Parallel Universes

Traditional Treatments vs
Emerging Disease-modifying Therapies
for Neuromuscular Disorders
MARCH
Day 1
25
March 25, 2021 | Time: 1:00 PM EST – 4:00 PM EST
x Lambert-Eaton Myasthenic Syndrome (LEMS)

x Myasthenia Gravis
Watch archived

x Amyotrophic Lateral Sclerosis (ALS)

sessions on-demand at:
NeuroSeriesLive.com
APRIL
Day 2
11 April 1, 2021 | Time: 2:00 PM EST – 4:00 PM EST
 Spinal Muscular Atrophy (SMA) Current
Session
 Rett Syndrome

This activity is supported by educational grants from Acadia Pharmaceuticals Inc.; Alexion Pharmaceuticals, Inc.; 1
Biogen; Catalyst Pharmaceuticals; and Mitsubishi Tanabe Pharma America, Inc.
SMA: Early Detection to Enhance Access
to Genetic Testing and Disease-modifying
Therapies
Presented by:

Julie A. Parsons, MD
Haberfeld Family Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine
Children’s Hospital Colorado

David N. Lieberman, MD, PhD

Attending Child Neurologist
Assistant, Department of Neurology
Instructor of Neurology, Harvard Medical School
Boston Children’s Hospital
Department of Neurology

This activity is supported by educational grants from Acadia Pharmaceuticals Inc.; Alexion Pharmaceuticals, Inc.; 2
Biogen; Catalyst Pharmaceuticals; and Mitsubishi Tanabe Pharma America, Inc
Faculty Disclosures

 Julie A. Parsons, MD
− Consulting Fees: Biogen, Genentech Roche,
Novartis, Scholar Rock
− Contracted Research: AveXis, Biogen, Scholar
Rock
 David N. Lieberman, MD, PhD
− Consulting Fees: AveXis, Taysha Gene Therapies,
− Contracted Research: Site PI for clinical trials
supported by Acadia Pharmaceuticals, Anavex Life
Sciences, GW Research Limited, and the Rett
Syndrome Research Trust
3
Learning Objectives

 Describe the link between genetic mutations, the onset of

symptoms, and the importance of early recognition and
diagnosis of SMA to prevent irreversible loss of nerve
function and ensure early access to effective and potentially
curative treatment

 Differentiate current and emerging treatment options to

produce functional SMN protein levels

 Explain the importance of a multidisciplinary team approach,

including gastroenterology, nutritionist, pulmonology,
orthopedics, and physical-therapy members, to maximize
quality of life in patients with SMA
4
Spinal Muscular Atrophy (SMA)

 A clinically and genetically heterogeneous group of

diseases in which there is a loss of anterior horn
cells and progressive muscle atrophy without
involvement of the corticospinal tract 5
Audience Polling Question

How confident are you in your

ability to diagnose SMA?

A. Very confident
B. Confident
C. Not confident

6
Role of SMN Protein in SMA

 SMA is caused by insufficient SMN involved in:

production of the survival of  RNA metabolism
motor neuron (SMN) protein,  Actin cytoskeleton
which is expressed in all dynamics
cells, but is particularly  Ubiquitin homeostasis
critical in motor neurons  Bioenergetics pathways
 The SMN protein has  Synaptic vesicle
multiple regulatory roles in release
cells
 The precise mechanism by
which lack of SMN leads to
SMA is not clear
D’Amico AD et al. Orphanet J Rare Dis. 2011;6:71. Bowerman M et al. Dis Model Mech. 2017;10(8):943-954. 7
SMN Expression in a Healthy Individual

Normal SMN protein levels Low SMN protein levels

8
Burghes AHM et al. Nat Rev Neurosci. 2009;10(8):597-609.
SMN Expression in a Patient with SMA

Low SMN protein levels

Normal SMN protein levels

9
Burghes AHM et al. Nat Rev Neurosci. 2009;10(8):597-609.
SMN 2 Is a Modifying Gene

 In humans, SMA disease severity

correlates with SMN2 gene copy
number and SMN protein levels
 SMA type I: 1-2 copies of SMN2
 SMA type II: 2-3 copies of SMN2
 SMA type III: 4 copies of SMN2
 Individuals with more than 5
copies of SMN2 are clinically
unaffected

