Corporate Overview - Alnylam

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Corporate Overview November 2016

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© 2016 Alnylam Pharmaceuticals, Inc.

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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 forwardlooking statements. These important factors include our ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of our product candidates; pre-clinical and clinical results for our product candidates; actions or advice of regulatory agencies; delays, interruptions or failures in the manufacture and supply of our product candidates; our ability to obtain, maintain and protect intellectual property, enforce our intellectual property rights and defend our patent portfolio; our ability to obtain and maintain regulatory approval, pricing and reimbursement for products; our progress in establishing a commercial and ex-United States infrastructure; competition from others using similar technology and developing products for similar uses; our ability to manage our growth and operating expenses, obtain additional funding to support our business activities and establish and maintain business alliances; the outcome of litigation; and the risk of government investigations; 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.

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RNAi Therapeutics New Class of Innovative Medicines

Harness natural pathway

Catalytic mechanism Silence any gene in genome

Upstream of today’s medicines Clinically proven approach

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Key Features of Alnylam Investigational RNAi Therapeutics Potential Attributes for Differentiation and Value MAXIMUM KNOCKDOWN (KD) EFFICACY

CLAMPED PHARMACODYNAMICS (PD)

Up to

NOT

99% UNDRUGGABLE TARGETS ROOM TEMP DURABILITY As few as

2 VS.

26

doses per year

or more doses per year

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SUBCUTANEOUS (SC) ROUTE

Alnylam Reproducible and Modular Platform Strategic Framework for Innovative Medicines

1

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Genetically validated, liverexpressed target gene

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Biomarker for POC in Phase 1

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Definable path to approval and market

• • •

High unmet need disease Opportunity for highly competitive profile Delivery with GalNAc conjugate platform

• • •

Blood or urine based Informative disease correlation Establish dose/regimen for late-stage development



Clinical development plans with established endpoints Demonstrable value for payers



Alnylam Strategic Therapeutic Areas (STArs) Investigational pipeline focused in 3 STArs

Genetic Medicines RNAi therapeutics for rare diseases

Cardio-Metabolic Diseases RNAi therapeutics for dyslipidemia, NASH, type 2 diabetes, hypertension, and other major diseases

Hepatic Infectious Diseases RNAi therapeutics for major liver infections beginning with hepatitis B & D

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Alnylam Development Pipeline

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Hereditary ATTR Amyloidosis Patisiran and ALN-TTRsc02

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Hereditary ATTR Amyloidosis DESCRIPTION

PATIENT POPULATION*

Orphan disease caused by mutant transthyretin (TTR) amyloid deposits in nerves, heart and other tissues

~50,000

Significant morbidity and fatal within

2-15

hATTR Amyloidosis with polyneuropathy (hATTR-PN)

hATTR Amyloidosis with cardiomyopathy (hATTR-CM)

10,000

40,000

years from symptom onset

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worldwide

* Ando et al., Orphanet J Rare Dis, 2013; Ruberg et al., Circulation, 2012

RNAi Therapeutics for hATTR Amyloidosis Potential for Disease Modification by Reducing Pathogenic Protein

1

2

Genetically validated, liverexpressed target gene

Mutant Transthyretin (TTR) is disease-causing protein • Potential for highly competitive profile vs. TTR stabilizers

Biomarker for POC in Phase 1

Serum biomarker TTR • Causal in amyloid deposits in nerves (hATTR-PN) and heart (hATTR-CM) Streamlined clinical development plans

3

11

Definable path to approval and market

Established Endpoints: • Neurological Impairment Score (hATTR-PN) • 6 Minute Walk Distance (hATTR-CM)

Alnylam ATTR Amyloidosis Portfolio* Committed to Continued Innovation for Patients

patisiran

ALN-TTRsc02

hATTR-PN

ATTR

• IV administration

hATTR-PN, hATTR-CM & wtATTR

• Phase 2 completed

• ESC “second generation” chemistry

• Phase 2 Open-Label Extension (OLE) study ongoing

• Expect quarterly SC dose regimen



• Phase 1 ongoing; initial data expected in late-2016

Phase 3 trial ongoing; fully enrolled with topline results expected in mid2017

• APOLLO-OLE study ongoing

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*In October 2016, Alnylam decided to discontinue development of revusiran, which used STC “first generation” GalNAc chemistry and was being developed for treatment of hATTR-CM

