Hemophilia Overview Guy Young, M.D....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

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)


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++



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


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++



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


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


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




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


• 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%


AT lowering after weekly dosing in patients with hemophilia A and B



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)


AT lowering after monthly dosing in patients with hemophilia A and B



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


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


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


47


Post hoc analysis of thrombin generation by AT lowering quartiles

*Data as of 12 November 2015; reruns conducted of samples with analytical errors


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 (%)



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


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


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


51


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

57

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.

58

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

59

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

60

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

Documents

Hemophilia Overview Guy Young, M.D....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