Charlotte J et al. Spinal Muscular Atrophy. In: Gilman S. Neurobiology of Disease. Elsevier; 2007:501-511. 10
SMN2 Copy Number is a Highly
Predictive Biomarker of Clinical Phenotype
Based on known epidemiology, 97% of patients with 2 copies of
SMN2 will be diagnosed with SMA type I; 80% of patients with 3
copies of SMN2 will be diagnosed with SMA type II
1 SMN2 copy
Phenotype frequency 2 SMN2 copies
3 SMN2 copies
4 SMN2 copies
100

80
Patients (%)

60

40

20

0
SMA Type I SMA Type II SMA Type III
(n = 188) (n = 110) (n = 77)

Adapted from: Feldkötter M et al. Am J Hum Genet. 2002;70(2):358-368. 11

Spinal Muscular Atrophy (SMA)

 Types I, II, III depend on clinical severity

12
New Classification of SMA Subtypes

 Non-sitters

 Sitters

 Walkers

Mercuri E et al. Neuromuscul Disord. 2018;28(2):103-115. 13

SMA Clinical Patient Groups Based on
Maximal Achieved Motor Function
Clinical Age of
Motor Milestones Prognosis*
Group Onset
Most common form (~50% of
2 weeks to None; unable to sit cases); severe hypotonia; death
Non-sitters
6 months or roll or need for permanent
ventilation assistance by 2 years
6 to 18 Sitting; unable to Proximal weakness; survival into
Sitters
months walk independently adulthood
Range of motor impairment from
>18 mild to moderate; some may
Walkers Walking
months lose ability to walk; normal life
span

*Prognosis varies with phenotype and supportive care interventions.

14
Farrar MA et al. Ann Neurol. 2017;81(3):355-368. Mercuri E et al. Neuromuscul Disord. 2018;28(2):103-115 .
SMA: Progressive Loss of Motor Function

15
Sumner CJ et al. J Clin Invest. 2018;128(8):3219-3227.
Natural History of Type 1 SMA

Onset of Type 1 SMA by 6 months

Survival for Finkel1 = no death and no need for ≥16-hr/day ventilation continuously for ≥2 weeks, in the absence of an acute reversible
illness; n = 23 (2 copies of SMN2)
Survival for Kolb2 = no death and no tracheostomy; n = 20

1. Finkel RS et al. Neurology .2014;83(9):810-817. 16

2. Kolb SJ et al. Ann Neurol.2017;82(6):883-891.
Spinal Muscular Atrophy (SMA)

17
Newborn Screening

 In July 2017, Missouri was the first state to pass

legislation adding SMA to their screening panel
 Utah became the first state to implement
permanent SMA newborn screening on
January 29, 2018
 Approved by the RUSP (Recommended Uniform
Screening Panel) committee on February 9,
2018 and signed into effect on July 3, 2018

18
Information Courtesy of Cure SMA. 19
Suggested Protocol for Therapy After
Newborn Screening

Glascock J et al. J Neuromuscul Dis. 2018;5(2):145-158. 20

SMA Consensus Care Guidelines

21
Consensus on Standards of Care

 Diagnosis and genetics

 Nutrition, growth, and bone health
 Pulmonary
 Orthopedic
 Physical therapy and rehabilitation
 Other organ-system involvement
 Acute care in the hospital setting
 Ethics and palliative care
 Medication
22
Mercuri E et al. Neuromuscul Disord. 2018;28(2):103-115. Finkel RS et al. Neuromuscul Disord. 2018;28(3):197-207.
SMA Type I: Changing Survival and
Impact of Standards of Care

 Retrospective study* of 33 infants with SMA type 1, with symptom onset <6 months of age
 Highest motor function score (HINE-2) seen at initial visit
 Prolongation of survival does not impact (non-) achievement of motor milestones

Oskoui M et al. Neurology. 2007;69(20):1931-1936.

*De Sanctis R et al. Neuromuscul Disord. 2016;26(11):754-759. 23
Consensus of Care Guidelines for SMA

 Important that, in light of new therapies,

care guidelines continue to be followed in
patients with SMA
 New therapies are not a replacement for
good general health care in patients with
SMA
 Reminder: there is no cure for SMA

Mercuri E et al. Neuromuscul Disord. 2018;28(2):103-115.

