Slide 1: Targeting HBV Core Protein to Achieve Higher Cure Rates
Targeting HBV Core Protein to Achieve Higher Cure Rates Richard Colonno Targeting HBV New Drug Development for HBV & Other Infectious Diseases September 25, 2017 Boston, MA
Slide 2: Cautionary Note Regarding Forward-looking Statements
Cautionary Note Regarding Forward - looking Statements Some of the information in this presentation contains forward - looking statements regarding future events, including statements about the clinical and therapeutic potential of Assembly’s development programs and drug candidates. Certain forward
Slide 3: Significant Need Remains for Curative Therapies
Significant Need Remains for Curative Therapies □ Number of chronically - infected HBV patients exceeds the number of patients infected with HCV (~170M ) plus HIV (~37M) combined □ The majority are undiagnosed – often asymptomatic for years □ Chronic HBV infection results in chronic inflammation and
Slide 4: Current HBV Therapies
Current HBV Therapies □ Currently Approved ─ Nucleoside Analogs: Entecavir, Lamivudine, Telbivudine ─ Nucleotide Analogs: Tenofovir, Adefovir , Tenofovir Alafenamide ─ Interferons (IFN and peg - IFN ) □ Entecavir and Tenofovir ─ Safe , highly effective therapies and the current drugs of choice ─ Tar
Slide 5: Deficiencies of Current Approved Therapies
Deficiencies of Current Approved Therapies HBV Patients ETV 1,2 TFV 3 Peg - IFN 4,5 HBeAg Positive N = 354 N = 176 N = 271 HBV DNA Undetectable 67% 76% 25% a HBeAg Seroconversion 21% 21% 27% ALT Normalization 68% 68% 39% HBsAg Loss 2.0% 3.2% 2.9% HBeAg Negative N = 325 N = 250 N = 177 HBV DNA Undete
Slide 6: Woodchuck Hepatitis B Virus Model
Woodchuck Hepatitis B Virus Model □ WHBV infection at 3 days of age results in a carrier state with life - long viremia □ Chronically - infected animals mimic the HBV carrier state in man (viral pathogenesis & development of HCC) □ Infected woodchucks have a >90% chance of dying of HCC within 4 year
Slide 7: Long-Term Woodchuck Study: Cure and Survival
Long - Term Woodchuck Study : Cure and Survival □ ETV Treatment (0.5 mg/kg) ─ Two months of daily treatment ─ 12 or 34 months of weekly treatment □ Sustained suppression (≥ 8 logs) of viral DNA levels for 1 - 3 years – no rebounds or evidence of resistance □ cccDNA levels reduced >4 logs □ WHBsAg le
Slide 8: HBV Life Cycle: Complex and Poorly Understood
HBV Life Cycle: Complex and Poorly Understood cccDNA Maintenance cccDNA Maintenance 8
Slide 9: HBV Life Cycle: Failure of Nucs to Inhibit cccDNA
HBV Life Cycle: Failure of Nucs to Inhibit cccDNA cccDNA Maintenance cccDNA Maintenance Nucleos(t)ides 9
Slide 10: Aspirational Objectives for Clinical Cure in Humans
Aspirational Objectives for Clinical Cure in Humans □ We want what we achieved in woodchucks! □ Must cause depletion of cccDNA pools ─ Inhibit generation of new cccDNA ─ Direct silencing or elimination of existing cccDNA (more challenging) □ Decrease HBsAg levels to restore/enhance immune response □
Slide 11: Strategic Approaches Being Pursued for Cure
Strategic Approaches Being Pursued for Cure 11 Direct Acting Antivirals that cause a decrease in cccDNA levels Immune activation and modulation Targeted HBsAg reduction to restore immunologic control
Slide 12: Assembly Biosciences Focused on Targeting Core Protein to Decrease cccDNA Levels
Assembly Biosciences Focused on Targeting Core Protein to Decrease cccDNA Levels
Slide 13: ASMB Focused on Inhibitors of Core Protein
cccDNA Maintenance ASMB Focused on Inhibitors of Core Protein CpAMs CpAMs CpAMs cccDNA Maintenance 13 • CpAM = Core protein Allosteric Modifiers
Slide 14: CpAMs Inhibit HBV Life Cycle at Several Steps
CpAMs Inhibit HBV Life Cycle at Several Steps □ CpAMs (Core protein Allosteric Modifiers) target Core protein and inhibit key functional steps required for to cccDNA generation □ Bind at dimer - dimer interface and disrupt the orderly folding of Core protein dimers into functional nucleocapsids, gen
Slide 15: Antiviral Effects of CpAMs: Capsid Disruption
cccDNA Maintenance Antiviral Effects of CpAMs CpAMs CpAMs cccDNA Maintenance Control + CpAM Addition of CpAMs causes formation of aberrant capsids that are larger, cracked and asymmetrical Electron Micrographs (100 nm) In Vitro Capsid Disruption Assay CpAMs 15
Slide 16: Antiviral Effects of CpAMs: Encapsidation
cccDNA Maintenance Antiviral Effects of CpAMs CpAMs CpAMs cccDNA Maintenance CpAMs 16 0 50 100 150 pgRNA DNA DMSO ETV (17x EC50) CpAM (10x EC50) % of Control CpAMs prevent encapsidation of pgRNA and subsequent synthesis of DNA in nucleocapsids Intracellular Encapsidation Study
Slide 17: Antiviral Effects of CpAMs: Nucleocapsid Melting
