ALN-HBV Roundtable Slides.FINAL - Alnylam | … of global population exposed ~290M patients...

ALN-HBVInvestigational RNAi Therapeutic for the Treatment of

Chronic Hepatitis B Virus (HBV) Infection

Tuesday, October 11, 2016

AgendaWelcome• Josh Brodsky, Associate Director, Investor Relations & Corporate Communications

Introduction• Pushkal Garg, M.D., Senior Vice President, Clinical DevelopmentALN-HBV Program• Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence

Overview of Chronic Hepatitis D Virus (HDV) Infection• Heiner Wedemeyer, M.D., Managing Senior Physician and Assistant Professor in

the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School

Q&A Session

Reminders

Event will run for approximately 60 minutes

Q&A Session at end of presentation• Submit questions at bottom of webcast screen• Questions may be submitted at any time

Replay, slides and audio available at www.alnylam.com

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 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.

Q&A Session

RNAi TherapeuticsNew Class of Innovative Medicines

Harness natural pathway

Catalytic mechanism

Silence any gene in genome

Upstream of today’s medicines

Clinically proven approach

Alnylam Strategic Therapeutic Areas (STArs)

Investigational pipeline focused in 3 STArs

Genetic Medicines

Cardio-Metabolic Diseases

Hepatic Infectious Diseases

RNAi therapeutics for rare diseases

RNAi therapeutics for dyslipidemia, NASH, type 2 diabetes, hypertension, and other major diseases

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

Alnylam Development Pipeline

Q&A Session

DRUG MECHANISM

By silencing all viral products including tolerogenic antigens, ALN-HBV is expected to have direct antiviral effects and increase seroconversion rates

Phase 1/2 StartedJuly 2016

PATIENT POPULATION*

1/3 of global population exposed

~290M patients worldwide25M in U.S./EU/Japan with

chronic infection

DESCRIPTION

Viral infection leading to cirrhosis and hepatocellular carcinoma (HCC)

Hepatitis B Virus (HBV) InfectionALN-HBV

Schweitzer et al. Lancet 386:1546-1555, 2015; Basnayake, S.K. and Easterbrook, P.J., J. Viral Hepatitis 23: 545-559, 2016

ALN-HBV for Chronic HBV Infection

Geneticallyvalidated, liver-expressed target gene

Hepatitis B Virus• Direct acting RNAi against infectious agent• Multiple, synergistic antiviral mechanisms

• Silencing of viral lifecycle (pgRNA, POL, S, X, core)

• Silencing of tolerogenic antigens (S Ag and e Ag, core)

2 Biomarker for POC in Phase 1

Serum viral biomarkers• Viral DNA• Viral antigens: HBsAg, HBeAg• Hepatitis: ALT

3Definable path to approval andmarket

Endpoint: sustained virological response off all therapies after finite therapy

Combination with standard of care Polymerase inhibitors (NUCs) and novel agents

3980 HBV complete genomes, A-H

pg RNA 3.5 kbPreS1 2.4 kbPreS2 2.1 kb

X 0.7 kbALN-HBV

Sepp-Lorenzino, Liver Meeting, November 2015

ALN-HBV Targets a Highly Conserved Sequence in HBV X Orf

• Target site is conserved across genotypes A-J• Perfect homology (2-18): 97.2%• Allow 1 mismatch: 99.7%

• Site is upstream from integration hotspot

• Up to 3.6 log10 HBsAg reduction• Single SC dose achieves >2 log10 HBsAg reduction lasting >30 days

Sepp-Lorenzino, Liver Meeting, November 2015

ALN-HBV Mediates Potent and Highly Durable HBsAg Knockdown in AAV-HBV Murine Model

5′-AS

5′-SS

HBsAgIHC

Control

ALN-HBV 3 mg/kg

ALN-HBV Target Product Profile

Indication • Chronic hepatitis B (CHB) treatment – enable functional cures

Dose and Regimen

• 100-200 mg fixed dose monthly • 12-24 months in combination standard of care

Route of Administration • Subcutaneous injection, 1-2 mL injection volume, self-administration

Efficacy • Long-term treatment-free suppression of HBV DNA

POM/POC Endpoints

• Proof-of-mechanism (1o endpoint)• >2 log10 nadir in serum HBsAg (or <100 IU/mL)

• Clinical proof-of-concept: 6 months post-treatment suppression of HBV DNA

Safety• <1% incidence of drug discontinuation due to ALN-HBV related AEs• Well-tolerated, including in combination with immune-modulator therapy

