Slide 1: Interferon-α Receptor Agonist Research Webcast
Interferon-α Receptor Agonist Research Webcast July 26, 2022 Nasdaq: ASMB ©2020 ASSEMBLY BIOSCIENCES, INC. 1
Slide 2: Today's Speakers
Today’s Speakers John McHutchison AO, MD William Delaney, PhD Edward J. Gane, MBCHB, MD, Chief Executive Officer Chief Scientific Officer FRACP, FAASLD, FRSNZ, MNZM Professor of Medicine at the University of Auckland, New Zealand 2
Slide 3: Cautionary Note Regarding Forward-Looking Statements
Cautionary Note Regarding Forward-Looking Statements The information in this presentation contains forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to materially differ. These risks and uncertainties include: Assembly Bio’s ability to suc
Slide 4: Agenda
Agenda • Leveraging Assembly Bio's Expertise in Small Molecules and Viral Hepatitis to Expand the Company's Portfolio – John McHutchison AO, MD, Chief Executive Officer at Assembly Bio • The Role of Interferon in HBV Cure – Professor Ed Gane • Assembly Bio’s Small Molecule Liver-Focused Interferon-α
Slide 5: HBV is a Major Global Public Health Problem
HBV is a Major Global Public Health Problem Diagnosed Treated Prevalence: 296M1 30M1 5M1 Up to 1M people Treatments are life- ~12M individuals Opportunity to die each year from long and reduce but infected with HBV improve outcomes HBV-related do not eliminate the are also infected with and increase
Slide 6: Interferon's History as an HBV/HDV Antiviral
Interferon’s History as an HBV/HDV Antiviral DEMONSTRATED EFFICACY POOR TOLERABILITY • Approved for treatment of hepatitis B for over 30 years • Substantial side effects, including flu-like symptoms, cytopenias, serious depression and psychiatric effects – Also used off-label for treatment of hepati
Slide 7: Advancing a Clinical & Research Stage Portfolio of Small Molecules
Advancing a Clinical & Research Stage Portfolio of Small Molecules for HBV and Other Viral Diseases RESEARCH DEVELOPMENT Lead IND China Worldwide Drug Candidate Optimization Phase 1 Phase 2 Phase 3 Identification Enabling Rights Rights Next Gen CI† 3733 HBV* 4334 HBV/HDV HBV/HDV Entry Inhibitor Inte
Slide 8: Agenda
Agenda • Leveraging Assembly Bio's Expertise in Small Molecules and Viral Hepatitis to Expand the Company's Portfolio – John McHutchison AO, MD, Chief Executive Officer at Assembly Bio • The Role of Interferon in HBV Cure – Professor Ed Gane • Assembly Bio’s Small Molecule Liver-Focused Interferon-α
Slide 9: Edward J. Gane, MBCHB, MD, FRACP, FAASLD, FRSNZ, MNZM
Edward J. Gane, MBCHB, MD, FRACP, FAASLD, FRSNZ, MNZM • Professor of Medicine at the University of Auckland, New Zealand; Hepatologist and Deputy Director of the New Zealand Liver Unit at Auckland City Hospital. • Trained in hepatology at the Institute of Liver Studies, King’s College School of Medi
Slide 10: The Role of Interferon in HBV Cure
The Role of Interferon in HBV Cure Professor Ed Gane, University of Auckland, New Zealand
Slide 11: Need for a finite CURE
Safe, effective long-term oral therapy is available Guidelines Recommendations APASL2016 Entecavir, or Tenofovir EASL 2017 Entecavir, Tenofovir, or TAF AASLD2018 Entecavir, Tenofovir, or TAF Need for a finite 1. EASL. J Hepatol 2017;67:370–98; 2. Terrault NA, et al. Hepatology 2018; doi: 10.1002/hep
Slide 12: Therapeutic Approaches to HBV Cure
Therapeutic Approaches to HBV Cure Inhibit Viral Replication Lower Viral Antigen Burden Boost Immune Response Inhibit Viral Replication
Slide 13: Therapeutic Approaches to HBV Cure
Therapeutic Approaches to HBV Cure Inhibit Viral Replication Lower Viral Antigen Burden Boost Immune Response Inhibit Viral Replication Lim S-G, et al. Nat Rev Gastro Hepatol 2022 (in press).
