Hemophilia/Fitusiran

Hemophilia Overview
Guy Young, M.D.
A brief history of hemophilia
Talmud—2nd Century
“If she circumcised her
first son and he died
and a second one also
died, she must not
circumcise the third
son”
R. Judah, the Patriarch, redactor of the
Mishnah
Refinement of Talmud Language—12th Century
Moses Maimonedes was a physician and religious scholar
who refined the teachings of the Talmud as follows:
“If a woman had her first son
circumcised and he died as a
result of the circumcision, which
enfeebled his strength, and she
similarly had her second [son]
circumcised and he died as a
result of the circumcision whether [the latter child] was
from her first husband or her
second husband - the third son
may not be circumcised at the
proper time [on the eighth day of
life]…”2
1. Rosner F. Ann Intern Med. 1965;372:1135-1204.
2. Mishneh Torah, Hilkhot Milah. 1:18.
He understood that hemophilia is X-linked
Conrad Otto
 In 1803, the first clear description
of hemophilia in the medical
literature titled:
“An Account of an Hemorrhagic
Disposition Existing in Certain
Families”
 He was able to trace the origin to a
woman who settled in Plymouth,
New Hampshire in 1720
Otto JC. The Medical Repository 1803;6:1-4.
First transfusion and lab test
 Samuel Lane was the first to treat hemophilia by
giving a patient a blood transfusion in 18401
 The first blood test for hemophilia was
developed in 1893 demonstrating that blood did
not clot normally in a capillary tube2
1. Farr AD. J Royal Soc Med 1981;74:301-305.
2. Wright AE. Br Med J 1893;2:223-225.
Physiologic Mechanism of Hemophilia
Thrombin’s procoagulant effects on coagulation
VIII
VIIIa
XI
XIa
XIII
V
Thrombin (IIa)
XIIIa
Va
TAFI
Fibrinogen (I)
Fibrin
TAFIa
Physiologic Coagulation
VII
TF
Ca++
IX
VIII
VIIIa
Thrombin (IIa)
V
VIIa
IXa
Ca++
X
Xa
Va
XIII
Prothrombin (II)
Ca++
Thrombin (IIa)
Fibrinogen (I)
Fibrin
XIIIa
Cross-linked fibrin
Natural Coagulation Inhibitors
Inhibits (
)
Thrombin (IIa)
VII
Ca++
XI
XIa
Tissue factor pathway
inhibitor (TFPI)
TF
Ca++
IX
X
Thrombin (IIa)
V
Ca++
Ca++
VIII
VIII
VIIa
IXa
Xa
X
Antithrombin
Xa
Va
XIII
Protein S
Protein S
Prothrombin (II)
Protein Ca
Ca++
Thrombin (IIa)
Fibrinogen (I)
Thrombin (IIa)
Fibrin
XIIIa
Protein C
Cross-linked fibrin
Coagulation in Hemophilia
VII
TF
VIIa
Ca++
X
Prothrombin (II)
Xa
Ca++
Thrombin (IIa)
The lack of thrombin generation is the
cause of bleeding in hemophilia
Clinical Presentation
Unusual Bruising
Joint Bleeding
Muscle Bleeding
Mucus Membrane Bleeding
Post-traumatic Bleeding
Internal Bleeding
How can we generate thrombin in
patients with hemophilia?
Recombinant
factors
Plasma-derived
high purity
concentrates
Plasma-derived
intermediate purity
concentrates
First extended
half-life factors
First gene
therapy trials
Cryoprecipitate
Plasma
2010s
2000s
1990s
1980s
1970s
1960s
1950s
1900
Whole
Blood
Treatment Drawbacks
• Replacement of missing protein
– Requires intravenous infusion
• Leads to use of central venous catheters
– Frequent infusions
• High treatment burden
– Antibody (inhibitor development)
• These patients can no longer use replacement therapy
– Not curative
– Cost
How can these be overcome?
• Can we treat without replacing the missing protein?
–
–
–
–
Alternative administration routes (s.c.)
Less frequent administrations
Reduced/No immunogenicity
Treat patients with inhibitors
• If we have to treat with replacement therapy, can it
be made less burdensome?
• Can we cure hemophilia with gene correction?
