Hemophilia Overview Guy Young, M.D....Refinement of Talmud Language—12th Century “If a woman had...
Transcript of Hemophilia Overview Guy Young, M.D....Refinement of Talmud Language—12th Century “If a woman had...
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
“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.
Moses Maimonedes was a physician and religious scholar who refined the teachings of the Talmud as follows:
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
Thrombin (IIa)
Fibrinogen (I) Fibrin
XIII
XIIIa
TAFI
TAFIa
VIII VIIIa
V
Va
XI XIa
IX IXa
Ca++
X Xa
Ca++ VIIIa VIII
VII
VIIa
TF
Prothrombin (II) Thrombin (IIa)
Fibrinogen (I) Fibrin
XIII
XIIIa
Cross-linked fibrin
V Va
Thrombin (IIa)
Physiologic Coagulation
Ca++
XI XIa Ca++
IX IXa
Ca++
X Xa
Ca++ VIII VIII
VII
VIIa
TF
Xa X
Ca++
Prothrombin (II) Thrombin (IIa)
Fibrinogen (I) Fibrin
XIII
XIIIa
Cross-linked fibrin
V Va
Thrombin (IIa)
Natural Coagulation Inhibitors
Antithrombin
Protein C Protein Ca Thrombin (IIa)
Pro
tein
S
Pro
tein
S
Thrombin (IIa)
Ca++
Tissue factor pathway inhibitor (TFPI)
Inhibits ( )
X Xa
Ca++
VII
VIIa
TF
Prothrombin (II) Thrombin (IIa)
Coagulation in Hemophilia
Ca++
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?
19
00
Whole Blood
19
50
s
Plasma
19
60
s
Cryoprecipitate
Plasma-derived intermediate purity concentrates
19
70
s
Plasma-derived high purity concentrates
19
80
s
Recombinant factors
19
90
s
20
00
s
First gene therapy trials
20
10
s
First extended half-life factors
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
• Factor replacement – Proven
– Easily understood
– “Natural”
• Less frequent than standard factor concentrates
Cons
• Risk for inhibitors
• IV infusion – Still at least once every two
weeks and for most patients twice weekly
• Inconvenience of storing a lot of boxes and ancillary supplies
XI XIa Ca++
IX IXa
Ca++
X Xa
Ca++ VIII VIII
VII
VIIa
TF
Xa X
Ca++
Prothrombin (II) Thrombin (IIa)
Fibrinogen (I) Fibrin
XIII
XIIIa
Cross-linked fibrin
V Va
Thrombin (IIa)
#2: Rebalancing the Coagulation System: Natural Coagulation Inhibitors
Antithrombin
Thrombin (IIa)
Ca++
Tissue factor pathway inhibitor (TFPI)
Inhibits ( )
FVIII FIX FX FII
TFPI AT PC PS
#2: Rebalancing the Coagulation System
FIX FX FII
TFPI AT PC PS
No FVIII—Bleeding Disorder
FVIII FIX FX FII
TFPI PC PS
No AT—Clotting Disorder
FIX FX FII
TFPI PC PS
Absent FVIII and absent AT—Rebalancing the Coagulation System
#2: Rebalancing the Coagulation System Rebalancing agents
Pros
• Subcutaneous route of administration
• Long half-life – Infrequent injections
• No risk for antibody formation against clotting factors
• Effective in inhibitor patients
• Can be effective in all factor deficiency disorders
Cons
• Less intuitive than factor replacement
• Theoretical risk for thrombosis
• Laboratory monitoring
#3: Bispecific antibody
#3: Bispecific antibody Pros
• Subcutaneous route of administration
• Long half-life so infrequent injections required
• Mimics FVIII activity so relatively easily understood
• Effective in inhibitor patients
Cons
• Only effective in hemophilia A
• Antibody formation
• Theoretical risk for thrombosis
• Laboratory monitoring
#4: Gene Therapy Pros
• Potentially curative
Cons
• “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”
36
Fitusiran (ALN-AT3) for Hemophilia
& Rare Bleeding Disorders
Benny Sorensen, M.D., Ph.D.
