Eculizumab (ECU) in Atypical Hemolytic Uremic Syndrome (aHUS) Patients with

Progressing Thrombotic Microangiopathy (TMA): 2-Year Data

2084

Larry Greenbaum,1 Christophe Legendre,2 Sunil Babu,3 Richard R. Furman,4 Neil Sheerin,5 David Cohen,6 Frank Eitner,7 Yahsou Delmas,8 Camille L. Bedrosian,9 Chantal Loirat10
Emory University, Atlanta, GA, USA; 2Universite Paris Descartes and Hpital Necker, Paris, France; 3Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN, USA; 4Weill Cornell Medical College, New York, NY, USA; 5Newcastle University, Newcastle upon Tyne, UK;
6
Columbia University Medical Center, New York, NY, USA; 7University of Aachen, Aachen, Germany; 8CHU Pellegrin-Bordeaux, Bordeaux, France; 9Alexion Pharmaceuticals, Inc., Cheshire, CT, USA; 10Assistance Publique-Hpitaux de Paris, Hpital Robert-Debr, Paris, France
1

evidence of progressing TMA (trial C08-002).

aHUS is caused by inherited and/or acquired defects of regulators of the complement system,

Eculizumab Blocks Terminal Complement

Eculizumab (Soliris; Alexion Pharmaceuticals, Inc., Cheshire, CT), a terminal complement

inhibitor, is a humanized monoclonal antibody that binds with high affinity to the human C5
complement protein, blocking the generation of pro-inflammatory C5a and C5b-9 (Figure 1).
It is the first approved treatment for aHUS in pediatric and adult patients.5-7

Figure 1. Eculizumab Binds with High Affinity to C5 Complement Protein

Complement Cascade7,8
Eculizumab

C3

C3b

C5

METHODS
Study Design and Parameters

X C5b

C5b-9

despite 4 PE/PI sessions 1 week before screening, were enrolled in an open-label, single-arm
phase 2 trial and long-term extension.
Eculizumab was administered at 900 mg/week for 4 weeks, 1200 mg in week 5, and 1200 mg
every 2 weeks thereafter.
Endpoints (with prospective analysis of primary and secondary endpoints at 26 weeks) included:
TMA reduction as measured by platelet count change from baseline (primary endpoint).
Hematologic normalization (normal platelet and lactate dehydrogenase [LDH] levels for
2 consecutive measurements, 4 weeks apart).
Change from baseline in estimated glomerular filtration rate (eGFR)
TMA eventfree status (12 weeks stable platelet count and no PE/PI or new dialysis).
Data were analyzed using repeated measure models and response through the data cutoff for
each patient.

Baseline Disease Characteristics

Table 1. Trial C08-002: Baseline Disease Characteristics

Characteristic
Median age, years (range)
Female, n (%)
Median duration from aHUS diagnosis to screening, months (range)
Median time from current aHUS manifestation to screening, months (range)
Prior kidney transplant, n (%)
Median number of PE/PI sessions 7 days prior to first eculizumab dose (range)a
Baseline eGFR, mean (SD)
Dialysis within 8 weeks prior to the first dose of eculizumab, n (%)b
Identified complement genetic mutationc or autoantibody, n (%)
Median eculizumab treatment duration, weeks (range)d

Eculizumab Multinational, Multicenter Clinical Program in aHUS (N=67)

The efficacy and safety of eculizumab therapy in aHUS patients with clinical evidence of

progressing TMA (prospective trial C08-002) and aHUS patients with long duration of disease and
chronic kidney damage who were undergoing prolonged PE/PI (prospective trial C08-003) were
evaluated in two separate 26-week phase 2 studies with long-term extensions, as well as in a
retrospective study (C08-001) in 30 patients with aHUS in a medical practice setting (Figure 2).
A total of 37 aHUS patients were enrolled in the two prospective trials.
The 2-year results from trial C08-002 are presented.