Patisiran Interim Phase 2 OLE Study Results* Ongoing Study in hATTR-PN Patients Mean max

Mean

93%

-6.7

TTR KD clamped thru

point change in

24 months

24

mNIS+7 at months

>70%

TTR KD

patients show

improvement in

correlated with improvement in

mNIS+7

mNIS+7

scores

scores

Evidence for Potential Halting or Improvement of Neuropathy Progression Safety: Generally well tolerated out to 25 months • • •

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9 non-drug related SAEs in 6 patients Majority of AEs mild to moderate, including mild flushing (22.2%) and mild infusion-related reactions (18.5%) No significant lab findings, including platelets, and no drugrelated discontinuations

PLANNED NEXT STEPS

36-month Phase 2 OLE data in 2017

*Preliminary Phase 2 OLE results based on data in database as of May 12, 2016; Suhr, ISA, July 2016

APOLLO Phase 3 Study Design Enrollment Complete N=225

• Neurological impairment score (NIS) of 5-130 • Prior tetramer stabilizer use permitted

Patisiran IV q3W, 0.3 mg/kg

2:1 RANDOMIZATION

Patient Population • hATTR-PN: any TTR mutation, Stages 1 and 2

OR

Placebo IV q3W

Primary Endpoint at 18 months • mNIS+7 Key Secondary Endpoints • Norfolk QOL-DN • NIS-weakness • mBMI • 10-meter walk

All completers eligible for patisiran treatment on Phase 3 OLE study (APOLLO-OLE)

Enrollment completed; mid-2017 data readout, supporting 2017 NDA and MAA if positive Statistical Considerations • Placebo-estimated mNIS+7 progression rate of 17.8 points/year derived



from natural history study of 283 hATTR-PN patients 90% Power to detect as little as 37.5% difference in ΔmNIS+7 between treatment groups with 2-sided alpha=0.05

• Based on original target enrollment of 200 patients 14

Clinicaltrials.gov # NCT01960348

ALN-TTRsc02 Opportunity Potential for Best-in-Class Profile Revusiran/IONIS-TTRRx

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ALN-TTRsc02

4

DOSES PER YEAR

DOSES PER YEAR ANTICIPATED

PLANNED NEXT STEPS

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Phase 1 started

Initial Data

Phase 3 start

in June 2016

late 2016

in 2017

Decision to Discontinue Revusiran Development Description of Safety Findings as of October 4, 2016 Following ISA in July 2016, reports of new onset or worsening peripheral neuropathy in some revusiran Phase 2 OLE patients • Diligence with independent neurology experts led to conclusion that events likely consistent with disease • Data reviewed with ENDEAVOUR DMC; no changes to conduct of study recommended • Regulatory authorities and study investigators notified

Subsequently, additional reports of peripheral neuropathy and elevated blood lactate levels in Phase 2 OLE At Company request, ENDEAVOUR DMC met October 4, 2016 to review Phase 3 data in light of new safety information and to assess overall benefit-risk profile of revusiran • DMC reported no conclusive evidence of drug-related peripheral neuropathy signal • However, recommended suspension of dosing based on lack of favorable benefit-risk • Company subsequently reviewed unblinded ENDEAVOUR data which revealed imbalance of mortality in revusiran arm vs. placebo

Decision to discontinue all ongoing studies and further development of revusiran Conducting comprehensive evaluation of revusiran data - further update on progress of evaluation expected at December 16th R&D Day No evidence of drug-related peripheral neuropathy or cardiovascular mortality signal based on current assessment of safety data from >800 subjects/patients dosed across 9 other clinical programs, with 16 exposure of up to 34 months (as of Sep 30, 2016)

Hemophilia and Rare Bleeding Disorders Fitusiran

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Hemophilia and Rare Bleeding Disorders DESCRIPTION

PATIENT POPULATION*

Genetic deficiency resulting in inability to generate thrombin and to stop bleeding

Hemophilia A and B

178,500 worldwide

Highest need is prophylaxis for inhibitor patients and to avoid inhibitor formation in all patients

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Global need due to frequent IV infusions, ability to manufacture, and cold chain

3,500

* World Federation of Hemophilia, Report on the Annual Global Survey 2014 (October 2015)

with inhibitors

Fitusiran for Hemophilia Potential Game-Changing SC Therapy that Restores Hemostasis