cccDNA Maintenance Antiviral Effects of CpAMs CpAMs CpAMs cccDNA Maintenance CpAMs 17 CpAMs cause premature melting of existing nucleocapsids and prevent trafficking of rcDNA to nucleus DMSO Control ETV 167x EC 50 Capsid DNA CpAM 158x EC 50 Southern Blot of HBV DNA from HepG2 - NTCP Cells 3 h r Post
Slide 18: Antiviral Effects of CpAMs: cccDNA Inhibition
cccDNA Maintenance Antiviral Effects of CpAMs CpAMs CpAMs cccDNA Maintenance CpAMs ETV >10K x EC 50 cccDNA CpAMs inhibit cccDNA generation/formation DMSO Control CpAM 8x EC 50 CpAM 38x EC 50 DMSO Control Southern Blot of HBV cccDNA From Infected HepG2 - NCTP Cells 18
Slide 19: Clinical POC of CpAMs as Effective HBV Antivirals
Clinical POC of CpAMs as Effective HBV Antivirals □ Satisfactory safety at all dose levels, no pattern of treatment - related clinical AEs or lab abnormalities □ Oral doses of 600 mg BD in chronic HBV patients resulted in a potent antiviral response in 28 days ─ Mean 1.72 log 10 IU/mL HBV DNA reduct
Slide 20: Assembly Biosciences Establishing A Pipeline of CpAMs
Assembly Biosciences Establishing A Pipeline of CpAMs
Slide 21: Drugable Properties Will Play an Important Role
Drugable Properties Will Play an Important Role □ Higher concentrations of CpAMs will be required to decrease cccDNA levels relative to inhibiting viral DNA levels □ Premium will be placed on CpAMs with favorable DMPK properties that are able to achieve and maintain higher effective concentrations i
Slide 22: Assembly Pipeline of CpAMs
HBV CpAM Discovery Lead Optimization IND Enabling Phase 1a Phase 1b Phase 2 ABI - H0731 ABI - H2158 Next Generation Assembly Pipeline of CpAMs □ ABI - H0731 has completed Phase 1a evaluation, and is currently being studied in HBV patients in a 28 - day, double - blind , placebo - controlled Phase 1b
Slide 23: ABI-H0731 Preclinical Overview
ABI - H0731 Preclinical Overview □ Selective targeting of dimer - dimer interface of HBV Core protein, leading to i nhibition of cccDNA generation in infected cell assays □ Pangenotypic coverage of HBV genotypes (A – D) □ No significant activity noted against a panel of other viruses or in cytotoxic
Slide 24: ABI-H0731 Clinical Overview
ABI - H0731 Clinical Overview Phase 1a Completed □ Single oral doses from 100 to 1,000 mg, multiple doses of 800 mg QD and 800 mg BID x 7 days evaluated □ Favorable PK profile with a half - life consistent with QD dosing □ Well absorbed, with achievement of concentrations believed to be sufficient t
Slide 25: ABI-H2158 - Next Generation CpAM
0.1 1 10 100 1000 10000 ABI - H2158 - Next Generation CpAM 25 Antiviral Activity in AD38 Induced Cells (Viral Load) Antiviral Activity in HepG2 - NTCP Infected Cells (Viral Load and HBeAg) • EC 50 (nM) 0.1 1 10 100 1000 10000 • EC 50 (nM) 0.6 281 216 22 8580 0.8 540 307 28 4950 390 HBV DNA HBV DNA H
Slide 26: CpAMs Profiling in Primary Human Hepatocytes
CpAMs Profiling in Primary Human Hepatocytes □ CpAMs reduced viral HBV DNA levels and known surrogate markers for cccDNA (HBeAg, HBsAg and pgRNA) □ ETV was highly effective at inhibiting HBV DNA levels, but exhibited limited effect on cccDNA surrogate markers CpAM HBV DNA EC 50 (nM) HBeAg EC 50 (nM)
Slide 27: Profile of ASMB Clinical Candidates
Profile of ASMB Clinical Candidates Virology Parameters SBA - R01 ABI - H0731 ABI - H2158 AD38 VL EC 50 (nM ) 281 170 14 HC9AT HBeAg EC 50 (nM ) 8,580 4,950 390 PHH VL EC 50 (nM) 1,130 150 23 PHH HBeAg EC 50 (nM) 2,502 2,210 230 DMPK Parameters Human Liver Microsomes (% remaining at 45 min) 100 87 9
Slide 28: Will CpAM Treatment Result in Higher Cure Rates?
Will CpAM Treatment Result in Higher Cure Rates? Studies underway using patient samples to gain insight into both topics □ Lamivudine (LVD) and Telbivudine (LdT) treatment results in rapid emergence of resistant variants due to their low barrier to resistance □ LVD/LdT resistance maps to L180M and M
Slide 29: cccDNA Studies – Initial Results
cccDNA Studies – Initial Results □ All biological molecules have a half - life, including cccDNA □ Longitudinal study conducted on samples (serum and biopsies) from patients with emerging resistance to LVD and TBV □ Appearance and enrichment of resistant mutations used as a genetic marker in monitor
Slide 30: CpAM Summary
CpAM Summary 30 □ M echanism - based studies demonstrated that CpAMs bind to Core protein and disrupt viral replication at multiple steps □ Importantly, and distinct from Nucs, CpAMs appear to block the generation of new cccDNA molecules! □ ASMB’s CpAM pipeline consists of candidate compounds select
Slide 31: Acknowledgements
Acknowledgements 31 Assembly Biosciences HBV Team Qi Huang Dawei Cai Ran Y an Yi Zhou Yuhua Zong Alex Mercier Pao - Chen Li Emily Connelly Lida Guo Lichun Li Esteban Carabajal Xuman Tang Uri Lopatin Sandy Laiw Eric Ruby Virology Clinical/Regulatory Chemistry/DMPK Leping Li Bill Turner Simon Haydar L