A Subcutaneously Administered Investigational RNAi

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 Hill1, Jorg Taubel2, Jim Bush3, Anna Borodovsky4, Noriyuki Kawahata4, Helen Mclean4, Christine
Powell4, Prasoon Chaturvedi4, Garvin Warner4, Pushkal Garg4 , Benny Sorensen4 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
December 6, 2015 | ASH 2015 | Orlando, FL
1
ALN-CC5 and Complement-Mediated Diseases
Excessive complement activity drives
disease pathophysiology in many
indications
•
•
•
•
•
Paroxysmal nocturnal hemoglobinuria (PNH)
Atypical hemolytic uremic syndrome (aHUS)
Neuromyelitis optica (NMO)
Myasthenia gravis (MG)
Many others
Alternative Pathway
C3
Initiation
Complement C5 is a clinically
validated target
• Eculizumab is an anti-C5 mAb
◦ Approved for use in patients with PNH and
aHUS
2
C1
C4 and C2
C3 Convertase
Factor B
C3bBb
C4bC2a
C3b
Opsonization
C5 Convertase
C3bBbC3b
C4bC2aC3b
Inflammation
• Human C5 deficiency associated with
minimal complications
◦ Increased susceptibility to Neisseria infections
Lectin Pathway
C3
C3a
Complement C5 is a genetically
validated target
Classical Pathway
C5a
Terminal Pathway
C5
C5b
C5b-C9
Membrane attack complex (MAC)
ALN-CC5
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Background
• Bone marrow defect due to acquired PIG-A gene mutation leading to deficiency of GPI-anchored
surface proteins that protect red blood cells against complement mediated cell lysis
• Concomitant quantitative bone marrow failure in ~50% of patients with anemia and increased risk
of infection
• Life threatening complications include:
◦ Arterial or venous thromboembolism
◦ Kidney failure
◦ Pulmonary hypertension
• Risk of complications highest during inflammation
• Eculizumab is a monoclonal antibody targeting C5 approved for treatment of PNH and aHUS
Current treatment challenges
• Complement C5 is acute phase protein and inflammation causes C5 fluctuations of up to ~100% 1
• Considerable proportion of PNH patients on eculizumab experience breakthrough or occult
hemolysis2
• Wide inter-individual variation in pharmacodynamics and clearance of eculizumab 2-4
• Discrepancy between eculizumab’s labeled effective trough level of 35 mcg/mL (ref label) versus
expert recommendations of at least 150 mcg/mL 2
Unmet need for new complement inhibitors remains
1 Int
3
Archs Allergy Appl Immun; 48: 706-720 (1975), 2de Latour RP, et al, Blood;125:775-83 (2015)
S, et al. BBMT (2015), 4Gatault P, et al, mAbs; 7:1205-11 (2015)
3Jodele
ALN-CC5: SC-Administered GalNAcConjugated siRNA Targeting C5
GalNAc3
ALN-CC5
• siRNA conjugated to N-acetylgalactosamine
(GalNAc) ligand
• Efficient delivery to hepatocytes following
subcutaneous (SC) administration
• Wide therapeutic index
• Utilizes enhanced stabilization chemistry (ESC)
ALN-CC5
ASGPR
(pH>5)
Clathrin-coated pit
C5 protein
Recycling
ASGPR
Clathrin-coated
vesicle
◦ Significantly improved potency and durability
Recognition of GalNAc ligand by
asialoglycoprotein receptor (ASGPR)
•
•
•
•
4
Highly expressed in hepatocytes
High rate of uptake
Recycling time ~15 minutes
Conserved across species
RISC
Endosome
mRNA
Nucleus
ALN-CC5 Phase 1/2 Study Design
Healthy Volunteers and Patients with PNH
Part A: Single-Ascending Dose (SAD): Healthy Volunteers
Randomized 3:1, double blind, placebo controlled, N=4
50 mg x 1 SC
200 mg x 1 SC
400 mg x 1 SC
600 mg x 1 SC
900 mg x 1 SC
Part B: Multiple-Ascending Dose (MAD): Healthy Volunteers
