alludes to how this toxicity could be magnified in hemophilia B, given that
he would expect to use double the amount of FIX to treat to the same levels as FVIII in hemophilia A.
Expert Insight on N9-GP
Topic Quote
The future of EHL FIX and problems with “The long-acting IX is here to stay and will take a major share from Benefix and Rixubis. It will take a
predictability of dosing while to really have a major uptake, but it will and it’s good stuff. I think doctors don’t know exactly how
to use any of these products, like when do you switch and how do you switch. Nobody really knows, and
even PK doesn’t always tell you how it affects bleeding. I’m involved in a case now from Pittsburgh in
which they’re using the long-acting Alprolix, three times a week, at a very high dose to essentially keep
the person from bleeding. So that’s kind of nuts, but they don’t know exactly how to manage it. Then
they’re going to work backwards, and if you work backwards, you’re talking about a huge amount of
money. Right now, the guy is costing one million dollars a year.”
Immunogenicity of EHL FIX products “Factor IX immunogenicity is such a big nothing that it’s not going to rear its head except in gene
therapy.”
PEGylation of N9-GP “If N9-GP were significantly cheaper than Alprolix or Idelvion, it’s very difficult to know what would
happen. I think our pediatric colleagues might still not want to give it to children. I think the adult treaters
would be happier with it.”
PEGylation of N9-GP “The fear around PEG is purely theoretical. Because PEG doesn’t get secreted very easily, can stay in
the body, even though it’s actually a very, very small quantity compared with other drugs, people just
say, well, how do you know it’s safe to give it for 50 years? It just raises a theoretical worry.”

Expectations for Launch and Sales Opportunity of N9-GP in Hemophilia B
N9-GP will be the last-to-market EHL FIX in our forecast window, launching in 2017.
There is a physician-perceived class concern with PEGylated molecules that we believe will dampen N9-GP
uptake. Interviewed physicians consistently express concern about the safety and long-term toxicity of
PEGylated molecules administered intravenously. Some of our KOLs say they would refuse to prescribe any
PEGylated molecule, including PEGylated rFVIIIs for hemophilia A. Some would be more willing to prescribe
PEGylated molecules in adults but much less so in children.
Fitusiran will have many advantages versus N9-GP or any other rFIX (SHL or EHL). We expect fitusiran will take
some market share from all rFIX products, but most notably, the late entrants (including N9-GP) will lose out
because we expect many patients who want to switch away from an SHL, or switch from one EHL to another
EHL, will be happy to wait for the launch of fitusiran, bypassing N9-GP. The short time that Novo Nordisk can
establish N9-GP ahead of the fitusiran launch will negatively impact the uptake of N9-GP.
We anticipate that N9-GP will not be able to command a price premium, particularly in the EU5, instead going
for price parity or lower, and will aim for increasing its market share instead.
We anticipate discussions with payers concerning N9-GP, as with other rFIX products, around the peak “drop-
off” levels of N9-GP. A once-weekly infusion may be more convenient for patients, but patients might end up
spending much more time closer to the FIX trough than closer to the FIX peak levels seen immediately post-
infusion. A once-weekly infusion could decrease the predictability of bleeding for patients as they go about their
activities of daily living and increase their risk of spontaneous bleeds, especially just before the next infusion is
due. This concern may dampen N9-GP sales. However, we recognize that hemophilia B patients potentially
bleed less than hemophilia A patients.
Phase III emerging therapies for hemophilia with inhibitors include a recombinant factor VIIa (BAX 817), an
EHL FVIIa (CSL 689), and a bispecific antibody (ACE 910).
Shire’s BAX 817 is a recombinant factor VIIa and will be the second SHL factor VIIa to market. It will be used for
the on-demand treatment of hemophilia with inhibitors. CSL Behring’s CSL 689 is a recombinant fusion protein
linking coagulation factor VIIa with albumin and is the first EHL factor VIIa to market. ACE 910 is a humanized
monoclonal modified IgG4 antibody that binds both factors IXa and X, replacing the function of the missing
factor VIII in patients with hemophilia A with or without inhibitors to factor VIII. ACE 910 will be the first
non-rFVIII to market in the inhibitor space and will be indicated only in hemophilia A (with or without
inhibitors).

BAX 817
Shire is developing BAX 817, a recombinant FVIIa for the treatment of acute bleeding episodes per an on-
demand regimen. BAX 817 will be the second SHL FVIIa to market, after NovoSeven, which is well entrenched.
Although BAX 817 is no longer listed in Shire’s online clinical pipeline, we believe this molecule is still in
development and anticipate a launch during our forecast period.
BAX 817 Profile
Drug class/mechanism of action Recombinant factor VIIa
Efficacy BAX 817’s Phase III trial met its primary end point of successful resolution of acute bleeding
episodes at 12 hours with both on-demand treatment regimens, dosing either 3x90 µg/kg or
1x270 µg/kg, with an overall success rate of 92% (98% and 85% in each dosing group,
respectively). Further, 89% of patients in the trial achieved sustained bleeding control for all
acute bleeding episodes 24 hours after infusion.
Side effects No patients developed inhibitors or binding antibodies to BAX 817, and none discontinued
treatment due to an adverse event (AE). One patient was hospitalized following a traumatic
muscle bleed that did not respond to BAX 817. Nonserious AEs observed in the trial were
generally consistent with the underlying disease or other etiology, and were all deemed to be
unrelated to treatment.
Dosing frequency Every 3 hours or one high-dose single bolus on-demand
BAX 817 Clinical Development
In comparing the development program of BAX 817 with that of already approved agents, we perceive its closest
clinical comparator to be NovoSeven. The table “BAX 817 Clinical Development: Trial Design Analysis” gives our
opinions on the clinical development strategy of BAX 817.

BAX 817 Clinical Development: Trial Design Analysis
Patient population N=40, male patients aged 12-65, with hemophilia A or B with None.
inhibitors, is currently using or has used bypass agents, has
high-titer inhibitors (greater than or equal to 5 BU), or a
historical high anamnestic response.
End points Primary: percentage of bleeding episodes with treatment Linking adherence to outcomes will support uptake of BAX
success. Time frame: within 12 hours of first dose. No 817. Linking joint status to quality of life may provide a
additional hemostatic product required within 12 hours of first more sophisticated method of looking at disease
dose other than the prescribed dosing regimen. Secondary: progression. It may also be useful to examine predictors of
available at NCT01757405 QOL.
Comparator(s) None. NovoSeven could reasonably have been used as a

comparator, so there is a gap in comparative evidence. In this
case, to close the gap, it may be useful to make indirect
comparisons looking at differences (change) in (a) annual
bleeding rate and (b) rFVIIa utilization between, for example,
NovoSeven and BAX 817. It would also be useful to outline
how similar or dissimilar the patient populations are in each
cohort.
Trial design and duration Allocation: randomized. End point classification: The study compares percentage of bleeding episodes with
safety/efficacy study. Intervention model: single group treatment success using either a high-dose bolus or 3 low
assignment. Masking: open label. Primary purpose: doses that equal the amount of factor used in the higher-
treatment. Arm 1: less than or equal to 3 doses of 90 dose bolus, with no comparison of on-demand vs.
microgram/kg every 3 hours. Arm 2: one dose of 270 prophylaxis use.
microgram/kg as a single bolus.
Other evidence N.A. A dedicated surgical trial may be useful since we anticipate
current bypass agents to retain a foothold in surgical
procedures. Studies in PUPs and studies examining PK-
guided dosing may be useful if Shire intends to expand the
development of BAX 817.
Key Ongoing Clinical Trials for BAX 817 for the Treatment of Hemophilia A or B
with Inhibitors

NCT01757405 III 40 BAX 817. Arm 1: Percentage of bleeding episode with treatment success. Completed
less than or equal Timeframe: within 12 hours of first dose. November 2014
to 3 doses of 90
microgram/kg
every 3 hours.
Arm 2: one dose
of 270
microgram/kg as
a single bolus.
Expert Insight
Most interviewed KOLs believe that BAX 817 is a “me too” product, with little or no additional benefit over
NovoSeven. Some KOLs express disappointment that BAX 817 does not address the unmet need of treating
inhibitor patients prophylactically.

Expert Insight on BAX 817
Topic Quote
Similarity to NovoSeven “If it’s very similar to NovoSeven, I think it’s a biosimilar. Unless the price is right, then it won’t be used.”
Similarity to NovoSeven “NovoSeven is the same as this one. It’s not for prophylaxis.”
Expectations for Launch and Sales Opportunity of BAX 817 in Hemophilia with
Inhibitors
BAX 817 will be the second-to-market rFVIIa and, for this reason, may struggle to pick up market share over
current entrenched rFVIIa NovoSeven. A potentially positive influence is the heritage underlying BAX 817;
physicians and patients will be familiar with other brands in Shire’s hemophilia franchise (e.g., Advate,
Adynovate) and may feel more confident to prescribe or accept this agent, which would aid uptake of BAX 817.
We see BAX 817 facing intense competition from ACE 910 (in hemophilia A only), fitusiran, CSL 689, and further
down the line, the ATFPI class; BAX 817’s competitors may be able to offer a prophylactic and/or on-demand
option to inhibitor patients, some with potentially large improvements in convenience (subcutaneous
injections).
We anticipate that BAX 817 will not be able to command a price premium over NovoSeven and may be priced at
parity or lower.
CSL 689
CSL Behring is developing CSL 689, a recombinant fusion protein linking coagulation FVIIa with albumin (rFVIIa-
FP) for on-demand treatment in patients with hemophilia A or B with inhibitors. The fusion protein linkage is
designed to extend the half-life of CSL 689. CSL 689 will be the first EHL rFVIIa product to launch in our forecast
window. The Phase II/III trial uses NovoSeven as a clinical comparator.
CSL 689 Profile
Drug class/mechanism of action Extended half-life recombinant factor VIIa fusion protein
Efficacy In a Phase I study in healthy volunteers, CSL 689 showed good tolerance and a 3- to 4-fold
increase in half-life compared with NovoSeven (median 8.5h).
Side effects In a Phase I study, tolerance of CSL 689 was good at all dose levels. No serious adverse events
were observed. None of the subjects developed antidrug antibodies.
Dosing frequency Unclear; potentially has a 3- to 4-fold increase in half-life versus NovoSeven