1

2

3

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Genetically validated, liverexpressed target gene

Biomarker for POC in Phase 1

Definable path to approval and market

Antithrombin (AT) is key natural anticoagulant • Undruggable with mAbs or small molecules (SM)

Co-inheritance of AT deficiency with hemophilia associated with milder bleeding phenotype Plasma biomarkers measure components in coagulation cascade: • AT • Thrombin Generation

Two separate pivotal trials in inhibitor and on-demand patients Established Endpoint: Annualized Bleeding Rate (ABR)

Fitusiran Interim Phase 1 Study Results* Ongoing Study in Hemophilia A & B Patients, Including Inhibitors Up to mean

Up to

91%

290% increase in thrombin generation

AT lowering

Median estimated ABR of

0 in non-inhibitor patients

AT lowering, thrombin generation increases, and preliminary evidence of reduced bleeding in first inhibitor cohort

DURABILITY

Monthly SC fixed dose regimen

Evidence for Potential Restoration of Hemostasis in Severe Hemophilia A and B

Safety: Generally well tolerated •

No SAEs; majority of AEs mild or moderate o



Mild ISRs in 11 (35%) patients

One discontinuation due to AE considered severe, possibly drug-related o o o



Non-cardiac chest pain; associated transient increases in LFTs, D-dimer, CRP Extensive evaluation unremarkable; VTE excluded Event resolved with symptomatic management; antacids, analgesics

No thromboembolic events; no lab evidence for pathologic clot formation 20

*Interim Phase 1 study results as of July 11, 2016; Pasi et al., WFH, July 2016

PLANNED NEXT STEPS

Additional data at ASH in December 2016

Start Phase 3 studies in early 2017

Complement-Mediated Diseases ALN-CC5

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Complement-Mediated Diseases DESCRIPTION

PATIENT POPULATIONS*

Numerous debilitating diseases caused by abnormal complement activity In PNH, manage

breakthrough hemolysis and reduce burden of frequent IV infusions

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* Estimated based on Alexion’s Third Quarter 2015 Financial Results 1 eculizumab, trade name Soliris®, Alexion Pharmaceuticals, Inc.

- Paroxysmal noctural hemoglobinuria (PNH)

- Atypical hemolytic uremic syndrome (aHUS) - Neuromyelitis optica - Myasthenia gravis - and many others…

>5,000 Patients with PNH & aHUS on eculizumab1, initially

ALN-CC5 for Complement-Mediated Diseases Potential New Approach for Optimized Therapy

1

2

Genetically validated, liverexpressed target gene

Complement C5 is key component of terminal complement pathway; clinically validated in PNH & aHUS

Biomarker for POC in Phase 1

Serum biomarkers: • C5 • Serum hemolytic activity • Lactate dehydrogenase (LDH)

Small pivotal study in PNH patients

3

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Definable path to approval and market

Established endpoints: • LDH reduction • Blood transfusions

ALN-CC5 Initial Phase 1/2 Study Results* Initial Results in 6 PNH Patients Up to

LDH normalized for 1 month with

99%

75%

C5 KD

DURABILITY

Expect quarterly SC dose regimen

reduction in Ecu dose

Disease control in Ecu inadequate responder patient experiencing

breakthrough hemolysis

Significant improvement of Ecu PK with

>3x increase in Ecu trough levels

Potential opportunity to transform PNH with reduced burden of Ecu dose and frequency and to improve disease control in Ecu inadequate responder patients PLANNED NEXT STEPS

Safety: Generally well tolerated • • •

No SAEs, no discontinuations due to AEs In one patient, asymptomatic, transient grade 3 elevation of LFTs observed; possibly related Mild, transient ISRs observed in 3 patients

Start PNH Phase 2 at ASH in December 2016

Start monotherapy Phase 2 studies in other indications In 2017

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*Preliminary Phase 1/2 study results based on data transferred up to June 6, 2016; Hill, EHA, June 2016

Acute Hepatic Porphyrias ALN-AS1

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Acute Hepatic Porphyrias DESCRIPTION

PATIENT POPULATION*

Family of ultra-rare orphan diseases causing incapacitating and potentially fatal attacks

~5,000 ~1,000

Patients with sporadic attacks in U.S./EU

Patients with recurrent attacks in U.S./EU

Symptoms include:

- Severe Abdominal Pain - Peripheral and Autonomic Neuropathy - Neuropsychiatric Symptoms

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* ORPHANET; The Porphyria Consortium

Predominantly

female, commonly misdiagnosed

ALN-AS1 for Acute Hepatic Porphyrias Potential Transformative Therapy to Prevent Debilitating Attacks

1

2

Genetically validated, liverexpressed target gene

Biomarker for POC in Phase 1

ALAS1 is upstream of genetic defect in acute hepatic porphyrias • Liver-specific inhibition undruggable with SM

Up-regulation of ALAS1 results in accumulation of toxic intermediates – ALA and PBG – that drive disease

Serum and urinary biomarkers: • ALA • PBG

Small pivotal study in recurrent attack patients

3

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Definable path to approval and market

Endpoints: • Porphyria attack frequency and severity • ALA and PBG levels

ALN-AS1 Interim Phase 1 Study Results* Ongoing Study in Asymptomatic & Symptomatic Porphyria Patients Up to

Up to

Up to

64%

86%

95%

lowering of ALA

lowering of PBG

silencing of ALAS-1 mRNA

Durable ALA and PBG reductions, with effects lasting

>10 months after single dose

DURABILITY

Monthly and possibly quarterly SC dose regimen

Potent and Durable Lowering of Toxic Heme Synthesis Intermediates that Mediate Attacks

Safety: Generally well tolerated • 3 SAEs all deemed unlikely related to study drug, and no discontinuations • Majority of AEs reported were mild-moderate in severity • No clinically significant laboratory abnormalities related to study drug 28

PLANNED NEXT STEPS

Recurrent attack patient data at ASH in December 2016

Start Phase 3 in 2017

*Interim Phase 1 study results as of June 28, 2016; Sardh et al., SSIEM, September 2016

Hypercholesterolemia ALN-PCSsc

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Hypercholesterolemia DESCRIPTION

PATIENT POPULATION*

Highly prevalent disease caused by elevated levels of LDL-C that increase risk of atherosclerotic cardiovascular disease (ASCVD)

31 million

50%

About of patients discontinue statin therapy within one year, and adherence decreases with time

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* Mozaffarian et al., Circulation, 2015

in U.S. have LDL-C levels >240 mg/dL

Genetically defined patient subgroups:

Heterozygous FH Homozygous FH

ALN-PCSsc* for Hypercholesterolemia First-in-Class PCSK9 Synthesis Inhibitor

1

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Genetically validated, liverexpressed target gene

2

Biomarker for POC in Phase 1

3

Definable path to approval and market

* ALN-PCSsc also known as “PCSK9si”

PCSK9 protein decreases LDL-C receptor levels, resulting in elevated cholesterol in blood • Potential for highly competitive profile vs. anti-PCSK9 mAbs

Loss-of-function mutations in PCSK9 associated with lower LDL-C and decreased CV risk Serum biomarkers for regulation of cholesterol levels: • PCSK9 • LDL-C

Pivotal trial in broad population of ASCVD patients; focused FH studies Established Endpoint: LDL-C

ALN-PCSsc* Interim Phase 1 Study Results† Study in Volunteers with Elevated LDL-C Up to

94% PCSK9 KD

Up to

At 6

64% mean maximum LDL-C lowering

months

47% LDL-C after 1 dose

LSM reduction in

Potential Bi-annual SC Dosing Regimen with LDL-C Lowering Comparable to Bi-monthly mAbs** Safety: Generally well tolerated • No SAEs, no drug-related discontinuations; all AEs mild or moderate • At higher drug exposures, 4 mild ISRs (8%) • One subject with ALT ~4x ULN, attributed to concomitant statins

Phase 2 enrollment completed with

501 ASCVD patients in June 2016

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* ALN-PCSsc also known as “PCSK9si” † Preliminary Phase 1 study results as of September 24, 2015; Fitzgerald, AHA, November 2015 ** Based on reported data (Zhang et al., BMC Med., 2015); no direct head-to-head studies have been performed ‡ The Medicines Company is leading and funding development of the ALN-PCSsc program from Phase 2 onward and will commercialize the program, if successful

PLANNED NEXT STEPS‡

Initial Phase 2 data at AHA in November 2016

Start Phase 3 in 2017

Other Programs to Watch in 2016

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Primary Hyperoxaluria Type 1 (PH1) ALN-GO1 DESCRIPTION

