November 10-13, 2013

International Symposium on Familial Amyloidotic Polyneuropathy

Clinical Updates on ALN-TTR Programs Patisiran (ALN-TTR02) and ALN-TTRsc for the Treatment of Transthyretin

Amyloidosis

RNA Interference (RNAi) A New Class of Innovative Medicines

RNAi Therapeutics Harness natural pathway

» Catalytic mechanism

» Mediated by small interfering RNAs or “siRNAs”

Treat disease with therapeutic gene silencing » Any gene in genome

2

Transthyretin (TTR) and ALN-TTR Program

Mutant TTR is genetic cause of ATTR Autosomal dominant with >100 defined mutations

Misfolds and forms amyloid deposits in nerves, heart, other tissues

Wild-type TTR also accumulates in amyloid plaques

» Limits benefits of liver transplantation

ALN-TTR siRNA suppresses hepatic production of mutant and WT TTR

Gly6Ser

Leu12Pro

Val20Ile

Pro24Ser

Val28Met

Phe33Cys

Phe33Ile

Phe33Leu

Phe33Val

Lys35Asn

Asp38Ala

Glu42Asp

Glu42Gly

Ala45Asp

Ala45Ser

Ala45Thr

Thr49Ala

Thr49Pro

Glu51Gly

Gly53Glu

Leu55Arg

Leu55Pro

Leu55Gln

Thr59Lys

Glu61Lys

Ile68Leu

Lys70Asn

Ile73Val

Ser77Phe

Ser77Thy

Glu89Gln

Glu89Lys

Ala97Gly

Ala97Ser

Pro102Arg

Ile107Val

Leu111Met

Tyr114Cys

Tyr114His

Ala120Ser

Pro125Ser

Ala91Ser Thr118Met

Asp18Glu

Asp18Gly

Ala25Ser

Ala25Thr

Arg34Thr

Ala36Pro

Trp41Leu

Gly47Ala

Gly47Arg

Gly47Glu

Gly47Val

Ser50Arg

Glu54Gln

Glu54Gly

Leu58Arg

Leu58His

Thr60Ala

Phe64Leu

Phe64Ser

Tyr69His

Tyr69Ile

Val71Ala

Asp74His

Ile84Asn

Ile84Ser

His90Asn

Gln92Lys

Gly101Ser

Arg104Cys

Arg104His

Ala109Thr

Ala109Val

Ala109Ser

Ser112Ile

Tyr116Ser

Thr119Met

Val122Ala

Val122Ile Val122 (-) Cys10Arg

Ser23Asn Phe44Ser

Ser52Pro

Val30Ala

Val30Gly

Val30Leu

Val30 Met

5’ UTR

3’ UTR

siRNA

target site

3

RNAi Delivery to Liver Solved IV and SC Platforms: Pre-clinical

Enables advancement of innovative medicines to patients Potent, rapid, and durable target gene silencing with lipid nanoparticle (LNP)

technology and IV dosing

Potent, rapid, and durable target gene silencing with proprietary GalNAc-conjugate

technology and SC dosing with wide therapeutic index

Keystone: Adv in Biopharm., Jan 2010; Oligo Ther Soc., Sep 2011

GalNAc-siRNA (SC)

mg/kg

100

80

60

40

20

0

-20

% T

TR

mR

NA

Sil

en

cin

g

(Re

lati

ve

to

Co

ntr

ol)

100

80

60

40

20

0

-20

% T

TR

mR

NA

Sil

en

cin

g

(Re

lati

ve

to

Co

ntr

ol)

0.03 0.1 0.3

LNP-siRNA (IV)

mg/kg

Control 5.0 1.0 0.2 Control

4

RNAi Therapeutic Hypothesis

for Treatment of ATTR

Production of mutant and

wild type TTR

Neuropathy, cardiomyopathy

Organ deposition of monomers,

amyloid (β-pleated) fibril

Unstable circulating TTR

tetramers

Patisiran (ALN-TTR02) and ALN-

TTRsc act to knock down both mutant

and wild type TTR production

Neuropathy, cardiomyopathy

Stabilization and recovery,

Organ deposition of monomers,

amyloid (β-pleated) fibril

prevented, clearance

promoted

Unstable circulating TTR

tetramers reduced

5

Patisiran (ALN-TTR02) Familial Amyloidotic Polyneuropathy (FAP)