Finkel RS et al. Neuromuscul Disord. 2018;28(3):197-207. 24
Difficulty Finding
Treatment
Caregiver Story
Objectives for Care of
Neuromuscular Patients
 Partnering with primary care practitioners
 Facilitating early diagnosis
 Ensuring best practice with uniform
standard of care
 Empowering patients
 Access to multidisciplinary care
 Enrolling in disease registries
 Enrolling in clinical trials
26
Multidisciplinary Care Team

 Neurology  RN
 Rehabilitation  Cardiology
 Physical Therapy/OT  Endocrinology
 Clinic coordinator  Neuropsychology
 Pulmonary  MDA Representative
 Gastroenterology  Orthopedics
 Respiratory therapy  Orthotist
 Social worker  DME Vendors
 Genetic counselor
27
Audience Polling Question

In addition to symptomatic patients,

disease-modifying therapies have been
studied in pre-symptomatic patients:

A. Yes
B. No
C. I am not sure

28
Current and Emerging Therapies for SMA


*FDA-approved
29
Schorling DC et al. J Neuromuscul Dis. 2020;7(1):1-13.
Mechanistic Strategies to Treat SMA

SMN-dependent
SMN-independent

Splicing modification Gene replacement Muscle activation

Modification of SMN2 mRNA Replacement of faulty Improvement of muscle force-frequency
splicing to increase production SMN1 gene using response in skeletal muscle via activation
of functional SMN protein viral-vector-based gene of fast skeletal muscle troponin
(nusinersen, risdiplam, branaplam) therapy (onasemnogene) (CK‐2127107)

Farrar MA et al. Ann Neurol. 2017;81(3):355-368. Finkel RS et al. Lancet. 2016;388(10063):3017-3026.

Dominguez E et al. Hum Mol Genet. 2011;20(4):681-693. Naryshkin NA et al. Science. 2014;345(6197):688-693. 30
Antisense Oligonucleotide (ASO)
Modulation of SMN 2

31
Nusinersen: First ASO

 Injected intrathecally
 Increases SMN protein in motor neuron cells
 Half-life (intrathecal) 4-6 months
 Favorable safety profile
 Approved by FDA (2016) for all 5q SMA types

Chiriboga CA et al. Expert Rev Neurother. 2017;17(10):955-962.

Hoy SM et al. Drugs. 2017;77(4):473-479;
Claborn MK et al. Ann Pharmacother. 2019;53(1):61-69. 32
Nusinersen: Administration

 Intrathecal drug administration

− Lumbar puncture bolus injection
 ASOs have long half-lives (several
months) in CNS tissue
 Loading doses – to saturate
motor neurons as the primary
target
 Maintenance doses – to maintain
effective drug levels
 Favorable safety profile

Image adapted from: www.cancer.gov.

33
 Evidence Supporting Early Diagnosis +
Treatment in SMA: Nusinersen Clinical Trials
HINE Motor Milestone Scores Over Time Across Studies
Greatest improvements observed in those treated presymptomatically
28
Max 26 NURTURE (presymptomatic
infantile-onset SMA; 3 SMN2 NURTURE (presymptomatic
score 24 copies; 5/2018 data cut) infantile-onset SMA; 2 SMN2
22 (n = 10) copies; 5/2018 data cut) (n = 15)
20
18
Mean (SE) 16 CS3A (infantile-onset SMA; 2 SMN2
14 ENDEAR and SHINE nusinersen copies; final analysis) (n = 17)
total motor (infantile onset-SMA; 2 SMN2 copies;
12
milestones 10 6/2017 data cut) (n = 81)
score 8
6
4
2 ENDEAR sham/SHINE nusinersen (infantile-onset SMA; 2 SMN2 copies; 6/2017 data cut) (n = 23)
0 ENDEAR sham control (infantile-onset SMA; 2 SMN2 copies; final analysis) (n = 40)
-2
29

337

568

778
1
15

64
85
92
169
183
253
302

365
379
394
421
442
505
540

578
631
659
694
698
700
757

818
820
883
938
946
1009
1072
1135
1198
Scheduled visit day
NURTURE (3 SMN2 copies) 10 10 10 10 10 10 9 6 5
NURTURE (2 SMN2 copies) 15 15 15 15 15 15 13 11 10 9
CS3A (2 SMN2 copies) 17 17 16 17 16 15 15 12 13 11 12 10 13 13 13 13 13 11 10 9 9 6
ENDEAR/SHINE nusinersen 81 70 65 51 48 31 17 10 5
ENDEAR sham/SHINE nusinersen 23 19 12 6
ENDEAR sham control 40 32 24 16 11

HINE-2 = Hammersmith Infant Neurological Examination – section 2.