Randomized 3:1, double blind, placebo controlled, N=4
100 mg qW x 5 SC
200 mg qW x 5 SC
400 mg qW x 5 SC
Part C: Multiple Dose (MD): Patients with PNH
Open label, N ~ 16
TBD
ALN-CC5 dosed subcutaneously in 200 mg/mL solution
5
Materials and Methods
Pharmacodynamic (PD) assays
• Serum concentrations of C5 assayed using validated LCMS assay
• Complement activity
◦ Serum samples assessed using CAP and CCP Wieslab ELISA assays (alternative and
◦
classical pathways respectively)
Serum samples assessed using sheep erythrocyte hemolysis assay (exploratory)
Data from Phase 1/2 Part A (SAD) and Part B (MAD)
• Part A – Double blind safety and tolerability single ascending dose study ALN-CC5
in healthy volunteers (20) randomized 3:1 (ALN-CC5:placebo)
• Part B - Double blind safety and tolerability multiple ascending dose study ALNCC5 in healthy volunteers (12) randomized 3:1 (ALN-CC5:placebo)
Results preliminary as study is ongoing
6
Complement Assays Benchmarks from
Select Published Literature
Assay
Disease
Values reported
in literature
Notes
Free C5
aHUS
(patients treated
with eculizumab)
93.5%1
(Max % C5 inhibition)
Results from clinical study of aHUS patients
treated with eculizumab at 900 mg (4xqW) and
maintained at 1200 mg q2W 1 (pediatrics dosed
per body weight)
(Electrohemiluminescence
immunoassay)
Studies : C08-002A/B, C08-003A/B, C09-001r1
CAP/CCP
(Wieslab ELISA assays)
Genetic C5b-9
complement
deficiency
<10%2
compared to normal
serum
Data from serum samples from 18 pts with C5,
C6, C7, C8 or C9 deficiencies2
Values <10% also observed in study of aHUS
where disease activites was determined by
platelets, LDH, haptoglobin and creatinine
levels3
Sheep erythrocyte hemolysis
assay
aHUS
(patients treated
with eculizumab)
10-60%3
Wide range of values observed for aHUS
patients treated with eculizumab 3
CAP/CCP values <10% measured in same
samples3
1ASCPT
Annual Meeting, Atlanta, GA, march 18-22, 2014, Abstract #387
MA, et al. J of Immunological Methods; 296:187-198 (2005)
3Cugno M, et al. JThromb Haemost;12:1440-8 (2014)
2Seelen
7
ALN-CC5 Phase 1/2 Part A - SAD
Demographics and Baseline Characteristics
20 healthy volunteers dosed with ALN-CC5 or placebo (3:1)
Part A: Single Ascending Dose (SAD)
Single subcutaneous injection
50 mg
N=4
200 mg
N=4
400 mg
N=4
600 mg
N=4
900 mg
N=4
23.8
(20, 26)
22.5
(21, 24)
22.0
(20, 27)
28.5
(23, 38)
26.8
(22, 33)
Gender: Male(%)
100%
100%
75%
0%
50%
BMI (kg/m2), Mean
24.08
22.35
21.38
24.80
23.53
Race (%)
- Asian
- Black/African
- Caucasian
- Other
0%
25%
50%
25%
0%
50%
25%
25%
25%
0%
50%
25%
50%
0%
50%
0%
0%
25%
75%
0%
115
243
208
173
138
Age (years), Mean
(Min, Max)
Time on study, Mean
(days)
8
*Data as of 10/19/2015
This is a double-blinded study; each cohort above remains blinded with one placebo per cohort.
ALN-CC5 Phase 1/2 Part B - MAD
Demographics and Baseline Characteristics
12 healthy volunteers dosed with ALN-CC5 or placebo (3:1)
Part B: Multiple Ascending Dose (MAD)
Weekly × 5 subcutaneous injections
100 mg
q1w x 5
N=4
200 mg
q1w x 5
N=4
400 mg
q1w x 5
N=4
Age (years), Mean
(Min, Max)
33.8
(24, 39)
28.0
(24, 32)
25.0
(20, 30)
Gender: Male (%)
75%
25%
50%
BMI (kg/m2), Mean
24.55
23.68
25.48
Race (%)
- Asian
- Black/African
- Caucasian
- Other
0%
0%
100%
0%
0%
0%
100%
0%
0%
0%
100%
0%
196
147
99
Time on study, Mean (days)
9
*Data as of 10/19/2015
This is a double-blinded study; each cohort above remains blinded with one placebo per cohort.
