Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — Technical Presentation (October 2016)
62 slides from Alnylam Pharmaceuticals's technical presentation, Oct 11, 2016
Slide 1: ALN-HBV Investigational RNAi Therapeutic for Chronic HBV Infection
ALN-HBV Investigational RNAi Therapeutic for the Treatment of Chronic Hepatitis B Virus (HBV) Infection Tuesday, October 11, 2016 1
Slide 2: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • Pushkal Garg, M.D., Senior Vice President, Clinical Development ALN-HBV Program • Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence Overview of Chronic Hepatitis D Vir
Slide 3: Reminders
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 3
Slide 4: Alnylam Forward Looking Statements
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 material
Slide 5: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • Pushkal Garg, M.D., Senior Vice President, Clinical Development ALN-HBV Program • Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence Overview of Chronic Hepatitis D Vir
Slide 6: RNAi Therapeutics
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 6
Slide 7: Alnylam Strategic Therapeutic Areas (STArs)
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 t
Slide 8: Alnylam Development Pipeline
Alnylam Development Pipeline 8
Slide 9: Alnylam Development Pipeline
Alnylam Development Pipeline 9
Slide 10: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • Pushkal Garg, M.D., Senior Vice President, Clinical Development ALN-HBV Program • Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence Overview of Chronic Hepatitis D Vir
Slide 11: Hepatitis B Virus (HBV) Infection
Hepatitis B Virus (HBV) Infection ALN-HBV DESCRIPTION Viral infection leading to cirrhosis and hepatocellular carcinoma (HCC) DRUG MECHANISM PATIENT POPULATION* By silencing all viral products including 1/3 of global population tolerogenic antigens, ALN-HBV is expected to have direct antiviral effec
Slide 12: ALN-HBV for Chronic HBV Infection
ALN-HBV for Chronic HBV Infection Hepatitis B Virus • Direct acting RNAi against infectious agent Genetically • Multiple, synergistic antiviral mechanisms validated, liver- • Silencing of viral lifecycle (pgRNA, 1 expressed target POL, S, X, core) gene • Silencing of tolerogenic antigens (S Ag and e
Slide 13: ALN-HBV Targets a Highly Conserved Sequence in HBV X Orf
ALN-HBV Targets a Highly Conserved Sequence in HBV X Orf 3980 HBV complete genomes, A-H pg RNA 3.5 kb PreS1 2.4 kb PreS2 2.1 kb X 0.7 kb ALN-HBV • 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 13 S
Slide 14: ALN-HBV Mediates Potent and Highly Durable HBsAg Knockdown in Murine Model
ALN-HBV Mediates Potent and Highly Durable HBsAg Knockdown in AAV-HBV Murine Model 5′-SS 5′-AS Control HBsAg ALN-HBV 3 mg/kg IHC • Up to 3.6 log10 HBsAg reduction • Single SC dose achieves >2 log10 HBsAg reduction lasting >30 days 14 Sepp-Lorenzino, Liver Meeting, November 2015
Slide 15: ALN-HBV Target Product Profile
ALN-HBV Target Product Profile Functional Cure of CHB ALN-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 Target Product Profile Indication • Chronic hepatitis B (CHB
Slide 16: ALN-HBV Phase 1/2 Study
ALN-HBV Phase 1/2 Study Primary objectives Secondary objectives Safety, tolerability PK & antiviral activity (sAg, eAg, HBV DNA) Part A: Single-Ascending Doses in HV (SAD) │Randomized 3:1, 4-6 cohorts, N=16-24 0.1 mg/kg dose 0.3 mg/kg dose Part A initiated July 2016 1.0 mg/kg dose 3.0 mg/kg dose 2 O
Slide 17: RNA Therapeutic Strategies for HBV Competitive Landscape
RNA Therapeutic Strategies for HBV Competitive Landscape ALN-HBV ARC-520 ARC-521 ABUS-1467 IONIS-HBV-LRx 0.3-0.4 log in eAg + Potency in ETV-Rx eAg +/- pt 0.2-0.3 & 0.6 log in Undisclosed Humans TBD eAg- pt at 0.2 Undisclosed (mean sAg ↓) 1 log in Rx naïve eAg+ pt mg/kg SD & MD at 4 mg/kg Phase Phas