Patisiran in clinical development

International Nonproprietary Name designation

for ALN-TTR02 = Patisiran (pa-TEE-sa-ran)

Positive Phase I results in human volunteers

» Data published in New England Journal of Medicine

Positive multi-dose Phase II results in FAP

patients

Phase II Open-Label Extension (OLE)

study initiated

» Includes clinical endpoints measured every 6 months

APOLLO Phase III trial initiated

6

Patisiran Phase I Study Results

Study Day

% M

ea

n S

eru

m T

TR

Kn

oc

kd

ow

n

Re

lative

to

Ba

se

line

Rapid, dose-dependent, durable, specific, and RNAi-mediated TTR knockdown Randomized, placebo-controlled, single-blind, single-dose escalation study in healthy volunteers (n=17)

Up to 94% TTR knockdown at nadir and 77% knockdown sustained at 28 days

RNAi mechanism of action confirmed by 5’RACE analysis of circulating mRNA

***

*** *** *** ***

***

*** ***

***

100

80

60

40

20

0

-20

-40

5 10 15 20 25 30 35 40 45 50 55 60

siRNA

Dose

Treatment Groups (mg/kg)

Placebo (n=4)

0.01 (n=3)

0.05 (n=3)

0.15 (n=3)

0.30 (n=3)

0.50 (n=1)

Control siRNA 0.4 mg/kg (n=6)

p<0.001 (***)

Coelho et al., N Engl J Med;369:819-29 (2013) 7

Patisiran achieves robust TTR knockdown with q4w and q3w regimens NHP multi-dose study provides key data for dose/dose regimen selection in Phase III

Nadir TTR levels of >85% with evidence for cumulative knockdown effects

Patisiran Multi-Dose Pharmacology Non-Human Primate

100

80

60

40

20

0

-20

0 4 8 12 16 20 24 28 32 36

% M

ea

n S

eru

m T

TR

Kn

ock

do

wn

Weeks

0.30 mg/kg, q4w x7

Start New Dosing Paradigm

0.30 mg/kg q4w x4; 0.30 mg/kg q3w x4

100

80

60

40

20

0

0 5 10 15 20 25

% M

ean

Seru

m T

TR

Kn

oc

kd

ow

n

human (0.30 mg/kg)

NHP (0.30 mg/kg)

Day

Peripheral Nerve Society, June 2013 8

Patisiran Phase II Study

Study Design Open-label, multi-dose, dose escalation study in FAP

patients » Cohorts of 3 subjects each

» Cohorts 1-3: 0.01, 0.05, 0.15 q4w x 2 doses

» Cohort 4-5: 0.30 mg/kg q4w x 2 doses

» Cohort 6-9: 0.30 mg/kg q3w x 2 doses

Primary Objective Evaluate safety and tolerability of multiple doses of patisiran

Secondary Objectives Assess preliminary clinical activity

» Serum TTR, retinol binding protein (RBP), Vitamin A levels

Status Dosing completed

9

Patisiran Phase II Study Results Baseline Characteristics

Characteristic Result

Number of subjects N=29 (Cohorts 1-9)

Median Age 62 years (range 28-76)

Gender 20 males, 9 females

Enrollment by Country • Portugal = 9

• France = 8

• Sweden = 6

• Spain = 3

• Germany = 1

• Brazil = 1

• USA = 1

TTR Genotype • Val30Met (V30M) = 22

• Ser77Tyr (S77Y) = 2

• Ser77Phe (S77F) = 2

• Tyr116Ser (Y116S) = 1

• Phe64Leu (F64L) = 1

• Arg54Thr (R54T) = 1

FAP Stage Stage 1 = 25

Stage 2 = 4

Concurrent Tetramer Stabilizer 14 tafamidis, 6 diflunisal, 9 none

Mean Serum TTR at Study Entry 246 mg/mL (range 163-397)

10

Patisiran Phase II Study Results Safety and Tolerability - TEAEs Related or Possibly Related

Preferred Term

0.01 mg/kg

q4w

(n=4)

0.05 mg/kg

q4w

(n=3)

0.15 mg/kg

q4w

(n=3)

0.30 mg/kg

q4w

(n=7)

0.30 mg/kg

q3w

(n=12)

Overall

Patisiran

(N=29)

n (%) n (%) n (%) n (%) n (%) n (%)

Infusion-related reaction 0 0 0 3 (42.9%) 0 3 (10.3%)