CSL 689 Clinical Development
In comparing the development program of CSL 689 with that of already approved agents, we perceive its closest
clinical comparator to be NovoSeven. In the table “CSL 689 Clinical Development: PROLONG-7FP Trial Design
Analysis” we discuss our opinion of CSL 689’s clinical development strategy.
CSL 689 Clinical Development: PROLONG-7FP Trial Design Analysis
Parameter Current Trial Design DRG Opinion on the Clinical Development Strategy
Patient population NCT02484638. N=54, male patients aged 12-65, with None.
hemophilia types A or B who have developed inhibitors to
FVIII or FIX, with high-responding inhibitors (greater than 5
BU/mL).
End points Primary: area under the curve (AUC0-t), incremental Linking adherence to outcomes will strongly support
recovery, elimination half-life, total clearance, treatment uptake of CSL 689. Linking joint status to QOL may
success with first CSL 689 injection, treatment success with provide a more sophisticated method of looking at disease
first CSL 689 injection at the population best dose, treatment progression. It may also be useful to examine predictors of
success with first or second CSL 689 injection at the QOL.
population best dose. Secondary: available
at NCT02484638.
Comparator(s) NovoSeven. This study is the only trial of the key emerging therapies we
examined that uses a comparator, and we think NovoSeven is
the correct choice. Thus, it is possible for CSL to demonstrate
additional clinical benefit against the comparator and
theoretically command a price premium in some regions. In
the future, investigating changes in ABR and/or bypass agent
use over time between bypass agent vs. ACE 910 could be
useful.
Trial design and duration Non-randomized, safety/efficacy, parallel, open label, Study is nonrandomized. We see this approach as a
primary, treatment. The study consists of 3 sequential weakness in the development program. Absence of an
parts (Parts 1, 2, 3): Part 1 (PK part) is to evaluate the PK RCT will require robust justification; one way around this
of a single treatment of CSL 689 (low dose or high dose) obstacle is obtaining real-world data on utilization post-
and compare with the PK of a single treatment of approval. Forethought is needed regarding how CSL 689
NovoSeven (low dose or high dose). Part 2 (dose- will benchmark against products such as ACE 910 or
evaluation part) is to identify which of the 2 tested dose fitusiran, although it is difficult to compare at this stage.
levels of CSL 689 shows the best efficacy and safety in
stopping acute bleeding events (this dose will be called
the "population best dose"). The purpose of the final Part 3
(repeated-dose part) is to confirm the efficacy and safety
of the "population best dose" identified in Part 2.
Other evidence N.A. Examining QOL data for patients with mild hemophilia may
give insights into what gene therapy, CSL 689’s future
competitor, may be able to achieve in QOL terms. In the real
world, identifying latent variables contributing to “good”
adherence-rate patients could limit the impact of treatment
failures if CSL 689 is injected twice weekly and the patient
misses or delays a dose.

Key Ongoing Clinical Trials for CSL 689 for the Treatment of Hemophilia A or B
with Inhibitors
Primary Outcome
Measures
and Timeframe of
Study Phase Study Size Intervention(s) Assessment Estimated Completion
PROLONG-7FP II/III 54 CSL 689 and Area under the curve January 2019
(NCT02484638) NovoSeven. 4 arms. The (AUC0-t); incremental
study consists of 3 recovery; elimination
sequential parts. Part 1 half-life; total clearance
(PK part) is to evaluate (all of the above
t h e PK of a single timeframes are before
treatment of CSL 689 injection and at up to 6
(low dose or high dose) time points until 24 hours
and compare with the after injection for
PK of a single treatment NovoSeven; and before
of NovoSeven (low dose injection and at up to 11
or high dose). In Part 1, time points until up to
CSL 689 and 120 hours after injection
NovoSeven will be given for CSL 689).
by the physician at the Treatment success with
study center. Part 2 first CSL 689 injection;
(dose-evaluation part) is treatment success with
to identify which of the 2 first CSL 689 injection at
tested dose levels of the population best dose;
CSL 689 shows the best both of the above time
efficacy and safety in frames up to 8 hours
stopping acute bleeding after first CSL 689
events (this dose will be injection for each
called the "population bleeding event.
best dose"). The purpose Treatment success with
of the final Part 3 first or second CSL 689
(repeated-dose part) is to injection at the
confirm the efficacy and population best dose;
safety of the "population timeframe up to 16 hours
best dose" identified in after first CSL 689
Part 2. In Parts 2 and 3, injection for each
subjects will self- bleeding event.
administer a specified
number of CSL 689
infusions at home on-
demand.
Expert Insight
Interviewed KOLs express comfort at seeing the use of protein fusion technology in the development of CSL 689.
They make comparisons to Idelvion, which uses a similar approach to extend half-life, and contrast these efforts
to the use of PEGylation and their concern for its toxicity.
CSL 689 could address the unmet need where the current rFVIIa half-life is short and requires infusions every
two or three hours in some patient groups (major bleeds or surgeries).
However, it is not all positive feedback for CSL 689. KOLs draw analogies between CSL 689 and previously
discontinued trials by Novo Nordisk for a similar EHL rFVIIa molecule and wonder if CSL 689 may face similar
problems in terms of either efficacy or safety in the future.

Expert Insight on CSL 689
Topic Quote
Where CSL 689 will position against “If ACE 910 works in the trials as well as it looks like it might, it’s really going to take that market away. I
NovoSeven and ACE 910 for hemophilia A think an extended half-life recombinant VIIa such as CSL 689 could fill in a real unmet need - unless
with inhibitors ACE 910 is too quick and takes over everything. I think one of the terrible problems we’ve had over the
last 10 or 15 years, is NovoSeven having such a short half-life and having to give it every two hours or
every three hours in people who have big bleeds or surgeries and things like that. So, I think an
extended half-life recombinant VIIa like CSL 689 will be a fantastic product, but I really think this ACE
910 has a potential of blowing the whole thing out of the water and everybody else having to go away.”
Potential safety issues with CSL 689 “Long acting, the CSL 689, I’m not in favor of because they are potentially quite thrombogenic and, in
fact, a more potent and long acting VIIa that was made by Novo Nordisk, they stopped the production.
So, I’m not very enthusiastic about any of that.”
Potential efficacy issues with CSL 689 “It’s fusion technology the same like they’ve used for years. They used for the factor IX, so I thinks it’s an
interesting approach. I have more concern about efficacy because you know that it’s a prolonged half-
life product with PEGylation from Novo Nordisk failed to show a dose response and efficacy. So, that
will be interesting to see the study. Prolongation in half-life is good because phase I in healthy
volunteers without, but if prolongation of half-life relies in prolongation of efficacy, that still has to be
proven.”
Market positioning “I think I’m more focused on the newer molecules like ACE 910 and ALN-AT3.”
Expectations for Launch and Sales Opportunity of CSL 689 in Hemophilia with
Inhibitors
CSL 689 will be the first EHL rFVIIa to market. We expect CSL 689 to take some market share from NovoSeven
and Feiba, but its uptake will be limited by the market impact of ACE 910, fitusiran, and the ATFPI products when
they launch.
Treatment with CSL 689 will decrease frequency between injections compared with current treatment options
in on-demand protocols. It will also increase the chance to achieve prophylaxis, offering a new treatment
approach for inhibitor patients. Less-frequent infusions reduce the likelihood of vein collapse associated with
multiple infusions of current agents.
ACE 910 and fitusiran have some advantages versus CSL 689 and other currently marketed bypass agents—
primarily, that they can be administered subcutaneously. We expect that these novel agents will take some
market share from NovoSeven and Feiba. CSL Behring will have limited time between CSL 689 launching and
ACE 910 and the other novel agents launching, which will negatively impact uptake of CSL 689.
We anticipate that CSL 689 will be able to command a price premium over NovoSeven because we believe it will
be able to show an additional medical benefit. However, given its launch date in relation to ACE 910, we see CSL
Behring potentially lowering the price and instead aiming for rapid uptake and increased market share instead,
before ACE 910 (or fitusiran) comes onto the market.

ACE 910
ACE 910 is being co-developed by Chugai Pharmaceutical and Roche. ACE 910 is a humanized monoclonal
modified IgG4 antibody with bispecific structure targeting factors IX, IXa, X, and Xa for the treatment of
hemophilia A with or without inhibitors. ACE 910 binds both factors IXa and X, replacing the function of the
missing factor VIII to improve clotting function and prevent spontaneous bleeding. By activating factor X, ACE
910 is expected to control hemophilia A because it acts directly on factor X, independently of factor VIII.
We anticipate that ACE 910 will provide the opportunity for these inhibitor patients to be treated
prophylactically with at least once-weekly dosing, in addition to the added patient convenience of being
administered by subcutaneous injection instead of IV infusion.
ACE 910 Profile
Drug class/mechanism of action Humanized monoclonal modified IgG4 antibody with bispecific structure targeting factors IX,
IXa, X, and Xa.
Efficacy HAVEN 1: No efficacy results reported yet for trial NCT02622321 (hemophilia A with inhibitors).
Side effects In November 2016, Roche reported four thrombotic SAEs were detected in its inhibitor trial in
patients treated for breakthrough bleeding. While the development of SAEs is often a major
concern in drug development, in this instance, it is the notion that ACE 910 has not prevented
breakthrough bleeding that is causing the most disappointment.
Dosing frequency Potentially at least once weekly
Dosage form Subcutaneous
ACE 910 Clinical Development
In comparing the development program of ACE 910 with that of already approved agents, we see its closest
clinical comparators as NovoSeven and/or Feiba. The table “ACE 910 Clinical Development: HAVEN 1 Trial
Design Analysis” highlights the trial of ACE 910 in hemophilia A with inhibitors (HAVEN 1) and our thoughts on
the clinical development strategy.