Slide 14: Therapeutic Approaches to HBV Cure
Therapeutic Approaches to HBV Cure Inhibit Viral Replication Lower Viral Antigen Burden Boost Immune Response InhibitInterferon-𝛼𝛼 Viral Replication Interferon-𝛼𝛼 Interferon-𝛼𝛼 Lim S-G, et al. Nat Rev Gastro Hepatol 2022 (in press).
Slide 15: Interferon for CHB: Mechanisms of Action
Interferon for CHB: Mechanisms of Action 1. Boost immune responses • Enhanced antigen presentation • Activation of NK cells • Increased cytokine production 2. Inhibit viral replication • Degradation of viral RNA • Inhibition of viral translation • Prevention of hepatocyte infection 3. Reduce HBV ant
Slide 16: Interferon for CHB: Short-term Efficacy
Interferon for CHB: Short-term Efficacy • Meta-analysis of 837 patients (in 15 RCTs) treated with Standard IFN 5- 10 MU tiw or placebo for 4 to 6 months 50 40 37% Interferon 33% Patients (%) Untreated 30 20 17% 12% 8% 10 2% 0 HBV DNA undetectable HBeAg loss HBsAg negative Efficacy Endpoints at 24 We
Slide 17: Interferon for CHB: Short-term Efficacy
Interferon for CHB: Short-term Efficacy • Peg-IFN 180mg/week for 24 weeks more effective than Standard IFN 50 IFN 4.5mU tiw (n=51) Peg-IFN 180ug/wk (n=46) 39% 40 35% 35% 33% Patients (%) 30 25% 25% 25% 25% 20 10 4% 0 0 HBeAg loss HBeAg seroconvert DNA<5log ALT normal HBsAg loss Efficacy Endpoints at
Slide 18: Interferon for CHB: Long-term Benefits
Interferon for CHB: Long-term Benefits HBsAg seroconversion increases with time • 165 patients treated with IFN 10MU tiw for 16 weeks 1.0 0.8 Proportion HBsAg loss HBeAg loss* 0.6 50% 0.4 0.2 No HBeAg loss 0 2 4 6 8 10 12 14 Time from start of therapy (years) *HBeAg loss within 12 months of treatmen
Slide 19: Interferon for CHB: Long-term Benefits
Interferon for CHB: Long-term Benefits IFN reduces risk of cirrhosis IFN reduces risk of liver cancer P =0.02 P =0.01 Lin S-M, et al. Journal of Hepatology 2007; 46:Cooksley 45–52. J Viral Hepat 2003
Slide 20: Many Novel Therapies in Development to Combine to Cure HBV Infection
Many Novel Therapies in Development to Combine to Cure HBV Infection Inhibit Viral Replication Lower Viral Antigen Burden Boost Immune Response Inhibit Viral Replication • Peg IFN-α • Peg IFN-α • Peg IFN-α • NUC • siRNA • RIG-I agonist • ASPIN • ASO/LNA • TLR7 agonist • CAM • RNA destabilisers • TLR
Slide 21: Replication Inhibitor and Peg-Interferon-α
Replication Inhibitor and Peg-Interferon-α Pegylated NUC Interferon Systematic review/meta-analysis of combining IFN with NUCs in CHB • Timing of Peg-IFN treatment determines rate of HBsAg loss Strategy Comparator Number of Risk Ratio (CI) Studies for HBsAg loss 4.5x Add IFN to NUC NUC 15 (2.0 – 10.
