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ALN-HBVInvestigational RNAi Therapeutic for the Treatment of
Chronic Hepatitis B Virus (HBV) Infection
Tuesday, October 11, 2016
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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
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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
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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 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.
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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
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RNAi TherapeuticsNew 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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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
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Alnylam Development Pipeline
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Alnylam Development Pipeline
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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
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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
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ALN-HBV for Chronic HBV Infection
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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
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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
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• 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
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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
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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
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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
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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
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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
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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
Hepatitis(Delta):AnUnderestimatedLiverDisease!
Heiner Wedemeyer
HannoverMedicalSchool
Germany
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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
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Heiner Wedemeyer: 10-2016Hepatitis Delta
HBsAg
HDAg
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
Heiner Wedemeyer: 10-2016Hepatitis Delta
AcuteHDV
95%recoveryMorefrequentfulminant
AcuteHBV
SimultaneousCo-Infection
AcuteHDV90%chronic
MoreseverediseaseChronicHepatitisB
HDVSuper-Infection
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Heiner Wedemeyer: 10-2016Hepatitis Delta
www.hepatitis-delta.org
PrevalenceofHepatitisDelta
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Heiner Wedemeyer: 10-2016Hepatitis Delta
Highanti-HDVprevalenceinHBsAg-positiveHIV-infectedindividuals
Sorriano et al., AIDS 2011
Overallprevalence:14.5%!
Fernandet-Montero,Sorrianoetal.,CID2014
HDVcoinfectionassociatedwithincreasedliver-relatedmorbidityandmortality(HR7.5)in
HIV-infectedpersons
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Heiner Wedemeyer: 10-2016Hepatitis Delta
OnlyasmallnumberofHBsAgpositivepatientsistestedforanti-HDV
…e.g.only8.5%ofHBsAg-positivepatientsweretestedforanti-HDVinaUSA–VAcohort
Kushneretal.JHepatolSept.2015
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Heiner Wedemeyer: 10-2016Hepatitis Delta
Hepatitisdeltatakesamoreseverelong-termcoursethanHBVmonoinfection
Manesis et al., J Hepatol 2013
HDV/HBV
HBV
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Heiner Wedemeyer: 10-2016Hepatitis Delta
1980 1990 2000 2010
ACUTEHEPATITISDELTACHRONICHEPATITISDELTA
% o
f HB
sAg+
pat
ient
sHepatitisdelta:evolutionofclinicalpresentation
youngpatientslocallyacquired
specialriskgroups(IVDU)
olderpatientsImmigrantpopulations
specialriskgroups
SevereAcute+ChronicDisease MildchronicDisease SeverechronicDisease
Romeo,Colombo:Gastroenterology2009+PlosOne2014Calle-Serrano,WedemeyerJVH2014
Niro,Rizzetto:JournalofHepatology2010Buti,Esteban:JVH2010
Highfrequencyofliver-relatedmorbidity
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Heiner Wedemeyer: 10-2016Hepatitis Delta
DifferentHDVgenotypesareassociatedwithdifferentclinicaloutcomes
Su et al, Gastroenterology 2006
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Heiner Wedemeyer: 10-2016Hepatitis Delta
HDVgenotype3infection:ParticularSevereCourses
Braga et al., J Hepatol 201431
Heiner Wedemeyer: 10-2016Hepatitis Delta
Identificationofpatientswithahigherriskfordiseaseprogression
32
Heiner Wedemeyer: 10-2016Hepatitis Delta
Presenceofanti-HDVIgMisassociatedwiththedevelopmentofclinicalevents
Wrankeetal.PlosOne201433
Heiner Wedemeyer: 10-2016Hepatitis Delta
Survival according to the BEA-score
CalleSerranoetal.JViralHepatitis201434
Heiner Wedemeyer: 10-2016Hepatitis Delta
Survival according to the BEA-score
Barcelona: n=77
M. Homs, M. Buti et al.
Düsseldorf: n=58
A. Erhardt et al.
CalleSerranoetal.JViralHepatitis201435
Heiner Wedemeyer: 10-2016Hepatitis Delta
TreatmentofHepatitisDelta
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Heiner Wedemeyer: 10-2016Hepatitis Delta
HBsAg
HDAg
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
Heiner Wedemeyer: 10-2016Hepatitis Delta
TreatmentofHepatitisDeltawithPEG-IFNa-2a:~25%SustainedHDVRNAclearance
Wedemeyer,Yurdaydinetal.NEJM201138
Heiner Wedemeyer: 10-2016Hepatitis Delta Wedemeyer,Yurdaydinetal.NEJM2011
PEG-IFNa-2a– AdefovircombinationresultedinamorepronouncedHBsAgsuppression
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Heiner Wedemeyer: 10-2016Hepatitis Delta
…andcombinationwithtenofovir?
