A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for
Treatment of PNH and Complement-Mediated Diseases: Interim Phase 1 Study Results
Anita Hill,1 Jorg Taubel,2 Jim Bush,3 Anna Borodovsky,4 Noriyuki Kawahata,4 Helen Mclean,4 Christine Powell,4 Prasoon Chaturvedi,4 Garvin Warner,4 Pushkal Garg,4 Benny Sorensen,4 and Nader Najafian4
1St
James' Institute of Oncology; Leeds Teaching Hospitals, Leeds, UK; 2St George's University of London, London, UK; 3Covance Clinical Research Unit, Leeds, UK; 4Alnylam Pharmaceuticals, Cambridge, USA
Part B (MAD): Serum C5 knockdown
BACKGROUND
Safety and Tolerability*
PNH
ALN-CC5 appears generally well tolerated in healthy volunteers
• Bone marrow defect due to acquired PIG-A gene mutation leading to deficiency of GPIanchored surface proteins that protect red blood cells against complement mediated
cell lysis
• Eculizumab is an anti-C5 monoclonal antibody approved for treatment of PNH and aHUS
• Current Treatment Challenges
Part A: Single Ascending Dose (SAD)
‒
Wide inter-individual variation in clearance of eculizumab with discrepancy between labeled effective
trough level (35 mcg/mL) vs expert recommendations of >150 mcg/mL1-3
AE by Preferred Term
occurring in ≥10% of
patients, n (%)
Nasopharyngitis
50 mg
N=4
0
0
0
1
0
0
0
2
1
2
1
5 (25%)
2 (10%)
Nausea
0
0
0
2
0
2 (10%)
ALN-CC5
Injection site pain
0
0
0
2
0
2 (10%)
•
Seasonal allergy
0
0
0
1
1
2 (10%)
siRNA conjugated to N-acetylgalactosamine (GalNAc) ligand
utilizing enhanced stabilization chemistry (ESC)
‒
•
•
•
•
Significantly improved potency and durability; wide therapeutic index
Efficient delivery to hepatocytes following SC administration
200 mg/mL solution
•
•
•
•
Serum C5 levels after multiple doses
of ALN-CC5 in healthy human
volunteers
Residual C5 levels measured using
validated LCMS assay
Maximum % inhibition residual C5: 99%
All reported AEs mild or moderate in severity; 3 possibly drug-related treatment
•
‒
ALN-CC5 PHASE 1 STUDY DESIGN
•
Concentration-effect relationship for
reduction in free C5 in
aHUS patients
Free C5 measured using validated
electrochemiluminescence
immunoassay
Maximum % inhibition free C5: 93.5%
ALN-CC5 and C5 levels
(mcg/mL)
No SAEs and no discontinuation due to AEs
Total of 29 AEs observed
‒
•
•
All cohorts
(N=20)
5 (25%)
Headache
Influenza-like illness
• Unmet need for new complement inhibitors remains
Eculizumab and free C5 levels
(mcg/mL)4
Serum C5 knockdown following 5 weekly doses of ALN-CC5
Part A: Single Ascending Dose (SAD)
20 healthy volunteers dosed with
ALN-CC5 or Placebo (3:1); single SC injection
200 mg
400 mg
600 mg
900 mg
N=4
N=4
N=4
N=4
2
2
1
0
RESIDUAL AND FREE C5
• Maximum C5 knockdown relative to baseline up to 99%
• Mean maximum (± SEM): 98 ± 0.5%
• Mean (± SEM): 98 ± 0.3% at Day 112 (200 mg q1wk x5)
Possibly drug-related AEs: nasopharyngitis, injection site pain, and injection site rash (coded as rash)
Part B (MAD): Complement Inhibition
ISRs seen in 2 subjects – all mild and transient
•
•
•
No clinically significant changes in vital signs, EKG, physical exams and
clinical laboratories (hematology, biochemistry, coagulation and urinalysis)
Part B: Multiple Ascending Dose (MAD)
Maximum CAP inhibition relative to baseline up to 97%
Mean maximum (± SEM): 95 ± 1.0%
CAP activity comparable to homozygous C5 deficient subjects5 in
MAD 200 mg & 400 mg
Part B: Multiple Ascending Dose (MAD)
AE by Preferred Term
occurring in ≥10% of
patients, n (%)
12 healthy volunteers dosed with
ALN-CC5 or Placebo (3:1); weekly ×5
100 mg
n=4
200 mg
N=4
400 mg
N=4
All cohorts
N=12
1
0
0
1
3
1
1
0
1
3 (25%)
3 (25%)
2 (17%)
Headache
Nasopharyngitis
Vulvovaginal Candidiasis
•
•
‒
Primary: Safety and tolerability