PATIENT POPULATION*

Genetic mutations lead to excessive oxalate production, resulting in recurrent kidney stones and extensive renal damage

~5,000

DRUG MECHANISM

ALN-GO1 targets glycolate oxidase (GO), an enzyme upstream from the genetic defect, for potential lowering of oxalate levels

Primarily affects children

Sustained through

85 days at highest dose

DURABILITY

Monthly and possibly quarterly SC dose regimen

Safety: Generally well tolerated • No SAEs or discontinuations due to AEs • All AEs mild or moderate, with exception of one subject with transient, asymptomatic CPK elevation deemed unrelated to study drug 34

* Cochat et al., N Engl J Med, 2013

worldwide

Up to

8-fold increase in plasma glycolate in healthy volunteers

PLANNED NEXT STEPS

Oxalate lowering data in PH1 patients in 2017

Milliner et al., IPNA, September 2016

Hepatitis B Virus (HBV) Infection ALN-HBV Pre-clinical results:‡ DESCRIPTION

up to

Viral infection leading to cirrhosis and hepatocellular carcinoma (HCC)

3.6

log10

HBsAg reduction PATIENT POPULATION*

1/3 of global

population exposed

>4

log10

reduction in viral DNA in chronically infected chimps

~290M patients worldwide, 25M in U.S./EU/Japan with chronic infection DRUG MECHANISM

Phase 1/2 Initiated in July 2016

ALN-HBV targets all four transcripts of viral genome for potential reduction of HBsAg levels and increase in seroconversion rates 35

PLANNED NEXT STEPS

Initial clinical data in mid-2017

* Schweitzer et al. Lancet 386:1546-1555, 2015; Basnayake, S.K. and Easterbrook, P.J., J. Viral Hepatitis 23: 545-559, 2016 ‡ Sepp-Lorenzino, Liver Meeting, November 2015

Guidance and Goals

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Potential Multi-Year Pipeline Progression

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Potential Multi-Year Pipeline Progression

>10 Clinical readouts in 2016

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Potential Multi-Year Pipeline Progression

>5 Programs in Phase 3 in 2017

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Potential Multi-Year Pipeline Progression

1st Phase 3 data readout and, if positive,

NDA in 2017

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Alnylam 2016 Pipeline Goals* *Goals as updated in 8/16 **Early is Q1-Q2, Mid is Q2-Q3, and Late is Q3-Q4

PATISIRAN

2016** Early

Complete APOLLO Phase 3 Accrual

(hATTR-PN)

Phase 2 OLE 24 Month Data

REVUSIRAN‡

Complete ENDEAVOUR Phase 3 Accrual

(hATTR-CM)

Phase 2 OLE 12 Month Data CTA Filing

ALN-TTRsc02 (ATTR Amyloidosis)

Start Phase 1 Initial Phase 1 Data

FITUSIRAN

Phase 1 Data

(Hemophilia and RBD)

Phase 1/2 OLE Data

ALN-CC5

Phase 1/2 Data

(Complement-Mediated Disease)

Phase 2 PNH Start

ALN-AS1

Phase 1 Data

(Hepatic Porphyrias) ALN-AAT‡ (Alpha-1 Antitrypsin Deficiency)

ALN-GO1

Initial Phase 1 Data

Start Phase 1

(Primary Hyperoxaluria)

Initial Phase 1 Data

New Genetic Medicine Program

CTA Filing

ALN-PCSsc

Initial Phase 2 Data

(Hypercholesterolemia)

ALN-HBV

CTA Filing

(Hepatitis B Virus Infection)

Start Phase 1

42 42 ‡ Alnylam discontinued development of ALN-AAT and revusiran in September and October 2016, respectively

Mid

Late

Select Scientific and Clinical Meetings Late 2016

ALN-PCSsc

Fitusiran ALN-CC5 ALN-AS1

Conference

Date (Location)

Expected Presentation(s)

American Heart Association (AHA) Scientific Sessions

November 15 (New Orleans)

ALN-PCSsc ORION-1 Phase 2

American Society of Hematology (ASH) Annual Meeting

December 3-6 (San Diego)

Fitusiran Phase 1, Parts C and D (highest and fixed dose cohorts, including inhibitor patients); Initial Fitusiran Phase 1/2 OLE; ALN-CC5 Phase 1/2 (PNH patients); ALN-AS1 Phase 1, Initial Part C data (recurrent attack patients)

