rnai roundtable - alnylam pharmaceuticals...july 22, 2014 rnai roundtable: advances in delivery of...

July 22, 2014

RNAi Roundtable: Advances in Delivery of RNAi Therapeutics

with Enhanced Stabilization Chemistry

(ESC)-GalNAc-siRNA Conjugates

Agenda

Welcome Josh Brodsky

Manager, Investor Relations and Corporate Communications

Introduction Laurence Reid, Ph.D.

Senior Vice President and Chief Business Officer

Advances in Delivery of RNAi Therapeutics with Enhanced Stabilization

Chemistry (ESC)-GalNAc-siRNA Conjugates Rachel Meyers, Ph.D.

Vice President of Research and RNAi Lead Development (RLD)

Q&A Session

2

Reminders

Event will run until ~12:00 p.m. ET

Q&A session at end presentation

» Submit questions by clicking “Ask a Question” button

» Questions may be submitted at any time

Replay and slides available at

www.alnylam.com/capella

3

Alnylam Forward Looking Statements

This presentation contains forward-looking statements, within the meaning of Section 27A

of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of

1934. There are a number of important factors that could cause actual results to differ

materially from the results anticipated by these forward-looking statements. These

important factors include our ability to discover and develop novel drug candidates and

delivery approaches, successfully demonstrate the efficacy and safety of our drug

candidates, obtain, maintain and protect intellectual property, enforce our patents and

defend our patent portfolio, obtain regulatory approval for products, establish and maintain

business alliances; our dependence on third parties for access to intellectual property; and

the outcome of litigation, as well as those risks more fully discussed in our most recent

quarterly report on Form 10-Q under the caption “Risk Factors.” If one or more of these

factors materialize, or if any underlying assumptions prove incorrect, our actual results,

performance or achievements may vary materially from any future results, performance or

achievements expressed or implied by these forward-looking statements. All forward-

looking statements speak only as of the date of this presentation and, except as required

by law, we undertake no obligation to update such statements.

4

Agenda








Q&A Session

5

Alnylam 5x15™ Strategy A Reproducible and Modular Path for Genetic Medicines

2. POC achieved in Phase 1 Blood-based biomarker with

strong disease correlation » e.g., Serum TTR, thrombin

generation, hemolytic activity,

LDL-C, HBsAg levels

GCCCCUGGAGGG

1. Liver-expressed target gene Involved in disease with high

unmet need

Validated in human genetics

GalNAc-siRNA enables SC dosing

with wide therapeutic index

3. Definable path to approval

and market Established endpoints

Focused trial size

Large treatment effect

Collaborative approach with

physicians, regulators,

patient groups, and payers

6

Discovery Development Phase 1 Phase 2 Phase 3

TTR-Mediated Amyloidosis

Hemophilia and

Rare Bleeding Disorders

Complement-Mediated Diseases

Hepatic Porphyrias

Hypercholesterolemia

Alpha-1 Antitrypsin Deficiency

Hepatitis B Virus Infection

Beta-Thalassemia and

Iron-Overload Disorders

Mixed Hyperlipidemia and

Hypertriglyceridemia

Hypertriglyceridemia

Additional Genetic Medicine

and Other Programs

Alnylam Development Pipeline

ALN-TTRsc

Patisiran (ALN-TTR02)

ALN-AT3

ALN-CC5

ALN-AS1

ALN-PCSsc

ALN-AAT

ALN-TMP

ALN-ANG

ALN-AC3

Standard Template Chemistry

(STC)-GalNAc Conjugate LNP Enhanced Stabilization Chemistry

(ESC)-GalNAc Conjugate Delivery Technology:

ALN-HBV

7

Alnylam IP on GalNAc-siRNA

8

Multiple Alnylam patent families cover

GalNAc-siRNA

Includes Tuschl and McSwiggen patents

Newly allowed Manoharan ’478 patent

provides additional protection

Claims cover modified RNA agent linked

to a biantennary or triantennary ligand

Includes GalNAc-conjugated, chemically

modified RNA

» Single or double stranded

» Any length

» Any sequence

» Toward any disease target

http://www.google.com/search?client=safari&rls=en&biw=1374&bih=654&tbm=isch&q=patent+seal&revid=17757196

http://www.google.com/search?client=safari&rls=en&biw=1374&bih=654&tbm=isch&q=patent+seal&revid=17757196