Senior Director, Clinical Research
37
Hemophilia and Rare Bleeding Disorders Program
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
◦ 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)
Unmet Need and Product Opportunity
38
Fitusiran for Hemophilia Alnylam Reproducible and Modular Platform
1
Genetically
validated, liver-
expressed target
gene
Antithrombin (AT) is key natural
anticoagulant
Co-inheritance of AT deficiency with
hemophilia associated with milder
bleeding phenotype
2 Biomarker for POC
in Phase 1
Blood-based biomarkers measure
components in coagulation cascade:
• AT
• Thrombin Generation
3 Definable path to
approval and
market
Two separate pivotal trials in inhibitor
and on-demand patients
Established Endpoint: Annualized
Bleeding Rate
39
Fitusiran
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
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
◦ 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 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)
Investigational RNAi Therapeutic for the Treatment of Hemophilia
AT
FIX
FVIII
FIXa
FVIIa FVII
FVIIIa
FVa FV
FX
FXa
Fibrinogen Fibrin
Thrombin Prothrombin
Blood clot
Hemophilia B
Hemophilia A
FVIII
FIX
AT
40
Fitusiran Phase 1 Study
1Akinc A et al. Goring Coagulation Conference (2015) 2Sorensen B, et al. ISTH (2015) 3Pasi KJ, et al. ASH (2015)
Dose-Escalation Study in Three Parts
Primary objectives
• Safety, tolerability
Secondary objectives
• AT lowering, thrombin generation
30 mcg/kg x 1 SC, N=4
45 mcg/kg qW x 3 SC, N=6
15 mcg/kg qW x 3 SC, N=3
Part A: Single-Ascending Dose (SAD) │Randomized 3:1, Single-blind, Placebo-controlled, Healthy volunteers
Part B: Multiple-Ascending Dose (MAD) – Weekly dosing │ Open-label, Patients with Hemophilia A or B
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
Presented January 20151
Presented June 20152
450 mcg/kg qM x 3 SC, N=3
900 mcg/kg qM x 3 SC, N=3
1800 mcg/kg qM x 3 SC, N=3
Up to 2 additional cohorts
Ongoing
Presented December 20153
41
Interim Fitusiran Phase 1 Study Results*
*Data as of 12 November 2015
Pasi KJ, et al. ASH (2015)
Demographics & Baseline Characteristics, Parts B & C
Part B
SC, Weekly × 3
Part C
SC, Monthly × 3
15
mcg/kg
45
mcg/kg
75
mcg/kg
225
mcg/kg
450
mcg/kg
900
mcg/kg
1800
mcg/kg
Age, mean (SD) 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
Weight (kg), mean (SD) 76
(10.1)
80
(21.7)
82
(8.5)
85
(12.3)
76
(16.0)
76
(1.6)
71
(11.8)
42
Interim Fitusiran Phase 1 Study Results*
• 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
*Data as of 12 November 2015: Pasi KJ, et al. ASH (2015) †Adverse event grouping based on MedDRA-coded terms, excluding bleed events
‡Hypertriglyceridemia
Safety/Tolerability, Parts B & C†
43
Mean Max
AT
Lowering
± SEM
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%
Interim Fitusiran Phase 1 Study Results*
AT lowering after weekly dosing in patients with hemophilia A and B
*Data as of 12 November 2015
Pasi KJ, et al. ASH (2015)
AT Lowering, Part B
% M
ea
n (
+/-
SE
M)
AT
Ac
tivit
y
Re
lati
ve
to
Ba
se
lin
e
0
25
50
75
100
125
Day
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210
Dose Group
15 mcg/kg (N=3)
45 mcg/kg (N=6)
75 mcg/kg (N=3)
220 230
AT
Lowering
< 25%
AT
Lowering
25-50%
AT
Lowering
50-75%
AT
Lowering
>75%
Analysis
Quartiles
44
% M
ea
n (
+/-
SE
M)
AT
Ac
tivit
y
Rela
tive
to
Bas
eli
ne
0
25
50
75
100
125
Day
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.2 Dose Group
225 mcg/kg (N=3)
450 mcg/kg (N=3)
900 mcg/kg (N=3)
1800 mcg/kg (N=3)
Interim Fitusiran Phase 1 Study Results*
AT lowering after monthly dosing in patients with hemophilia A and B
*Data as of 12 November 2015
Pasi KJ, et al. ASH (2015)
AT Lowering, Part C
Mean Max
AT
Lowering
± SEM