Figure 2. Eculizumab Therapy in aHUS: Multinational, Multicenter Clinical Program

TMA (measured by platelet count, hemolysis)

Organ damage (serum creatinine ULN)
ADAMTS13 >5%; no positive STEC test
No requirement for identified genetic mutation

Clinical Diagnosis of aHUS in

Patients Outside the Clinical Trials5,6

Prospective5,6 (26 weeks)

Patients with Long
aHUS Patients with
Patients
with
Long
aHUS PatientsTMA
with
Duration of aHUS
Progressing

Retrospective
Study C09-001
(N=30)

Study C08-003 (N=20)

Adult/adolescent

19 patients aged
<18 years

Study C08-002 (N=17)

Adult/adolescent

N=17
28 (1768)
12 (71)
10 (0.3236)
0.75 (0.233.7)
7 (41)
6 (07)
22.9 (14.5)
6 (35)
13 (76)
100 (2145)

Clinical Diagnosis of aHUS with5,6

One patient had no PE/PI 7 days prior to eculizumab, did not meet the inclusion criterion of a minimum of 4 PE/PI sessions prior to screening due
to a severe allergic reaction, and discontinued PE/PI after 2 sessions; b1 patient discontinued dialysis 5 weeks prior to the first dose of eculizumab;
c
1 patient included as a genetic mutation had a polymorphism (complement factor H-related 3/1 deletion); ddata collection is ongoing.

Terminal Complement Activity Through 104 Weeks of Eculizumab

Terminal complement activity reduction was demonstrated as early as 1 hour after first infusion of
eculizumab (Figure 3).
Reduction in terminal complement activity was sustained through end of study.

ULN=upper limit of normal; ADAMTS13=a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; STEC=Shiga toxinproducing
Escherichia coli.

Study Background and Rationale

Initial 26-week results from 2 prospective phase 2 clinical trials of adult and adolescent patients

demonstrated that eculizumab inhibited the systemic and progressive TMA process and
prevented and/or reversed organ damage.5,11,12
In an ongoing extension study, long-term eculizumab treatment in trial C08-002 (median duration
64 weeks) resulted in:
Inhibited TMA:
Significant and sustained increase in platelet count (98109/L; P=0.0001)
TMA eventfree status achieved by 15 of 17 patients (88%)
Improved renal function:
eGFR improvement of 29.3 mL/min (P=0.0007)
4 of 5 patients (80%) able to stop dialysis
Clinically meaningful improvement in health-related quality of life (HRQoL)9,10
Recent treatment recommendations reinforce the importance of early and ongoing eculizumab
therapy in aHUS.13
Presented at the 54th Annual Meeting of the American Society of Hematology
December 811, 2012, Atlanta, Georgia, USA

26-Week Treatment

Mean (%) Terminal Complement

Activity (SE)

86% of patients (32/37) continued chronic

eculizumab treatment in extension studies

*
*

120

*
*

* *

* *

* *

100

*
*

80

60
40

*P<0.001

P<0.01

P<0.05

20
0

Complement
Blocked

16 1615

14 2

20

88
(6499)

30 40 50 60 70 80
Weeks on Eculizumab Treatment
13 2

90

100

110
3

Based on a pharmacodynamic assay that quantified the complement activity in patients serum by measuring the degree of hemolysis; the measure of
hemolysis is the amount of hemoglobin released as determined via spectrophotometer. SE=standard error.

26-Week Treatment

88
(6499)

80
70
60
50
40
30
20
10
0

15/17

15/17

15/17

26 Weeks

1 Year

2 Years

Extension Treatment

0.45
*

0.35

0.40

*
*

* *

0.25

*
*

*
*

0.30

0.20
*P<0.0001

P<0.001

P<0.05

0.15
0.10
0.05

Clinically meaningful threshold=0.06

0
-0.05
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104

Study Week
Patients 8 15 131414

1213 13

13

12 7 12 4

10

11

11

10

11

11

10

Bars represent 95% CI. EQ-5D=EuroQol5 Dimensions Questionnaire.

8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104

Patients 17 16 14 16 15 15 14 15 15 15 15 15 14 15 6

13

13

13

12

11

12

11

12

13

13

12

10

11

11

Bars represent 95% confidence interval (CI).