ALN-TTRsc02 Corporate

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R&D Day 2016

December 16 (New York)

ALN-TTRsc02 Phase 1

Financial Summary and Guidance 2016 Q3 Financial Results • Cash ~$1.2B ◦ Includes $150.0 million in restricted investments • GAAP Revenues $13.7M • Total GAAP Operating Expenses $120.3M

◦ Research and Development Expense $97.9M ◦ General and Administrative Expense $22.4M • GAAP Net Loss of $104.1M • Shares Outstanding ~85.8M

2016 Guidance • Year-end cash >$1.0B

◦ Includes $150.0 million of restricted investments received from credit agreements related to build out of new drug substance manufacturing facility

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Thank You

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Backup Slides

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Exposure Levels with Revusiran Significantly Higher than other GalNAc Conjugate Programs Annualized Exposure Levels 30

STC-GalNAc conjugate

ESC-GalNAc conjugates

Exposure Year Equivalents Relative to Revusiran STC-GalNAc conjugate

Revusiran 500mg qW

25

Fitusiran 80mg qM

Grams of drug

20 ALN-PCSsc 300mg q3M

ESC-GalNAc conjugates

ALN-PCSsc 300mg q6M

15

ALN-CC5 600mg q3M 10 ALN-AS1 2.5mg/kg qM 0

5

20

30

Years

0 Revusiran 500mg qW

47

10

Fitusiran 80mg qM

ALN-PCSsc ALN-PCSsc ALN-CC5 ALN-AS1 300mg q3M 300mg q6M 600mg q3M 2.5mg/kg qM

40

50

Return to Previous Slide

Patisiran Phase 2 OLE Preliminary Study Results* Summary of Safety and Tolerability Common Adverse Events (AEs) in ≥10% of patients AE by Preferred Term

48

Patisiran (N=27)

Flushing

7 (25.9%)

Diarrhea

6 (22.2%)

Nasopharyngitis

6 (22.2%)

Urinary tract infection

6 (22.2%)

Vomiting

6 (22.2%)

Wound

6 (22.2%)

Infusion related reaction

5 (18.5%)

Nausea

5 (18.5%)

Insomnia

4 (14.8%)

Neuralgia

4 (14.8%)

Pyrexia

4 (14.8%)

Anemia

3 (11.1%)

Bronchitis

3 (11.1%)

Edema peripheral

3 (11.1%)

Macular degeneration

3 (11.1%)

Musculoskeletal pain

3 (11.1%)

Osteoporosis

3 (11.1%)

*Adams et al., ISA, June 2016; Data as of 12May2016

• 6 patients (22.2%) with 9 reports of serious adverse events (SAEs); not related to study drug ◦ One discontinuation for gastroesophageal cancer at ~20

◦ ◦

months; patient subsequently died One death due to myocardial infarction after patient completed 24 months of treatment One patient with 3 reports (distal femur fracture/proximal tibia fracture/osteonecrosis/ligament rupture, dehydration/acute prerenal failure/urinary tract infection and thermal burn); one patient with 2 reports (ankle fracture/foot fracture/ osteonecrosis and ankle arthrodesis); one patient with venous thrombosis of the lower limb; one patient with foot abscess and osteomyelitis

• Majority of AEs were mild or moderate ◦ 4 patients (14.8%) had severe AEs not related to study drug ◦ Most common related AEs reported in > 3 patients were flushing (6 patients [22.2%]) and infusion related reaction (5 patients [18.5%]), all of which were mild

• No clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelets

Return to Previous Slide

Patisiran Phase 2 OLE Preliminary Study Results*

Mean (SEM) % Serum TTR Knockdown Relative to Baseline

Serum TTR Knockdown Post-dose Pre-dose

0

20

40

60

N=22 80

N=23 N=24-27 at all other time points

N=21

100 0

2

4

6

8

10

12

14

16

18

20

22

24

26

Months

• • • • • 49

Mean serum pre-dose TTR knockdown of approximately 80% Mean serum TTR knockdown at 24 months of 84% Mean maximal serum post-dose TTR knockdown of 93% Maximal individual patient post-dose knockdown of 97% Similar TTR knockdown in patients on patisiran alone or on patisiran + TTR tetramer stabilizers SEM: Standard Error of the Mean *Adams et al., ISA, June 2016; Data as of 12May2016