ALN-HBV Target Product ProfileFunctional Cure of CHBALN-HBV, by suppressing the production of tolerogenic HBV antigens, promotes the emergence of effective host immunity to HBV, with potential to achieve long-term functional cure

ALN-HBV Phase 1/2 StudyPrimary objectivesSafety, tolerability

Part B: Single-Ascending Doses in Pts on NUC tx for >12 months (SAD) │Randomized 3:1, 4-7 cohorts, N=16-28

Part C: Multiple-Ascending Dose (MAD) in Pts on NUC tx for >12 months I Randomized 6:2, 3-6 cohorts, N=24-48

0.1 mg/kg as starting dose

Part A: Single-Ascending Doses in HV (SAD) │Randomized 3:1, 4-6 cohorts, N=16-24

0.1 mg/kg dose

Secondary objectivesPK & antiviral activity (sAg, eAg, HBV DNA)

0.3 mg/kg dose

1.0 mg/kg dose

3.0 mg/kg dose

2 Optional cohorts

0.3 mg/kg dose

1.0 mg/kg dose

3.0 mg/kg dose

3 Optional cohorts

Starting dose TBD, Q4W*4 doses

clinicaltrials.gov_NCT02826018

Part A initiated July 2016

RNA Therapeutic Strategies for HBVCompetitive Landscape

ALN-HBV ARC-520 ARC-521 ABUS-1467 IONIS-HBV-LRx

Potency in Humans

(mean sAg ↓)TBD

0.3-0.4 log in eAg +ETV-Rx eAg +/- pt

1 log in Rx naïve eAg+ ptat 4 mg/kg

0.2-0.3 & 0.6 log in eAg- pt at 0.2

mg/kg SD & MDUndisclosed Undisclosed

Phase Phase 1/2 Phase 2 Phase 1 Phase 1/2 Phase 2# of TargetSequences 1 2 2 3 1

Orf Targeted X X X and S X and S X

Delivery GalNAc-siRNA (ESC)

Cholesterol siRNA plus GalNAc-Mellitin-Like Peptide (MLP) Lipid Nanoparticle GalNAc-ASO

Administration SC injection IV infusion IV infusion IV infusion SC injection

Pre-medication None Oral Antihistamine Steroids None

Source: ARWR, ABUS and Ionis company websites

Chronic Hepatitis D Virus (CHD) Infection

• HDV is RNA sub-virus, which can only propagate in presence of HBV

• 15-20M patients infected WW, 80K in US• Acquired at same time or subsequent to HBV

infection• No curative therapies available

Target Product Profile for ALN-HBV in HDV ◦ HDV Suppression

– Chronic, on-going therapy to inhibit HBsAg production thereby suppressing HDV replication and HDV viremia

◦ HDV Cure– Finite treatment resulting in functional CHB cure thereby

resulting in CHD cure

Gish et al. 2013; Farci & Niro, 2012; Ciancio & Rizzetto 2014; http://hepatitis-delta.org/

Chronic HBV/HDV infection is more aggressive than CHBNo therapies available

ALN-HBV Product Opportunity with Target Profile

Potential for CHB functional cures & CHD chronic treatment• Potent and durable silencing of all HBV gene products◦ Elicit multiple synergistic antiviral mechanisms in both CHB and CHD

• Pan-genotypic, conserved site◦ Combination with NUCs increases barrier for development of resistance

• Tolerability profile supporting combination with immune therapies• Improved compliance expected due to convenience of infrequent subcutaneous

dosing• Expected efficacy across CHB patient segments, including young immune tolerant

and patients outside treatment guidelines• Rapid physician/patient acceptance of novel treatment paradigm• Room temperature stability simplifies global distribution

Q&A Session

Hepatitis(Delta):AnUnderestimatedLiverDisease!

Heiner Wedemeyer

HannoverMedicalSchool

Germany

Heiner Wedemeyer: 10-2016Hepatitis Delta

Disclosures

Honorariaforconsultingorspeaking(last5years):Abbott,AbbVie,Biolex,BMS,BoehringerIngelheim,Eiger,Gilead,ITS,JJ/Janssen-Cilag,Medgenics,Merck/Schering-Plough,MyrGmbH,Novartis,Roche,RocheDiagnostics,Siemens,Transgene,ViiV

Researchgrants:Abbott,Abbvie,BMS,Gilead,Merck,Novartis,Roche,RocheDiagnostics,Siemens

HDV-RNA• Thesmallestofallanimalviruses• Highlypaired– rodlikestructure• NoenzymesbutRibozymes• OnlyencodesS-HDAg