Slide 22: Translation Inhibitor and Peg-Interferon-α
Translation Inhibitor and Peg-Interferon-α Pegylated siRNA Interferon Week 0 4 8 12 16 20 24 • Adding peg-IFN might increase the rate of HBsAg VIR-2218 Cohort 1 decline and overcome the plateau seen with 200 mg Q4W Cohort 2 + pegIFN QW Wks 12-23 siRNA monotherapy at 3-6 months Cohort 3 + pegIFN QW W
Slide 23: Interferon has a predictable side-effect profile
Interferon has a predictable side-effect profile Neutropenia Anemia Hepatic changes Severity Fatigue Flu-like symptoms Depressive/anxiety symptoms 0 1 2 3 4 5 6 7 8 9 10 11 12 Duration of Therapy Adapted from Fried MW. Hepatology 2002; 36(5 Suppl 1): S237-S244.
Slide 24: Safety of Peg-Interferon-α in Chronic HBV
Safety of Peg-Interferon-α in Chronic HBV Chronic HBV (n=448) Any adverse event 88% Fatigue 40% Headache 26% Myalgia 26% Anorexia 15% Arthralgia 12% Insomnia 8% Irritability 7% Depression 4% Serious adverse events 5% Dose reduction 7% Discontinuation 5% Marcellin P, et al. Liver Int 2008; 28:477.
Slide 25: There are Many Contraindications to Interferon
There are Many Contraindications to Interferon • Advanced liver disease • Severe cardiac or pulmonary disease • Neutropenia or thrombocytopenia • Uncontrolled thyroid disease • Autoimmune disorders • Psychiatric illnesses • Solid organ transplantation • Young children, elderly • Pregnancy, breast fe
Slide 26: HBV-HDV (Delta) co-infection is associated with high morbidity and mortality
HBV-HDV (Delta) co-infection is associated with high morbidity and mortality • 5% all HBV-infected patients = ~12 million patients in Mediterranean, Middle East, Pakistan, Turkey, Mongolia, western/central Africa, Amazonian basin and Pacific islands • No proven benefit of nucleos(t)ide analogues • M
Slide 27: In HBV-HDV co-infection, IFN lowers serum HDV RNA and improves survival
In HBV-HDV co-infection, IFN lowers serum HDV RNA and improves survival Suppression of HDV RNA Improved Survival Farci P, et al. Gastroenterology 2004; 126:1740-9.
Slide 28: In HBV-HDV co-infection, IFN is synergistic with novel direct antivirals
In HBV-HDV co-infection, IFN is synergistic with novel direct antivirals With Entry Inhibitor With Prenylation Inhibitor 0 1.E+7 ∆ HDV RNA (Absolute, IU/mL) -0.5 1.E+6 Peg-IFN ∆ HDV RNA (log10 IU/mL) -1 Lonafarnib 25mg/ritonavir (RTV) 1.E+5 -1.5 1.E+4 -2 1.E+3 Bulevirtide (BVD) -2.5 1.E+2 -3 Lonafar
Slide 29: Summary
Summary • IFN has pleiotropic effects on HBV and the host immune system • IFN (alone or with NUCs) has led to the highest rates of HBsAg loss and improved clinical outcomes for patients with CHB • IFN has synergistic antiviral activity when combined with novel therapies against HBV mono-infection an
Slide 30: Agenda
Agenda • Leveraging Assembly Bio's Expertise in Small Molecules and Viral Hepatitis to Expand the Company's Portfolio – John McHutchison AO, MD, Chief Executive Officer at Assembly Bio • The Role of Interferon in HBV Cure – Professor Ed Gane • Assembly Bio’s Small Molecule Liver-Focused Interferon-α
Slide 31: Clear Rationale for an Oral, Well-tolerated Liver Focused IFN-α Pathway Activator
Clear Rationale for an Oral, Well-tolerated Liver Focused IFN-α Pathway Activator Interferon-α is approved for treatment of cHBV: • PEGINTRON (peginterferon alfa-2b) • Pegasys (peginterferon alfa-2a) Highest rate of HBsAg loss/functional cure, though in a subset of patients PEG IFN-α is delivered sy
Slide 32: IFN-α Engages both Antiviral and Immune Modulatory Components of HBV Cure Strategy