Initial ALN-CC5 Phase 1 Study Results
Blinded Safety and Tolerability Summary – Part A (SAD)
ALN-CC5 appears generally well tolerated in healthy volunteers
• No SAEs and no discontinuation due to AEs
• Total of 29 AEs observed
◦ All reported AEs mild or moderate in severity; 3 possibly drug-related‡
◦ 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)
Common Adverse Events (AEs) in ≥10% of subjects
50 mg
N=4
0
0
0
0
200 mg
N=4
2
1
0
0
Injection site pain
0
0
0
2
0
2 (10%)
Seasonal allergy
0
0
0
1
1
2 (10%)
AE by Preferred
Term
Nasopharyngitis
Headache
Influenza-like illness
Nausea
10
Part A: Single Ascending Dose (SAD)
Single subcutaneous injection
400 mg
600 mg
900 mg
N=4
N=4
N=4
2
1
0
0
2
2
0
1
1
0
2
0
*Data as of 10/19/2015
‡Possible drug-related adverse events include nasopharyngitis, injection site pain, and injection
site rash currently coded in database as rash
All dosing Cohorts
(N=20)
5 (25%)
5 (25%)
2 (10%)
2 (10%)
Initial ALN-CC5 Phase 1 Study Results
Blinded Safety and Tolerability Summary – Part B (MAD)
ALN-CC5 is generally well tolerated in healthy volunteers after multiple doses
• No SAEs and no discontinuation due to AEs
• Total of 30 AEs observed
◦ All reported AEs mild or moderate in severity; 12 possibly drug-related‡
◦ ISRs seen in 4 subjects – all mild, transient
• No clinically significant changes in vital signs, EKG, physical exams and clinical laboratories
(hematology, biochemistry, coagulation and urinalysis)
Common Adverse Events (AEs) in ≥10% of subjects
AE by Preferred Term
Headache
11
100 mg
N=4
1
Part B: Multiple Ascending Dose (MAD)
Weekly × 5 subcutaneous injections
200 mg
400 mg
All dosing cohorts
N=4
N=4
N=12
1
1
3 (25%)
Nasopharyngitis
0
3
0
3 (25%)
Vulvovaginal Candidiasis
0
1
1
2 (17%)
*Data as of 10/19/2015
‡
Possible drug-related adverse events included headache, bruise, cold symptoms, injection site edema,
vaginal thrush, redness at injection site, itching at injection site, mouth ulcer
ALN-CC5 Phase 1/2: Part A – SAD
Pharmacodynamics and Clinical Activity: Serum C5
Serum C5 knockdown following single dose of ALN-CC5
• Maximum C5 knockdown relative to baseline up to 99%
• Mean maximum C5 knockdown of 98 ± 0.9% (mean ± SEM)
• Mean C5 knockdown of 96 ± 1.0% (mean ± SEM) at Day 98 (900 mg)
Mean (+/- SEM) C5 Knockdown
Relative to Baseline
-20
0
20
Cohort
40
50 mg ALN-CC5 (N=3)
600 mg ALN-CC5 (N=3)
200 mg ALN-CC5 (N=3)
900 mg ALN-CC5 (N=3)
400 mg ALN-CC5 (N=3)
Placebo (N=5)
60
80
100
0
10
20
30
40
50
60
70
80
90
100
110
Days since first visit
12
* Data as of 10/19/2015
120
130
140
150
160
170
180
190
ALN-CC5 Phase 1/2: Part A – SAD
Complement alternative
pathway inhibition (CAP
C5b-9 ELISA)
• Single dose of ALN-CC5
• Maximum CAP reduction
relative to baseline up to 95%
• Mean maximum of 93 ± 1.3%
Mean (+/- SEM) CAP Reduction
Relative to Baseline
Pharmacodynamics and Clinical Activity: Complement Inhibition
-20
0
20
40
60
80
100
0
(mean ± SEM)
• Single dose of ALN-CC5
• Maximum CCP reduction
relative to baseline up to 97%
• Mean maximum 96 ± 0.7%
(mean ± SEM)
2
5
6
7
8
5
6
7
8
600 mg ALN-CC5 (N=3)
900 mg ALN-CC5 (N=3)
Placebo (N=5)
0
20
40
60
80
100
0
1
2
50 mg ALN-CC5 (N=3)
200 mg ALN-CC5 (N=3)