Slope
1 2 3

Hematologic Normalization Achieved and Maintained with Chronic Eculizumab

Through 2 Years
Hematologic normalization was achieved and maintained through 2 years (Figure 5).
3 of 4 patients (75%) with no known complement mutation achieved and maintained hematologic

normalization.14
12 of 13 patients (92%) with a known complement mutation achieved and maintained hematologic
normalization.14

Figure 5. Hematologic Normalization with Long-term Eculizumab Treatment

100
90
80
70
60
50
40
30
20
10
0

76
(5093)*

88
(6499)*

88
(6499)*

Events
Serious Adverse Eventsa
Hypertension
Accelerated hypertension
Asymptomatic bacteriuria
Adverse Events
Leukopenia
Nausea
Vomitting
Asthenia
Dermatitis
Diarrhea
Erythema
Fatigue
Headache
Hematocrit decreased
Hematuria
Hemoglobin decreased
Herpes zoster
Impetigo
Pyrexia
Tremor
Urinary tract infection
Vertigo

50
40
30
20
10
0
eGFR (estimated 3-piece trend)
95% CI
eGFR (simple mean)

10
20

8 4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100104

Study Week
Patients

5 5 6 17 17 16 15 15 15 15 15 15 15 13 15

15

14

13

12

11

12

11

13

12

13

13

12

12

12

10

Prior to eculizumab, all patients had eGFR <60 mL/min/1.73 m ; median (range) eGFR at baseline: 19 (95% CI, 559).

Ongoing Eculizumab Treatment: Sustained Improvements in Renal Function

over 2 Years
Improvement in renal function was sustained for 2 years (Figure 7; Table 2).

Table 2. Change in Renal Function with Eculizumab Treatment

13/17

15/17

15/17

26 Weeks

1 Year

2 Years

>25% from baseline and no PE/PI or new dialysis, was achieved and maintained through 2 years
by 88% of patients (Figure 6).
The median TMA intervention rate per patient was 0.88 during pretreatment and 0 from baseline
through data cutoff (P<0.0001).
TMA eventfree status was achieved regardless of whether a genetic complement mutation
was identified.14
3 of 4 patients (75%) with no known complement mutation achieved TMA eventfree status.
12 of 13 patients (92%) with known complement mutation achieved TMA eventfree status.

Ongoing Eculizumab Treatment: Rapid and Continuous Improvement in

eGFR over 2 Years

The model of change in eGFR demonstrated (Figure 7):

Slope 1: No significant change in eGFR prior to eculizumab treatment (P=NS).
Slope 2: Steep positive change from weeks 0 to 4 (P<0.0001).
Slope 2 was significantly superior to slope 1 (P=0.007).
Slope 3: Continuous positive increase from week 4 to week 100, showing ongoing eGFR
improvements (P=0.03).

Table 3. Safety of Long-term Eculizumab Treatment

Figure 7. eGFR Change from Baseline Through 2 Years of Eculizumab

11

TMA eventfree status, defined as 12 consecutive weeks with no decrease in platelet count

10

88
(6499)

Figure 8. Impact of Long-term Eculizumab Treatment on the Patients Quality of Life

*14 of 15 patients maintained response through 2 years; the 15th patient maintained TMA eventfree status for 6 months; 95% CI; median duration
64 weeks; median duration 100 weeks. The 2 patients who did not achieve TMA eventfree status at years 1 and 2 were those who withdrew from the
study within the initial-26 week treatment period

TMA EventFree Status Achieved Rapidly and Maintained Through 2 Years

with Ongoing Eculizumab

100
90

Renal Function Parameter

eGFR change from baseline, mean (95% CI)a

Extension Treatment

100
90
80
70
60
50
40
30
20
10
0

Patients

140

*95% CI; median duration 64 weeks; median duration 100 weeks. The 2 patients who did not achieve hematologic normalization at years 1 and 2
were those who withdrew from the study within the initial 26-week treatment period.

Figure 3. Effect of Eculizumab on Terminal Complement Activity

Long-term Extension Studies9,10

Study Week

In trial C08-002, patients with a median duration of 9.7 months from aHUS diagnosis to screening

Terminal

Extension Treatment

160

presented with progressing TMA (Table 1).