Cellulitis due to drug

extravasation 0 0 0 1 (14.3%) 0 1 (3.4%)

Polyuria 0 0 0 1 (14.3%) 0 1 (3.4%)

Nausea/Vomiting 0 0 0 0 1 (8.3%) 1 (3.4%)

Facial erythema 0 0 0 0 1 (8.3%) 1 (3.4%)

Dry mouth 0 0 0 0 1 (8.3%) 1 (3.4%)

Asthenia 0 0 0 0 1 (8.3%) 1 (3.4%)

Dysphagia 0 0 0 0 1 (8.3%) 1 (3.4%)

Majority of TEAEs were mild or moderate

Two SAEs reported

» Episode of severe nausea/vomiting in patient with autonomic involvement by FAP; discontinued study after 1 dose

» Episode of self-limiting cellulitis of the arm occurred as a result of drug extravasation at infusion site

No changes in liver function tests, renal function, or hematologic parameters

11

Patisiran Phase II Study Results Dose Response and Duration of TTR Knockdown

Robust knockdown of TTR in ATTR patients Results (n=28) show up to 96% TTR knockdown; 84% and 87% mean TTR knockdown after 1st and 2nd

doses in 0.30 mg/kg q3w cohort (p<0.001 vs. 0.01 mg/kg)

Patisiran Cohort 0.30 mg/kg q3w

Cohorts 0.01-0.30 mg/kg q4w

100

80

60

40

20

0

-20

0 10 20 30 40 50 60 70 80 90 100 110

Day

% M

ea

n S

eru

m T

TR

Kn

oc

kd

ow

n

Re

lative

to

Ba

selin

e

Patisiran

Treatment Groups

0.01 mg/kg q4w (n=4)

0.05 mg/kg q4w (n=3)

0.15 mg/kg q4w (n=3)

0.30 mg/kg q4w (n=6)

0.30 mg/kg q3w (n=12)

* Includes first dose data from additional patient prior to protocol amendment + Excludes post-day 28 data from patient that experienced drug extravasation during second infusion 12

Patisiran Phase II Study Results Summary of Serum TTR Knockdown by Dose Group

Dose

Group (mg/kg)

Dose 1 Dose 2

Maximum TTR

KD (%)

TTR KD

@ Nadir (Mean % SD)

Maximum TTR

KD (%)

TTR KD

@ Nadir (Mean % SD)

0.01 q4w

(n=4+) 37.8 22.1 ± 12.5 34.4 32.9 ± 2.3

0.05 q4w

(n=3) 58.0 48.4 ± 16.2 58.5 46.9 ± 15.0

0.15 q4w

(n=3) 81.7 74.5 ± 6.8*** 86.0 77.0 ± 7.8*

0.30 q4w

(n=6^) 87.5 82.6 ± 5.9*** 90.8 84.8 ± 10.5***

0.30 q3w

(n=12) 94.2 83.8 ± 5.1*** 96.0 86.7 ± 7.0***

+ Includes first dose data from additional patient prior to protocol amendment

^ Excludes post-day 28 data from patient that experienced drug extravasation during second infusion

* p <0.05 vs. 0.01 mg/kg group

*** p < 0.001 vs. 0.01 mg/kg group

p values from ANCOVA models including baseline TTR and dose groups as factors;

models significant at p < 0.001 for Dose 1, p < 0.001 for Dose 2

13

Patisiran Phase II Study Results TTR Knockdown in V30M Patients: WT vs Mutant

TT

R-V

30

M

(%

rem

ain

ing fro

m b

aselin

e)

0

50

100

0 50 100

TTR-Wild Type (% remaining from baseline)

r2 = 0.95

p < 10-15

Day

% M

ea

n S

eru

m T

TR

Kn

ock

do

wn

R

ela

tive t

o B

aselin

e

100

80

60

40

20

0

0 10 20 30 40 50 60 70 80 90 100

V30M Wild Type

*1 of 6 subjects not V30M (no data)

14

TTR Knockdown by Patisiran 0.30 mg/kg qw4 cohorts

Wild Type vs. Mutant V30M Patients

Peripheral Nerve Society, June 2013

Patisiran Phase II Study Results TTR KD with Patisiran in Patients on Tetramer Stabilizer

Patisiran + diflunisal (n=3) Patisiran (n=5)

Patisiran + tafamidis (n=10)