ACE 910 Clinical Development: HAVEN 1 Trial Design Analysis
Patient population N=118, males and females 12 years or older, with hemophilia None.
types A or B who have developed inhibitors to FVIII or FIX,
with high-responding inhibitors (greater than 5 BU/mL).
End points Primary: number of bleeds over time. Timeframe: 24 weeks or We note that Roche/Chugai has explicitly looked at “change”
discontinuation from the study, whichever occurs first (up to (reduction) in 4 parameters over time (secondary outcomes),
approximately 26 months). Secondary: available which will be favorable in the eyes of payers. Linking
at NCT02622321. improvements in adherence to outcomes, especially cost
offsets, will strongly support uptake of ACE 910. Linking joint
status to quality of life may provide a more sophisticated
method of looking at disease progression. Although health-
related QOL scores are investigated in 3 secondary
outcomes, it may also be useful to examine predictors of
QOL.
Comparator(s) None. Gap in comparative evidence is present, but a big positive

is that Roche/Chugai is making indirect comparisons
looking at reductions in (a) number of all bleeds, (b)
number of bleeds, (c) number of joint bleeds, and (d)
number of target joint bleeds over time, using a patient’s
regular bypass agent (brand not specified) vs. ACE 910.
Investigating changes in ABR and/or bypass agent used
over time between bypass agent vs. ACE 910 could be
useful, as would be outlining how similar or dissimilar the
patient populations are in each arm. These measures will
further close the gap in comparative effectiveness data.
Trial design and duration Randomized, safety/efficacy study, parallel, open label, The study is designed to demonstrate superiority of ACE
treatment. Prophylaxis (Arm A) versus no prophylaxis (Arm 910 prophylaxis to bypass agent use prophylactically and
B); Arm B patients will have the opportunity to switch to on-demand, with bypass agent on-demand as an active
ACE 910 prophylaxis after 24 weeks on-study. comparator, it but does not show how ACE 910
Prophylactic bypassing agent patients will switch to ACE benchmarks against what Roche/Chugai perceives as
910 prophylaxis (Arm C) from the start of the trial; episodic being the SoC in 2019 for hemophilia A with
bypassing agent patients who previously participated in a inhibitors (NovoSeven, Feiba, or something else, such as
non-interventional study BH29768 but were unable to a once-weekly regimen. And we do not know which
enroll in Arms A or B prior to their closure will have the bypass agent patients had been previously using. Failure
opportunity to enroll in Arm D until 24 weeks after the last to show additional medical benefit through lack of direct
patient has enrolled in Arms A or B or until approximately comparative effectiveness may mean price parity with the
35 patients have enrolled in Arm D, whichever occurs first. SoC in some regions. Some consideration is needed
Like patients in Arms A and C, Arm D patients will receive regarding how ACE 910 will benchmark against products
ACE 910 prophylaxis from the start of the trial. such as fitusiran or the ATFPIs, although it is difficult to
compare at this stage.
Other evidence N.A. In November 2016, four SAEs were reported with ACE 910,
which may require further examination of safety data. A
dedicated surgical trial, studies in PUPs, and studies
examining PK-guided dosing will support uptake of ACE 910
in hemophilia A with inhibitors. Examining QOL data for
patients with mild hemophilia may give insights into what gene
therapy, ACE 910’s future competitor, may be able to achieve
in QOL terms. In the real world, identifying latent variables
contributing to “good” adherence-rate patients could limit the
impact of treatment failures if ACE 910 is injected every one
or two weeks and the patient misses or delays a dose.

Key Ongoing Clinical Trials for ACE 910 for the Treatment of Hemophilia A with
Inhibitors
Primary Outcome
Measures and
Timeframe of
Study Phase Study Size Intervention(s) Assessment Estimated Completion
NCT02622321 III 118 ACE 910: Prophylaxis Number of bleeds over February 2018
(hemophilia A with (Arm A) versus no time; 24 weeks or
inhibitors) prophylaxis (Arm B); Arm discontinuation from the
B patients will have the study, whichever occurs
opportunity to switch to first (up to approximately
ACE 910 prophylaxis after 26 months).
24 weeks on-study.
Prophylactic bypassing
agent patients will switch
to ACE 910 prophylaxis
(Arm C) from the start of
the trial; episodic
bypassing agent patients
who previously
participated in a
noninterventional study
BH29768 but were unable
to enroll in Arms A or B
prior to their closure will
have the opportunity to
enroll in Arm D until 24
weeks after the last
patient has enrolled in
Arms A or B or until
approximately 35 patients
have enrolled in Arm D,
whichever occurs first.
Like patients in Arms A
and C, Arm D patients will
receive ACE 910
prophylaxis from the start
of the trial.
Expert Insight
Interviewed KOLs believe that ACE 910 will be the market leader in treating hemophilia A with inhibitors,
overtaking the use of products such as NovoSeven and Feiba in prophylactic treatment protocols.
KOLs indicate that NovoSeven and Feiba will retain their hold in surgical indications, however.
Where ACE 910 is not used first-line, physicians state that they are likely to use it second-line, in patients who do
not respond to NovoSeven or Feiba.

Expert Insight on ACE 910
Topic Quote
Where ACE 910 will position against “If ACE 910 works in the trials as well as it looks like it might, it’s really going to take that market away. I
NovoSeven and CSL 689 for hemophilia A think an extended half-life recombinant VIIa such as CSL 689 could fill in a real unmet need - unless
with inhibitors ACE 910 is too quick and takes over everything. I think one of the terrible problems we’ve had over the
last 10 or 15 years, is NovoSeven having such a short half-life and having to give it every two hours or
every three hours in people who have big bleeds or surgeries and things like that. So, I think an
extended half-life recombinant VIIa will be a fantastic product, but I really think ACE 910 has the
potential of blowing the whole thing out of the water and everybody else having to go away.”
ACE 910’s ability to address unmet need “From the trial data, it is good. It will certainly improve on the unmet need for the inhibitor patients.”
and probability of being the market leader —Hematologist, United Kingdom
in the inhibitor population
ACE 910’s probability of being the market “I would assume that ACE 910 will be the most widely used product for type A patients inhibitors
leader in the inhibitor population because what I’ve heard up to now, it’s safe and effective.”
Potential problems with subcutaneous “I can’t really foresee any problems. Maybe there is the possibility of localized reactions, like you get
injections of ACE 910 lipodystrophy if you keep injecting insulin in the same spot, it’s impossible to know right now.”

Expectations for Launch and Sales Opportunity of ACE 910 in Hemophilia A with
Inhibitors
Launching in 2019, ACE 910 will be the first non- rFVIII to reach the market in our forecast window. The launch of
ACE 910 will mark the start of a very different-looking hemophilia A with inhibitors market through 2025, in
terms of available products.
We expect ACE 910 to be a game changer for hemophilia A patients with inhibitors. ACE 910 launches in the
United States in 2019 and in the EU in 2020, with potentially huge advantages versus NovoSeven, Feiba, and
also CSL 689.
We expect ACE 910 to take some market share from NovoSeven and Feiba, but it may be relegated to second-
line treatment in some patients if NovoSeven and/or Feiba has not been efficacious.
Also working in ACE 910’s favor is the limited uptake time that CSL 689 will have between its launch and that of
ACE 910. However, not far behind ACE 910 is the launch of fitusiran and the ATFPi products. It is worth noting
that, unlike ACE 910, fitusiran and the ATFPis can also treat hemophilia B with inhibitors, in addition to
hemophilia A with inhibitors.
We expect ACE 910 to demonstrate an additional medical benefit over the SoC. As such, we forecast that it will
be able to command a price premium.
In November 2016, Roche reported four thrombotic SAEs were detected in its inhibitor trial in patients treated
for breakthrough bleeding. While the development of SAEs is often a major concern in drug development, in this
instance, it is the notion that ACE 910 has not prevented breakthrough bleeding that is causing the most
disappointment. We note that the patients’ established episodic bypass agent therapy (either NovoSeven or
Feiba) was used to treat these breakthrough bleeds. We know from physician insights, product label warnings,
and the literature that both NovoSeven and Feiba are potentially thrombogenic and that thrombotic events
have been reported in individuals with additional risk factors and/or when the dose administered has exceeded
licensed recommendations (Aledort L, 2004; Teitel & Poon, 2004). The impact of ACE 910 on the thrombotic SAEs
is undefined. Due to the lack of information regarding these findings and the physician confidence in the
product ahead of this news, our forecasts and market assessment have not been adjusted.