Novel treatments
1. Extended half-life factors
2. Rebalancing the coagulation system
• Anti-Antithrombin siRNA
• Anti-tissue factor pathway inhibitor
3. Factor VIII mimetics
• Bispecific antibodies
4. Gene therapy
#1: Extended Half-life Factors
Pros
Cons
• Factor replacement
• Risk for inhibitors
• IV infusion
– Proven
– Easily understood
– “Natural”
• Less frequent than standard
factor concentrates
– Still at least once every two
weeks and for most patients
twice weekly
• Inconvenience of storing a
lot of boxes and ancillary
supplies
#2: Rebalancing the Coagulation System:
Natural Coagulation Inhibitors
Inhibits (
Thrombin (IIa)
VII
Ca++
XI
XIa
Tissue factor pathway
inhibitor (TFPI)
TF
Ca++
IX
VIII
VIII
Thrombin (IIa)
V
VIIa
IXa
Ca++
Ca++
X
Xa
X
Antithrombin
Xa
Va
XIII
Prothrombin (II)
Ca++
Thrombin (IIa)
Fibrinogen (I)
Fibrin
XIIIa
Cross-linked fibrin
)
#2: Rebalancing the Coagulation System
FVIII
FIX
FX
FII
TFPI
AT
PC
PS
No FVIII—Bleeding Disorder
FIX
FX
FII
TFPI
AT
PC
PS
No AT—Clotting Disorder
TFPI
PC
PS
FVIII
FIX
FX
FII
Absent FVIII and absent AT—
Rebalancing the Coagulation System
FIX
FX
FII
TFPI
PC
PS
#2: Rebalancing the Coagulation System
Rebalancing agents
Pros
Cons
• Subcutaneous route of
administration
• Long half-life
• Less intuitive than factor
replacement
• Theoretical risk for
thrombosis
• Laboratory monitoring
– Infrequent injections
• No risk for antibody
formation against clotting
factors
• Effective in inhibitor patients
• Can be effective in all factor
deficiency disorders
#3: Bispecific antibody
#3: Bispecific antibody
Pros
Cons
• Subcutaneous route of
administration
• Long half-life so infrequent
injections required
• Mimics FVIII activity so
relatively easily understood
• Effective in inhibitor
patients
• Only effective in hemophilia
A
• Antibody formation
• Theoretical risk for
thrombosis
• Laboratory monitoring
#4: Gene Therapy
Pros
Cons
• Potentially curative
• “Messing” with our DNA
• Current technology leading
to immune reactions in
most patients
• Achievable levels with
current technology are not
truly “curative”
Improving the care
of hemophilia is a
“tall order”
Fitusiran (ALN-AT3) for Hemophilia
& Rare Bleeding Disorders
Benny Sorensen, M.D., Ph.D.
Senior Director, Clinical Research
36
Hemophilia and Rare Bleeding Disorders Program
Unmet Need and Product Opportunity
High unmet needs in hemophilia and rare bleeding
disorders (RBD)
• Hemophilias are recessive X-linked
monogenic bleeding disorders
◦ Hemophilia A: loss of function in Factor VIII
– >40,000 Patients in EU/U.S.
◦ Hemophilia B: loss of function in Factor IX
– ~9,500 Patients in EU/U.S.