% M

ea

n S

eru

m T

TR

Kn

oc

kd

ow

n

Re

lative

to

Ba

se

line

100

80

60

40

20

0

0 5 10 15 20

Day

TTR Knockdown by Patisiran 0.30 mg/kg cohorts

15

Baseline TTR Levels by Stabilizer Use All cohorts

0 No stabilizer

(n=9) Tafamidis

(n=14)

Diflunisal (n=6)

Me

an

Bas

eli

ne S

eru

m T

TR

(µ

g/m

L)

p<0.001 by ANOVA

100

200

300

Patisiran Open-Label Extension (OLE) Study

FAP patients dosed on Phase II trial eligible to roll over onto Phase II OLE study

Up to 2 years of dosing, with clinical endpoints evaluated every 6 months

» Clinical endpoints include those in APOLLO Phase III study

» Dosing at 0.30 mg/kg every 3 weeks

» After 2 years, patients may continue treatment on another extension study until

drug commercially available

Study objectives

» Primary: Safety and tolerability of long-term dosing with patisiran

» Secondary: Effects on neurologic impairment (mNIS+7), quality of life, mBMI,

disability, mobility, nerve fiber density in skin biopsies, and serum TTR levels

Status

» Open and enrolling

» Plan to report data once annually, beginning 2014

16

Phase III Trial of Patisiran in FAP Study Initiated

Randomized, double-blind, placebo-controlled, global study Sample size and randomization

» N=200

» 2:1, Patisiran vs Placebo

» Stratify for baseline NIS, early onset (age < 50) V30M vs all other mutations

(including late-onset V30M), prior tafamidis/diflunisal use vs no prior use

Key eligibility criteria » V30M and non-V30M FAP

» Baseline NIS 10-100 (FAP stages 1 and 2)

Treatment regimen » Patisiran 0.30 mg/kg vs Placebo IV q3 weeks x 18 months

» All completers eligible for patisiran treatment on Phase III OLE study

Primary Endpoint mNIS+7 at 18 months

Secondary Endpoints Norfolk QOL-DN, NIS-weakness, mBMI, timed 10-meter walk, COMPASS-31 autonomic

symptom score

Statistical Considerations Placebo mNIS+7 progression rate derived from natural history study of 283 FAP patients

Study with 90% power to detect as little as 37.5% difference in ΔmNIS+7 between

treatment groups with 2-sided alpha=0.05

Blinded interim analysis of variability planned for potential sample size re-estimation

17

ALN-TTRsc Familial Amyloidotic Cardiomyopathy (FAC)

ALN-TTRsc in clinical development

Subcutaneous delivery

Positive Phase I study results

» Normal healthy volunteer study in UK

» Data presented at Annual Scientific

Meeting of Heart Failure Society of

America, September 2013

Pilot Phase II study start expected in

late 2013

Phase III start planned for 2014

18

ALN-TTRsc Phase I Study

Study Design Randomized, double-blinded, placebo-controlled SAD and MAD

study in healthy volunteers » 3:1 randomization (ALN-TTRsc:Placebo)

» 4 subjects/cohort

» Cohort 1-4: single doses of 1.25, 2.5, 5.0 and 10 mg/kg

» Cohort 5-7: multiple doses of 2.5, 5.0 and 10 mg/kg – Multi-dose schedule: Daily x 5, followed by weekly x 5

Primary Objective Evaluate safety and tolerability of subcutaneously administered

single and multiple doses of ALN-TTRsc

Secondary Objectives Assess clinical activity

» Serum TTR, retinol binding protein (RBP), Vitamin A levels

Status Dosing completed; analysis ongoing

19

ALN-TTRsc Phase I Study TTR Knockdown in Multi-Dose Cohorts

100

80

60

40

20

0

-20

Time (days) ALN-TTRsc (mg/kg), qd x5; qw x5

% M

ea

n T

TR

Kn

oc

kd

ow

n

Re

lative

to

Ba

selin

e (

± S

EM

)

2.5 (n=3)

5.0 (n=3)

10.0 (n=3)

Placebo (n=4)

ALN-TTRsc dose groups

Rapid, dose-dependent, consistent, and durable knockdown of serum TTR Statistically significant knockdown of serum TTR at all doses evaluated (p<0.01)

Consistent level of TTR knockdown with weekly dosing; durable effects lasting weeks after last dose