Early-Phase Pipeline Analysis
Notable Developments in the Early-Phase Pipeline for Hemophilia
Transition away from development of EHL agents toward agents with novel mechanisms of action in
hemophilia A. We anticipate that BAX 826 and an XTENylated agent (Biogen/Amunix) will be the last of the
early-phase compounds to be marketed as an EHL rFVIII. Beyond this point, the pipeline shifts focus to agents
with novel, in some cases “curative” mechanisms of action such as bispecific antibodies, gene silencing, gene
therapies, gene editing, and ATFPIs. The reasons underlying this transition include the unimpressive extensions
in the circulating half-life of current recombinant factor VIII agents and the inability to achieve significant
improvements in clinical outcomes for hemophilia A patients.
Emergence of “broad-spectrum” agents, able to treat hemophilia A and hemophilia B patients with or
without inhibitors. We note the development of ATFPIs with great interest. With inhibitor formation currently
one of the largest unmet needs, any agent able to treat patients with inhibitors will be very much welcomed.
Co-evolution of gene therapy and gene editing for hemophilia A and B. We observe the development of
gene editing therapies for hemophilia by Sangamo and Casebia Therapeutics with interest because gene editing
is directed at specific sites, so their technology potentially offers greater precision compared with gene therapy.
However, while delivery of a gene using an integrating viral vector risks resulting in a largely random integration
pattern, gene editing runs the risk of off-target effects (e.g., insertions, deletions) depending upon the construct
and the length of the target site.
Continuing efforts to extend the half-life of recombinant factor IX for hemophilia B. Biogen/Amunix’s
efforts in the development of a preclinical factor IX using XTEN technology is notable. With gene therapy and
gene editing being hailed as “cures” that may work in only a percentage of people in whom they are
administered, and with current lack of long-term safety data, some companies appear to be taking a more
pragmatic view. We anticipate that Biogen/Amunix will be able to offer an alternative with an ultra-extended
half-life but with none of the risk associated with gene therapies and gene editing therapies.
Select Early-Phase Compounds in Development for Hemophilia
Compound Developing Companies Development Phase Comments
Fitusiran Alnylam Phase I/II Synthetic double-stranded siRNA

oligonucleotide against antithrombin
mRNA, for the treatment of
hemophilia A and B, with or without
inhibitors
BAX 826 Shire Phase I Recombinant factor VIII treatment

for hemophilia A that
uses polysialic acid (PSA)
technology to extend its circulating
half-life; BAX 826 is based on
the Advate brand molecular
backbone
BMN 270 Biomarin Phase I Adeno-associated virus vector

encoding the SQ variant of human
blood clotting factor VIII
SHP 654 (BAX 888) Shire Last known Phase I Gene therapy for hemophilia A
SB-525 Sangamo Preclinical Gene therapy for hemophilia A

SB-FVIII Sangamo Preclinical Adeno-associated virus vectors

encoding zinc finger nucleases
(ZFNs) and human F8 gene
Therapy indicated in the treatment of Uniqure Preclinical Therapy indicated in the treatment of
hemophilia A hemophilia A
SPK-FVIII Spark Therapeutics Preclinical Gene therapy for hemophilia A
DTX 201 Dimension Therapeutics, Bayer Preclinical Gene therapy for hemophilia A
SPK-FIX Spark Therapeutics, Pfizer Phase I/II Adeno-associated viral vector

composed of a bioengineered AAV
capsid and a codon-optimized
expression cassette encoding a high-
specific activity variant of human
coagulation factor IX
AMT-060 UniQure, Chiesi Phase I/II Adeno-associated viral vector

containing a codon-optimized human
factor IX gene (AAV5-hFIXco)
DTX 101 Dimension Therapeutics Phase I/II Adeno-associated virus serotype

rh10 vector encoding the human
factor IX gene
SB-FIX Sangamo Phase I Adeno-associated virus serotype 2/6

(rAAV2/6) vectors encoding zinc
finger nucleases (ZFNs) and human
F9 gene (SB- FIX)
PF-06741086 Pfizer Phase I Human monoclonal antibody directed

against tissue factor pathway inhibitor
SHP 648 Shire Unknown Shire’s factor IX backup program

(since BAX 335 program was
terminated); no further details known.
Therapy indicated in hemophilia Casebia Therapeutics Preclinical Gene editing therapy indicated for the
treatment of hemophilia; not known if
hemophilia A or B.
ATX-F8-117 Apitope Phase I Two small protein fragments based

on parts of factor VIII; thought to
activate suppressor T cells that
suppress the production of
antibodies against factor VIII; this
would allow patients with hemophilia
A to benefit from treatment with
medicines containing factor VIII
MOD-5014 OPKO Biologics Phase I/II Long-acting recombinant factor VIIa-

CTP3
BAY 1093884 Bayer Phase I Anti-TFP inhibitor antibody
Concizumab Novo Nordisk Phase I Monoclonal antibody against tissue

factor pathway inhibitor (TFPI)
intended for bleeding prevention after
subcutaneous administration
XTENylated FVIII Amunix, Biogen Preclinical Uses XTEN technology
XTENylated FIX Amunix, Biogen Preclinical Uses XTEN technology
XTENylated FVIIa Amunix, Biogen Preclinical Uses XTEN technology
Note: Companies listed in no particular order. Status is based on secondary research (e.g., company reports, websites, and press releases) as well as
databases such as Springer’s Adis R&D Insight.

Access and Reimbursement Overview
Region-Specific Reimbursement Practices
United States
The United States is the world’s largest pharmaceutical market and spends more on healthcare than any other
country in the world (approximately 18% of GDP). In the United States, health plans are administered by numerous
private insurance companies (e.g., managed by HMOs/PPOs, MCOs) and the federal and state governments (i.e.,
Medicare [for seniors and the disabled] and Medicaid [for low-income citizens]). Approximately 167 million U.S. lives
are covered under the commercial system, which contributes slightly more than half of total health expenditures,
and 121.5 million lives are covered by Medicare/Medicaid. With the passage of the Affordable Care Act (ACA) in 2010,
the federal government took on a greater role in the healthcare system. This law was designed to reduce the
number of uninsured citizens by expanding Medicaid and requiring them to enroll in federal or state-sponsored
health insurance exchanges or pay a penalty. Also, employers with at least 50 full-time workers that did not offer
coverage must offer coverage or pay a penalty.
The pharmaceutical industry enjoys a free-pricing environment in the United States, which leads to some of the
highest prices obtainable for branded therapies but also some of the most aggressive rates of generic erosion in the
world; this compares with a nascent biosimilars market. To bring drugs to market, drug manufacturers must engage
in pricing and formulary negotiations with numerous health plans and pharmacy benefit managers; formulary
inclusion or preferred status frequently depends on discounts and rebates offered by manufacturers (typically
confidential). Nevertheless, drug companies historically have been able to put through significant year-over-year
price increases in the United States. In particular, specialty biologics are driving significant growth in U.S. healthcare
costs while also attracting greater industry focus, thanks to generally higher prices. Moreover, orphan-drug
designation has become an increasingly popular way to command premium pricing and offers manufacturers
attractive exclusivity periods.
Supported by the ACA, government and private healthcare payers are exploring ways to emphasize disease
prevention and improving the quality of healthcare services. Pay-for-performance reimbursement systems may
gradually displace the fee-for-service model, while hospitals transition to value-based payments. This shift will
increasingly demand that pharmaceutical companies demonstrate that their products can improve outcomes and
reduce overall healthcare expenditures (e.g., through CER and health economics outcomes) to secure optimal
reimbursement terms in the U.S. market. Still, drug manufacturers benefit from minimal launch delays and direct
payer negotiations in the United States, and several regulatory concessions, including the new breakthrough
therapy designation, expedite the development and/or approval of landmark drugs.

Reimbursement Environment for Hemophilia Therapies in the United States
All hemophilia drugs licensed by the FDA are eligible for coverage and reimbursement subject to insurer-
imposed limitations. In the United States, we note more of a payer sentiment for willingness to pay that is
linked to convenience and patient preference, in contrast with the EU, where we note greater sentiment for
willingness to reimburse, based on the priorities of the healthcare system.
In the United States, there has been tremendous pressure from advocacy groups for every product to be added
to formularies, with many payers reluctant to place restrictions on this class because of fear of negative press.
Moderate hemophilia, in contrast with coverage of drugs for severe hemophilia, is a “gray area” with
interviewed insurance providers often wanting to see documentation of two or more episodes of spontaneous
bleeding into joints before granting coverage.
Health insurance providers typically contract pharmacy benefit managers who process and pay for hemophilia
drug claims and may develop and maintain the formulary of covered drugs. We note that an increasing number
of hemophilia products that were historically available on a medical benefit are being moved to a pharmacy
benefit, where there is greater capability for tracking and contracting.
Hemophilia reimbursement is a mixed picture in the United States. Hemophilia treatment centers are eligible to
purchase discounted factor concentrate through the 340B program. The majority of HTCs participate in or
operate 340B programs to enhance cost containment for outpatient use of factor concentrates. Currently, 340B
pricing provides a 17.1% discount off the average manufacturer’s price (The Veterans Health Care Act of 1992),
though the HTC may negotiate further discounts and rebates with the manufacturer. The 340B programs
typically offer discounted pricing in excess of the prices offered by other commercial pharmacy vendors. Since
some HTCs are still infusing factor for patients, some health insurance plans allow for “buy and bill” and
reimbursement of HTCs for a product. Some patients are also getting factor through specialty pharmacies.
Both efficacy and convenience drive U.S. hemophilia payer decisions. Interviewed experts report discussing
efficacy first and then elucidating how convenience translates into cost offsets. Payers currently report being
particularly focused on direct cost; given that a joint replacement may not be expected to happen until 20 years
from now, payers remain focused on what is going to happen over the next 18-24 months.
Owing to the fragmented payer system in the United States, upfront payment for a very expensive treatment
such as gene therapy poses problems. A key fear is that patients are able to switch health plans after starting
the gene therapy. Payers outline uncertainty on the types of payment models that will support innovation, in
addition to a reluctance to pay for something that does not have long-term value.
Interviewed payers suggest a willingness to pay more for improvements in quality of life only if cost offset data
and direct cost data are demonstrated. The payers admit that the United States is currently struggling to
understand what “quality of life” means when there are no visible returns on investment.

EU5
In the EU5 (France, Germany, Italy, Spain, and the United Kingdom), nationalized statutory healthcare systems
administer healthcare coverage to most citizens at little to no out-of-pocket expense, especially for severe chronic or
inpatient illnesses. Supplementary insurances are also available and frequently used (e.g., in France, Germany).
Waves of healthcare reforms in the EU5 continue to unroll as these nations, hampered with recessionary economies,
squeezed budgets, and aging populations, work to rein in burgeoning healthcare costs.
Europe’s major markets are firmly focused on treatment that delivers cost-effective outcomes. Following EMA
marketing authorization, country-specific HTA has become an essential input for pricing and reimbursement
decisions and the development of clinical guidance on the use of innovative technologies. Use of a drug may be
further controlled by a wide range of national, regional, or local regulatory and payer stipulations; budgets and
funding channels, formulary inclusion criteria, and prescribing controls can differ for outpatient and inpatient
medicines (e.g., DRG systems). Cost-containment strategies—including reference pricing, prescriber budgets,
hospital-based prescribing/delivery, limits on reimbursement for drugs based on level of cost-effectiveness, and
retroactive assessment of drugs already on the market—are utilized.
Each EU5 country operates a unique and complex suite of market access requirements (e.g., in dossiers submitted
for P&R), HTA metrics/scales (e.g., ASMR ratings in France, NICE cost per QALYs in the United Kingdom), and
processes with diverse stakeholders that must be carefully navigated. Though HTA practices differ meaningfully
across and within national boundaries, specific themes have emerged: in particular, demands for evidence of clinical
and/or economic benefit on new health technologies are increasing to justify preferential price points and formulary
inclusion. European countries generally maintain a societal perspective when undertaking HTA, increasingly
requiring an evaluation of the burden of disease in a specific population and evidence to support the real-world
clinical and fiscal benefits of new medicines. Navigating this complex environment requires significant preparation
and the ability for local planning and negotiation.