Agenda








Q&A Session

9

Reviewing ESC-GalNAc Conjugates Diseases and Targets

10

Goal: Review Advances in ESC-GalNAc conjugates as leading siRNA Delivery Modality Examples provided from 3 disease programs Transthyretin (TTR)-mediated amyloidosis

» TTR » Patisiran (Phase 3) and ALN-TTRsc (Phase 2)

Hemophilia and Rare Bleeding Disorders » Antithrombin (AT) » ALN-AT3 (Phase 1)

Hypercholesterolemia » PCSK9 » ALN-PCSsc (Pre-clinical)

Making Drugs Out of siRNAs The Challenge

Characteristics 21-23bp dsRNA

M.W 12,000-14,000

Size: 2 turns of helix

40 negative charges

Hydrophilic

Hydrated heavily

ca. 5.5 nm X 2 nm

Structure adapted from Klosterman et al.,

Biochemistry 38, 14784-14792 (1999)

11

The Delivery Challenge

12

PK/Tissue

Distribution

0

20

40

60

80

100

0 1 2 3 4

% I

nje

cte

d d

ose

Time (h)

Plasma Liver Spleen


13

Cellular Uptake

and Trafficking


14

RNA Release and

RISC Loading

RT-qPCR

RNAi Delivery to Liver Solved STC and ESC Platforms (NHP)

Enables advancement of innovative medicines to patients Advancement of proprietary conjugate platform for clinical translation and SC dosing

» Initial conjugates with Standard Template Chemistry (STC) achieve target knockdown with SC dosing

» Further improvements with conjugates employing Enhanced Stabilization Chemistry (ESC) platform

Maier, Oligo Ther Soc., Sep 2011; Akinc, ISTH, July 2013

100

80

60

40

20

0

-20

% T

TR

mR

NA

Sil

en

cin

g

(Rela

tive t

o C

ontr

ol)

ALN-TTRsc

(STC-GalNAc-conjugate)

mg/kg

5.0 1.0 0.2 Control

ALN-AT3

(ESC-GalNAc-conjugate)

mg/kg

100

80

60

40

20

0

-20

% A

T m

RN

A S

ilen

cin

g

(Rela

tive t

o P

re-d

ose)

0.5 0.25 0.125 Control

STC-Conjugate ESC-Conjugate

15






100

80

60

40

20

0

-20

% T

TR

mR

NA

Sil

en

cin

g

(Rela

tive t

o C

ontr

ol)

ALN-TTRsc


mg/kg

5.0 1.0 0.2 Control

ALN-AT3


mg/kg

100

80

60

40

20

0

-20

% A

T m

RN

A S

ilen

cin

g

(Rela

tive t

o P

re-d

ose)

0.5 0.25 0.125 Control


16

GalNAc-siRNA Conjugates Targeted Delivery to Hepatocytes via ASGPR-Mediated Uptake

17

ASGPR

Clathrin-coated pit

Clathrin-coated vesicle

Endosome

Recycling

ASGPR

GalNAc-siRNA

conjugate

RISC loading

mRNA

cleavage

Target protein

ASGPR Clears desialylated serum

glycoproteins via clathrin-mediated endocytosis

Highly expressed in hepatocytes » 0.5-1 million copies/cell

High rate of uptake Recycling time ~15 minutes Conserved across species

GalNAc-siRNA GalNAc ligand conjugated to

chemically modified siRNA for targeted delivery to hepatocytes

GalNAc carbohydrate cluster with high affinity for ASGPR (nM)

Administered subcutaneously (SC)

Adapted from

Essentials of Glycobiology (2009)

Design of High-Affinity Ligand for ASGPR

Adapted from Lee et al., Carbohydrates in Chemistry and

Biology; 4:549 (2000)

18

0 20 40 60 80 1000

1000

2000

3000

4000

(GalNAc)3

(GalNAc)2

Kd = 2.48 nM

Kd = 28.8 nM

[(GalNAc)n] nM

MF

I

Spacer length

Spacer length

C2-substituent

Valency

Branching point

Y-shaped linker

Attachment

to siRNA

Ligand Mouse

Hepatocyte Ki

GalNAc2 ~24 nM

GalNAc3 2.7 nM

Biessen et al., J. Med. Chem., 38:1538 (1995); Rensen et al., J. Med. Chem., 47:5798 (2004);

Biessen et al., Bioconjugate Chem., 13:295 (2002)