For each study n ≥ 5 were plotted.

Swoboda KJ et al. Presented at: Annual International Congress of the World Muscle Society (WMS-23); October 6, 2018; Mendoza, Argentina.
NURTURE Update
(nusinersen started in presymptomatic SMA)

All infants were ≥25 months old and alive, without permanent
ventilation
100% achieved sitting 88% achieved walking alone
 12/15 with 2 copies of SMN2
 10/10 with 3 copies of SMN2

Nusinersen demonstrated durability of effect with a median 2.9

years of follow-up
Nusinersen was well tolerated with no new safety concerns over
an extended follow-up
*Results emphasize proactive intervention after genetic diagnosis

De Vivo DC et al. Neuromuscul Disord. 2019;29(11):842-856. 35

ENDEAR: Impact of Nusinersen on
Motor Milestone Achievement

Full head control* Independent sitting† Standing‡

*Full head control was defined as all-the-time upright (HINE score = 2)

†Independent sitting includes HINE score categories: stable sit and pivots (rotates)
‡Standing includes HINE score categories stands with support and stands unaided

Finkel RS et al. N Engl J Med. 2017;377(18):1723-1732. 36

CHERISH: Primary Endpoint
Change in Hammersmith Functional Motor Scale Expanded from Baseline

Mercuri E et al. N Engl J Med. 2018;378(7)625-635.

37
Risdiplam: SMN2 Splicing Modifier

 Approved by FDA in 2020 (>2 months of age)

 Given once-daily orally
 Favorable side-effect profile
 A variety of trials in 1 month to 60 years for
all types of SMA including pre-symptomatic
 2.5 time increase in SMN protein level in
serum as compared to baseline (2-25 years)

Mercuri E. Presented at: World Muscle Society (WMS) 2018. Abstract P.255.
Dhillon S. Drugs. 2020;80(17):1853-1858.
Shorrock HK et al. Drugs. 2018;78(3):293-305. 38
Risdiplam: Clinical Trials

 FIREFISH - an open-label trial in infants aged 1-7 months

with Type 1 SMA

 SUNFISH - a double-blind, placebo-controlled trial in

children and young adults (2-25 years old) with Type 2 and 3 SMA

 JEWELFISH - an open-label exploratory trial in patients

aged 12-60 yrs with Type 2 or 3 SMA who have been previously
treated with SMN-targeting therapy as part of a clinical study

 RAINBOWFISH - an open-label trial in pre-symptomatic

SMA initiated in early 2019

Rao VK et al. J Manag Care Spec Pharm. 2018;24(12-a):S3-S16.

ClinicalTrials.gov. NCT03032172.
ClinicalTrials.gov. NCT03779334.
39
FIREFISH Part 1: 1-year Results

*Event free is defined as alive with no permanent ventilation (i.e., no tracheostomy or BiPAP ≥16 hours per day continuously for >3 weeks or continuous intubation
>3 weeks, in the absence of, or following the resolution of, an acute reversible event). †1 infant was unable to swallow at baseline. Cohort A: Low-dose cohort.
Cohort B: High-dose cohort. Dose adjusted per protocol. Data cut-off: February 27, 2019.

BSID-III = Bayley Scales of Infant and Toddler Development, Third Edition; CHOP-INTEND = Children's Hospital of Philadelphia Infant Test of Neuromuscular
Disorders; HINE-2 = Hammersmith Infant Neurological Examination, Module 2. 40
Onasemnogene Abeparvovec:
Gene Therapy
 Approved by the FDA May 2019
 Indicated for patients from birth to 24 months
old
 Delivery of a fully functional human SMN gene
into target motor neuron cells
 Production of sufficient levels of SMN protein
required to improve motor neuron function
 Rapid onset of effect in addition to sustained
SMN protein expression
Hoy SM. Drugs. 2019;79(11):1255-1262. Lowes LP et al. Pediatr Neurol. 2019;98:39-45. 41
Onasemnogene Abeparvovec:
START Trial

Cohort 2: 11/15 attained a CHOP-INTEND Score of >40

CHOP INTEND = Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders
42
Mendell JR et al. N Engl J Med. 2017;377(18):1713-1722.
 Onasemnogene Abeparvovec:
Clinical Trial – SMA Type 1 EFS (2/18)
Age (months*)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
6.7E13 vg/kg
Cohort 1
2.0E14 vg/kg
Cohort 2