Slide 18: Chronic Hepatitis D Virus (CHD) Infection
Chronic Hepatitis D Virus (CHD) Infection Chronic HBV/HDV infection is more aggressive than CHB No therapies available • 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 the
Slide 19: ALN-HBV Product Opportunity with Target Profile
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
Slide 20: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • Pushkal Garg, M.D., Senior Vice President, Clinical Development ALN-HBV Program • Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence Overview of Chronic Hepatitis D Vir
Slide 21: Hepatitis Delta: An Underestimated Liver Disease
Hepatitis (Delta): An Underestimated Liver Disease! Heiner Wedemeyer Hannover Medical School Germany 21
Slide 22: Disclosures
Disclosures Honoraria for consulting or speaking (last 5 years): Abbott, AbbVie, Biolex, BMS, Boehringer Ingelheim, Eiger, Gilead, ITS, JJ/Janssen-Cilag, Medgenics, Merck/Schering- Plough, MyrGmbH, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV Research grants: Abbott, Abbvie, BMS, Gil
Slide 23: The Hepatitis Delta Virus
The Hepatitis Delta Virus HDV-RNA • The smallest of all animal viruses • Highly paired – rod like structure • No enzymes but Ribozymes HBsAg • Only encodes S-HDAg • HBsAg particles can self assemble • HBV: 1 virion x 103-106 particles HDAg • 2 forms: S-HDAg and L-HDAg • S-HDAg: ↑ replication • L-HDA
Slide 24: Simultaneous Co-Infection and Super-Infection
Simultaneous Co-Infection Acute HBV 95% recovery Acute HDV More frequent fulminant HDV Super-Infection Acute HDV 90% chronic Chronic Hepatitis B More severe disease Heiner Wedemeyer: 10-2016 Hepatitis Delta 24
Slide 25: Prevalence of Hepatitis Delta
Prevalence of Hepatitis Delta www.hepatitis-delta.org Heiner Wedemeyer: 10-2016 Hepatitis Delta 25
Slide 26: High anti-HDV prevalence in HBsAg-positive HIV-infected individuals
High anti-HDV prevalence in HBsAg-positive HIV-infected individuals Fernandet-Montero, Sorriano et al., CID 2014 HDV coinfection associated with increased liver-related morbidity and mortality (HR7.5) in HIV-infected persons Overall prevalence: 14.5%! Heiner Wedemeyer: 10-2016 Hepatitis Delta 26 Sor
Slide 27: Only a small number of HBsAg positive patients is tested for anti-HDV
Only a small number of HBsAg positive patients is tested for anti-HDV … e.g. only 8.5% of HBsAg-positive patients were tested for anti-HDV in a USA–VA cohort Kushner et al. J Hepatol Sept. 2015 Heiner Wedemeyer: 10-2016 Hepatitis Delta 27
Slide 28: Hepatitis delta takes a more severe long-term course than HBV monoinfection
Hepatitis delta takes a more severe long-term course than HBV monoinfection HDV/HBV HBV Heiner Wedemeyer: 10-2016 Hepatitis Delta 28 Manesis et al., J Hepatol 2013
Slide 29: Hepatitis delta: evolution of clinical presentation
Hepatitis delta: evolution of clinical presentation young patients older patients locally acquired Immigrant populations special risk groups (IVDU) special risk groups Severe Severe chronic Disease Mild chronic Disease Acute + Chronic Disease % of HBsAg+ patients Romeo, Colombo: Gastroenterology 200
Slide 30: Different HDV genotypes are associated with different clinical outcomes
Different HDV genotypes are associated with different clinical outcomes Su et al, Gastroenterology 2006 Heiner Wedemeyer: 10-2016 Hepatitis Delta 30
Slide 31: HDV genotype 3 infection: Particular Severe Courses
HDV genotype 3 infection: Particular Severe Courses Heiner Wedemeyer: 10-2016 Hepatitis Delta 31 Braga et al., J Hepatol 2014
Slide 32: Identification of patients with a higher risk for disease progression