Spacing of

sugar residues

Uptake of GalNAc-siRNA Conjugates 1o Mouse Hepatocytes

• Glucose conjugate does not mediate uptake

• GalNAc3 BB and EGTA block uptake

• Substantially decreased uptake in ASGR2

KO cells

G3BB

0

300

600

900

1200

1500

1800

+EGTA +G3BB

(38)

ASGR2 KO

Cells

siRNA Glu2-siRNA GalNAc2-

siRNA

Rela

tive

Up

tak

e (

MF

I)

GalNAc3-

siRNA

GalNAc3-siRNA +

19

TTR-GalNAc siRNA Biodistribution After Single SC Administration

GalNAc-siRNA conjugates efficiently target liver Achieve liver levels of >50% delivered dose

Oligo Ther Soc., Sept. 2012

4 hours post-dose

0

20000

40000

60000

80000

100000

120000

Liver Spleen Kidney Heart Lung

siR

NA

/ ti

ss

ue

(n

g/g

)

20

GalNAc Conjugates: Clinically Validated Delivery Platform ALN-TTRsc Phase 1

Randomized, double-blind, placebo-controlled SAD and MAD study in healthy volunteers Rapid, dose-dependent, consistent, and durable knockdown of serum TTR

» Significant knockdown of serum TTR (p<0.01) up to 94% TTR knockdown; Mean knockdown up to 92.4%

Generally well tolerated

Excellent correlation of human to non-human primate TTR knockdown on mg/kg basis

100

80

60

40

20

0

-20

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

% M

ean

TT

R K

no

ckd

ow

n

Rela

tive t

o B

aselin

e (

± S

EM

)

2.5 (n=3) 5.0 (n=3)

10.0 (n=3)

Placebo (n=3)

ALN-TTRsc

dose groups

Zimmermann, Heart Failure Society of America, Sep. 2013

0

25

50

75

100

25 50 75 100

% Mean TTR KD in non-human primate %

Me

an

TT

R K

D in

hu

ma

n

R 2 = 0.83 p < 0.001

2.5

5.0

10.0

ALN - TTRsc (mg/kg)

21






100

80

60

40

20

0

-20

% T

TR

mR

NA

Sil

en

cin

g

(Rela

tive t

o C

ontr

ol)

ALN-TTRsc


mg/kg

5.0 1.0 0.2 Control

ALN-AT3


mg/kg

100

80

60

40

20

0

-20

% A

T m

RN

A S

ilen

cin

g

(Rela

tive t

o P

re-d

ose)

0.5 0.25 0.125 Control


22

Transitioning Standard Template Chemistry (STC) to

Enhanced Stabilization Chemistry (ESC)

5′-sense

5′-antisense

= 2′-F = 2′-O-methyl (GalNAc)3

Standard Template Chemistry, STC

(ALN-TTRsc)

5′-sense

5′-antisense


Enhanced Stabilization Chemistry, ESC

( ALN-AT3, ALN-PCS, ALN-AAT, ALN-CC5, ALN-AS1, etc. )

Lead

Optimization

by

Further

Stabilization

Chemistries

23 Manoharan, TIDES, May 2014

ESC Leads to Higher Liver Exposure Liver Exposure and Metabolic Stability

Metabolic profiling in liver 8h post dose

= Enzymatic cleavage site (thickness reflects frequency

of corresponding cleavage products observed)

Liver Exposure

Target Compound Tmax

(h)

Cmax

(µg/g)

AUC0-t

(h·µg/g)

AUC0-48

(h·µg/g)

AT3 STC 2 59.5 735 735

AT3 ESC 8 285 21546 9697

10

100

1000

10000

100000

1000000

0 50 100 150 200Liv

er

Co

ncen

trati

on

(n

g/g

)

Time (h)

SC

ESC

Liver Exposure

STC

24

= 2′-F = 2′-O-methyl

(GalNAc)3

S 5′

Standard Template Chemistry (STC)

AS 5′

5′ AS

S 5′

Enhanced Stabilization Chemistry (ESC)

Manoharan, TIDES, May 2014

ESC Significantly Enhances Efficacy and Duration Reduction of AT Protein After Single SC Dose in NHP

25

Potent and durable silencing achieved after single SC dose >10-fold improvement in efficacy over standard template chemistry

Substantially extended duration of effect

% K

no

ck

do

wn

Se

rum

AT

(R

ela

tive

to

Pre

-do

se

)

Day

100

80

60

40

20

1.0

1.2

-10 0 10 20 30 40

STC-AT3 (10 mg/kg)