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Heiner Wedemeyer: 10-2016Hepatitis Delta
TheHep-Net-InternationalDelta-HepatitisInterventionTrial2:HIDIT-2
RR
PEG-Interferonalpha-2a180µgoiw+Placebo
PEG-Interferonalpha-2a180µgoiw+Tenofovirdisoproxilfumarat245mgdaily
Follow-up
Follow-up
96weeks 5yearsFU
Primaryefficacyendpoint:HDVRNAnegativityWeek96
N=61
N=59Stratification:CountryPrevioustherapyGender
41
Heiner Wedemeyer: 10-2016Hepatitis Delta
Baseline W12 W24 W48
PEG-IFNa-2a+Tenofovir
PEG-IFNa-2a+Placebo%ofpatientsHDVRNAnegative
0
20
40
60
80
p=0.10
Week96
47%
33%
Relapse11/25(44%)
Relapse8/20(40%)
NegpostTx1patient
NegpostTx3patients
HDVRNAClearanceafterTherapy
Treatment
p=0.34
30%
23%
week12024wpostTx
FU
HDVRNAresponseuntilweek120(Intent-to-treatanalysis)
Wedemeyer,Yurdaydinetal.EASL201442
Heiner Wedemeyer: 10-2016Hepatitis Delta
%ofpatientswithHBsAg-decline>0.5Log10IU/ml
PEG-IFNa-2a+Tenofovir
PEG-IFNa-2a+Placebo
MeanHB
sAglevels[lo
g10IU/m
l]
MeanHBsAglevels
HBsAgresponseuntilweek120(Intent-to-treatanalysis)
0
20
40
60
80Treatment FU
1
2
3
4
5 Treatment FUHBsAgloss:4/59patients(6.7%)HBsAgloss:3/61patients(4.9%)
Wedemeyer,Yurdaydinetal.EASL201443
Heiner Wedemeyer: 10-2016Hepatitis Delta
Long-term-Follow-upafterIFNtherapy
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Heiner Wedemeyer: 10-2016Hepatitis Delta
LateHDVRNArelapsesafterinitialresponse!
Heidrichetal.,Hepatology2014
Therapy Therapy
Long Term Virological Response Late Relapse
45
Heiner Wedemeyer: 10-2016Hepatitis Delta
Clinicaleffectsofantiviraltherapy
46
Heiner Wedemeyer: 10-2016Hepatitis Delta Farcietal.,Gastroenterology2004
Improvedlong-termoutcomeofhepatitisdeltawithhighdoseofIFNa
47
Heiner Wedemeyer: 10-2016Hepatitis Delta
All patients
time (years)20,0015,0010,005,000,00
Cum
. eve
nt fr
ee s
urvi
val
1,0
0,8
0,6
0,4
0,2
0,0
Log rank: p<0.01
IFNa
No therapy & NUCs
time (years)20,0015,0010,005,000,00
Cum
. eve
nt fr
ee s
urvi
val
1,0
0,8
0,6
0,4
0,2
0,0
Log rank: p=0.04
IFNa
No therapy & NUCs
Patients with platelets >90000/µl only
ImprovedoutcomeofhepatitisdeltainIFNa-treatedpatients
Wrankeetal.,Hepatology 2016inpress48
Heiner Wedemeyer: 10-2016Hepatitis Delta
time (years)20,0015,0010,005,000,00
Cum
. fre
e su
rviv
al1,0
0,8
0,6
0,4
0,2
0,0
HBsAg loss
Log rank: p=0.08
positive HBsAg
HDVPatientsexperiencinganHBsAglosshadabetterclinicallong-termoutcome
Wrankeetal.,Hepatology 2016inpress49
Heiner Wedemeyer: 10-2016Hepatitis Delta
CurrentManagementofHepatitisDelta
§ Patientswithaverymildcoursecanbeidentifiedpossiblynotrequiringimmediatetreatment
§ PEG-IFNaremainstheonlyeffectivetreatmentoptionagainstHDV– however,long-termfollow-upisrequired- myrecommendation:TreatBea-Bpatients
§ TreatHBVaccordingtohepatitisBguidelines
50
Heiner Wedemeyer: 10-2016Hepatitis Delta
time (years)10,005,000,00
Cum
. fre
e su
rviv
al
1,0
0,8
0,6
0,4
0,2
0,0
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
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Heiner Wedemeyer: 10-2016Hepatitis Delta
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
52
Heiner Wedemeyer: 10-2016Hepatitis Delta
♀ 42years,borninRussiaHBsAgpositive(knownsince>10years)ALT64U/l;AST52U/lHBVDNA79IU/mlAnti-HDVpositiveHDVRNA7.6x106 cop/mlHistology:Livercirrhosis
Plateletcount93.000/µlINR1.2;bilirubinnormal
RelapseafterPEG-IFNa2a
Currentlytreatedwithtenofovir(Sorrianoetal.)
Anynovelclinicaltrials?
53
Heiner Wedemeyer: 10-2016Hepatitis Delta
HDVReplication
Hughes,Wedemeyer,HarrisonLancet201154
Heiner Wedemeyer: 10-2016Hepatitis Delta
EntryInhibitor„Myrcludex“
Hughes,Wedemeyer,HarrisonLancet201155
Heiner Wedemeyer: 10-2016Hepatitis Delta
PrenylationinhibitionBlocksvirionassemblyandpackingofviralparticles
Hughes,Wedemeyer,HarrisonLancet201156
Heiner Wedemeyer: 10-2016Hepatitis Delta Kohetal.LancetID201557
Heiner Wedemeyer: 10-2016Hepatitis Delta
Blockingofsubviralparticleformation
Hughes,Wedemeyer,HarrisonLancet201158
Heiner Wedemeyer: 10-2016Hepatitis Delta
Summary
Ø PEG-IFNa iscurrentlytheonlytreatmentoptionforHDVinfection
Ø HBVentryinhibition,prenylation inhibitionandblockofparticleformationarecurrentlyexploredinclinicaltrialsbuthavealllimitations
Ø NovelstrategiestoachieveHBsAg clearanceneedtobeexploredinhepatitisdelta!
CureofHBV=CureofHBV/HDV
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Heiner Wedemeyer: 10-2016Hepatitis Delta
And…ifyouwanttobemoreinvolvedinhepatitisdelta:
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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
62
Thank youwww.alnylam.com
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