Reimbursement Environment for Hemophilia Therapies in the EU5
In Europe, priority given to hemophilia treatment and care varies between member states. The EU
reimbursement landscape is very diverse because official reimbursement policies are allowed to deviate from
the outcome of the hemophilia product assessment itself and there is a general lack of transparency around the
technical methods used to assess these products. There is huge diversity across Europe in the process of
assessing “therapeutic value.” Currently, there is neither a harmonized definition of “value” nor a common
assessment practice. The evidence submitted for reimbursement comes from the clinical evidence submitted
for marketing authorization, which is not necessarily appropriate for assessing reimbursement of hemophilia
drugs.
In the EU, we note more of a payer sentiment on willingness to reimburse, linked to priorities in the healthcare
system. This is in contrast to the United States, where we note more of a payer sentiment on willingness to pay,
linked to convenience and patient preference.
Hemophilia therapies are evaluated by HTA bodies specific to each EU5 country, and HTAs enable payers to
derive recommendations for reimbursement policies. The EU has developed the Shaping European Early
Dialogue (SEED) program that allows manufacturers to ask for cooperation on HTAs from approximately ten
different payers, in order to gather and define the requirements for the reimbursement of hemophilia
products. EU5 HTA bodies are not obliged to approve reimbursement of new hemophilia products at the prices
set by the manufacturer, especially if the cost or the total budget increases significantly.
It is often difficult for payers who are used to assessing products for common diseases, which have a lower cost,
to understand why orphan medicinal products are so expensive. Typically, payers will look at the additional
benefits of new hemophilia drugs compared with alternative treatments. In the case of orphan drugs, this
assessment is already done through the orphan designation.
Events in Germany, which is considered a reference price country in the pharmaceutical industry, can have a
significant influence on the hemophilia community in other European member states. AMNOG legislation,
effected in 2011, regulates the pricing of newly authorized drugs and therefore their eligibility for
reimbursement. The manufacturer must demonstrate proof of an additional benefit over a comparator drug for
all new drugs. From previous case examples in hemophilia, IQWiG’s apparent requirement for direct
comparison with a comparator drug could spell trouble for gene therapies and some novel agents launching
around 2020, and given IQWiG’s preference for RCTs.

Considerations Specific to Hemophilia
Payer Value Drivers and Outcomes
Value messaging tries to quantify the clinical benefit of a hemophilia drug and translate it into economic value
for payers. Value messaging potentially drives differentiation and clinical/economic competitiveness. The
ability to demonstrate differentiated value will be crucial in the era of the evolving hemophilia landscape in
2020. Developers should focus on defining their hemophilia product’s key differentiator(s) and strengthening
the evidence base that supports each value message, especially data around economic benefit. This
strategy links back to unmet need, so we see therapeutic value drivers interacting with payer-relevant
outcomes in the following quadrant, ‘Therapeutic Value Drivers vs Payer Relevant Outcomes’:
Therapeutic Value Drivers vs. Payer-Relevant Outcomes

Procurement
Gene Therapies
In the eyes of payers, much uncertainty exists around the value and clinical effects of a gene therapy for
hemophilia and the percentage of patients likely to still be benefiting from a gene therapy in five or ten years
and beyond. As a result, payer concerns are focused on the pricing and reimbursement models being suggested
for hemophilia gene therapies.
Using Glybera in Germany as a proxy for hemophilia gene therapy: Glybera for familial lipoprotein lipase
deficiency (LPLD) was the first gene therapy approved in Europe in 2012, but it has so far failed to achieve broad
commercialization. Less-than-convincing outcomes were noted in Germany’s benefit assessment in which
mode of action was not a formal criterion, and the risk-benefit assessment was concluded as “nonquantifiable.”
This conclusion was due to a legal loophole; the G-BA cannot say “no additional benefit” by virtue of
Glybera having an ODD. Had Glybera not been given an ODD, it is likely it would have received an assessment of
“no additional benefit.” It is worth noting that LPLD is a rare disorder affecting around one person in a million,
and no truly effective treatment existed before the approval of Glybera.
The first-to-market gene therapy for hemophilia must focus on and demonstrate robust clinical data
(potentially having to prove superiority to the SoC in some countries) to have any chance of positioning itself
well on the market before a competitor gene therapy launches. In many countries, a gene therapy is likely to
encounter frameworks for clinical assessment (and with no formal benefit assigned to mode of action) before
they encounter any pricing or procurement assessment frameworks. A gene therapy unable to show any
additional medical benefit will likely have as its price comparator the annual cost of the SoC at that time.
No formal policy on gene therapy procurement exists yet in the EU5 and United States; the lack of a launched
“ground-breaking” gene therapy has attenuated any pressure to create and implement it. It is also a possibility
that developers of first- or second-to-market gene therapies for hemophilia will experience initial resistance
from health systems to change protocols for just one product; initially, payers may try to assess hemophilia
gene therapies using existing clinical assessment frameworks, clearly not adapted for gene therapies. As a
result, we believe that methods of gene therapy procurement in the future are likely to be disease specific, with
one specifically for hemophilia A and/or B.
In the absence of health system constraints, 59% of EU/U.S. payers prefer annuities (which could be declining,
capped, or ongoing), while 41% prefer lump sum or lump sum risk-sharing (Flume M, 2015). The same study also
showed that in a cost-constrained health system (real world), lump sum or lump sum risk-sharing was preferred
by 70% of payers while the remaining 30% preferred annuities, and this finding may reflect the difficulty in
implementing annuity-based payments in current health systems. Payers in the United States and Germany
were mainly not in favor of annuities while those in the United Kingdom were. This observation is likely a
reflection of differing health systems (insurance-based vs. government-controlled annual budgets).
We note with great interest that, when comparing theoretically constrained and nonconstrained health
systems, a similar percentage of interviewed payers favor the lump sum with risk-sharing approach. This finding
indicates to us that some countries may favor lump sum with risk-sharing in the real world as the most
pragmatic approach, at least in the short term and for the first-to-market gene therapy.

With Glybera, there was no comparator and no prior existing therapy; therefore, a country may be inclined to
accept a higher price-tag. It is not the same for hemophilia; the competitive landscape looks entirely different
because there will be (1) a comparator (prophylaxis) and (2) prior existing therapies that have already set the
bar high, particularly in hemophilia B. This landscape alone may drive annuity payments with/without risk-
sharing agreements. Existing hemophilia B EHL prices may drive down hemophilia B gene therapy prices, and
vice versa, with an eventual equilibrium established beyond 2025.
There may be an ethical and public-acceptance perspectives to consider in the procurement of high-cost gene
therapies for hemophilia patients because, while hemophilia cannot be 100% controlled, EU5 and U.S.
physicians can offer patients a life expectancy approaching that of the general population with existing
treatments. This situation may drive down high prices of gene therapies, particularly for hemophilia B, in which
the magnitude of unmet need is currently smaller than in hemophilia A.
Payers tend to think in terms of annualized budgets, and this mindset could prove to be a problem for
hemophilia gene therapies. Developers should expect risk-sharing agreement contracts for hemophilia gene
therapies to be complex and take a considerable amount of time to implement, reflecting the way in which risk
is to be shared among stakeholders.
Interviewed payers have difficulty understanding the concept of paying a lump sum for a hemophilia gene
therapy, given that 10- or 20-year treatment outcomes are not a certainty. The changes in the hemophilia
landscape from 2019 onward, in terms of several new product launches, suggest that authorities will not be
willing to pay an upfront lump sum for a gene therapy and, even if they are willing, they may expect a return on
investment within 3-5 years. A fair price in 2020 may not hold through 2030, and it will be difficult to persuade
payers otherwise, without longer-term data demonstrating cost offsets. Availability of several new products
from 2019 onward opens the discussion for a long-term (15 years+) initiative of declining annuities frameworks
with risk sharing built in for hemophilia gene therapies.

Non-Gene Therapies
Procurement of hemophilia products helps to ensure that patients have access to treatment in sufficient
quantities and to treatments that meet standards in safety, efficacy, and quality.
In the United States, there is no single price or formulary for the procurement of factor concentrates. Absence of
a centralized tender mechanism means that pharmaceutical companies can implement market-based pricing
strategies. As outlined earlier, the 340B program allows HTCs to procure “outpatient” factor at heavily
discounted prices, and, in addition, HTCs are allowed to negotiate further discounts and rebates. In many
European countries, instead of each organization purchasing its own supply of a particular hemophilia product,
the government purchases what is needed for the entire country or population. National systems for
procurement in European countries can either be a tender or alternative or a mix of both.
Currently, procurement is done on a price per unit basis, but this approach may change through 2025. This
potential change is related to the number of new pipeline agents launching that payers are able to select from,
in addition to uncertainties about their long-term clinical outcomes. However, switching from price per unit to a
price per effectively treated patient or price per outcome may present difficulties because it depends on the
definition of an “outcome.” Interviewed U.S. payers cite a data transparency issue and lack of knowledge
around (1) which outcomes are and should be captured and (2) what these outcomes actually mean in real
terms. If these issues cannot be ironed out, it may not make sense to negotiate based on outcomes.
In Europe, a new procurement directive (2014/24/ EU) came into effect in April 2016. It seeks to make
procurement simpler and more efficient and to discourage selection on the sole basis of price. The new directive
includes provision for increased discussion of the competitive procedure, with negotiation and evaluation of life
cycle costs such as estimating total factor consumption differences between products, which can be carried out
as part of a tender process. This new directive will impact the emerging therapies because the number of units
to be procured will not be the same for SHLs as for EHLs; it is no longer a comparison of like with like because 1
unit of SHL does not equal 1 unit of EHL.
Hemophilia drugs in the United States have relatively higher price points than in Europe; in the United States,
payers are at the mercy of developers as they set their own prices. Interviewed payers are considering how to
leverage the competitive hemophilia landscape post-2019, given how many products are on the market now
and will be after 2019. Developers should consider the future prospect of U.S. health plan providers covering a
smaller number of products, contracted, and raising the minimum prior authorization criteria.