ESC-AT3 (10 mg/kg)

ESC-AT3 (1 mg/kg)


Target KD Correlates with RISC-loaded siRNA

Tmax of RISC-loaded siRNA shifted relative to total siRNA

Rate of depletion of RISC-loaded siRNA slower than total siRNA

Amount of RISC-loaded siRNA correlates well with silencing activity

0 100 200 300 400 500 600 700 800 900

0

8000

16000

Time (h)

100

80

60

40

20

0

-20

% K

no

ckd

ow

n A

T m

RN

A

Rela

tive t

o c

ontr

ol

To

tal s

iRN

A in

liver (n

g/g

)

Total siRNA vs. mRNA Silencing

ALN-AT3 2.5 mg/kg

4.0

100

80

60

40

20

0

-20

0.0

2.0

0 100 200 300 400 500 600 700 800 900

Time (h)

% K

no

ckd

ow

n A

T m

RN

A

Rela

tive t

o c

ontr

ol

RIS

C-lo

ad

ed

siR

NA

(ng

/g)

RISC-loaded siRNA vs. mRNA Silencing

ALN-AT3 2.5 mg/kg

26 OTS, October 2013

Target Gene Silencing Very Low RISC-loaded siRNA Concentrations

27

EC50 for liver drug is ~100 ng siRNA/g tissue (>120 h post-dose)

EC50 for RISC-loaded drug is ~1.5 ng siRNA/g tissue (~800 molecules/cell)

» ~100x lower than EC50 values obtained for total siRNA

100

80

60

40

20

0

-20

1.0 10 100 1000 10000

% A

T m

RN

A S

ilen

cin

g

Total siRNA in liver (ng/g)

R2 = 0.859

% A

T m

RN

A S

ile

nc

ing

R² = 0.7111

100

80

60

40

20

0.1 10.0

RISC-loaded siRNA in liver (ng/g)

1.0

Total liver siRNA RISC-loaded siRNA

OTS, October 2013

ALN-PCSsc Achieves Potent, Highly Durable PD Pre-Clinical Efficacy in NHP with Single Dose

LDL-C PCSK9

Days

0 20 40 60 80 100

1.0 3.0 6.0 10.0

% P

CS

K9

Kn

oc

kd

ow

n

(re

lative

to

pre

-ble

ed

)

Days

0 20 40 60 80 100 120

% L

DL

-C L

ow

eri

ng

(re

lative

to

pre

-ble

ed

)

100

80

60

40

20

0

-20

80

60

40

20

0

-20

100

ALN-PCSsc (mg/kg)

ALN-PCSsc (mg/kg)

1.0 3.0 6.0 10.0

ALN-PCSsc achieves highly durable PCSK9 knockdown and LDL-C reduction with single dose Single SC dose 1-10 mg/kg

Up to 96% PCSK9 knockdown

Up to 77% LDL-C lowering in absence of statins

Highly durable effects, supports once-monthly and possibly once-quarterly dosing » >50% LDL-C lowering maintained for over 3 months in 10 mg/kg group

28 Fitzgerald, ATVB, May 2014

GalNAc Platform Improves With Multidosing ALN-AT3 in NHP

29

Rela

tive

Se

rum

AT

Leve

ls

(Pre

-do

se

=1

)

SD ED50 ~1 mg/kg

SD ED80 ~10 mg/kg

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

-14 0 14 28 42 56

Days

30 mg/kg 10 mg/kg 3 mg/kg 1 mg/kg

Single Dose

MD ED80 ~0.5 mg/kg

Equivalent to QM ~1-2 mg/kg

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

-5 0 5 10 15 20 25 30 35 40 45 50 55

Re

lati

ve

AT

Ac

tivit

y (

pre

do

se

= 1

)

Saline 0.25 mg/kg 0.5 mg/kg

QW x 6 Days

Multiple Dose

GalNAc Conjugates: Repeat-Dose Platform Chronic Dosing in Mice with ESC-mTTRsc

Steady knockdown maintained with chronic dosing Sustained knockdown at both ED50 (1 mg/kg) and ED80 (2.5 mg/kg) dose levels

Absence of tachyphylaxis or sensitization

No changes in serum TTR levels in PBS control group

30

% K

no

ck

do

wn

Se

rum

TT

R

(Fra

ction

P

re-d

ose

)