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Patisiran Phase 2 OLE Preliminary Study Results* Change in mNIS+7 Over 24 Months 150 125

mNIS+7

100 75 50 25 0 0

6

12

18

Months

Change from Baseline to Month 24 (N=24) mNIS+7 component

Mean (SEM)

Median (range)

Total+

-6.7 (2.3)

-6.8 (-34.6, 15.4)

NIS-weakness

1.38 (1.5)

0 (-13.5, 24.4)

NIS-reflexes

-0.1 (0.5)

0 (-6.0, 7.0)

QST

-7.7 (2.2)

-6.0 (-40.0, 16.0)

NCS Σ5

-0.2 (0.2)

-0.3 (-2.0, 2.5)

Postural BP

-0.1 (0.1)

0 (-1.0, 0.5)

+Partial

imputation was used to recover mNIS+7 data points where components were missing at one or more replicate measurements (per patient/visit)

50

*Data as of 12May2016

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Patisiran Phase 2 OLE Preliminary Study Results* Change in mNIS+7 at 24 Months 17 out of 24 patients (71%) with no change or an improvement in mNIS+7 at 24 months compared to baseline

Mean ΔmNIS+7 from baseline at 24mos

20 15 10 5 0 -5 -10

-15 -20

20 15

Patisiran Ph 2 OLE†* (N=24)

5 0 -5 -10

-15

//

//

Diflunisal Ph 3 Study2+

-6.7 (2.3)

-20 -25

-30

-30

Individual ΔmNIS+7 at 24mos in Patisiran Ph 2 OLE

9.2 (2.7)

10

-25

-35

51

25

25.8 (9.4)

Placebo (N=66) Diflunisal (N=64)

Mean (SEM) ΔmNIS+7 from baseline at 24mos~

25

29.6 (3.1)

30

Natural History (nonlinear; N=283)1#

30

-35

Mean ΔmNIS+7 Across hATTR-PN Studies at 24 mos~

SEM: Standard Error of the Mean ~ Assessments drawn from studies in patients with similar baseline neurologic impairment and not based on head-to-head studies 1Adams D et al., Neurology. 85;675-682 (2015); #Predicted progression of median NIS value from Gompertz curve fit1 2Berk JL et al., JAMA. 310:2658-67 (2013); +Linear interpolation from 2-year NIS progression measurement in longitudinal analysis set † Patisiran results similar in patients with/without concurrent TTR stabilizer therapy; mNIS+7 using full mNIS+7 set; partial imputation was used to recover mNIS+7 data points where components were missing at one or more replicate measurements (per patient/visit) *Adams et al., ISA, June 2016; Data as of 12May2016

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Patisiran Phase 2 OLE Preliminary Study Results* Correlation of TTR Knockdown with ΔmNIS+7 40

40

6 months (N=27)

30

(N=27)

20

ΔmNIS+7

ΔmNIS+7

20 10 0

10 0

-10

-10

-20

-20

-30

12 months

30

r= -0.49 , p= 0.0099 50

60

70

r= -0.55 , p= 0.0029

-30 80

90

100

50

60

Percent (%) TTR KD† 40

18 months

30

(N=27)

10 0

-10

90

100

40

24 months

30

(N=24)

90

100

10 0

-10

-20

-20

r= -0.37 , p= 0.055 50

60

70

r= -0.31 , p= 0.15

-30 80

90

100

50

Percent (%) TTR KD† 52

80

20

ΔmNIS+7

ΔmNIS+7

20

-30

70

Percent (%) TTR KD†

Note: three patients had missing D17 TTR: one was replaced by D7 and two replaced by D84. † Percent (%) TTR knockdown from baseline at Day 17 post-first dose of patisiran *Adams et al., ISA, June 2016; Data as of 12May2016

60

70

80

Percent (%) TTR KD†

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Superior TTR Knockdown with ALN-TTRsc02 ALN-TTRsc02 Compared to Revusiran in NHP** 1 mg/kg ALN-TTRsc02

5 mg/kg Revusiran; QD x 5, QW x 4

Serum TTR (Fraction Pre-dose)

1.2 1.0 0.8

QDx5, QWx4 5 mg/kg Revusiran

0.6

SD 1 mg/kg ALN-TTRsc02

0.4 0.2 0.0 0

10

20

ALN-TTRsc02

30

40

50

60 Days

70

80

53

Meyers, OTS, Oct. 2015

100

110

120

Cumulative Dose (mg/kg)

eAUC (ug/mL*day)

Revusiran

45

19405 ± 1559

ALN-TTRsc02

1

8626 ± 1774

Revusiran **Data on graph does not represent a side by side study. The two NHP studies were performed independently.