EU5 Procurement Systems for Factor Products
Clinicians or
Procurement patient
Type of Legal framework Who is committee organizations
procurement existing to govern responsible for involved in the involved in the
Country process procurement? procurement? process? process? Other comments
France Alternative Yes Hospitals Yes Patient All licensed products

organizations, must be made
informally available, mitigating
the use of a tender
system.
Germany Alternative No Hospitals No No, neither in the Hemophilia

procurement treatment center
process nor choice hospitals and
of product clinicians decide
which products
should be used and
these agents are
then reimbursed by
health insurance.
Italy Alternative Yes Ministries of Health Yes Clinicians and None.

or regional patient
government organizations,
informally
Spain Alternative Yes Hospitals No Patient organization None.

can make
recommendations
on products used to
treat PUPs
United Kingdom Tender N.A. N.A. N.A. Clinicians formally, Patients can stay on
patient organization their current product
groups formally but if the outcome of the
only in the scientific tender results in the
and technical selection of a
aspects different product
than they are
currently using.
Source: O’Mahony B, Noone, D, and Prihodova L. Survey of coagulation factor concentrates tender and procurement procedures in 38 European
countries. Haemophilia, 2015;21(4):436–443.

Factors Influencing Price Paid for Factor Concentrates in EU Procurement Processes
Factor Influence on Price Paid Decision Resources Group’s View
Presence of a legal framework or law Trend of reduced price per IU across all factor concentrates if there was a Germany has no legal framework, so
that governs the tender or legal framework. this observational trend echoes
procurement process DRG’s findings when we modeled the
annual mean per-patient factor costs
(all regimens) in Germany; costs for
both factor VIII and IX in Germany
were the highest out of all EU5
countries.
Patient organization and physician For both plasma-derived and recombinant, patient organization involvement These findings are echoed in DRG’s
involvement resulted in lower prices being paid for factor concentrates with a statistically models. We found annual mean per-
significant difference in the price of recombinant FVIII (23% lower). A similar, patient factor VIII/IX costs (all
though less marked, impact is observed for the involvement of clinicians. The regimens) were highest in Germany.
formal involvement of clinicians in a tender process and the informal Of all EU5 countries, Germany has
involvement of the patient organization in the United Kingdom has previously the lowest formal involvement of
been reported to have led to an almost 50% reduction in unit cost over a six- patient organizations.
year period.
Presence of a competitive tender In countries using a tender system when compared with an alternative These findings are echoed in DRG’s
system system, the mean prices of recombinant factor VIII products, plasma-derived models; we found annual mean per-
factor VIII products, and plasma-derived factor IX products were lower. There patient factor VIII/IX costs (all
was no appreciable difference in the mean price of recombinant factor IX regimens) were lowest in the United
because there was only one recombinant factor IX product (Benefix) licensed Kingdom, the only EU5 country using
in Europe at the time of the survey. a national tender system.
Note: Based on information from O’Mahony B, Noone D, and Prihodova L. Survey of coagulation factor concentrates tender and procurement procedures in
38 European countries. Haemophilia, 2015;21(4):436–443.

Methodology
Methodology
Bottom-Up Market Forecasting Overview
Decision Resources Group creates its forecast from the bottom up, an approach also known as a patient-based or
epidemiology-based methodology. Simply put, we built our model based on the number of patients receiving
treatment in the base year and out year, layering on the drugs they use, the regimens they use, the drug’s price per IU,
the price per kg of treated patient, number of days treated per year, and the compliance rate to reach total sales. Our
model estimates ex-manufacturer sales.

Patient Share and Sales Calculations
Based on our estimate of the number of drug-treated patients in each population in the market, we apply a patient-
share assumption for each drug across our treated populations. This calculation informs us about how many
patients are on each drug. A generalized patient share calculation example:
Drug-treatable population: 100,000
Drug treatment rate at 80%:
Drug-treated population: 80,000
Drug A—patient share of 15%
Drug A—treated population = 12,000
Hemophilia-specific example (simplified): To determine the sales that these patients will generate for each drug, we
multiply the number of patients on the drug by the number of treated days per year that they receive within a given
setting (prophylactically or on-demand treatment), by the average IU/treatment dose/kg, multiplied by the drug’s
price/IU (ex-manufacturer), to arrive at the cost per patient and then apply the compliance rate. This calculation
goes as follows, where Drug A treats hemophilia A only (U.S. sales, simplified version):
Drug A—treated population = 1,130 (represents a patient share of 20%).
Drug A—number of treated days per year = 124 (prophylaxis protocol) +36 (on-demand protocol). Based on
infusion frequency per week (e.g., twice weekly, three times weekly) and proportion of patients using each
regimen.
Drug A—average IU/treatment dose/kg = 37 IU/kg.
Drug A—price per IU = $1.50.
Drug A—compliance rate = 80% (prophylaxis with SHL), 85% (prophylaxis with EHL), 97% (on-demand).
Drug A sales = $323 million.

Drug-Treatment Rate Assumptions
Drug Treatment Rate in Hemophilia
Drug Treatment Rate
US EU5
2015 2025 2015 2025
Hemophilia A
Severe 100% 100% 100% 100%
Hemophilia B
Severe 100% 100% 100% 100%
Severe A and B 100% 100% 100% 100%
Patient Share Assumptions
Patient Share Assumptions in Hemophilia
Patient Share
US EU5
2015 2025 2015 2025
Hemophilia A
Advate 22% 12% 26% 10%
Kogenate FS 17% 6% 18% 4%
Kovaltry/Iblias N.A. 3% N.A. 5%
ReFacto/Xyntha 14% 5% 14% 5%
NovoEight 4% 3% 8% 3%
Nuwiq N.A. 5% 11% 6%
Helixate 14% 5% 12% 5%
Afstyla N.A. 4% N.A. 4%
Adynovate 2% 3% N.A. 3%
Eloctate 18% 9% N.A. 9%
BAY 94-9027 N.A. 4% N.A. 4%
N8-GP N.A. 3% N.A. 3%
BAX 826 N.A. 5% N.A. 5%
ACE 910 N.A. 17% N.A. 15%
Fitusiran N.A. 8% N.A. 7%
BMN 270 N.A. 2% N.A. 3%
BAX 888 N.A. 1% N.A. 2%
Other recombinant products, e.g., Recombinate 2% 1% 2% 1%
Plasma-derived products 5% 4% 9% 6%
Hemophilia B

Benefix 54% 21% 79% 21%
Rixubis 8% 5% 16% 4%
Ixinity 3% 3% N.A. N.A.
Alprolix 31% 19% N.A. 17%
Idelvion N.A. 33% N.A. 35%
N9-GP N.A. 5% N.A. 8%
SPK-FIX N.A. 1% N.A. 1%
AMT-060 N.A. 1% N.A. 1%
DTX 101 N.A. 1% N.A. 1%
Other recombinant drugs 1% 2% 1% 2%
Plasma-derived products 3% 5% 4% 5%
Hemophilia with inhibitors (includes on-demand and prophylaxis regimens in adult males 20+)
Feiba 50% 15% 50% 15%
NovoSeven 50% 18% 50% 18%
BAX 817 N.A. 6% N.A. 6%
CSL 689 N.A. 15% N.A. 15%
ACE 910 N.A. 23% N.A. 23%
MOD-5014 N.A. 8% N.A. 8%
General Sources of Data
Estimates for the 2015 market for hemophilia in the six major pharmaceutical markets we cover (United States,
France, Germany, Italy, Spain, and United Kingdom) are based on a variety of sources, including physician
interviews, sales audits, published articles, company reports, press releases, and general news media. Market totals
for patient share that exceed 100% within a population occur when patients are prescribed more than one drug.
The estimated days of therapy for each drug or regimen and the corresponding estimated compliant days of therapy
with each drug or drug regimen are determined from prescribing surveys, physician interviews, and estimated
compliance rates.

Sources for Drug Prices
Country Source
United States Symphony Health’s Pharmaceutical Audit Suite (PHAST)

Centers for Medicare & Medicaid Services (CMS)
Federal Supply Schedule (FSS)
Red Book (RedBook Online)
France Thériaque (CNHIM; Centre National Hospitalier D’Information Sur Le Medicament)

Vidal
Germany OdV National (Insight Health)

Rote Liste
Italy Compendio Farmaceutico Telematico (CFT) (Farmadati Italia)

Pharmaceutical Products Database (Petrone Group)
L’informatore Farmaceutico
Spain Pharmaceutical Products Database (Petrone Group)

Ministry of Health, Social Services, and Equality (Integra)
Vademecum
United Kingdom Prescription Cost Analysis (NHS Information Centre)

C+D Data (UBM Information Limited [UBM Medica])
British National Formulary (BNF)
2015 Exchange Rates
Base Currency 2015 Average Exchange Rate to U.S. Dollar ($)
1 euro (€) $1.11
1 pound (£) $1.53
Dosing, Days of Therapy, and Compliance
Dosing: For hemophilia drugs dosed in IU/kg or µg/kg, we assume an average male (20+ years) body weight of
75 kg. For prophylaxis protocols, we use the average IU or µg per kg of the intended dose range stated by the
manufacturer, or where this does not exist, we use physician-reported dose ranges. For on-demand protocols,
we use the average IU or µg per kg of the intended dose ranges to treat all severity of bleeds, or where this does
not exist, we use physician-reported ranges.
Days of therapy: In prophylaxis protocols, we apply to each drug its specified dose infusion intervals per week
as stated by the manufacturer, juxtaposed with real-world per-week utilization estimates by interviewed
physicians, and multiply this to get an average annual number of infusions for each drug. In on-demand
protocols, we assume an average number of spontaneous bleeds per patient per year, based upon physician
interviews and whether it is hemophilia A, hemophilia B, or hemophilia with inhibitors.
Compliance: The compliance rates represent adherence to the intended treatment protocol (prophylaxis or
on-demand) and vary depending on whether the drug is SHL, EHL, or other. Estimates of compliance rates are
based on multiple data sources, including published clinical trial data when possible and comments from
interviewed thought leaders.

