Slide 1: Investor Update
INVESTOR UPDATE September 13 , 2021 Nasdaq: HEPA
Slide 2: Forward-Looking Statements
2 This presentation may contain forward - looking statements within the meaning of Section 27 A of the Securities Act of 1933 and Section 21 E of the Securities Exchange Act of 1934 . Such forward - looking statements are characterized by future or conditional verbs such as “may,” “will,” “expect,”
Slide 3: Executive Management
3 Executive Management Introduction to • Dr. Robert Foster, Chief Executive Officer • Dr. Todd Hobbs, Chief Medical Officer • Dr. Daren Ure , Chief Scientific Officer • Dr. Patrick Mayo, Senior Vice President, Clinical Pharmacology & Analytics • Mr. John Cavan , Chief Financial Officer
Slide 4: Background
BACKGROUND
Slide 5: NASH Drug Development: The Need and Opportunity
5 NAFLD n on - a lcoholic f atty l iver d isease • “Fatty liver” disease associated with obesity, diabetes, hypertension, etc. • Approx. 25% of global population (up to 100 million in U.S.) NASH leads to cirrhosis, liver cancer (HCC), end stage liver disease, and death NASH n on - a lcoholic s teato
Slide 6: Through Cyclophilin Inhibition Multiple Therapeutic Actions
6 Through Cyclophilin Inhibition Multiple Therapeutic Actions Cyclophilin A (cytosol and secreted) Secreted from injured cells and acts as proinflammatory cytokine by binding to CD147 Cyclophilin B (endoplasmic reticulum) Promotes fibrotic scarring by controlling collagen production CRV431 Non - imm
Slide 7: Overview of Phase 2a 'AMBITION' Trial
OVERVIEW OF PHASE 2A ‘AMBITION’ TRIAL
Slide 8: Phase 2a AMBITION Study Design
8 SAFETY TOLERABILITY PHARMACOKINETICS FIBROSCAN BIOMARKERS Day 1 Randomization * Day 28 End of treatment Day 42 End of trial CRV431 225 mg (n=17) Placebo (n=8) O ff - treatment O ff - treatment F2/F3 NASH Patients (N=43) Fasted Oral Dosing Day 29 Placebo (n=6) O ff - treatment CRV431 75 mg (n=12) O
Slide 9: Baseline Demographics Phase 2a: AMBITION Study
9 Baseline Demographics Phase 2a: AMBITION Study CRV431 75 mg (n = 12) CRV431 225 mg (n = 17)* Pooled Placebo (n = 14) Age (years) Mean (SD) 61.9 (8.0) 54.0 (13.3) 61.1 (12.0) Range 48 - 72 27 - 71 27 - 72 Gender Male n (%) 7 (58.3) 7 (41.2) 9 (64.3) Female n (%) 5 (41.7) 10 (58.8) 5 (35.7) Race Whi
Slide 10: Primary Endpoint: Safety - Well Tolerated
10 Dose AE Term Severity Outcome Relation to Study Drug Placebo Body Aches Moderate Ongoing Possible 75 mg Sensation of Heart Beating Strongly Moderate Resolved Probable 75 mg Constipation Mild Resolved Probable 225 mg Diarrhea Mild Resolved Probable 225 mg Constipation Severe Resolved Probable 225
Slide 11: Primary Endpoint: Pharmacokinetics - Adequate Exposures Anticipated for Efficacy
11 Adequate Exposures Anticipated for Efficacy Primary Endpoint: Pharmacokinetics –
Slide 12: Importance of Baseline ALT & Pro-C3
IMPORTANCE OF BASELINE ALT & PRO - C3 1. NASH subjects may have advanced disease (F3 or higher), but have ‘NORMAL’ ALT or Pro - C3 2. Elevation of ALT suggests active inflammation in the liver 3. Elevation of ProC3 suggests active formation of collagen 4. Elevated baseline biomarkers suggest ACTIVE
Slide 13: ALT, Area Under the Curve (AUC)
13 ALT, Area Under the Curve (AUC) p = 0.0493 ANOVA % Change From Baseline Dose Placebo 75 mg 225 mg Mean ± SD - 6.1 ± 13.3 - 18.4 ± 25.8 - 21.1 ± 21.0 Median (Range) - 5.2 ( - 23.8 – 13.8) - 15.9 ( - 58.3 – 17.2) - 20.0 ( - 81.5 – 11.1) N (%) Reduction ALT 7/14 (50%) 8/12 (67%) 13/15 (87%) AUC of A
Slide 14: PK-PD Model Successfully Predicts ALT
14 Volume (L) Absorption Ka (h - 1 ) Elimination (k h - 1 ) Inhibitory Imax Model - Baseline (ALT) IC50:Half - Maximal Inhibition • Assess patient characteristics (COVARIATES) that help refine prediction of both PK and PD • Final Covariate Model: ↑Cholesterol ~ ↓Absorption ↑Baseline AST ~ ↑Effect ↑L
Slide 15: ALT Responder Analysis