0 30 60 90 120 150 180 210 240 270

Long-Term Dosing: QW Dosing with ESC-mTTRsc

100

80

60

40

20

0

-20

PBS 1.0 mg/kg 2.5mg/kg

Day

ALN-AT3 Pre-Clinical Efficacy Potent AT Knockdown and Normalization of Thrombin Generation

31

ALN-AT3 achieves potent AT knockdown and fully corrects thrombin generation in non-human primates (NHP)

Weekly SC doses for >5 months result in potent, dose-dependent, and durable AT knockdown

In NHP hemophilia “inhibitor” model, ALN-AT3 fully restores thrombin generation to normal levels

Akinc, ISTH, July 2013

Recovery

Recovery 0.25 mg/kg qw x 12

Recovery 1.5 mg/kg qw x 5

100

80

60

40

20

0

-20 0 20 40 60 80 100 120 140 160

% M

ea

n A

T K

no

ck

do

wn

(P

re-d

ose

= 1

)

Day

1 mg/kg q2w x 4

0.125 mg/kg qw x 12 0.5 mg/kg qw x 8

Normal Hemophilia A (Induced)

Pre-dose

ALN-AT3 (mg/kg) qw

Rela

tive

Th

rom

bin

Ge

nera

tio

n

(Pe

ak T

hro

mb

in)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Saline

1.6

0.25

~60%

AT

KD

0.5

p<0.01

~80%

AT

KD

ALN-AT3 Phase 1 Study Dose-escalation Study in Two Parts

Study Design Randomized, single-blinded,

placebo-controlled SAD study in

healthy volunteers

Max allowable knockdown of 40%

Positive Topline Results At 0.03 mg/kg, AT knockdown of up

to 32% and increases in thrombin

generation (p<0.01) » Major implications for ESC-GalNAc

conjugate platform; ~50x improved

potency vs. ALN-TTRsc

Well tolerated, no significant AEs

Study Design Open-label, MAD study in

subjects with moderate to severe

hemophilia A or B (N=up to 18)

Primary Objective Safety and tolerability of multi-

dose in hemophilia subjects

Secondary Objectives Assess clinical activity

» AT knockdown

» Increase in thrombin generation

Status Part A SAD completed; Positive top-line results

Advanced to Part B MAD in patients

Initial data from Part B in late ’14

Part

A Part

B

32

Key Translational Data for GalNAc-Conjugates Standard Template Chemistry vs. Enhanced Stabilization Chemistry

Dose (mg/kg)

Single-dose

Nadir KD (%)

Multi-dose

(q weekly)

Nadir KD (%)

0.1 19 ± 20 27 ± 12

0.3 25 ± 11 48 ± 22

1 52 ± 12 81 ± 13

1.5 NT >95

3 70 ± 13 NT

10 82 ± 7 NT

Dose (mg/kg)

Single-dose

Nadir KD (%)

Multi-dose

(qdx5, q weekly)

Nadir KD (%)

1.25 22 ± 1 NT*

2.5 38 ± 12 58 ± 11

5.0 47 ± 1 88 ± 7

10.0 53 ± 8 92 ± 2

Standard Template Chemistry: ALN-TTRsc in Human

Dose (mg/kg)

Single-dose

Nadir KD (%)

0.03 28-32%

Enhanced Stabilization Chemistry: ALN-AT3 in Human

Enhanced Stabilization Chemistry: ALN-AT3 in NHP

Akinc, WFH, May 2014 33

A

5-10x Increased potency

with ALN-AT3 vs. ALN-

TTRsc

A

B

B 10x Increased potency

with SD to MD

C

C 10x Increased potency in

human vs. NHP

D

D ~50x Increased potency

in humans with ALN-AT3

vs. ALN-TTRsc

ESC-GalNAc Conjugates Appear More Stable in Human

vs. NHP

34

% FL siRNA

Remaining

Mouse liver cytosol 5

NHP liver cytosol 6

Human liver cytosol 66

Cytosol Stability

NHP liver S9 Human liver S9

Metabolite Profile

5′-sense


Standard Template Chemistry 5′-sense

5′-antisense


Enhanced Stabilization Chemistry


GalNAc-siRNA Conjugates: Safety Assessment Wide Therapeutic Index

ALN-TTRsc GalNAc-Conjugate Cytokine/Complement Assessment

» No evidence of inflammation (cytokine, complement) in vitro or in vivo, including NHP

GLP Toxicology Study Results » Rat doses up to 300 mg/kg (10 doses) well tolerated