• Segments of high unmet need remain
◦ E.g., “Inhibitor” patients1,2
– 2,000 Patients in major markets; up to 6,000 WW
– >15-25 Bleeds/year; >5 in-hospital days/year
– ~$300,000/year avg. cost; up to $1M/year
• Hemophilia A and B represent >$9B market
◦
◦
◦
◦
37
Premium pricing established
Value supported by pharmacoeconomics
Well organized patient advocacy
Significant opportunity for global expansion
1 WFH
2012 Global Survey; 2 Antunes et al., Haemophilia. 20:65-72 (2014)
Fitusiran for Hemophilia
Alnylam Reproducible and Modular Platform
1
2
3
38
Genetically
validated, liverexpressed target
gene
Biomarker for POC
in Phase 1
Definable path to
approval and
market
Antithrombin (AT) is key natural
anticoagulant
Co-inheritance of AT deficiency with
hemophilia associated with milder
bleeding phenotype
Blood-based biomarkers measure
components in coagulation cascade:
• AT
• Thrombin Generation
Two separate pivotal trials in inhibitor
and on-demand patients
Established Endpoint: Annualized
Bleeding Rate
Fitusiran
Investigational RNAi Therapeutic for the Treatment of Hemophilia
Fitusiran (ALN-AT3)
• SC-administered small interfering RNA (siRNA)
therapeutic targeting antithrombin (AT)
◦ Non-biologic, chemically-synthesized, with targeting
ligand to specifically deliver to liver—site of AT
synthesis
◦ Harnesses natural RNA interference (RNAi)
mechanism for regulation of plasma AT levels
Hemophilia A
FVIII
FVIIIa
FVIIa
FX
FVII
Hemophilia B
Therapeutic hypothesis
• Hemophilia A and B are bleeding disorders
characterized by ineffective clot formation due to
insufficient thrombin generation
• Fitusiran is designed to lower AT, with goal of
promoting sufficient thrombin generation to restore
hemostasis and prevent bleeding
FIX
FIX
FIXa
FVa
Prothrombin
◦ Observation of ameliorated bleeding phenotype in
patients with co-inheritance of thrombophilic
traits in hemophilia1-4
◦ Supported by pre-clinical data5 and emerging
Phase 1 clinical results6
1Kurnik
39
AT
AT
FXa
et al., Haematologica; 92:982-5 (2007); 2Ettingshausen et al., Thromb Haemost;
85:218-20 (2001); 3Negrier et al., Blood; 81:690-5 (1993); 4Shetty et al., Br J Haematol;
138:541-4 (2007); 5Seghal et al., Nat Med, 21:492-7 (2015); 6Sorensen B, et al, ISTH (2015)
Thrombin
Fibrinogen
Fibrin
Blood clot
FV
Fitusiran Phase 1 Study
Dose-Escalation Study in Three Parts
Primary objectives
Secondary objectives
• Safety, tolerability
• AT lowering, thrombin generation
Part A: Single-Ascending Dose (SAD) │Randomized 3:1, Single-blind, Placebo-controlled, Healthy volunteers
30 mcg/kg x 1 SC, N=4
Presented January 20151
Part B: Multiple-Ascending Dose (MAD) – Weekly dosing │ Open-label, Patients with Hemophilia A or B
15 mcg/kg qW x 3 SC, N=3
45 mcg/kg qW x 3 SC, N=6
Presented June 20152
75 mcg/kg qW x 3 SC, N=3
Part C: Multiple-Ascending Dose (MAD) – Monthly dosing │ Open-label, Patients with Hemophilia A or B
225 mcg/kg qM x 3 SC, N=3
450 mcg/kg qM x 3 SC, N=3
Presented December 20153
900 mcg/kg qM x 3 SC, N=3
1800 mcg/kg qM x 3 SC, N=3
1Akinc
A et al. Goring Coagulation Conference (2015)
B, et al. ISTH (2015)
3Pasi KJ, et al. ASH (2015)
2Sorensen
40
Up to 2 additional cohorts
Ongoing
Interim Fitusiran Phase 1 Study Results*
Demographics & Baseline Characteristics, Parts B & C
Part B
SC, Weekly × 3
15
mcg/kg
45
mcg/kg
75
mcg/kg