Price per Treated Patient, 2025
Annual Cost of Treatment per Patient ($) in 2025
Drug Name United States EU5
Hemophilia A
Advate 414,665 310,649
Kogenate FS 421,102 251,411
ReFacto/Xyntha 414,665 208,965
NovoEight 450,581 231,261
Helixate 424,554 214,003
Adynovate 378,452 252,301
Eloctate 394,508 252,301
Kovaltry/Iblias 463,641 264,471
Nuwiq 460,376 264,471
Afstyla 450,581 259,471
BAY 94-9027 378,452 252,301
N8-GP 372,245 246,301
BAX 826 416,297 277,531
ACE 910 552,311 353,222
Fitusiran 433,958 277,531
BMN 270 1,036,663 776,623
BAX 888 1,036,663 776,623
Hemophilia B
Benefix 409,032 272,688
Rixubis 612,830 256,183
Ixinity 485,456 N.A.
Alprolix 667,368 476,307
Idelvion 737,240 589,376
N9-GP 667,368 476,307
SPK-FIX 613,548 409,032
AMT-060 613,548 409,032
DTX101 613,548 409,032
Fitusiran 737,240 589,376
Hemophilia with inhibitors (cost of on-demand and prophylactic protocols combined, except ACE 910 and fitusiran which will be used prophylactically only)
Feiba 1,668,222 880,451
NovoSeven 3,975,534 1,891,971
BAX 817 3,379,204 1,608,175
CSL 689 4,373,087 2,081,168
ACE 910 5,424,565 2,581,570
Fitusiran 5,424,565 2,581,570
MOD-5014 4,262,158 2,028,376
Note: Prices listed here do not take into consideration rebates or discounts.

Emerging Therapy Prices
Generally speaking, we estimate emerging therapy prices by seeking relevant analogues among current and
emerging therapies within and/or outside the hemophilia market. Price estimates are country-specific based on
pricing levels in each market. Our expectations for new product prices attempt to reflect the relative clinical
advantages/drawbacks of these products compared with current and other emerging drugs based on information
currently available and in view of the general reimbursement context in each region.

Appendix
Key Abbreviations Related to Hemophilia
Acronym/Initialism Definition
ABR annualized bleed rate
AE adverse event
aPTT activated partial thromboplastin time
ATFPI anti-tissue factor pathway inhibitor
AUC area under curve
BAP bypass agent prophylaxis
BU Bethesda unit
CCC comprehensive care center
CVA central venous access
EHL extended half-life
F8 gene encoding factor VIII
F9 gene encoding factor IX
FIX factor IX
FVIII factor VIII
FVIIa factor VII (activated)
HTC hemophilia treatment center
ITI immune tolerance induction
MRI magnetic resonance imaging
MTG maximum thrombosis generation
PD plasma derived
PEG polyethylene glycol
PTP previously treated patient
PUP previously untreated patient
rFIX recombinant factor IX
rFVIIa recombinant factor VII (activated)
rFVIII recombinant factor VIII
SAE serious adverse event
SHL standard half-life
Brands, Marketers, and Generic Availability of Key Therapies for Hemophilia, by

Market
Therapy United States France Germany Italy Spain United Kingdom
Antihemophilic Shire’s Advate Shire’s Advate Shire’s Advate Shire’s Advate Shire’s Advate Shire’s Advate
factor (recombinant)

Antihemophilic Shire’s Adynovate Shire’s Adynovi Shire’s Adynovi Shire’s Adynovi Shire’s Adynovi Shire’s Adynovi
factor
(recombinant), PEG
ylated
Antihemophilic CSL CSL Behring’s CSL Behring’s CSL Behring’s Afstyla CSL Behring’s CSL Behring’s
factor Behring’s Afstyla Afstyla Afstyla Afstyla Afstyla
(recombinant),
single chain
Antihemophilic Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate
factor/von Willebrand
factor complex
(human)
Coagulation factor IX Grifols’ Alphanine Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate Grifols’ Alphanate
(human)
Coagulation factor IX Biogen’s Alprolix SOBI’s Alprolix SOBI’s Alprolix SOBI’s Alprolix SOBI’s Alprolix SOBI’s Alprolix
(recombinant),
Fc fusion protein
Factor IX complex Shire’s Bebulin Shire’s Bebulin Shire’s Bebulin Shire’s Bebulin Shire’s Bebulin Shire’s Bebulin
Coagulation factor IX Pfizer’s Benefix Pfizer’s Benefix Pfizer’s Benefix Pfizer’s Benefix Pfizer’s Benefix Pfizer’s Benefix
(recombinant)
Human coagulation CSL CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
factor VIII Behring’s Beriate Beriate Beriate Beriate Beriate Beriate
Human coagulation CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s Berinin CSL Behring’s CSL Behring’s
factor IX Berinin P Berinin P Berinin P P Berinin P Berinin P
Human von CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
Willebrand Biostate Voncento Biostate Voncento Biostate Biostate Voncento Biostate Voncento Biostate Voncento
factor/FVIII complex Voncento
Antihemophilic factor Biogen’s Eloctate SOBI’s Elocta SOBI’s Elocta SOBI’s Elocta SOBI’s Elocta SOBI’s Elocta
(recombinant),
Fc fusion protein
Human coagulation Grifols’ Fanhdi Grifols' Fanhdi Grifols’ Fanhdi Grifols' Fanhdi Grifols' Fanhdi Grifols’ Fanhdi
factor VIII
Anti-inhibitor Shire’s Feiba Shire’s Feiba Shire’s Feiba Shire’s Feiba Shire’s Feiba Shire’s Feiba
coagulant complex
Willebrand Haemate P Haemate P Haemate P Haemate P Haemate P Haemate P
factor/FVIII complex
Human coagulation Biotest’s Biotest’s Biotest’s Biotest’s Haemonine Biotest’s Biotest’s

factor IX Haemonine Haemonine Haemonine Haemonine Haemonine
Recombinant CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
coagulation factor VIII Helixate FS Helixate FS Helixate FS Helixate FS Helixate FS Helixate FS
Recombinant CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
coagulation factor VIII Helixate NexGen Helixate NexGen Helixate NexGen Helixate NexGen Helixate NexGen Helixate NexGen
Antihemophilic factor Shire’s Hemofil-M Shire’s Hemofil-M Shire’s Hemofil-M Shire’s Hemofil-M Shire’s Hemofil-M Shire’s Hemofil-M
(human)
Willebrand Humate P Humate P Humate P Humate P Humate P Humate P
factor/FVIII complex
Coagulation factor IX CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
(recombinant), Idelvion Idelvion Idelvion Idelvion Idelvion Idelvion
albumin fusion
protein
Coagulation factor IX Emergent Emergent Emergent Emergent Emergent Emergent

(recombinant) Biosolutions’ Ixinity Biosolutions’ Ixinity Biosolutions’ Biosolutions’ Ixinity Biosolutions’ Ixinity Biosolutions’ Ixinity
Ixinity
Antihemophilic factor Bayer’s Bayer’s Kogenate Bayer’s Kogenate Bayer’s Kogenate FS Bayer’s Kogenate Bayer’s Kogenate
(recombinant) Kogenate FS FS FS FS FS
Antihemophilic factor Bayer’s Kovaltry Bayer’s Iblias Bayer’s Iblias Bayer’s Iblias Bayer’s Iblias Bayer’s Iblias
(recombinant)

Human coagulation CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
factor VIII Monoclate-P Monoclate-P Monoclate-P Monoclate-P Monoclate-P Monoclate-P
Human coagulation CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s CSL Behring’s
factor IX Mononine Mononine Mononine Mononine Mononine Mononine
Antihemophilic factor Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s
(recombinant) NovoEight NovoEight NovoEight NovoEight NovoEight NovoEight
Coagulation factor Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s Novo Nordisk’s
VIIIa (recombinant) NovoSeven NovoSeven NovoSeven NovoSeven NovoSeven NovoSeven
Human coagulation Octapharma’s Octapharma’s Octapharma’s Octapharma’s Nuwiq Octapharma’s Octapharma’s

factor VIII (rDNA), Nuwiq Nuwiq Nuwiq Nuwiq Nuwiq
simoctocog alfa
Antihemophilic factor Shire’s Obizur Shire’s Obizur Shire’s Obizur Shire’s Obizur Shire’s Obizur Shire’s Obizur
(recombinant),
porcine sequence
human coagulation Octapharma’s Octapharma’s Octapharma’s Octapharma’s Octapharma’s Octapharma’s

factor VIII Octanate Octanate Octanate Octanate Octanate Octanate
Human coagulation Octapharma’s Octapharma’s Octapharma’s Octapharma’s Octapharma’s Octapharma’s

factor IX Octanine F Octanine F Octanine F Octanine F Octanine F Octanine F
Human coagulation Bio Products Bio Products Bio Products Bio Products Bio Products Bio Products
factor IX Laboratory’s Laboratory’s Laboratory’s Laboratory’s Optivate Laboratory’s Laboratory’s
Optivate Optivate Optivate Optivate Optivate
Antihemophilic factor Shire’s Shire’s Shire’s Shire’s Recombinate Shire’s Shire’s