IFN-α Engages both Antiviral and Immune Modulatory Components of HBV Cure Strategy Inhibit HBV T B IFN-α IFN-α Augment Immune Response 32
Slide 33: IFN-α is a Critical Host Defense Cytokine Against Infection
IFN-α is a Critical Host Defense Cytokine Against Infection 1 Induce cellular antiviral state 2 Activate innate immunity Macrophage: ↑ regulatory functions NK Cell: ↑ recruitment & activation ↑ Mx ↑ OAS DC: ↑ antigen presentation, migration IFN-α ↑ RNAseL ↑ PKR 3 Activate adaptive immunity T ↑ Expan
Slide 34: HBV Replication Cycle Antiviral Mechanisms of IFN-α
HBV Replication Cycle Antiviral Mechanisms of IFN-α 34
Slide 35: HBV Replication Cycle Antiviral Mechanisms of IFN-α
HBV Replication Cycle Antiviral Mechanisms of IFN-α X X X X Epigenetic Degradation Accelerate Destabilize Regulation of cccDNA of cccDNA RNA turnover Capsids Belloni JCI 2012 Stadler EMBO Reports 2021 Uprichard PNAS 2003 Uprichard PNAS 2003 Wieland PNAS 2005 35
Slide 36: Assembly is Developing a Small Molecule IFNAR Agonist
Assembly is Developing a Small Molecule IFNAR Agonist 165 amino acids, MW = 19,241 MW = ≤500 PEG-IFN-α Small Molecule • Dosed as a weekly injection high circulating • Liver focused PK exposure aims to interferon levels – Activate antiviral effects in infected hepatocytes – Engage innate and adapti
Slide 37: Strategy for Liver-Focused Activation of the IFN-α Pathway
Strategy for Liver-Focused Activation of the IFN-α Pathway Oral Administration Liver exposure IFN-α pathway activation Long pharmacodynamic effect Drug elimination Low Rapid Systemic Absorption Exposure 37
Slide 38: All Cell types in the Liver Express IFN-α Receptors
All Cell types in the Liver Express IFN-α Receptors Including Hepatocytes, Endothelial Cells, and Immune Cells Kupffer Cells Hepatocytes T Cells NK Cells Liver Sinusoidal Endothelial Cells (LSECs) B Cells 38
Slide 39: Expected In Vitro Activities of a Small Molecule That Activates the IFN-α Pathways
Expected In Vitro Activities of a Small Molecule That Activates the IFN-α Pathways Broad Antiviral Activity Inhibition of HBV Replication Signaling through JAK/STAT; and Antigens ISG Induction 39
Slide 40: Establishing the Broad Antiviral Activity of our Small Molecule IFNAR Agonists
Establishing the Broad Antiviral Activity of our Small Molecule IFNAR Agonists Cell-based Preclinical Antiviral Activity HCV Replicon Antiviral Assay Zika Replicon Antiviral Assay EMCV Whole Virus Antiviral Assay HCV 1b replicon Zika replicon in Huh-7 cells in BHK cells A549 cells (liver cell line)
Slide 41: Broad Antiviral Activity of Multiple Lead Compound Series
Broad Antiviral Activity of Multiple Lead Compound Series Cell-based Preclinical Antiviral Activity HCV Antiviral Activity Zika Antiviral Activity EMCV Antiviral Activity to Uninhibited Control (DMSO) to Uninhibited Control (DMSO) to Uninhibited Control (DMSO) 125 125 125 % Replicon Activity Relativ
Slide 42: Further Specific Evaluation of Activity Against HBV
Further Specific Evaluation of Activity Against HBV Cell-based Preclinical Antiviral Activity Early Treatment Assay (pre cccDNA formation) Human Hepatocytes HBsAg ELISA 3 Hours 7 Days Late Treatment Assay (post cccDNA formation) Human Hepatocytes HBsAg ELISA 2 Days 5 Days 42
Slide 43: IFNAR Agonists Inhibit HBV Antigen Production Whether Added Early or Late