All patients had substantial renal damage (100% with eGFR <60 mL/min/1.73 m2, for a
median duration of 17 days).
All but 1 patient (who was PE/PI intolerant) received PE/PI 1 to 6 hours prior to
eculizumab initiation.

C3b , a cleavage product of C3, is a component of C5 convertase. Cleavage of C5 into C5a and C5b by
C5 convertase initiates the terminal complement cascade: C5a is a potent anaphylatoxin; C5b recruits the
complement components to form the terminal complement complex. Eculizumab prevents cleavage of C5
(represented by X in the figure).

26-Week Treatment

aHUS patients 12 years of age with progressing TMA (platelets <150109/L at screening),

C5a

Proximal

Figure 4. Eculizumab Treatment Increased Platelet Count

RESULTS

X
C3a

had low platelets at baseline and was maintained through 2 years in 12 of 13 patients
(Figure 4).

Mean Change in Platelet Count

from Baseline

resulting in chronic, uncontrolled complement activation that causes platelet activation,

thrombosis, hemolysis, and thrombotic microangiopathy (TMA).1
More than one-third of aHUS patients die or progress to end-stage renal disease (ESRD) with the
first clinical manifestation of aHUS.1-4
Up to 65% of aHUS patients require dialysis, develop permanent kidney damage, or die within
1 year despite plasma exchange/plasma infusion (PE/PI).2

Platelet normalization (150109/L) was achieved by 26 weeks in 13 of 15 patients (87%) who

Figure 6. TMA EventFree Status Achieved with Ongoing Eculizumab Treatment*

EQ-5D Mean Change from Baseline

Report the results of 2 years of ongoing eculizumab treatment in aHUS patients presenting with

Patients Achieving Hematologic

Normalization (%)

Atypical Hemolytic Uremic Syndrome (aHUS): Background

Eculizumab Continued to Inhibit Complement-Mediated TMA over 2 Years as

Measured by Increased Platelet Count

Patients Achieving TMA EventFree

Status (%)

OBJECTIVE

eGFR Mean Change from Baseline

INTRODUCTION

eGFR increase of 15 mL/min/1.73 m2, n (%)

CKD improvement 1 stage, n (%)
Serum creatinine decrease 25%, n (%)
Proteinuriae decrease 1 grade, n/N (%)f

26 Weeks
(N=17)
32.0
(14.549.4)
P=0.001
9 (53)d
10 (59)
11 (65)
12/15 (80)

2 Yearsb
(N=17)
35.2c
(17.353.1)
P=0.0005
10 (59)d
12 (71)
13 (76)
7/9 (78)c

REFERENCES
1. Loirat C, Frmeaux-Bacchi V. Orphanet J Rare Dis. 2011;6:60.
2. Caprioli J, Noris M, Brioschi S, et al. Blood. 2006;108:1267-1279.
3. Noris M, Caprioli J, Bresin E, et al. CJASN. 2010;5:1844-1859.
4. Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T. Semin Thromb Hemost. 2010;36:673-681.
5. Soliris (eculizumab) [prescribing information]. Cheshire, CT: Alexion Pharmaceuticals, Inc.; 2011.
6. Soliris (eculizumab) [summary of product characteristics]. Paris, France: Alexion Europe SAS; 2011.
7. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Nature Biotech. 2007;25:1256-1264.
8. Walport MJ. N Engl J Med. 2011;344:1058-1066.

9. Licht C, Muus P, Legendre CM, et al. Presented at ASN; November 813, 2011; Philadelphia, PA. Poster TH-PO366.
10. Greenbaum L, Babu S, Furman R, et al. Presented at ASN; November 813, 2011; Philadelphia, PA. Poster TH-PO367.
11. Greenbaum L, Babu S, Furman R, et al. Blood. 2011;118: Abstract 193.
12. Licht C, Muus P, Legendre CM, et al. Blood. 2011;118: Abstract 3303.
13. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frmeaux-Bacchi V. Nat Rev Nephrol. 2012;8:643-657.
14. Goodship T, Smith RJH, Legendre C, et al. Presented at ASN; October 30November 4, 2012; San Diego, CA.
Poster TH-PO442.