400 mg ALN-CC5 (N=3)
* Data as of 11/6/2015
4
-20
Cohort
13
3
Months
50 mg ALN-CC5 (N=3)
200 mg ALN-CC5 (N=3)
400 mg ALN-CC5 (N=3)
Mean (+/- SEM) CCP Reduction
Relative to Baseline
Complement classical
pathway inhibition (CCP
C5b-9 ELISA)
1
Cohort
3
4
Months
600 mg ALN-CC5 (N=3)
900 mg ALN-CC5 (N=3)
Placebo (N=5)
ALN-CC5 Phase 1/2: Part A – SAD
Pharmacodynamics and Clinical Activity: Hemolysis Inhibition
Inhibition of sheep erythrocyte hemolysis
Mean (+/- SEM) Hemolysis Reduction
Relative to Baseline
• Following single dose of ALN-CC5
• Maximum serum hemolysis inhibition relative to baseline up to 79%
• Mean maximum hemolysis inhibition of 74 ± 4.2% (mean ± SEM)
-40
-20
0
20
40
60
Cohort
80
100
0
10
20
30
40
50
60
70
Days since first visit
14
* Data as of 9/3/2015
50 mg ALN-CC5 (N=3)
600 mg ALN-CC5 (N=3)
200 mg ALN-CC5 (N=3)
900 mg ALN-CC5 (N=3)
400 mg ALN-CC5 (N=3)
Placebo (N=5)
80
90
100
110
120
ALN-CC5 Phase 1/2 Part A – SAD
Summary of Preliminary Results
50 mg
Part A : Single Ascending Dose (SAD)
Single subcutaneous injection
200 mg
400 mg
600 mg
900 mg
Placebo
Residual C5
Mean nadir; mcg/mL ± SEM
Nadir; mcg/mL
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
C5 knockdown
Mean max; % ± SEM
Max; %
CCP inhibition
Mean max; % ± SEM
Max; %
CAP inhibition
Mean max; % ± SEM
Max; %
Hemolysis inhibition
Mean max; % ± SEM
Max; %
15
*C5 data as of 10/19/2015; CCP/CAP data as of 11/6/2015; Hemolysis data as of 9/3/2015; Statistically
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
ALN-CC5 Phase 1/2: Part B – MAD
Pharmacodynamics and Clinical Activity: Serum C5
Serum C5 knockdown following 5 weekly doses of ALN-CC5
•
•
•
Maximum C5 knockdown relative to baseline up to 99%
Mean maximum C5 knockdown of 98 ± 0.5% (mean ± SEM)
Mean C5 knockdown of 98 ± 0.3% (mean ± SEM) at Day 112 (5 x qw, 200 mg)
Mean (+/- SEM) C5 Knockdown
Relative to Baseline
-20
0
20
Cohort
40
100 mg ALN-CC5 q1w x 5 (N=3)
200 mg ALN-CC5 q1w x 5 (N=3)
400 mg ALN-CC5 q1w x 5 (N=3)
Placebo (N=3)
60
80
100
0
10
20
30
40
50
60
70
80
90
100
Days since first visit
16
* Data as of 10/19/2015
110
120
130
140
150
160
170
ALN-CC5 Phase 1/2: Part B – MAD
• 5 weekly doses of ALN-CC5
• Maximum CAP inhibition relative to
baseline up to 97%
• Mean maximum CAP inhibition of
95 ± 1.0% (mean ± SEM)
• CAP activity comparable to homozygous
C5 deficient subjects1 in MAD 200 & 400 mg
Complement Classical Pathway
inhibition (CCP C5b-9 ELISA)
• 5 weekly doses of ALN-CC5
• Maximum CCP inhibition relative to
baseline up to 97%
• Mean maximum CCP inhibition of
96 ± 0.9% (mean ± SEM)
• CCP activity comparable to homozygous
C5 deficient subjects1 in MAD 200 & 400 mg
17
* Data as of 11/6/2015
1Seelen et al. J Immunol Methods;296:187-98(2005)
-20
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
90
100 110 120 130 140 150 160 170
Days since first visit
Cohort
100 mg ALN-CC5 q1w x 5 (N=3)
200 mg ALN-CC5 q1w x 5 (N=3)
Mean (+/- SEM) CCP Reduction
Relative to Baseline
Complement Alternative Pathway
inhibition (CAP C5b-9 ELISA)
Mean (+/- SEM) CAP Reduction
Relative to Baseline
Pharmacodynamics and Clinical Activity: Complement Inhibition
400 mg ALN-CC5 q1w x 5 (N=3)
Placebo (N=3)
-20
0
20
40
60