IFNAR Agonists Inhibit HBV Antigen Production Whether Added Early or Late Activity is Distinguished from that of Nucleoside Analogs and Core Inhibitors NrtI Core Inhibitor IFNAR Agonist (entecavir) (3733) (Series 1) 125 125 125 Uninhibited Control (DMSO) Uninhibited Control (DMSO) Uninhibited Contro
Slide 44: Small Molecule IFNAR Agonists Act Through Jak-STAT Signaling
Small Molecule IFNAR Agonists Act Through Jak-STAT Signaling IFNAR Agonist DMSO IFN-α (Series 1) Jak Inhibitor: - + - + - + pSTAT1 GAPDH 44
Slide 45: Small Molecule IFNAR Agonists Induce Transcription of Expected Interferon Stimulated Genes
Small Molecule IFNAR Agonists Induce Transcription of Expected Interferon Stimulated Genes Induction of interferon-stimulated genes in human hepatocytes 20 IFNα ISG fold-change (log2) IFITM3 ISG15 15 OAS1 MX1 10 IRF1 5 R2=0.90 0 0 5 10 15 20 Series 1 ISG fold-change (log2) 45
Slide 46: IFNAR Agonist Target Product Profile
IFNAR Agonist Target Product Profile Activity Profile PK Profile Safety Profile • In vitro antiviral activity • Orally administered with • Well tolerated (enhanced against HBV and HDV rapid absorption tolerability compared to comparable to IFN-α PEG-IFN) • High liver exposure • In vitro immune gene
Slide 47: IFNAR Agonist: Progress and Goals
IFNAR Agonist: Progress and Goals Project is in Lead Optimization • Multiple chemically-differentiated lead series – Confirmed activation through IFN-α signal transduction pathway – Broad activity against multiple viruses including HBV demonstrated – Optimizing PK (T1/2 can be tuned based on chemica
Slide 48: HBV DNA Decline During 28 Days of PEG-IFN Therapy
HBV DNA Decline During 28 Days of PEG-IFN Therapy n=19 Patients Median HBV DNA reduction = 0.45 log10 Ter Borg et al. Antiviral Therapy; 12:1285-1294 48
Slide 49: Small Molecule IFNAR Agonist: Summary
Small Molecule IFNAR Agonist: Summary IFN-α is an approved drug for HBV with a demonstrated ability to achieve functional cure Despite efficacy, use of IFN-α is limited due to poor X X X X tolerability and contraindications An oral, small molecule agonist that engages IFN-α pathway in the liver whil
Slide 50: Agenda
Agenda • Leveraging Assembly Bio's Expertise in Small Molecules and Viral Hepatitis to Expand the Company's Portfolio – John McHutchison AO, MD, Chief Executive Officer at Assembly Bio • The Role of Interferon in HBV Cure – Professor Ed Gane • Assembly Bio’s Small Molecule Liver-Focused Interferon-α
Slide 51: Q&A
O assemblybio Q&A
Slide 52: Agenda
Agenda • Leveraging Assembly Bio's Expertise in Small Molecules and Viral Hepatitis to Expand the Company's Portfolio – John McHutchison AO, MD, Chief Executive Officer at Assembly Bio • The Role of Interferon in HBV Cure – Professor Ed Gane • Assembly Bio’s Small Molecule Liver-Focused Interferon-α
Slide 53: Expanded Research Engine - Expectations for 2022
Expanded Research Engine - Expectations for 2022 Q3 2022 Assembly to host series of Virtual Investor Events to reveal: July 26, 2022 Introduce antiviral March 31, 2022 mechanisms in other viruses (non-HBV) Interferon Receptor Agonist HBV/HDV Entry Inhibitor 53
Slide 54: Key Objectives and Anticipated Progress
Key Objectives and Anticipated Progress o Initiate Phase 1b Study – 3733 o Introduce HBV/HDV entry inhibitor program 2022 o Introduce orally-bioavailable small molecule interferon-α receptor (IFNAR) agonist o Introduce R&D initiatives aimed at other viruses (non-HBV) – Q3 2022 o Initiate Phase 1a St
Slide 55: Interferon-α Receptor Agonist Research Webcast
Interferon-α Receptor Agonist Research Webcast July 26, 2022 ©2020 ASSEMBLY BIOSCIENCES, INC. 55