1 (6)

1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)

2 (12)
2 (12)
3 (18)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)
1 (6)

Mild
Mild
Mild
Moderate
Mild
Mild
Moderate
Moderate
Mild
Mild
Mild
Mild
Mild
Moderate
Mild
Moderate
Mild
Mild

Ongoing treatment with eculizumab in patients with progressing TMA led to continued

Ongoing Eculizumab: Sustained and Significant Improvement in Quality of Life

over 2 Years

associated with eculizumab as identified by the investigator (through a median treatment duration
of 100 weeks).
Adverse events rates remained steady or declined with longer duration eculizumab treatment.
No infection-related serious adverse events were reported.

2 (12)
2 (12)
2 (12)
1 (6)
1 (6)
1 (6)
1 (6)

Severe
Moderate
Mild

CONCLUSIONS

was associated with greater increases in eGFR (P<0.01) (Table 2).

Table 3 lists adverse events or serious adverse events considered possibly, probably, or definitely

1 (6)
1 (6)

1 (6)
2 (12)
1 (6)

A serious adverse event was defined as any event that results in death, is immediately life-threatening, requires hospitalization or
prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

Earlier eculizumab intervention (shorter duration of aHUS clinical manifestation prior to treatment)

Eculizumab Was Safe and Well Tolerated over the 2-Year Study Period

1 (6)
1 (6)

All

Worst
Severity

For all parameters, improvement was seen in at least 2 consecutive measurements over 4 weeks. aBased on ANOVA; bat data cutoff
(median 100 weeks), unless otherwise noted; c104 weeks; dsimilar results were reported regardless of the identification of a genetic
complement mutation; ecategorical measure based on urinalysis; fevaluable patients. CKD=chronic kidney disease.

Eculizumab significantly improved HRQoL over 2 years (change of 0.06 is clinically meaningful).
The mean increases in EQ-5D scores at week 26 were 0.32 (95% CI, 0.240.39; P<0.001).

No. (%) of Patients (N=17)

1 d6 mo 612 mo 1218 mo 18 mo

improvement in patient outcomes at 26 weeks, 1 year, and 2 years:

Sustained inhibition of complement-mediated TMA
Significant and sustained increase in platelet count
Sustained hematologic normalization at 1 and 2 years
Reduced need for PE/PI and dialysis
Continuous improvements in renal function
Decrease in serum creatinine levels
Rapid, continuous, and time-dependent improvements from baseline in eGFR
Improvement in CKD stage
Similar efficacy, regardless of identified complement mutation
Earlier and ongoing eculizumab treatment associated with better renal outcomes
Adverse events rates remained the same or declined with ongoing eculizumab treatment.
No patients died during the median 100-week study period.
These 2-year efficacy and safety outcomes underscore the importance of early and ongoing
eculizumab treatment in patients with aHUS and progressing TMA.
Eculizumab provides an ongoing positive benefit/risk advantage for patients with aHUS.

DISCLOSURES AND ACKNOWLEDGMENTS

Dr. Licht has received fees for consultancy, research funding, and honoraria from Alexion Pharmaceuticals.
Dr. Muus has been a member of an advisory board for Alexion Pharmaceuticals. Dr. Legendre has received
compensation for participation in a speakers bureau for Alexion Pharmaceuticals. Dr. Bedrosian is an employee
of Alexion Pharmaceuticals. Dr. Loirat has been a coordinator of eculizumab trials for, and received honoraria
for conferences from, Alexion Pharmaceuticals. Drs. Furman, Sheerin, Cohen, Eitner, and Babu have nothing
to disclose.

This study was sponsored by Alexion Pharmaceuticals, Inc. Editorial support was provided by John Kincaid, MD, of
Alexion Pharmaceuticals, Inc. Medical writing support was provided by Infusion Communications and supported by
Alexion Pharmaceuticals, Inc.