Identification of patients with a higher risk for disease progression Heiner Wedemeyer: 10-2016 Hepatitis Delta 32
Slide 33: Presence of anti-HDV IgM is associated with clinical events
Presence of anti-HDV IgM is associated with the development of clinical events Heiner Wedemeyer: 10-2016 Hepatitis Delta 33 Wranke et al. PlosOne 2014
Slide 34: Survival according to the BEA-score
Survival according to the BEA-score Heiner Wedemeyer: 10-2016 Hepatitis Delta 34 Calle Serrano et al. J Viral Hepatitis 2014
Slide 35: Survival according to the BEA-score
Survival according to the BEA-score Barcelona: n=77 Düsseldorf: n=58 M. Homs, M. Buti et al. A. Erhardt et al. Heiner Wedemeyer: 10-2016 Hepatitis Delta 35 Calle Serrano et al. J Viral Hepatitis 2014
Slide 36: Treatment of Hepatitis Delta
Treatment of Hepatitis Delta Heiner Wedemeyer: 10-2016 Hepatitis Delta 36
Slide 37: The Hepatitis Delta Virus: No viral enzyme, no direct acting antiviral
The Hepatitis Deltas Virus: No viral enzyme → no direct acting antiviral HDV-RNA • The smallest of all animal viruses • Highly paired – rod like structure • No enzymes but Ribozymes HBsAg • HBsAg particles can self assemble • HBV: 1 virion x 103-106 particles HDAg • 2 forms: S-HDAg and L-HDAg • S-HD
Slide 38: Treatment of Hepatitis Delta with PEG-IFNa-2a
Treatment of Hepatitis Delta with PEG-IFNa-2a: ~25% Sustained HDV RNA clearance Heiner Wedemeyer: 10-2016 Hepatitis Delta 38 Wedemeyer, Yurdaydin et al. NEJM 2011
Slide 39: PEG-IFNa-2a and Adefovir combination: HBsAg suppression
PEG-IFNa-2a – Adefovir combination resulted in a more pronounced HBsAg suppression Heiner Wedemeyer: 10-2016 Hepatitis Delta 39 Wedemeyer, Yurdaydin et al. NEJM 2011
Slide 40: ... and combination with tenofovir?
… and combination with tenofovir? Heiner Wedemeyer: 10-2016 Hepatitis Delta 40
Slide 41: The Hep-Net-International Delta-Hepatitis Intervention Trial 2: HIDIT-2
The Hep-Net-International Delta-Hepatitis Intervention Trial 2: HIDIT-2 96 weeks 5 years FU PEG-Interferon alpha-2a 180µg oiw + Placebo Follow-up N=61 R Stratification: Country PEG-Interferon alpha-2a 180µg oiw + Tenofovir disoproxilfumarat 245mg daily Follow-up N=59 Previous therapy Gender Primary
Slide 42: HDV RNA response until week 120
HDV RNA response until week 120 (Intent-to-treat analysis) PEG-IFNa-2a + Tenofovir PEG-IFNa-2a +Placebo % of patients HDV RNA negative 80 Treatment FU p=0.10 60 Relapse 11/25 (44%) 47% Relapse 8/20 (40%) p=0.34 40 33% 30% HDV RNA Clearance 23% after Therapy 20 Neg post Tx 1 patient Neg post Tx 3 pat
Slide 43: HBsAg response until week 120
HBsAg response until week 120 (Intent-to-treat analysis) PEG-IFNa-2a + Tenofovir PEG-IFNa-2a +Placebo % of patients with HBsAg-decline >0.5 Log10IU/ml 80 Mean HBsAg levels Treatment FU 5 Treatment FU HBsAg loss: 4/59 patients (6.7%) Mean HBsAg levels [log10 IU/ml] 60 HBsAg loss: 3/61 patients (4.9%)
Slide 44: Long-term Follow-up after IFN therapy
Long-term-Follow-up after IFN therapy Heiner Wedemeyer: 10-2016 Hepatitis Delta 44
Slide 45: Late HDV RNA relapses after initial response
Late HDV RNA relapses after initial response! Long Term Virological Response Late Relapse Therapy Therapy Heiner Wedemeyer: 10-2016 Hepatitis Delta 45 Heidrich et al., Hepatology 2014
Slide 46: Clinical effects of antiviral therapy
Clinical effects of antiviral therapy Heiner Wedemeyer: 10-2016 Hepatitis Delta 46
Slide 47: Improved long-term outcome of hepatitis delta with high dose of IFNa
Improved long-term outcome of hepatitis delta with high dose of IFNa Heiner Wedemeyer: 10-2016 Hepatitis Delta 47 Farci et al., Gastroenterology 2004
Slide 48: Improved outcome of hepatitis delta in IFNa-treated patients