80
100
0
10
20
30
40
50
60
70
80
90
100 110 120 130 140 150 160 170
Days since first visit
Cohort
100 mg ALN-CC5 q1w x 5 (N=3)
200 mg ALN-CC5 q1w x 5 (N=3)
400 mg ALN-CC5 q1w x 5 (N=3)
Placebo (N=3)
ALN-CC5 Phase 1/2 Part B – MAD
Pharmacodynamics and Clinical Activity: Hemolysis Inhibition
Inhibition of sheep erythrocyte hemolysis
Mean (+/- SEM) Hemolysis Reduction
Relative to Baseline
• 5 weekly doses of ALN-CC5
• Maximum serum hemolysis inhibition relative to baseline up to 98%
• Mean maximum serum hemolysis inhibition of 84 ± 7.6% (mean ± SEM)
0
20
40
Cohort
60
100 mg ALN-CC5 q1w x 5 (N=3)
200 mg ALN-CC5 q1w x 5 (N=3)
400 mg ALN-CC5 q1w x 5 (N=3)
Placebo (N=3)
80
100
0
10
20
30
40
50
60
70
Days since first visit
18
* Data as of 10/5/2015
80
90
100
110
120
ALN-CC5 Phase 1/2 Part B – MAD
Summary of Preliminary Results
100 mg
Part B: Multiple Ascending Dose (MAD)
Weekly × 5 subcutaneous injections
200 mg
400 mg
Placebo
Residual C5 levels
Mean nadir; mcg/mL ± SEM
Nadir; mcg/mL
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
C5 knockdown
Mean max; % ± SEM
Max; %
CCP inhibition
Mean max; % ± SEM
Max; %
CAP inhibition
Mean max; % ± SEM
Max; %
Hemolysis inhibition
Mean max; % ± SEM
Max; %
19
*C5 data as of 10/19/2015; CCP/CAP data as of 11/6/2015; Hemolysis data as of 10/5/2015
Statistically significant difference in mean max for all parameters across all cohorts vs placebo (P-value<0.05)
Free and Residual C5
ALN-CC5 and residual C5 levels (μg/mL)*
• Eculizumab concentration-effect relationship for
reduction in free C5 in aHUS patients
• Free C5 measured using validated
electrochemiluminescence immunoassay
• Maximum % inhibition free C5 of 93.5%
• 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 of 99%
120
Eculizumab and free C5 levels (μg/mL)1
Cohort
80
60
40
0
20
Mean (+/- SEM)
Residual C5 mcg/mL
100
100 mg ALN-CC5 q1w x 5 (N=3)
200 mg ALN-CC5 q1w x 5 (N=3)
400 mg ALN-CC5 q1w x 5 (N=3)
Placebo (N=3)
-10 0
20
40
60
80
100
120
Days since first visit
Residual C5 levels achieved with ALN-CC5 healthy volunteers comparable with free C5 levels
in aHUS patients on eculizumab‡
20
*Data as of 10/19/2015; ‡There are no head to head studies comparing eculizumab and ALN-CC5
1ASCPT Annual Meeting, Atlanta, GA; March 18-22, 2014; Abstract # 387
140
160
ALN-CC5 Phase 1/2 Study Results*
Summary and Next Steps
• 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
◦ No reported SAEs; all AEs mild or moderate; no discontinuations; low incidence of mild
injection site reactions (ISRs)
• Robust, dose-dependent and durable KD of serum C5
◦
◦
◦
◦
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 complement inhibition
◦ Nadir residual C5 values as low as 0.6 mcg/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 %
• On track to initiate dosing in PNH patients (Part C) by year-end 2015
21
*Safety and C5 data as of 10/19/2015; CAP/CCP data as of 11/6/2015; Hemolysis data as of 9/3/2015 (SAD) and
10/5/2015 (MAD)
Acknowledgements
Trial participants
Principal investigators
Country
PI Name
Location
United
Kingdom
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, Hospital Clinic, University of Barcelona, Barcelona, Spain
Spain
22
Thank You
23