225
mcg/kg
450
mcg/kg
900
mcg/kg
1800
mcg/kg
27
(9)
42
(14)
39
(4)
37
(21)
37
(15)
37
(17)
46
(12)
Hemophilia A
Hemophilia B
2
1
6
0
2
1
2
1
2
1
3
0
3
0
Severe
Moderate
3
0
6
0
3
0
2
1
3
0
2
1
3
0
76
(10.1)
80
(21.7)
82
(8.5)
85
(12.3)
76
(16.0)
76
(1.6)
71
(11.8)
Age, mean (SD)
Weight (kg), mean (SD)
41
Part C
SC, Monthly × 3
*Data as of 12 November 2015
Pasi KJ, et al. ASH (2015)
Interim Fitusiran Phase 1 Study Results*
Safety/Tolerability, Parts B & C†
• No SAEs related to study drug and no discontinuations
◦ One subject was hospitalized due to re-activation of hepatitis C, not drug related
• AEs reported
◦ Total of 35 AEs occurred in 14 patients
– 33 single AEs + 2 AE episodes of arthritis
– 34 Mild/Moderate, 1 Severe‡
◦ 3 drug related AEs were observed – all mild:
– Injection site reactions:
» One patient (45 mcg/kg) experienced mild transient pain
» One patient (1800 mcg/kg) experienced mild transient erythema & pain
– Other:
» Headache, transient
◦ No thromboembolic events or clinically significant D-dimer increases
◦ No drug related clinically significant changes in physical exams, vital signs, ECG or
◦
laboratory parameter (LFTs, CBC, coagulation)
Bleed events successfully managed with standard replacement factor administration
• No instances of anti-drug antibody (ADA) formation
42
*Data as of 12 November 2015: Pasi KJ, et al. ASH (2015)
†
Adverse event grouping based on MedDRA-coded terms, excluding bleed events
‡
Hypertriglyceridemia
Interim Fitusiran Phase 1 Study Results*
AT Lowering, Part B
AT lowering after weekly dosing in patients with hemophilia A and B
% Mean (+/- SEM) AT Activity
Relative to Baseline
125
Max
AT
Lowering
15 mcg/kg
(N=3)
29 ± 12%
53%
45 mcg/kg
(N=6)
55 ± 9%
86%
75 mcg/kg
(N=3)
61 ± 8%
74%
100
AT
Lowering
< 25%
75
AT
Lowering
25-50%
50
Dose Group
25
15 mcg/kg (N=3)
45 mcg/kg (N=6)
75 mcg/kg (N=3)
AT
Lowering
50-75%
AT
Lowering
>75%
0
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
Day
43
Mean Max
AT
Lowering
± SEM
Analysis
Quartiles
*Data as of 12 November 2015
Pasi KJ, et al. ASH (2015)
Interim Fitusiran Phase 1 Study Results*
AT Lowering, Part C
AT lowering after monthly dosing in patients with hemophilia A and B
125
% Mean (+/- SEM) AT Activity
Relative to Baseline
Dose Group
1.2
225 mcg/kg (N=3)
900 mcg/kg (N=3)
450 mcg/kg (N=3)
1800 mcg/kg (N=3)
100
Max
AT
Lowering
225 mcg/kg
(N=3)
70 ± 9%
80%
450 mcg/kg
(N=3)
77 ± 5%
85%
900 mcg/kg
(N=3)
78 ± 7%
88%
1800 mcg/kg
(N=3)
79 ± 3%
84%
1.0
AT
Lowering
< 25%
0.9
0.8
75
AT
Lowering
25-50%
50
0.7
0.6
0.5
AT
Lowering
50-75%
0.4
0.3
25
AT
Lowering
>75%
0
0
0.2
0.1
0.0
10
20
30
40
50
60
70
80
Day
44
Mean Max
AT
Lowering
± SEM
Analysis
Quartiles
*Data as of 12 November 2015
Pasi KJ, et al. ASH (2015)
90
100 110 120 130 140 150 160
Interim Fitusiran Phase 1 Study Results*
AT Lowering, Parts A, B & C
Mean maximum AT lowering by monthly equivalent dose
Mean Maximum AT Lowering (%)
100
#
80
60
40
Part A
Part B
Part C
20
0
0
135
450
900
Monthly Equivalent Dose (mcg/kg)
45
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
#Single dose only (1 of 3)
1800
Interim Fitusiran Phase 1 Study Results*
Thrombin Generation, Part B & C
Post hoc analysis of thrombin generation by AT lowering quartiles
250
Peak Thrombin Generation (nM)
Boxes denote median and interquartile range
Peak