– No in-life findings or ISRs

– NOAEL = 30 mg/kg

» Minimal to moderate histopathology in liver (vacuolation and single-cell necrosis of hepatocytes) with

correlating increased LFTs (minimal, less than 2-fold)

» NHP doses up to 300 mg/kg (10 doses) no adverse findings – No in-life findings or adverse ISRs

– No clin path or histopath findings

– NOAEL >300 mg/kg: Likely predictive species

GLP Chronic Toxicology ongoing » Rat and NHP up to 300 mg/kg well tolerated at 6 mo mark

ESC-GalNAc Conjugates Cytokine/Complement Assessment

» No evidence of inflammation (cytokine, complement) in vitro or in vivo, including NHP

Preliminary Toxicology Results » QW x 5 at 30, 100, 300

» 3 species: mouse, rat, NHP

» NOAEL >300 mg/kg – No in-life findings or adverse ISRs

– No significant changes in serum chem, ALT/AST

– No adverse histopath findings

35

Summary

36

Alnylam has developed an effective, well tolerated, SC-administered

GalNAc-conjugate platform with proven human clinical translation Human POC established with ALN-TTRsc and ALN-AT3

Enhanced Stabilization Chemistry (ESC) of siRNA-GalNAc conjugates

has led to increased metabolic stability Increased liver exposure

Improved potency: Up to 10-fold SD potency improvement and less

injection volume

Increased duration of effect, which further increases from rodents to

NHP to humans

Greater apparent stability in humans due to attenuated nuclease

environment as compared with other species

No compromise in tolerability

ESC-GalNAc conjugates enable a reproducible and modular platform

for RNAi therapeutics as new class of medicines

Agenda








Q&A Session

37

Upcoming RNAi Roundtables

ALN-HBV for the treatment of Hepatitis B Virus (HBV) Infection Tuesday, July 29 @ 9:30 a.m. – 10:30 a.m. ET Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence

Moderator: Laurence Reid, Ph.D., Senior Vice President and Chief Business Officer

Guest Speaker: Graham Foster, Ph.D., FRCP, Professor of Hepatology at Queen Mary University of London

ALN-AT3 for the treatment of Hemophilia and Rare Bleeding Disorders Thursday, August 7 @ 9:30 a.m. – 10:30 a.m. ET Akin Akinc, Ph.D., Director, Research

Moderator: John Maraganore, Ph.D., Chief Executive Officer

Guest Speaker: Flora Peyvandi, M.D., Ph.D., Head of the Department of Internal Medicine and Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, IRCCS Maggiore Hospital, University of Milan

ALN-CC5 for the treatment of Complement-Mediated Diseases Wednesday, August 13 @ 9:30 a.m. – 10:30 a.m. ET Benny Sorenson, M.D., Ph.D., Medical Director, Clinical Development

Moderator: Barry Greene, President and Chief Operating Officer

Guest Speaker: Anita Hill, MBChB (Hons), MRCP, FRCPath, Ph.D., Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Honorary Senior Lecturer at the University of Leeds

More roundtables to be scheduled in the coming weeks; visit www.alnylam.com/capella for updates ALN-AS1 for the treatment of hepatic porphyrias

ALN-PCSsc for the treatment of hypercholesterolemia

ALN-AAT for the treatment of AAT deficiency-associated liver disease

38

Select Scientific and Clinical Meetings Mid to Late ’14

ALN-AT3, ALN-CC5,

ALN-TMP American Society of Hematology (ASH)*

» December 6-9, San Francisco, CA

ALN-CC5 International Complement Society Workshop (ICSW)*

» September 14-18, Rio de Janeiro, Brazil

Patisiran American Neurological Association (ANA)

» October 12-14, Baltimore, MD

* Pending acceptance of abstracts

ALN-TTRsc

ALN-PCSsc American Heart Association (AHA)*

» November 15-19, Chicago, IL

Alnylam 5x15

GalNAc Conjugates Oligonucleotide Therapeutics Society (OTS)*

» October 12-15, San Diego, CA

American Society of Nephrology (Kidney Week)* » November 11-16, Philadelphia, PA

Alnylam 5x15

Alnylam 5x15 High Blood Pressure Research (HBPR)*

» September 9-12, San Francisco, CA

ALN-HBV AASLD (The Liver Meeting)*

» November 7-11, Boston, MA

39

www.alnylam.com

Thank You

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