Secondary & Exploratory: Pharmacokinetics; Pharmacodynamics - C5 levels, Complement
activity assessment (CAP, CCP, Sheep RBC hemolysis), LDH (Part C), Quality of life (Part C)
Complement Assay Benchmarks from Select Published Literature
Assay
Disease
Values reported
in literature
Notes
Free C5
(Electrohemiluminescence
immunoassay)
aHUS
(patients treated
with eculizumab)
93.5%4
(Max % C5
inhibition)
Results from clinical study of aHUS patients treated
with eculizumab at 900 mg (4xqW) and maintained at
1200 mg q2W 4 (pediatrics dosed per body weight)
Studies : C08-002A/B, C08-003A/B, C09-001r4
CAP/CCP
(Wieslab ELISA assays)
Genetic C5b-9
complement
deficiency
<10%5
compared to
normal serum
Data from serum samples from 18 pts with C5, C6,
C7, C8 or C9 deficiencies5
Values <10% also observed in study of aHUS where
disease activites was determined by platelets, LDH,
haptoglobin and creatinine levels5
Sheep erythrocyte hemolysis
assay
aHUS
(patients treated
with eculizumab)
10-60%6
‡There
• ALN-CC5 represents novel investigational approach for potential
treatment of complement-mediated diseases, including PNH
• In ongoing Phase 1/2 study in healthy volunteers (N=32), single and
multi-dose subcutaneous administration of ALN-CC5 generally well
tolerated
Possibly drug-related AEs headache, bruise, cold symptoms, injection site edema, vaginal thrush,
redness at injection site, itching at injection site, mouth ulcer
ISRs seen in 4 subjects – all mild and transient
No clinically significant changes in vital signs, EKG, physical exams and
clinical laboratories (hematology, biochemistry, coagulation and urinalysis)
Pharmacodynamics and Clinical Activity*
‒
Part B (MAD): Serum Hemolysis Inhibition
Part A (SAD): Serum C5 knockdown
•
•
• Maximum C5 knockdown relative to baseline up to 99%
• Mean maximum (± SEM): 98 ± 0.9%
• Mean (mean ± SEM): 96 ± 1.0% at Day 98 (900 mg)
•
Maximum serum hemolysis inhibition relative to baseline up to 98%
Mean maximum (± SEM): 84 ± 7.6%
‒
Inhibition of Sheep Erythrocyte Hemolysis Following 5 weekly doses of ALN-CC5
‒
Serum C5 Knockdown Following Single Dose of ALN-CC5
‒
•
‒
‒
•
Part A: Single Ascending Dose (SAD)
20 healthy volunteers dosed with
ALN-CC5 or Placebo (3:1); single SC injection
50 mg
N=4
200 mg
N=4
400 mg
N=4
600 mg
N=4
900 mg
N=4
100 mg
N=4
200 mg
N=4
Mean age, years
(Min, Max)
23.8
(20, 26)
22.5
(21, 24)
22.0
(20, 27)
28.5
(23, 38)
26.8
(22, 33)
33.8
(24, 39)
28.0
(24, 32)
25.0
(20, 30)
Gender: Male, %
100
100
75
0
50%
75
25
50
Mean BMI, kg/m2
Race, %
Asian
Black/African
Caucasian
Other
Mean Time on
study, days
24.08
0
25
50
25
115
22.35
0
50
25
25
243
21.38
25
0
50
25
208
This is a double-blinded study; each cohort above remains blinded with one placebo per cohort.
24.80
50
0
50
0
173
23.53
0
25
75
0
138
24.55
0
0
100
0
196
23.68
0
0
100
0
147
25.48
Part B (MAD): Summary of preliminary activity
Part B: Multiple Ascending Dose (MAD)
12 healthy volunteers dosed with
ALN-CC5 or Placebo (3:1); weekly ×5
Part A: Single Ascending Dose (SAD)
20 healthy volunteers dosed with
ALN-CC5 or Placebo (3:1); single SC injection
400 mg
N=4
Mean nadir ±SEM;
mcg/mL
Residual
C5
Nadir; mcg/mL
C5
knockdown
CCP
inhibition
0
0
100
0
CAP
inhibition
99
Hemolysis
inhibition
Mean max ±SEM; %
Max; %
Mean max ±SEM; %
Max; %
Mean max ±SEM; %
Max; %
Mean max ±SEM; %
Max; %
Nadir residual C5 values as low as 0.6 mg/mL achieved
Complement activity (CAP &CCP) reduced up to 97% with mean max inhibition
of 95 ± 1% for CAP and 96 ± 0.9% for CCP
Reduction of serum hemolytic activity up to 98% with mean max inhibition
of 84 ± 7.6%
Transitioning from healthy volunteers to Part C in PNH patients
ACKNOWLEDGEMENTS
Part A (SAD): Summary of preliminary activity