Thrombin
Generation,
nM
(Mean ± SD)
% Increase
in Peak
Thrombin
Generation
(Mean ± SD)
AT Lowering
<25%
18 ± 9
20 ± 72%
AT Lowering
25-50%
26 ± 12
48 ± 61%
AT Lowering
50-75%
47 ± 29
218 ± 272%
AT Lowering
>75%
62 ± 27**
285 ± 165%**
200
150
100
50
**p < 0.001, compared with AT lowering less than 25%
0
N=4
Healthy
Volunteers
46
AT Lowering
< 25%
N=24
AT Lowering
25-50%
N=21
AT Lowering
50-75%
N=18
AT Lowering
>75%
N=9
Patients with Hemophilia
*Data as of 12 November 2015; reruns conducted of samples with analytical errors
Pasi KJ, et al. ASH (2015)
Interim Fitusiran Phase 1 Study Results*
Thrombin Generation, Part B & C
Post hoc analysis of thrombin generation by AT lowering quartiles
250
Peak Thrombin Generation (nM)
Boxes denote median and interquartile range
Peak
Thrombin
Generation,
nM
(Mean ± SD)
% Increase
in Peak
Thrombin
Generation
(Mean ± SD)
AT Lowering
<25%
18 ± 9
20 ± 72%
AT Lowering
25-50%
26 ± 12
48 ± 61%
AT Lowering
50-75%
47 ± 29
218 ± 272%
AT Lowering
>75%
62 ± 27**
285 ± 165%**
200
150
100
50
**p < 0.001, compared with AT lowering less than 25%
Dargaud et al.Thromb Haemost, 93, 475-480 (2005)
0
N=4
Healthy
Volunteers
47
AT Lowering
< 25%
N=24
AT Lowering
25-50%
N=21
AT Lowering
50-75%
N=18
AT Lowering
>75%
N=9
Patients with Hemophilia
*Data as of 12 November 2015; reruns conducted of samples with analytical errors
Pasi KJ, et al. ASH (2015)
Interim Fitusiran Phase 1 Study Results*
Exploratory Analysis of Factor Equivalence
•
Pre-dose factor administration used to establish individualized factor-peak thrombin relationship (in all 3 patients
with pre-dose factor data)
◦ Plasma collected at -0.5, 1, 2, 8, 24, and 48 hours post factor administration
◦ Samples analyzed for FVIII level and thrombin generation
Peak thrombin achieved post fitusiran dose compared to peak thrombin achieved with FVIII
C4-2 (1800 mcg/kg qM)
Peak Thrombin
(nM)
Peak Thrombin
(nM)
60
40
20
0
0
50
60
50
40
40
30
20
20
10
AT
Peak Thrombin
0
0
14 28 42 56 70 84 98
126
90
80
70
80
60
60
50
40
40
30
20
20
10
AT
Peak Thrombin
0
0
Day
28
Day
100
50
0
20
40
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
80 100
56
120
100
90
100
80
70
80
60
60
50
40
40
30
20
20
AT
10
Peak Thrombin
0
0
0
28
Day
Achieved peak thrombin generation values equivalent to >40% factor VIII
48
60
FVIII (%)
100
0
150
0
150
100
% Relative AT Activity
60
200
% FVIII Equivalent Peak Thrombin
70
50
100
FVIII (%)
% FVIII Equivalent Peak Thrombin
80
80
0
120
% FVIII Equivalent Peak Thrombin
90
100
% Relative AT Activity
50
0
100
0
100
100 150 200 250
FVIII (%)
120
C4-3 (1800 mcg/kg qM)
150
Peak Thrombin
(nM)
C1-1 (225 mcg/kg qM)
80
% Relative AT Activity
•
Interim Fitusiran Phase 1 Study Results*
Exploratory Analysis of Bleed Events, Parts B & C
Post hoc analysis of bleed events by AT lowering quartiles
ABR Estimate, Mean (SEM)
(Bleeds Per Year)
40
30
20
10
0
AT Lowering
<25%
AT Lowering
25-50%
AT Lowering
50-75%
AT Lowering
>75%
Patients†
24
21
18
9
Cumulative Days
602
838
862
304
Cumulative Bleeds
43
34
35
3
ABR‡, Mean (SEM)
34 ± 10
20 ± 7
14 ± 4
6±3
13
11
10
0
ABR, Median
49
**p<0.05
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
†
Number of patients with time spent in quartile
‡
For each subject, the ABR in each quartile is calculated by 365.24*(number of bleed events/number of days in quartile).