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%
AT
Lowering
< 25%
AT
Lowering
25-50%
AT
Lowering
50-75%
AT
Lowering
>75%
Analysis
Quartiles
45
Interim Fitusiran Phase 1 Study Results*
Mean maximum AT lowering by monthly equivalent dose
AT Lowering, Parts A, B & C
Monthly Equivalent Dose (mcg/kg)
Me
an
Ma
xim
um
AT
Lo
we
rin
g (
%)
0 135 450 900 1800
0
20
40
60
80
100
Part A Part B Part C
#
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
#Single dose only (1 of 3)
46
Interim Fitusiran Phase 1 Study Results*
Post hoc analysis of thrombin generation by AT lowering quartiles
Thrombin Generation, Part B & C
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%**
Pe
ak
Th
rom
bin
Ge
nera
tio
n (
nM
)
N=4 AT Lowering
< 25%
N=24
AT Lowering
25-50%
N=21
AT Lowering
50-75%
N=18
AT Lowering
>75%
N=9
0
50
100
150
200
250
Healthy
Volunteers Patients with Hemophilia
Boxes denote median and interquartile range
**p < 0.001, compared with AT lowering less than 25%
*Data as of 12 November 2015; reruns conducted of samples with analytical errors
Pasi KJ, et al. ASH (2015)
47
Interim Fitusiran Phase 1 Study Results*
Post hoc analysis of thrombin generation by AT lowering quartiles
*Data as of 12 November 2015; reruns conducted of samples with analytical errors
Pasi KJ, et al. ASH (2015)
Thrombin Generation, Part B & C
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%**
Pe
ak
Th
rom
bin
Ge
nera
tio
n (
nM
)
N=4 AT Lowering
< 25%
N=24
AT Lowering
25-50%
N=21
AT Lowering
50-75%
N=18
AT Lowering
>75%
N=9
0
50
100
150
200
250
Healthy
Volunteers Patients with Hemophilia
Boxes denote median and interquartile range
**p < 0.001, compared with AT lowering less than 25%
Dargaud et al.Thromb Haemost, 93, 475-480 (2005)
48
0
20
40
60
80
0 50 100 150 200 250
Peak T
hro
mb
in
(nM
)
FVIII (%)
0
50
100
150
0 50 100 150
Peak T
hro
mb
in
(nM
)
FVIII (%)
0
50
100
150
200
0 20 40 60 80 100
Peak T
hro
mb
in
(nM
)
FVIII (%)
Interim Fitusiran Phase 1 Study Results*
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
Exploratory Analysis of Factor Equivalence
C1-1 (225 mcg/kg qM) C4-2 (1800 mcg/kg qM) C4-3 (1800 mcg/kg qM)
• 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
Achieved peak thrombin generation values equivalent to >40% factor VIII
0
20
40
60
80
100
120
% R
ela
tive
AT
Ac
tivit
y
0 14 28 42 56 70 84 98 126
AT
Peak Thrombin
0
10
20
30
40
50
60
70
80
90
100 % F
VIII E
qu
iva
len
t Pe
ak
Th
rom
bin
Day
0 28 56
% R
ela
tive
AT
Ac
tivit
y
% F
VIII E
qu
iva
len
t Pe
ak
Th
rom
bin
0
20
40
60
80
100
120
0
10
20
30
40
50
60
70
80
90
100
AT
Peak Thrombin
Day 0 28
% R
ela
tive
AT
Ac
tivit
y
% F
VIII E
qu
iva
len
t Pe
ak
Th
rom
bin
Day
0
20
40
60
80
100
120
0
10
20
30
40
50
60
70
80
90
100
AT
Peak Thrombin
49
Interim Fitusiran Phase 1 Study Results*
Post hoc analysis of bleed events by AT lowering quartiles
Exploratory Analysis of Bleed Events, Parts B & C
*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
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
ABR, Median 13 11 10 0
0
10
20
30
40 A
BR
Es
tim
ate
, M
ea
n (
SE
M)
(B
lee
ds P
er
Ye
ar)
**p<0.05
50
Interim Fitusiran Phase 1 Study Results*
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)
Exploratory Analysis of Bleed Events, Part C
C3-3 (900 mcg/kg qM)
0
20
40
60
80
100
120
% R
ela
tive
AT
Ac
tivit
y
0 28 56 84
0
10
20
30
40
50
60
70
Pe
ak
Th
rom
bin
(nM
)
Onset Observation
AT
Peak Thrombin
Bleed Event
Factor Administration
Day
*Data as of 12 November 2015; Pasi KJ, et al. ASH (2015)
51
Interim Fitusiran Phase 1 Study Results*
Post hoc analysis of bleed events by individual and Part C median
Exploratory Analysis of Bleed Events, Part C†
• 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)
225 mcg/kg 450 mcg/kg 900 mcg/kg