Improved outcome of hepatitis delta in IFNa-treated patients All patients Patients with platelets >90000/µl only 1,0 1,0 0,8 0,8 Cum. event free survival IFNa Cum. event free survival IFNa 0,6 0,6 Log rank: p<0.01 Log rank: p=0.04 0,4 0,4 No therapy & NUCs 0,2 0,2 0,0 No therapy & NUCs 0,0 0,00 5,00
Slide 49: HBsAg loss associated with better long-term outcome
HDV Patients experiencing an HBsAg loss had a better clinical long-term outcome 1,0 HBsAg loss 0,8 Log rank: p=0.08 Cum. free survival 0,6 0,4 positive HBsAg 0,2 0,0 0,00 5,00 10,00 15,00 20,00 time (years) Heiner Wedemeyer: 10-2016 Hepatitis Delta 49 Wranke et al., Hepatology 2016 in press
Slide 50: Current Management of Hepatitis Delta
Current Management of Hepatitis Delta § Patients with a very mild course can be identified possibly not requiring immediate treatment § PEG-IFNa remains the only effective treatment option against HDV – however, long-term follow-up is required - my recommendation: Treat Bea-B patients § Treat HBV ac
Slide 51: HDV RNA loss associated with better long-term outcome
Patients experiencing an HDV RNA loss have a better clinical long-term outcome 1,0 0,8 Cum. free survival 0,6 Log rank: p<0.01 vs positive HDV RNA HDV RNA loss Log rank: p=0.01 vs relapse 0,4 positive HDV RNA 0,2 Log rank: p=0.5 vs relapse HDV RNA relapse 0,0 0,00 5,00 10,00 time (years) Heiner Wede
Slide 52: Current Management of Hepatitis Delta
Current Management of Hepatitis Delta Ø Patients with a very mild course can be identified (possibly not requiring immediate treatment) Clinical markers: Calle Serrano J Viral Hepatitis 2014 Anti-HDV IgM Levels: Wranke et al., PlosOne 2014 NK cell responses: Lunemann et al., GUT 2015 Ø PEG-IFNa rema
Slide 53: Relapse after PEG-IFNa2a, currently treated with tenofovir
♀ 42 years, born in Russia Relapse after PEG-IFNa2a HBsAg positive (known since >10 years) Currently treated with ALT 64 U/l; AST 52 U/l tenofovir (Sorriano et al.) HBV DNA 79 IU/ml Any novel clinical trials? Anti-HDV positive HDV RNA 7.6 x106 cop/ml Histology: Liver cirrhosis Platelet count 93.000/
Slide 54: HDV Replication
HDV Replication Heiner Wedemeyer: 10-2016 Hepatitis Delta 54 Hughes, Wedemeyer, Harrison Lancet 2011
Slide 55: Entry Inhibitor Myrcludex
Entry Inhibitor „Myrcludex“ Heiner Wedemeyer: 10-2016 Hepatitis Delta 55 Hughes, Wedemeyer, Harrison Lancet 2011
Slide 56: Prenylation inhibition
Prenylation inhibition Blocks virion assembly and packing of viral particles Heiner Wedemeyer: 10-2016 Hepatitis Delta 56 Hughes, Wedemeyer, Harrison Lancet 2011
Slide 57: Koh et al. Lancet ID 2015
Heiner Wedemeyer: 10-2016 Hepatitis Delta 57 Koh et al. Lancet ID 2015
Slide 58: Blocking of subviral particle formation
Blocking of subviral particle formation Heiner Wedemeyer: 10-2016 Hepatitis Delta 58 Hughes, Wedemeyer, Harrison Lancet 2011
Slide 59: Summary
Summary Ø PEG-IFNa is currently the only treatment option for HDV infection Ø HBV entry inhibition, prenylation inhibition and block of particle formation are currently explored in clinical trials but have all limitations Ø Novel strategies to achieve HBsAg clearance need to be explored in hepatitis
Slide 60: If you want to be more involved in hepatitis delta
And… if you want to be more involved in hepatitis delta: Heiner Wedemeyer: 10-2016 Hepatitis Delta 60
Slide 61: Agenda
Agenda Welcome • Josh Brodsky, Associate Director, Investor Relations & Corporate Communications Introduction • Pushkal Garg, M.D., Senior Vice President, Clinical Development ALN-HBV Program • Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence Overview of Chronic Hepatitis D Vir
Slide 62: Thank you
Thank you www.alnylam.com 62
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