**Based on negative binomial regression model
Interim Fitusiran Phase 1 Study Results*
Exploratory Analysis of Bleed Events, Part C
Post hoc analysis of bleed events during Onset and Observation periods
• Prospectively collected bleed events during Onset (Day 0-28) and Observation periods (Day
29 to last available, to maximum of Day 112)
C3-3 (900 mcg/kg qM)
120
70
AT
Peak Thrombin
Bleed Event
60
Factor Administration
50
80
40
60
30
40
20
20
10
0
0
0
28
Onset
50
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
Day
56
84
Observation
Peak Thrombin (nM)
% Relative AT Activity
100
Interim Fitusiran Phase 1 Study Results*
Exploratory Analysis of Bleed Events, Part C†
Post hoc analysis of bleed events by individual and Part C median
Part C: Summary of Median ABR
30
Historical On-Demand ABR
Onset
50
Observation
40
30
20
10
#
0
C1-1
C1-2
•
•
#
#
C1-3
225 mcg/kg
51
ABR Estimate (Bleeds Per Year)
ABR Estimate (Bleeds Per Year)
Individual ABR
60
C2-1
C2-2
C2-3
450 mcg/kg
25
20
-85%
15
-92%
10
5
0
C3-1
C3-2
C3-3
900 mcg/kg
Cohort
1-3
Historical
On-Demand
Cohort
1-3
Onset
Cohort
1-3
Cohort
2-3
Observation
Available Median Part C (Cohorts 1-3) Observation Period ABR = 4.3 (85% reduction relative
to median Historical On-Demand ABR)
Median Cohort 2 & 3 Observation Period ABR = 2.2 (92% reduction relative to median
Historical On-Demand ABR)
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
†
Observation Period data for Cohort 4 (1800 mcg/kg) not yet available
#Historical On-Demand ABR value not available; excluded from summary median ABR calculation
ABR Results in Select Prospective Studies*
Median ABR ranges from 1.1 to 7.9
50
On Demand
Prophylaxis
A B R - M e d ia n
40
30
20
10
0
*The above graph does not reflect data from head-to-head studies and direct comparisons can not be made
52
Haemophilia. 2013 Sep;19(5):691-7, N Engl J Med. 2013 Dec 12;369(24):2313-23, Blood. 2014 Jan 16;123(3):317-25, J Thromb Haemost.
2012 Mar;10(3):359-67, Haemophilia. 2014 Jan;20(1):65-72, Blood. 2015 Aug 27;126(9):1078-85, ASH 2015
Potential Product Features*
GalNAc
Fitusiran
ACE910
Yes
Yes
Hem A,
Hem B,
potentially other RBDs
Hem A
S.C., <1mL
S.C., >1mL
Once Monthly
Once Weekly
None – 0%
3/18 patients1 – 17%
Injection Site Reactions
2/24 patients – 8%
4/18 patients1 – 22%
Storage Conditions
Room temperature
Refrigeration
Evidence for Reduced ABR
Potential Indications
Administration & Volume
Frequency
Development of ADA
53
*Analysis not based on comparative studies
1Shima et al., WFH, May 2014
Fitusiran Product Opportunity
Significant potential for new therapeutic approach in
hemophilia and rare bleeding disorders
• Differentiated approach with monthly, subcutaneous dosing that could
change disease management by restoring hemostasis
• Potential to eliminate risk of inhibitor formation
• Potential to address hemophilia A and B, all patient segments, including
inhibitors
• Value supported by pharmacoeconomics
• Well organized patient advocacy
• Significant opportunity for global expansion
54
Current Market Needs
HA and HB Needs

Longer Duration: Frequency of infusion
(prophylaxis up to 3x’s / week) and potential
for treatment with longer duration

Route of Administration: IV is
burdensome due to set-up and
administration time, and pain associated
with ‘poking’ the vein


Device: Mixing devices, and vial /
diluent sizes that make administration
of IV factor products easier
Inhibitor Development:
Concern because of
immense burdens of
treatment and management
Inhibitor Needs
Burden of Treatment: very high burden –
particularly in ITT which
requires daily infusions and in prophylaxis
therapy

Cost: ”Cost is an enormous burden” to system
due to high volumes and frequent infusions
demanded in inhibitor management

NovoSeven®: Half-life too short

FEIBA: Viscosity requires long
mixing and infusion times

“Infusion is the biggest problem for me as I find
it difficult to hit the vein in my first attempt.”