0
10
20
30
40
50
60
C1-1 C1-2 C1-3
AB
R E
sti
ma
te (
Ble
ed
s P
er
Ye
ar)
Historical On-Demand ABR
Onset
Observation
Individual ABR
Observation Onset Historical
On-Demand
0
5
10
15
20
25
30
Cohort
1-3
Cohort
1-3
Cohort
1-3
Cohort
2-3
AB
R E
sti
ma
te (
Ble
ed
s P
er
Ye
ar)
Part C: Summary of Median ABR
# # #
C2-1 C2-2 C2-3 C3-1 C3-2 C3-3
-92%
-85%
*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
52
ABR Results in Select Prospective Studies*
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
Median ABR ranges from 1.1 to 7.9
0
10
20
30
40
50 A
B R
- M
e d
i a n
On Demand
Prophylaxis
*The above graph does not reflect data from head-to-head studies and direct comparisons can not be made
53
Potential Product Features*
*Analysis not based on comparative studies 1Shima et al., WFH, May 2014
Fitusiran ACE910
Evidence for Reduced ABR Yes Yes
Potential Indications
Hem A,
Hem B,
potentially other RBDs
Hem A
Administration & Volume S.C., <1mL S.C., >1mL
Frequency Once Monthly Once Weekly
Development of ADA None – 0% 3/18 patients1 – 17%
Injection Site Reactions 2/24 patients – 8% 4/18 patients1 – 22%
Storage Conditions Room temperature Refrigeration
GalNAc
54
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
55
Current Market Needs
Alnylam market research: physicians and patients
Longer Duration: Frequency of infusion
(prophylaxis up to 3x’s / week) and potential
for treatment with longer duration
HA and HB Needs
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
56
Potential Target Bleeding Disorder Segments
0
50,000
100,000
150,000
200,000
250,000
300,000
Total Bleeding
Disorders
Other
Bleeding
Disorders
Addressable,
Severe RBDs
VWD Type 3 VWD Mild
Hemophilia
Mod/Severe
HA/HB
Inhibitors
Mod/Severe
HA/HB Non-
Inhibitors
~3,500
Fitusiran Initial Opportunity
Total Population
309,265 30,138
~5,000 69,169
70,878
6,583 123,999
Nu
mb
er
of
Pa
tien
ts
Adapted from WFH Annual Global Survey 2013, extrapolated to 2015
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Fitusiran Target Product Profile Hemophilia A and B
Fitusiran Target Product Profile
Indication • 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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Phase 1 Phase 3
Clinical Development Plan
Broad-based development plan to maximize product opportunity
Fitusiran for the Treatment of Hemophilia and RBD
Pediatric (< 12 y.o.)
± Inhibitor N=10/N=40,
ETC late 2020
Inhibitor N=45, ETC late 2017
Phase 3 Open Label Extension/Safety
Non-inhibitor/Inhibitor N=TBD, ETC late 2020
RBDs
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation)
• Initial dose finding
Key Objectives
• Safety, PK, clinical activity (AT
knockdown, thrombin generation,
bleeding frequency)
• Extended dosing
OLE: Open Label Extension ETC: Estimated Time to Completion
Phase 1 OLE
Hemophilia A/B N= 24+/N=6 inhibitor, ETC late-
2018
On-demand
(Non-Inhibitor) N=100, ETC mid-2018
Adult Healthy Volunteers and
Hemophilia A/B
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Preliminary Fitusiran Phase 3 Design*
STUDY 1†
Population:
• Adults and
adolescents with
Severe Hemophilia
A or B
• N~100
3:1
RA
ND
OM
IZA
TIO
N
Fitusiran
Placebo
Endpoints (at 9
months):
• Annualized Bleed
Rate
• Total number of
bleeds
• Factor VIII/IX
consumption
• QoL
• Safety
OR
*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
STUDY 2†
Population:
• Adults and
adolescents with
Severe Hemophilia
A or B with
inhibitors
• N~45 2:1
RA
ND
OM
IZA
TIO
N
Fitusiran
Placebo
Endpoints (at 9
months):
• Annualized Bleed
Rate
• Total number of
bleeds
• By-passing agent
consumption
• QoL
• Safety
OR
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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