(recombinant) Recombinate Recombinate Recombinate Recombinate Recombinate
Antihemophilic factor Pfizer’s Xyntha Pfizer’s ReFacto AF Pfizer’s ReFacto Pfizer’s ReFacto AF Pfizer’s ReFacto AF Pfizer’s ReFacto AF
(recombinant) AF
Human coagulation Bio Products Bio Products Bio Products Bio Products Bio Products Bio Products
factor IX Laboratory’s Laboratory’s Laboratory’s Laboratory’s Laboratory’s Laboratory’s
Replenine-VF Replenine-VF Replenine-VF Replenine-VF Replenine-VF Replenine-VF
Coagulation factor IX Shire’s Rixubis Shire’s Rixubis Shire’s Rixubis Shire’s Rixubis Shire’s Rixubis Shire’s Rixubis
(recombinant)
Human von Octapharma’s Wilat Octapharma’s Octapharma’s Octapharma’s Wilate Octapharma’s Octapharma’s
Willebrand e Wilate Wilate Wilate Wilate
factor/human
coagulation factor
VIII

Experts Interviewed
In 2016, the insights we gain into the opinions and practices of leading physicians and researchers in this area derive
from 5 hemophilia specialists from Europe and 2 from the United States. We also interviewed 1 payer from the
United States. The insights of leading physicians from previous editions of this report are also used. Names of our
German and interviewees are not listed here, in compliance with the EphMRA Code of Conduct.
The interviews were conducted from May to July 2016.
Each interview was conducted by phone and lasted 45 minutes.
All experts we interviewed have active medical practices with a specific interest in hemophilia.
Louis Aledort, M.D., The Mary Weinfeld Professor of Clinical Research in Hemophilia, Department of Hematology and
Medical Oncology, Mount Sinai School of Medicine, New York, New York
David Keeling, M.D., Co-Director and Consultant Hematologist, Oxford Hemophilia & Thrombosis Centre, Oxford,
United Kingdom
Gary Kupfer, M.D., Director, Yale University School of Medicine. Yale-New Haven Hemophilia Center, Department of
Pediatrics, New Haven, CT
Thierry Lambert, M.D., Director, Paris Hemophilia Centre (Kremlin Bicetre) Hospital, France
Maria Lopes, M.D., Chief Medical Officer of Magellan Rx Management (Magellan Health, Inc.), Scottsdale, AZ
Matteo Luciani, M.D., Chief of Center, Div. Ematologia Ospedale Ped. Bambino Gesu., Rome, Italy
Rafael Parra Lopez, M.D., Director, Hospital Vall d'Hebron. Unitat Hemofilia (Hospital Traumatologia), Barcelona,
Spain
Savita Rangarajan, M.D., Director, Basingstoke Haemophilia Centre. North Hampshire Hospital, Basingstoke, United
Kingdom
Elena Santagostino, M.D., Ph.D., Direttore, Unità Emofilia, Centro Emofilia e Trombosi Angelo Bianchi Bonomi, Milan,
Italy
Chefarzt, Hämophiliezentrum/Gerinnungssprechstunde, Berlin, Germany

Hemophilia Bibliography
Listed here are the key sources referenced across the DRG research stream in hemophilia.
Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII
inhibitor bypass activity. Journal of Thrombosis and Haemostasis, 2004, 2, 1700–1708
Broderick CR, Herbert RD, Latimer J et al. Association between physical activity and risk of bleeding in children with
hemophilia. JAMA 2012; 308: 1452–9.
Gouw SC, van der Bom JG, Ljung R et al. Factor VIII Products and Inhibitor Development in Severe Hemophilia A. N
Engl J Med 2013; 368: 231–9
Gouw SC, van der Bom JG, van den Berg HM. Treatment-related risk factors of inhibitor development in previously
untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109: 4648–54
Iorio A, Halimeh S, Holzhauer S et al. Rate of inhibitor development in previously untreated hemophilia A patients
treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010;
8: 1256–65.
O'Mahony B, Noone D. and Prihodova L. Survey of coagulation factor concentrates tender and procurement
procedures in 38 European Countries. Haemophilia, 2015, 21: 436–443
Pavlova A, Delev D, Lacroix-Desmazes S et al. Impact of polymorphisms of the major histocompatibility complex
class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor
development in severe hemophilia A. J Thromb Haemost 2009;7(12):2006-2015
Santagostino E, Auerswald G, Benson G et al. Switching treatments in haemophilia: is there a risk of inhibitor
development? European Journal of Haematology 2014; 94: 284–289
Teitel J & Poon MC. The safety of recombinant factor VIIa: a rebuttal. Journal of Thrombosis and Haemostasis, 2004,
2, 2078
Touchot N, Flume M. The payers’ perspective on gene therapies. Nature Biotechnology Correspondence Volume 33,
number 9, September 2015

About Decision Resources Group

Decision Resources Group—a subsidiary of Piramal Enterprises—is a cohesive portfolio of products that offers best-
in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this
analysis and data to make informed, knowledgeable decisions.
With over 900 employees worldwide in 14 global locations, analysts at Decision Resources Group provide the
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aggressive acquisition strategy, Decision Resources Group has become the premier provider of healthcare analysis
and data in the world.
About the Analyst(s)
Kerri Brown, M Pharm

Analyst
Kerri Brown, M.Pharm., is an analyst with Decision Resources Group, focused on finding stories in data and
developing products to inform strategic decisions in the hemophilia and diabetes spaces. Kerri holds a master of
pharmacy degree from King’s College London with 1st class honors. Prior to joining DRG, she was a national clinical
educator at a UK diabetes start-up, and has extensive experience of diabetes medical devices. Kerri has worked at
AstraZeneca, and as a pharmacist in a national psychiatric clinical trial center. In addition to her work at DRG, Kerri is
a practicing pharmacist with extensive clinical experience of UK physician prescribing in diabetes.
© 2018 DR/Decision Resources, LLC. All rights reserved.

Contact Information
For more information, including telephone access to analysts, please reach out to the dedicated contacts for your
region below:
AMERICAS, EUROPE, MIDDLE EAST, AND AFRICA

Email: questions@teamdrg.com
Phone: +1.855.380.4850
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Email: ssaito@teamdrg.com
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Hemophilia: Landscape & Forecast

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Hemophilia: Landscape & Forecast

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Landscape & Forecast

Published November 2016

Written by Kerri Brown, M Pharm

© 2018 DR/Decision Resources, LLC. All rights reserved. 2

© 2018 DR/Decision Resources, LLC. All rights reserved. 3

© 2018 DR/Decision Resources, LLC. All rights reserved. 4

© 2018 DR/Decision Resources, LLC. All rights reserved. 5

Disease Landscape & Forecast

© 2018 DR/Decision Resources, LLC. All rights reserved. 6

Hemophilia Market Parameters and Forecast

Drug Treatment Rate Drug-Treated Cases

U.S./EU5 U.S./EU5 U.S./EU5 U.S./EU5

Top drugs by patient share—2015

Eloctate 18% (US), 400-500 (US),

Kogenate 17% (US), 400-450 (US), 250-300

Severe hemophilia B 100/100 1217/1107 Benefix 54% (US), 200-250 (US),

Alprolix 31% (US), 200-250 (US),

Rixubis 8% (US), 40-50 (US),

Severe hemophilia A 100/100 21/19 Feiba 50% (US), 5-6 (US),

NovoSeven 50% (US), 10-12 (US),

Top drugs by patient share—2025

Advate 12% (US), 350-450 (US),

Eloctate 9% (US), 250-300 (US),

Severe hemophilia B 100/100 1517/1300 Idelvion 33% (US), 300-350 (US),

Benefix 21% (US), 75-125 (US),

Alprolix 19% (US), 150-200 (US),

CSL 689 15% (US), 10-15 (US)

Fitusiran 15% (US), 5-10 (US),

Source: Decision Resources Group

© 2018 DR/Decision Resources, LLC. All rights reserved. 7

Hemophilia SWOT Analysis

Source: Decision Resources Group.

© 2018 DR/Decision Resources, LLC. All rights reserved. 8

Actionable Recommendations in Hemophilia

Actionable Recommendation Supporting Expert Insight

Source: Decision Resources Group

© 2018 DR/Decision Resources, LLC. All rights reserved. 9

© 2018 DR/Decision Resources, LLC. All rights reserved. 10

We expect continued use of plasma-derived agents, particularly in the context of ITI.

Hemophilia Market Landscape

© 2018 DR/Decision Resources, LLC. All rights reserved. 11

2025 Number of Drug-Treated

Advate 2003/2004 970/702 12%/10%

Kogenate FS 1993/2000 485/281 6%/4%

Kovaltry/Iblias 2016/2017 243/351 3%/5%

ReFacto/Xyntha 2001/1999 404/351 5%/5%

NovoEight 2015/2014 242/210 3%/3%

Nuwiq 2016/2014 404/420 5%/6%

Helixate 1993/2000 404/351 5%/5%

Afstyla 2016/2017 323/281 4%/4%

Adynovate 2015/2016 243/210 3%/3%

Eloctate 2014/2016 728/631 9%/9%

BAY 94-9027 2017/2018 323/281 4%/4%

N8-GP 2018/2019 243/210 3%/3%

BAX 826 2021/2022 404/351 5%/5%

ACE 910 2019/2019 1374/1052 17%/15%

Fitusiran 2020/2020 647/491 8%/7%

BMN 270 2021/2022 162/210 2%/3%

BAX 888 2023/2024 81/140 1%/2%

Benefix 1997/1997 319/273 21%/ 21%

Rixubis 2013/2015 76/52 5%/4%

Ixinity 2015/ ---- 46/0 3%/0%

Alprolix 2014/2016 288/221 19%/17%