90

Return to Previous Slide

Interim Fitusiran Phase 1 Study Results* Safety/Tolerability†, Parts B, C, & D

• No SAEs related to study drug • Majority of AEs mild or moderate in severity

◦ AEs (excluding ISRs) in ≥10% of patients

– Upper respiratory tract infection (10%), arthralgia (10%)

• 11 (35%) patients reported drug-related ISRs, all mild

◦ Mostly pain and/or erythema at injection site

• One patient discontinued due to AE of non-cardiac chest pain; considered severe and possibly related

◦ Associated with transient elevations of ALT (10x ULN), AST (8x ULN), CRP and D-dimer; no ◦ ◦

increase in total bilirubin Extensive evaluation unremarkable; VTE excluded by serial CT angiograms and liver and lower extremity ultrasound This event resolved with symptomatic management, including antacids and analgesics

• No thromboembolic events or laboratory evidence of pathologic clot formation (D-dimer, platelet count, fibrinogen, and/or PT/INR) • With exception of case noted above, no other clinically significant drug-related changes in laboratory parameters • No instances of anti-drug antibody (ADA) formation • Bleed events successfully managed with infusion of standard replacement factor or bypass agents 54

*Data transfer up to 11July2016 Pasi et al., WFH, July 2016 †Adverse event grouping based on MedDRA-coded terms, excluding bleed events

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Interim Fitusiran Phase 1 Study Results* AT Lowering, Part C AT lowering after monthly dosing in patients with hemophilia A and B 125

% Mean (+/- SEM) AT Activity Relative to Baseline

Cohort 1 225 mcg/kg (N=3) Cohort 4 1800 mcg/kg (N=3)

Cohort 2 450 mcg/kg (N=3) Cohort 5 80 mg (N=6)

Cohort 3 900 mcg/kg (N=3)

100

75

50

25

0 0

20

40

60

80

100

120

140

Days since first dose Onset

55

*Data transfer: 30Jun2016 Pasi et al., WFH, July 2016

Observation

160

180

200

220

Return to Previous Slide

Interim Fitusiran Phase 1 Study Results* AT Lowering, Parts A, B & C Dose-dependent AT lowering Mean maximal AT lowering of 87 ± 1% at 80 mg fixed dose Relative Nadir AT Level (Mean +/- SEM, %)



100 90 80 70

60 50 40 30 20 10 0 30 mcg/kg (n=3)

Part A (Single dose)

56

*Data transfer: 30Jun2016 Pasi et al., WFH, July 2016

15 mcg/kg (n=3)

45 mcg/kg (n=6)

Part B (Weekly dose)

75 mcg/kg (n=3)

225 mcg/kg (n=3)

450 mcg/kg (n=3)

900 mcg/kg (n=3)

Part C (Monthly dose)

1800 mcg/kg (n=3)

80 mg (n=6)

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Interim Fitusiran Phase 1 Study Results* Thrombin Generation, Part B & C Post hoc analysis of thrombin generation by AT lowering quartiles • Mean thrombin generation increase of 289% relative to baseline at AT lowering >75% (p2 log10 HBsAg reduction lasting >30 days ◦ Multiple SC doses achieve >2 log10 HBsAg reduction lasting >90 days Single SC Dose

Multiple SC Doses Control 9 mg/kg 3mg/kg 1mg/kg 0.3mg/kg

10

(Normalized to d0)

% HBsAg serum levels (normalized to pre-dose)

100

% HBsAg Plasma Levels

1000

100

10

1

LLOQ

LLOQ 0.1 ng/ml 0.1

1 0

20

40

60

80

-14 -7 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98105112119126133140147

Time (days)

Time (days) Pre-dose HBsAg titer range ~10-500 ng/mL

76

Sepp-Lorenzino, Liver Meeting, November 2015

AAV-HBV 1011 VG

ALN-HBV 3 mg/kg qWx3, SC

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