1

Path to Alnylam 2020

R&D Day 2015

John Maraganore, Ph.D., Chief Executive Officer

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What we’re about: RNAi Therapeutics

• Harness natural pathway

◦ Catalytic mechanism

◦ Mediated by small interfering RNA

or “siRNA”

• Therapeutic gene silencing

◦ Any gene in genome

◦ Distinct mechanism of action vs. other

drug classes

◦ Unique opportunities for innovative

medicines

• Clinically validated platform

◦ Human POC in multiple programs

– Papers in NEJM and Lancet

A New Class of Innovative Medicines

3

RNAi therapeutics as genetic medicines

• In 2011: 5 Key products in clinical

development through 2015

• Expect to greatly exceed 2011 guidance ◦ 8 in Clinic

◦ 2 in Phase 3

◦ 6-7 with Human POCs

Product characteristics

Genetically defined target/disease

Existing Alnylam delivery platform

Phase 1 proof of concept

Clear and rapid development

Significant commercial opportunity

Focused Product Development Pipeline for Genetic Medicines

Where we were: Alnylam 5x15TM

4 4

Where we’re going…

5

6

>10 Clinical

Read-outs

in 2016

7

>5 Programs in

Phase 3 in

2017

8

1st Phase 3 data read out

in 2017

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How do we get there?

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#1: Capital

Strong Cash Position

• Q3 ’15 cash ~$1.34B

• Year-end cash guidance >$1.2B

Alnylam-Genzyme Genetic

Medicine Alliance

• Valued at well over $1B

◦ Equity

◦ R&D funding

◦ Milestones

◦ Royalties

Financial Resources to Drive Pipeline Forward

CAMBRIDGE, MA

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#2: Reproducible and Modular Platform Risk-Mitigating Development Strategy Applied Across Programs

1

Genetically

validated, liver-

expressed target

gene

• Liver-expressed targets involved in

disease with high unmet need and

validated through human genetics

• Delivery with GalNAc conjugate

platform

2 Biomarker for POC

in Phase 1

• Blood- or urine-based biomarkers

with strong disease correlation

• Establish dose/regimen for late-

stage development

3 Definable path to

approval and

market

• Clinical development plans with

focused trial size and established

endpoints

• Definable value for payers

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#2: Reproducible and Modular Platform Rapid Path from Idea to Human POC with 100% Success to Date

IDEA DEVELOPMENT

CANDIDATE

CTA/IND HUMAN POC

6 months 12-18 months 6-9 months

Success Rate at

each stage to date: 100% 100% 100%

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#2: Reproducible and Modular Platform Fundamentally New Approach to Drug Development

0

100

100 % Mean KD in NHP

% M

en

KD

in

hu

man

Excellent

Translation

Select

Dose/Regimen

Increased POS

due to Genetically

Validated Targets Phase 3

Data

100

80

60

40

20

0

0 1 2 3 4

Months

% M

ean

KD

Start of

Phase 3

Human

POC

Pre-

clinical

POC

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#3: Competitive and Differentiated Profiles Robust Human Experience to Date*

Number of Programs 7

Number of Clinical Studies 16

Total Patients or Volunteers

Dosed >300

Longest Duration of Exposure >24 months

Total siRNA Doses Administered >4,500

*Numbers are approximate as many studies are ongoing

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#3: Competitive and Differentiated Profiles Potent and Durable Knockdown of Target Proteins

Mean

(S

EM

) %

AL

A R

ed

ucti

on

-100

-75

-50

-25

0

25

50

0 5 10 15 20 25 30 35 40 45

Time (Days)

Placebo

0.035 mg/kg

0.1 mg/kg

0.35 mg/kg

1.0 mg/kg

ALN-AS1

Mean

(S

EM

) %

AT

Lo

weri

ng

Time (Days)

0

25

50

75

100

125

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160

225 mcg/kg

450 mg/kg

900 mcg/kg

1800 mcg/kg

Fitusiran

Mean

(S

EM

) %

C5 K

no

ckd

ow

n

Time (Days)

100

80

60

40

20

0

-20

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190

50 mg 200 mg 400 mg

600 mg 900 mg

Placebo

ALN-CC5

Mean

(S

EM

) P

CS

K9 K

no

ckd

ow

n

100

80

60

40

20

0

-20

-40

-60

Time (Months) 0 1 2 3 4 5 6

Placebo

25 mg

100 mg

300 mg

500 mg

800 mg

ALN-PCSsc

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#3: Competitive and Differentiated Profiles RNAi vs. Monoclonal Antibody (MAb)

mRNA

Protein Synthesis

Nucleus

RNAi siRNA durably blocks protein

synthesis in catalytic process

26 doses/year

2 doses/year

MAbs Transiently block protein in

stoichiometric process, consumed

by ongoing protein synthesis

Clamped effect

Saw-tooth effect

GalNAc

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#3: Competitive and Differentiated Profiles RNAi vs. Monoclonal Antibody (MAb)

mRNA

Protein Synthesis

Nucleus

RNAi siRNA durably blocks protein

synthesis in catalytic process Clamped effect

26 doses/year

2 doses/year

MAbs Transiently block protein in

stoichiometric process, consumed

by ongoing protein synthesis

Potential resurgence of

disease symptoms

Sustained suppression

of disease symptoms

GalNAc

Saw-tooth effect

Clamped effect

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#3: Competitive and Differentiated Profiles

2nd Gen ESC-

GalNAc siRNA

ESC-GalNAc siRNA vs. ASO Dosing

Gen 2.0/2.5 ASO &

1st Gen STC-GalNAc

siRNA

GalNAc-ASO aka

“LICA”

52 DOSES PER YEAR 2 12 DOSES PER YEAR DOSES PER YEAR

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#4 Large Number of Opportunities Liver Targets across 3 Strategic Therapeutic Areas (STArs)

Cardio-Metabolic Disease

Genetically validated liver

targets for dyslipidemia,

NASH, type 2 diabetes,

and hypertension

Development path in

genetically defined,

high unmet need

subpopulations

o Access to larger

populations thereafter

Emerging genetics

qM, qQ, or potentially

bi-annual SC dosing

Partnership opportunities

Hepatic Infectious Disease

Liver pathogen and/or

host targets

Sub-acute duration of

treatment (~12 mo)

Multiple siRNAs possible,

if needed

Defined opportunities with

very large markets

qM or qQ SC dosing

Partnership opportunities

Genetic Medicines

• Genetically validated

liver targets for rare

orphan diseases

• High unmet needs in

focused markets

• SC dosing

• Alnylam direct

commercial in NA and

EU

• Genzyme alliance for

ROW commercial

◦ Through end-2019