Part B: Multiple Ascending Dose (MAD)
12 healthy volunteers dosed with
ALN-CC5 or Placebo (3:1); weekly ×5
After single dose, up to 99% C5 KD with mean max KD of 98 ± 0.9%
After 5 weekly doses, up to 99% C5 KD with mean max KD of 98 ± 0.5%
Clamped lowering of C5 with very low inter-subject variability
Durable effects lasting months, supportive of once monthly and potentially once
quarterly SC dose regimen
Initial evidence for potentially clinically meaningful reductions in
complement activity
‒
ALN-CC5 PHASE 1 PRELIMINARY STUDY RESULTS*
No reported SAEs; all AEs mild or moderate; no discontinuations; low incidence
of mild injection site reactions
Robust, dose-dependent and durable knockdown (KD) of serum C5
‒
Wide range of values observed for aHUS patients
treated with eculizumab6
CAP/CCP values <10% measured in same samples6
Demographics and Baseline Characteristics
are no head to head studies comparing eculizumab and ALN-CC5
SUMMARY AND NEXT STEPS
All reported AEs mild or moderate in severity; 12 possibly drug-related
•
Objectives
Residual C5 levels achieved with ALN-CC5 in healthy volunteers comparable with free
C5 levels in aHUS patients on eculizumab‡
No SAEs and no discontinuation due to AEs
Total of 30 AEs observed
‒
•
Complement Alternative Pathway inhibition (CAP C5b-9 ELISA) Following
5 weekly doses of ALN-CC5
50 mg
200 mg
400 mg
600 mg
900 mg
Placebo
15.3 ± 2.5
5.2 ± 0.5
3.8 ± 1.0
2.2 ± 0.8
1.8 ± 0.2
60.5 ± 3.3
10.8
4.3
1.8
1.1
1.4
53.5
78 ± 3.2
93 ± 0.9
95 ± 1.4
98 ± 0.9
98 ± 0.3
13 ± 2.6
84
95
97
99
98
20
59 ± 6.5
84 ± 1.6
86 ± 3.2
96 ± 0.7
92 ± 1.1
16 ± 6.0
72
86
93
97
94
37
59 ± 7.3
79 ± 1.2
80 ± 5.7
93 ± 1.3
93 ± 0.7
25 ± 8.5
73
81
91
95
94
44
35 ± 7.9
41 ± 4.4
37 ± 6.5
74 ± 4.2
71 ± 4.7
9 ± 1.4
51
47
50
79
78
13
Statically significant difference in mean max for all parameters across all cohorts vs placebo (P-value<0.05), except for CAP mean max 50 mg cohort vs placebo
Residual
C5
C5
knockdown
CCP
inhibition
CAP
inhibition
Hemolysis
inhibition
Mean nadir ±SEM;
mcg/mL
Nadir; mcg/mL
Mean max ±SEM; %
Max; %
Mean max ±SEM; %
Max; %
Mean max ±SEM; %
Max; %
Mean max ±SEM; %
Max; %
100 mg
200 mg
400 mg
Placebo
4.2 ± 0.5
1.3 ± 0.3
1.3 ± 0.2
67.5 ± 2.1
3.5
0.6
1.0
63.2
95 ± 0.4
98 ± 0.5
98 ± 0.2
23 ± 2.7
96
99
99
27
85 ± 2.6
96 ± 0.9
95 ± 1.5
18 ± 7.5
91
97
96
33
84 ± 2.1
95 ± 1.0
95 ± 1.1
20 ± 3.3
88
97
96
24
52 ± 4.9
75 ± 8.0
84 ± 7.6
5 ± 2.9
58
91
98
10
Statically significant difference in mean max for all parameters across all cohorts vs placebo (P-value<0.05)
Thank you to the trial participants and the following principal investigators / trial sites for their participation:
• Jorg Taubel; Richmond Pharmacology Ltd, Tooting, UK
• Jim Bush; Covance Clinical Research Unit Limited, Leeds, UK
• Anita Hill; Department of Haematology, Leeds Teaching Hospitals, Leeds, UK
• Alvaro Urbana-Ispizua; Department of Hematology, University of Barcelona, Barcelona, Spain
REFERENCES
1. de Latour RP, et al, Blood;125:775-83 (2015)
2. Jodele S, et al. BBMT (2015)
3. Gatault P, et al, mAbs; 7:1205-11 (2015)
4. ASCPT Annual Meeting, Atlanta, Abstract #387 (2014)
5. Seelen MA, et al. J of Immunological Methods; 296:187-198 (2005)
6. Cugno M, et al. J Thromb Haemost;12:1440-8 (2014)
DISCLOSURES
ALN-CC5 is an investigational RNAi therapeutic targeting complement C5; this study is sponsored by Alnylam
Pharmaceuticals
*Safety results currently blinded to treatment with ALN-CC5 or placebo; Safery data as of 19Oct2015; C5
knockdown data as of 19Oct2015; CAP/CCP inhibition data as of 06Nov2015; Hemolysis inhibition data as of
03Sept2015 (SAD) and 05Oct2015 (MAD)
Poster 2413; 57th ASH Annual Meeting and Exposition (December 2015). Orlando, FL USA