Mean TTR knockdown of 87.5% and 92.4% at 5.0 and 10.0 mg/kg, respectively » Maximum TTR knockdown of up to 94%

Heart Failure Society of America, Sept. 2013 20

ALN-TTRsc Phase I Study Human Translation of GalNAc-siRNA Conjugate Platform

Excellent correlation of

human to non-human

primate TTR knockdown

on mg/kg basis

Demonstrates human

translation of GalNAc-

siRNA conjugate

platform

0

25

50

75

100

0 25 50 75 100

Mean (SEM) % TTR KD in NHP

Me

an

(S

EM

) %

TT

R K

D i

n h

um

an

R2 = 0.83

p < 0.001

2.5

5.0

10.0

ALN-TTRsc (mg/kg)

Heart Failure Society of America, Sept. 2013 21

ALN-TTRsc Phase I Study Safety and Tolerability

All TEAEs mild or moderate in severity; no SAEs

ISRs: generally mild, resolving within ~2 hours of onset

No study discontinuations, flu-like symptoms, or lab abnormalities

Reported AEs

Single Dose Multiple Doses Total

TTRsc

(n=21)

PBO

(n=7)

1.25 mg/kg

(n=3)

2.5 mg/kg

(n=3)

5.0 mg/kg

(n=3)

10 mg/kg

(n=3)

2.5 mg/kg

(n=3)

5.0 mg/kg

(n=3)

10 mg/kg

(n=3)

n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Injection Site

Reaction (ISRs) 0 0 0 0 1 (33%) 1 (33%) 3 (100%) 5 (24%) 1 (14%)

Headache 0 1 (33%) 1 (33%) 0 0 0 0 2 (10%) 1 (14%)

Local Erythema 0 0 0 0 0 1 (33%) 0 1 (5%) 0

Local Bruise 0 0 0 1 (33%) 0 0 0 1 (5%) 0

Local

Tenderness 0 0 0 1 (33%) 0 0 0 1 (5%) 0

Abdominal

Tenderness 0 0 0 0 0 0 1 (33%) 1 (5%) 0

TEAEs Definitely or Possibly Related

Adverse events through Day 28 (Cohorts 1-4), through Day 63 (Cohort 5-6) and through Day 42 (Cohort 7)

Heart Failure Society of America, Sept. 2013 22

Patisiran and ALN-TTRsc Programs Summary

Patisiran (ALN-TTR02) for FAP

Robust and durable TTR knockdown demonstrated in patients with

multi-dose regimen in Phase II

» Similar activity against mutant and wild-type TTR

» Favorable safety profile

Phase II OLE study currently enrolling

» Evaluating safety of long-term dosing and includes clinical endpoints

APOLLO Phase III study in FAP initiated

ALN-TTRsc for FAC

Positive data from Phase I trial in healthy volunteers

» Human POC for GalNAc-siRNA delivery approach

Pilot Phase II trial in FAC patients expected to start in Q4

Phase III trial expected to start in 2014

23

Acknowledgments Patisiran (ALN-TTR02) Phase II Investigators David Adams

» CHU Hospital Bicetre, Le Kremlin-Bicetre, France

Teresa Coelho, Ana Silva

» Hospital Geral de Santo Antonio, Porto, Portugal

Ole Suhr

» Umea University Hospital, Umea, Sweden

Isabel Conceicao

» Centro Hospitalar Lisboa Norte-Hospital de Santa

Maria, Lisboa, Portugal

Juan Buades

» Hospital Son Llatzer, Palma de Mallorca, Spain

Josep Campistol

» Hospital Clinic Barcelona Instituto, Barcelona, Spain

Jean Pouget

» Hôpital de La Timone, Marseille, France

Hartmut Schmidt

» University Hospital of Muenster, Muenster, Germany

Marcia Waddington-Cruz

» Hospital Universitário, Rio de Janeiro, Brazil

John Berk

» Boston University, Boston, MA USA

TTR Program - Scientific Collaborators

Maria Saraiva

» Institute of Cellular and Molecular

Biology, Porto, Portugal

Yukio Ando and Hiro Jono

» Kumamoto University, Japan

Alnylam has licenses to Tekmira LNP intellectual

property for use in RNAi therapeutic products using

LNP technology

ALN-TTRsc Phase I Investigators

Joseph Chiesa

» Covance Clinical Research Unit,

Leeds, United Kingdom

Gary Peters

» Hammersmith Medicines Research,

London, United Kingdom

24