A Randomized, Single-Blind, Placebo-Controlled, Phase 1/2
Study of ALN-AAT, an Investigational RNAi Therapeutic for the
Treatment of Alpha-1 Antitrypsin Deficiency Associated Liver
Disease: Interim Study Results
12th Annual Meeting of the Oligonucleotide
Therapeutics Society (OTS)
28 September 2016
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Alpha 1 Antitrypsin (AAT) Deficiency
Background
AAT is a serine proteinase inhibitor (serpin)
• Inhibits neutrophil elastase, trypsin, thrombin, chymotrypsin, etc
• Abundant plasma protein , primarily synthesized in hepatocytes
AAT deficiency
•
•
•
•
“PiZZ” phenotype accounts for 95% of AAT-deficient patient population
Z allele likely arose in N Europe, present in up to 5% of the population
Z allele has point mutation Glu342Lys
Autosomal codominant inheritance of disease
• PiZ has slow rate of protein folding, permitting polymerization of intermediate which
accumulates in hepatocyte ER
• Failure of secretion results in peripheral deficiency
◦ Lack of protease inhibition primarily manifests as lung disease: early onset emphysema
• Hepatocyte accumulation results in liver disease
◦
◦
◦
◦
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Infantile cholestatic hepatitis - usually self-limiting, but progressive liver disease in minority
Progressive liver fibrosis
Cirrhosis
Hepatocellular carcinoma
ALN-AAT
Therapeutic Hypothesis
GalNAc3
ALN-AAT
Z-AAT mRNA expression
in hepatocytes
Misfolded Z-AAT protein
Reduced Z-AAT polymers
aggregates in hepatocytes
in hepatocytes
forming polymers
Suppression of hepatocyte
Z-AAT protein production
permits clearance of the
accumulated abnormal
protein from the liver,
permitting stabilization and
potentially reversal of liver
disease
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Reduced
hepatocyte
Z-AAT
polymers
cause
damage
hepatocyte
damage
Results
in liver
fibrosis
and
Decrease
in liver
fibrosis
HCC
and
HCC
ALN-AAT Phase 1/2 Study Design
Part A: Single-Ascending Dose (SAD) │Randomized 3:1, Single-blind, Placebo-controlled
Healthy adult volunteers
Outcome evaluations: Safety and Pharmacodynamic
Response (reduction in plasma AAT level)
0.1 mg/kg x 1 SC, N=4
0.3 mg/kg x 1 SC, N=4
1.0 mg/kg x 1 SC, N=4
3.0 mg/kg x 1 SC, N=4
6.0 mg/kg x 1 SC, N=4
Part B: Multiple-Ascending Dose (MAD) │ Randomized 4:2, Single-blind, Placebo-controlled
1.0 mg/kg, q28d ×4 SC, N=6
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Clinicaltrials.gov identifierNCT02503683
Healthy adult volunteers
Outcome evaluations: Safety and Pharmacodynamic
Response (reduction in plasma AAT level)
ALN-AAT Phase 1/2 Interim Study Results
Demographics: Part A + B (Healthy Volunteers)
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Demographic
Results
Number enrolled
N=26
(ALN-AAT:Placebo = 19:7)
Median Age
28 years (range: 18 - 60)
Gender, n
Female: 13
Males: 13
Race, n
White / Caucasian: 13
African: 5
Asian: 3
Other: 5
ALN-AAT Phase 1/2 Interim Study Results
Summary of Safety
ALN-AAT was generally well-tolerated in Parts A and B of Study ALN-AAT-001
No drug-related serious adverse events (SAEs) or discontinuations due to
adverse events (AEs)
Part A: Total of 57 AEs reported in 5 placebo and 14 ALN-AAT subjects
• 15 related or possibly related AEs were reported in 7 subjects
◦ Diarrhea, dyspnea (normal spirometry), nasopharyngitis, elevated ALT/AST, elevated CK, influenza,
worsening allergy, headache, injection site bruise, injection site dysesthesia, abdominal pain
• No injection site reactions were reported
Part B: Total of 23 AEs reported in 2 placebo and 4 ALN-AAT subjects