• HBsAgparticlescanselfassemble• HBV:1virionx103-106 particles

• 2forms:S-HDAgandL-HDAg• S-HDAg:↑replication• L-HDAg:↑assembly(↓replication)

TheHepatitisDeltaVirus

CalleSerrano,Manns&Wedemeyer,SeminarsinLiverDisease201223

AcuteHDV

95%recoveryMorefrequentfulminant

AcuteHBV

SimultaneousCo-Infection

AcuteHDV90%chronic

MoreseverediseaseChronicHepatitisB

HDVSuper-Infection

www.hepatitis-delta.org

PrevalenceofHepatitisDelta

Highanti-HDVprevalenceinHBsAg-positiveHIV-infectedindividuals

Sorriano et al., AIDS 2011

Overallprevalence:14.5%!

Fernandet-Montero,Sorrianoetal.,CID2014

HDVcoinfectionassociatedwithincreasedliver-relatedmorbidityandmortality(HR7.5)in

HIV-infectedpersons

OnlyasmallnumberofHBsAgpositivepatientsistestedforanti-HDV

…e.g.only8.5%ofHBsAg-positivepatientsweretestedforanti-HDVinaUSA–VAcohort

Kushneretal.JHepatolSept.2015

Hepatitisdeltatakesamoreseverelong-termcoursethanHBVmonoinfection

Manesis et al., J Hepatol 2013

HDV/HBV

1980 1990 2000 2010

ACUTEHEPATITISDELTACHRONICHEPATITISDELTA

sHepatitisdelta:evolutionofclinicalpresentation

youngpatientslocallyacquired

specialriskgroups(IVDU)

olderpatientsImmigrantpopulations

specialriskgroups

SevereAcute+ChronicDisease MildchronicDisease SeverechronicDisease

Romeo,Colombo:Gastroenterology2009+PlosOne2014Calle-Serrano,WedemeyerJVH2014

Niro,Rizzetto:JournalofHepatology2010Buti,Esteban:JVH2010

Highfrequencyofliver-relatedmorbidity

DifferentHDVgenotypesareassociatedwithdifferentclinicaloutcomes

Su et al, Gastroenterology 2006

HDVgenotype3infection:ParticularSevereCourses

Braga et al., J Hepatol 201431

Identificationofpatientswithahigherriskfordiseaseprogression

Presenceofanti-HDVIgMisassociatedwiththedevelopmentofclinicalevents

Wrankeetal.PlosOne201433

Survival according to the BEA-score

CalleSerranoetal.JViralHepatitis201434

Survival according to the BEA-score

Barcelona: n=77

M. Homs, M. Buti et al.

Düsseldorf: n=58

A. Erhardt et al.

CalleSerranoetal.JViralHepatitis201435

TreatmentofHepatitisDelta

HDV-RNA• Thesmallestofallanimalviruses• Highlypaired– rodlikestructure• NoenzymesbutRibozymes

• HBsAgparticlescanselfassemble• HBV:1virionx103-106 particles

• 2forms:S-HDAgandL-HDAg• S-HDAg:↑replication• L-HDAg:↑assembly(↓replication)

TheHepatitisDeltasVirus:Noviralenzyme→nodirectactingantiviral

CalleSerrano,Manns&Wedemeyer,SeminarsinLiverDisease201237

TreatmentofHepatitisDeltawithPEG-IFNa-2a:~25%SustainedHDVRNAclearance

Wedemeyer,Yurdaydinetal.NEJM201138

Heiner Wedemeyer: 10-2016Hepatitis Delta Wedemeyer,Yurdaydinetal.NEJM2011

PEG-IFNa-2a– AdefovircombinationresultedinamorepronouncedHBsAgsuppression

…andcombinationwithtenofovir?

TheHep-Net-InternationalDelta-HepatitisInterventionTrial2:HIDIT-2

PEG-Interferonalpha-2a180µgoiw+Placebo

PEG-Interferonalpha-2a180µgoiw+Tenofovirdisoproxilfumarat245mgdaily

Follow-up

96weeks 5yearsFU

Primaryefficacyendpoint:HDVRNAnegativityWeek96

N=59Stratification:CountryPrevioustherapyGender

Baseline W12 W24 W48

PEG-IFNa-2a+Tenofovir

PEG-IFNa-2a+Placebo%ofpatientsHDVRNAnegative

p=0.10

Week96

Relapse11/25(44%)

Relapse8/20(40%)

NegpostTx1patient

NegpostTx3patients

HDVRNAClearanceafterTherapy

Treatment

p=0.34

week12024wpostTx

HDVRNAresponseuntilweek120(Intent-to-treatanalysis)