 Gene therapy infusion

Last trial visit
Pulmonary event

75% 50% 25% Age at Last Follow-up

PNCR (Finkel) 2014 8%
event- event- event- event- Cohort 1: 48 months* (median)
Natural History Study:
free free free free Cohort 2: 29.5 months (median)

All reached 20-month event-free survival

*A month is defined as 30 days
43
Al-Zaidy S et al. Presented at: American Academy of Neurology Annual Meeting 2018. April18; Los Angeles, CA.
Onasemnogene Abeparvovec:
SPR1NT Trial
 Presymptomatic patients treated achieved
age-appropriate motor milestones
 Rapid motor-function improvements
 No patients required ventilatory support of
any kind
 Nearly all patients were fed orally without
feeding support

Schultz M et al. Ann Neurol. 2019;86(suppl 23):S133. 44

Enhancing Muscle Function

 Apitegromab (SRK-015)
− Myostatin inhibitor in development
− Monthly IV infusion
− Prevents myostatin activation leading to
increased muscle-cell growth
− Improved muscle function in preclinical
− Fully human anti-pro-myostatin monoclonal
antibody targeting muscle

Long KK et al. Hum Mol Genet. 2019;28(7):1076-1089. 45

Non-SMN: Apitegromab (TOPAZ study)

 IV administration monthly over 52 weeks

 Phase II, n=58 (TOPAZ study)
− SMA types 2 and 3
− Age 2 to 21 years old
− IV administration monthly over 52 weeks
− Safety, tolerability, efficacy; est completion 4/2023
 *Interim analysis – met primary efficacy
endpoint in all cohorts; no safety signals
ClinicalTrials.gov. NCT03921528. 46
*Pharmaletter. October 28, 2020.
SMA PATIENTS

47
SMA PATIENTS

48
Summary

 The face of SMA is changing

 Early diagnosis leads to early treatment and
more optimal outcomes
 Multidisciplinary care and using care
consensus guidelines leads to improved
outcomes and quality of life

49
Q&A
with the experts

50
Patient Advocacy
•Collaborates with local, state, and federal agencies on policies that  Has supported the
encompass the needs of rare-disease patients
identification, treatment,
Patient Organization Mentorship
and cure of rare disorders
•Supports the establishment and growth of disease-specific for nearly 40 years
organizations so they can better serve their patients

 Partners with >300

Patient and Professional Education
•Educates patients and their families, physicians, and
disease-specific patient
other health care professionals about rare diseases
and their dedicated organizations organizations
Research Support  Access resources at:
•Provides grants to facilitate rare-disease research and
establish disease-specific registries − https://rarediseases.org

Patient Assistance Program

•Offsets the costs of treatment, clinical-trial participation,
and access to services

International Partnerships
•Represents the US and collaborates with global partners dedicated
to addressing the global health challenge of rare diseases
51
More Information and Support

www.cureSMA.org

www.mda.org

www.childneurologyfoundation.org
52
What’s Available from the 2021
Neuromuscular Series?
Available Day 1
On-Demand at:
March 25, 2021 | Time: 1:00 PM EST – 4:00 PM EST
x 1:00pm
 Lambert-Eaton Myasthenic Syndrome (LEMS)
Earn up to 3 credits; x 2:00pm
 Myasthenia Gravis
CME/CE-certified x 3:00pm
 Amyotrophic Lateral Sclerosis (ALS)

Day 2
Available
April 1, 2021 | Time: 2:00 PM EST – 4:00 PM EST
x 2:00pm
On-Demand at:
 Spinal Muscular Atrophy (SMA)
 3:00pm Rett Syndrome
Earn up to 2 credits;
CME/CE-certified

53
Stay Tuned for Our Next Session

Rett Syndrome: Early Recognition and Emerging

Agents to Reduce Disease Burden
Today from 3:00PM - 4:00PM EST

Speakers
David N. Lieberman, MD, PhD
Attending Child Neurologist
Assistant, Department of Neurology
Instructor of Neurology, Harvard Medical School
Boston Children’s Hospital
Department of Neurology
Julie A. Parsons, MD
Haberfeld Family Endowed Chair in Pediatric
Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine
Children’s Hospital Colorado

54
Thank you for
participating today!

Visit NeuroSeriesLive.com for Additional Live and

Endured CME/CE Neurology Activities.