• 6 related or possibly related AEs were reported in 2 subjects*
◦ Nasopharyngitis, headache, injection site bruise, oropharyngeal pain, psoriasis, subacute spongiotic
dermatitis
• No injection site reactions were reported
No clinically significant changes in vital signs or EKG
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Data transfer: 30Jun2016
*One AE of ligament sprain with missing relatedness assessment is not included in this count
ALN-AAT Phase 1/2 Interim Study Results
Mean [± SEM] AAT Level
Relative to Baseline
Pharmacodynamics: Serum AAT Levels, Part A (Single Dose)
1.6
1.5
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Placebo (N=5)
0.1 mg/kg (N=3)
0.3 mg/kg (N=3) 1.6
1.0 mg/kg (N=3)
3.0 mg/kg (N=3)
6.0 mg/kg (N=3)
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
60
80
100
120
140
160
180
200
Days since dose
6.0 mg/kg dose group • Max AAT knockdown (KD): 88.9%
• Mean maximal KD: 83.9 ± 2.6%
• Mean AAT KD at ~6 months: 75.0 ±1.2%
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1.5
Data transfer: 30Jun2016
220
240
260
280
300
ALN-AAT Phase 1/2 Interim Study Results
Pharmacodynamics: Serum AAT Levels, Part B (Multiple Doses)
1.4
Placebo (N=2)
1.3
1.0 mg/kg q28d ×4 (N=4)
Mean [± SEM] AAT Level
Relative to Baseline
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
20
40
60
80
100
120
140
160
180
Days since dose
8
Data transfer: 30Jun2016
200
220
240
260
280
300
ALN-AAT Phase 1/2 Interim Study Results
Pharmacodynamics: Serum AAT Levels, Part A + B
Mean [± SEM] AAT Level
Relative to Baseline
AAT Knockdown at 1mg/kg multidose comparable to 3 and 6 mg/kg single doses
1.5
1.5
1.4
1.3
1.2
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
60
80
100
120
140
160
180
200
220
240
260
280
300
Days since first dose
Single Dose 3.0 mg/kg
9
Data transfer: 30Jun2016
Single Dose 6.0 mg/kg
Multiple Doses 1.0 mg/kg q28d ×4
ALN-AAT Phase 1/2 Interim Study Results
Pharmacodynamics: Dichotomous Pattern Explained by Target SNP
AAT Values (mcg/mL)
SNP confers a single base mismatch between drug and target
Prevalence up to 30% in some populations
SNP is not co-inherited with Z allele
3000
2800
2600
2400
2200
2000
1800
1600
1400
1200
1000
800
600
400
200
0
SNP
Wild Type
-10
10
30
50
70
90
110
130
150
170
190
210
230
250
270
290
310
Days since first dose
Placebo
10
Placebo
Data transfer: 30Jun2016
1.0 mg/kg
1.0 mg/kg
1.0 mg/kg
1.0 mg/kg
ALN-AAT Phase 1/2 Interim Study Results
Liver Transaminases, Part A
Dose
8
Placebo
4
ALT
AST
N
5
1X ULN
1
8
3
4
0.1 mg/kg
0.3 mg/kg
Amount X ULN
1
8
1.0 mg/kg
3
4
1
8
3
4
1
8
3.0 mg/kg
4
3
1
8
6.0 mg/kg
4
1
-10
11
Data transfer: 30Jun2016
3
0 10 20 30 40 50 60 70
Days Since Dose
-10
0 10 20 30 40 50 60 70
Days Since Dose
ALN-AAT Phase 1/2 Interim Study Results
Liver Transaminases, Part B
Placebo
ALT
AST
Amount X ULN
8
4
1
1X ULN
1.0 mg/kg
Amount X ULN
8
4
1
1X ULN
Days Since First Dose
12
Data transfer: 30Jun2016
Days Since First Dose
ALN-AAT Phase 1/2 Interim Study Results
Summary and Next Steps
ALN-AAT clinically well tolerated with single or multiple (4) doses
Dose-dependent , potent and durable suppression of AAT was observed
Diminution of PD effect in presence of SNP in target sequence demonstrates specificity
of drug mechanism
Asymptomatic, reversible, dose-dependent increase in hepatic transaminase observed
Next Steps
• Since the target patient population has established liver disease, plan to hold further
development of this molecule
• Identification of a 2nd generation molecule is in progress, CTA expected in 2017
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Thank you
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