– Person with Hemophilia
55
Alnylam market research: physicians and patients
Potential Target Bleeding Disorder Segments
309,265
30,138
300,000
~5,000
Total Population
69,169
Fitusiran Initial Opportunity
Number of Patients
250,000
~3,500
70,878
200,000
150,000
6,583
123,999
Mod/Severe
HA/HB
Inhibitors
Mod/Severe
HA/HB NonInhibitors
100,000
50,000
0
Total Bleeding
Disorders
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Other
Bleeding
Disorders
Addressable,
Severe RBDs
VWD
Adapted from WFH Annual Global Survey 2013, extrapolated to 2015
Type 3 VWD
Mild
Hemophilia
Fitusiran Target Product Profile
Hemophilia A and B
Fitusiran
Indication
Target Product Profile
•
Prevention of bleeding in patients with hemophilia A/B without or with inhibitors
Dose and
Regimen
•
≤ 1 mg/kg monthly (qM)
Route of
Administration
•
≤ 1ml, subcutaneous injection via auto-injector
Efficacy
Primary
• >75% reduction in all bleeding episodes
Secondary
• Reduction in annualized joint, spontaneous, & traumatic bleeding episodes
• Reduction in factor usage
• Improvement in Hem-QoL
• Impact on joint structure (MRI) and function
Safety
•
•
Very low incidence of mild-moderate ISRs
No significant impact on liver or kidney function
Target product profiles for investigational RNAi therapeutics reflect current thinking on desired product characteristics and are subject to change.
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Clinical Development Plan
Fitusiran for the Treatment of Hemophilia and RBD
Broad-based development plan to maximize product opportunity
Phase 1
Adult Healthy Volunteers and
Hemophilia A/B
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation)
• Initial dose finding
Phase 1 OLE
Hemophilia A/B
N= 24+/N=6 inhibitor, ETC late2018
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation,
bleeding frequency)
• Extended dosing
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OLE: Open Label Extension
Phase 3
Inhibitor N=45, ETC late 2017
On-demand
(Non-Inhibitor) N=100, ETC mid-2018
Phase 3 Open Label Extension/Safety
Non-inhibitor/Inhibitor N=TBD, ETC late 2020
RBDs
Pediatric (< 12 y.o.)
± Inhibitor N=10/N=40,
ETC late 2020
ETC: Estimated Time to Completion
Population:
• Adults and
adolescents with
Severe Hemophilia
A or B
• N~100
STUDY 2†
Population:
• Adults and
adolescents with
Severe Hemophilia
A or B with
inhibitors
• N~45
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2:1 RANDOMIZATION
STUDY 1†
3:1 RANDOMIZATION
Preliminary Fitusiran Phase 3 Design*
Fitusiran
OR
Placebo
Fitusiran
OR
Placebo
*Preliminary plans subject to further diligence and health authority feedback
†Patients in both Study 1&2 will be allowed to roll over into open-label extension
Endpoints (at 9
months):
• Annualized Bleed
Rate
• Total number of
bleeds
• Factor VIII/IX
consumption
• QoL
• Safety
Endpoints (at 9
months):
• Annualized Bleed
Rate
• Total number of
bleeds
• By-passing agent
consumption
• QoL
• Safety
Fitusiran Program Summary & Next Steps
Fitusiran is promising investigational approach for treatment of
hemophilia and rare bleeding disorders (RBD)
• Potential to address significant unmet need and could represent attractive
commercial opportunity
Positive data from ongoing Phase 1 Study
• Generally well tolerated in hemophilia A and B patients with both weekly and
monthly SC dose regimens (N=24)
• Clinical activity results support further advancement
◦ Up to 88% AT lowering achieved, with once-monthly subcutaneous dose regimen
◦ Clinically meaningful increases in thrombin generation
◦ 85-92% reduction in median estimated ABR
Next Steps
• Phase 1 OLE study initiated
• Additional Phase 1 clinical results expected in mid and late 2016
• Plan to advance to Phase 3 studies in mid 2016
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