Wedemeyer,Yurdaydinetal.EASL201442

%ofpatientswithHBsAg-decline>0.5Log10IU/ml

PEG-IFNa-2a+Tenofovir

PEG-IFNa-2a+Placebo

MeanHB

sAglevels[lo

g10IU/m

MeanHBsAglevels

HBsAgresponseuntilweek120(Intent-to-treatanalysis)

80Treatment FU

5 Treatment FUHBsAgloss:4/59patients(6.7%)HBsAgloss:3/61patients(4.9%)

Wedemeyer,Yurdaydinetal.EASL201443

Long-term-Follow-upafterIFNtherapy

LateHDVRNArelapsesafterinitialresponse!

Heidrichetal.,Hepatology2014

Therapy Therapy

Long Term Virological Response Late Relapse

Clinicaleffectsofantiviraltherapy

Heiner Wedemeyer: 10-2016Hepatitis Delta Farcietal.,Gastroenterology2004

Improvedlong-termoutcomeofhepatitisdeltawithhighdoseofIFNa

All patients

time (years)20,0015,0010,005,000,00

Log rank: p<0.01

No therapy & NUCs

time (years)20,0015,0010,005,000,00

Log rank: p=0.04

No therapy & NUCs

Patients with platelets >90000/µl only

ImprovedoutcomeofhepatitisdeltainIFNa-treatedpatients

Wrankeetal.,Hepatology 2016inpress48

time (years)20,0015,0010,005,000,00

HBsAg loss

Log rank: p=0.08

positive HBsAg

HDVPatientsexperiencinganHBsAglosshadabetterclinicallong-termoutcome

Wrankeetal.,Hepatology 2016inpress49

CurrentManagementofHepatitisDelta

§ Patientswithaverymildcoursecanbeidentifiedpossiblynotrequiringimmediatetreatment

§ PEG-IFNaremainstheonlyeffectivetreatmentoptionagainstHDV– however,long-termfollow-upisrequired- myrecommendation:TreatBea-Bpatients

§ TreatHBVaccordingtohepatitisBguidelines

time (years)10,005,000,00

HDV RNA relapse

PatientsexperiencinganHDVRNAlosshaveabetterclinicallong-termoutcome

Wrankeetal.,EASL2016oralpresentation

positive HDV RNA

HDV RNA lossLog rank: p=0.01 vs relapse

Log rank: p<0.01 vs positive HDV RNA

Log rank: p=0.5 vs relapse

CurrentManagementofHepatitisDelta

Ø Patientswithaverymildcoursecanbeidentified(possiblynotrequiringimmediatetreatment)Clinicalmarkers:CalleSerranoJViralHepatitis2014Anti-HDVIgMLevels:Wrankeetal.,PlosOne2014NKcellresponses:Lunemannetal.,GUT2015

Ø PEG-IFNaremainstheonlyeffectivetreatmentoptionagainstHDV- stoppingrulesweek24:Keskinetal.,CGH2015- however,long-termfollow-upisrequired- myrecommendation:TreatBea-Bpatients

Ø TreatHBVaccordingtohepatitisBguidelines

♀ 42years,borninRussiaHBsAgpositive(knownsince>10years)ALT64U/l;AST52U/lHBVDNA79IU/mlAnti-HDVpositiveHDVRNA7.6x106 cop/mlHistology:Livercirrhosis

Plateletcount93.000/µlINR1.2;bilirubinnormal

RelapseafterPEG-IFNa2a

Currentlytreatedwithtenofovir(Sorrianoetal.)

Anynovelclinicaltrials?

HDVReplication

Hughes,Wedemeyer,HarrisonLancet201154

EntryInhibitor„Myrcludex“

PrenylationinhibitionBlocksvirionassemblyandpackingofviralparticles

Heiner Wedemeyer: 10-2016Hepatitis Delta Kohetal.LancetID201557

Blockingofsubviralparticleformation

Summary

Ø PEG-IFNa iscurrentlytheonlytreatmentoptionforHDVinfection

Ø HBVentryinhibition,prenylation inhibitionandblockofparticleformationarecurrentlyexploredinclinicaltrialsbuthavealllimitations

Ø NovelstrategiestoachieveHBsAg clearanceneedtobeexploredinhepatitisdelta!

CureofHBV=CureofHBV/HDV

And…ifyouwanttobemoreinvolvedinhepatitisdelta:

Q&A Session

Thank youwww.alnylam.com

ALN-HBV Roundtable Slides.FINAL - Alnylam | … of global population exposed ~290M patients...

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