15 ALT Responder Analysis By Flexible Discriminate Analysis: Misclassification Error = 0.04255 ALT Non - Responder Responder Unknown Age 61.6 57.2 60.6 BMI 40.2 36.1 36.1 Sex > Male > Female 2.0 Day 1, 2h 284.2 596.5 264.8 Day 14, 0h 483.4 882.5 667.9 Day 28, 0h 557.9 1040.7 706.0 Day 28, 2h 724.0 1
Slide 16: FDA: ALT Responder Analysis
16 FDA:ALT Responder Analysis 1 = non - responder 2 = responder 3 = no baseline
Slide 17: Note Stratification by Baseline Example: Resmetirom
17 Note stratification by Baseline Example: Resmetirom Harrison, Stephen A., et al . Lancet 2019; published online Nov 11. http:// dx.doi.org /10.1016/S0140 - 6736(19)32517 - 6. Note stratification by Baseline
Slide 18: Pro-C3: Collagen Formation
18 Released N - terminal Pro - Peptide of Type III Collagen Pro - C3: Collagen Formation ProC3 indicates ACTIVE FIBROSIS and pharmacodynamic modulation Source: HEPA:CRV431 - 201: Phase2A Trial on NASH FUNCTION: ACTIVE FIBROSIS
Slide 19: PK-PD Model Successfully Predicts Pro-C3
19 Volume (L) Absorption Ka (h - 1 ) • No Covariates were required to predict both PK and PD. • Final Covariate Model: PK 1 - Compartment PD: Inhibitory Imax Model with Baseline Pro - C3 • Quantitative Concentration - Effect for Pro - C3 • Allows simulation of Phase 2b and Phase 3 trials PK PD Obser
Slide 20: Pro-C3 Responder Analysis
20 Pro - C3 Responder Analysis By Mixture Discriminate Analysis: Misclassification Error = 0.02128 Pro - C3 Non - Responder Responder Sex >Male >Female Age 60.4 55.4 BMI 36.3 39.1 CHOL 177.9 163.5 TRIGs 181.0 150.1 AST 45.6 62.5 ALT 55.3 69.0 PLT 239.8 221.3 Day 1, 2h 449.8 528.2 Day 14, 0h 732.3 78
Slide 21: Pro-C3 CRV431 Responder Analysis
21 PRO - C3 CRV431 Responder Analysis 1=Non - Responder 2=Responder 1 = non - responder 2 = responder
Slide 22: Phase 2a: Transcriptomics & AI
AI - POWR TM (n=6 out of 12 total subjects) • Assessed patient demographics and baseline labs • AST/ALT, C6M, TIMPs, MMP Responders • CRV431 concentration > 800 ng / mL Potential Genomic Biomarke r Responder Panel • 12/12 Active Subjects AI - machine learning has selected responders The AI is still
Slide 23: Clinical Collagen-Related Gene Regulatory Network
23 A1BG SDC2 MMP 23B FBN2 EMID1 LOXL1 SERP INB8 ORM1 ICAM1 VCAN CLEC3B PXDN HTRA1 F13A1 COCH COL9A2 COL4A3 EMILIN2 MMRN1 LAMB1 COL6AE LAMA5 ADAM9 LTBP1 TIMP2 COL 26A1 HRNR COLQ HSPG2 C1QB CLU ADAM 19 BCAM MXRA7 PLSCR1 PCSK6 BCHE N1D1 F5 FN1 FBN1 HGF PKLR NID2 COL3A1 LAMB2 LAMC1 IL2RA EGFL7 PLSCR4 US
Slide 24: Phase 2a Study Conclusions
24 Phase 2a Study Conclusions • Phase 2a study provided safety and exposure data in NASH subjects • Phase 2a study demonstrated signals of efficacy (inflammation and fibrosis) within 4 weeks • Phase 2a study provided post - hoc responder analysis data to further train AI - POWR for a priori responde
Slide 25: Phase 2b 'ASCEND-NASH' Trial
PHASE 2B ‘ASCEND-NASH’ TRIAL
Slide 26: Phase 2b ASCEND-NASH Trial Design
26 Primary Objective: Evaluate the efficacy and safety of once - daily 75mg, 150 mg, and 225 mg doses of CRV431 compared to placebo in subjects with biopsy proven NASH and stage 2 liver fibrosis (F2) / stage 3 liver fibrosis (F3) Phase 2b ASCEND - NASH F2/F3 NASH Patients (N=336) RANDOMIZED 1:1:1:1
Slide 27: Endpoints
27 Primary Efficacy Endpoint: Superiority of CRV431 (75mg, 150 mg, 225 mg) compared to placebo on liver histology at month 12 relative to the screening biopsy, by assessing the proportion of subjects with improvement in fibrosis by at least 1 stage (NASH CRN system) OR NASH resolution without worsen
Slide 28: Financial Snapshot
FINANCIAL SNAPSHOT
Slide 29: Financial Position as of June 30, 2021
29 Financial Position as of June 30, 2021 Cash - $110.1 MM Working Capital - $106.6 MM No Debt Common Shares Outstanding - 76,225,245
Slide 30: Summary
SUMMARY
Slide 31: Summary
31 • CRV431, once - daily oral, multi - modal • Cyclophilin inhibition allows for several benefits, including anti - fibrotic, anti - inflammatory, cytoprotective • Phase 2a NASH trial completed with success • Safe, well - tolerated, PK defined • Efficacy signals in only 4 weeks • Phase 2b activitie