Hepion Pharmaceuticals, Inc. · OTC:HEPA
Hepion Pharmaceuticals — 4th NASH Summit 2020
22 slides from Hepion Pharmaceuticals's conference presentation, December 2020
Slide 1: Pleiotropic Actions of the Cyclophilin Inhibitor, CRV431, in Preclinical Models
Pleiotropic Actions of the Cyclophilin Inhibitor, CRV431, in Preclinical Models Daren Ure, Ph.D. Chief Scientific Officer dure@hepionpharma.com
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation may contain 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. Such forward-looking statements are characterized by future or conditional verbs such as “may,”
Slide 3: NASH Clinical Trial Outcomes
NASH Clinical Trial Outcomes Han et al (2019) Placebo Responders ≥ 2-point Improvement in NAS Score NASH Resolution and No Worse Fibrosis What can we learn from 13.2% Zein 23.7% 18.1% 22.8% placebo and treatment responses in NASH trials? Wong 2013-52 (JGH) Wong 2013-51 (AH) Wah Kheong Vilar Gomez Va
Slide 4: Cyclophilins
Cyclophilins Proline Peptide Bond cis-trans Isomerization Pleiotropic effects arising from multiple cyclophilin isoforms • Enzymes that accelerate proline peptide bond cis-trans isomerization • cis-trans switching = regulation of protein interactions and functions • 17 human isoforms in all major ce
Slide 5: CRV431 Modes of Action
CRV431 Modes of Action CRV431 blocks cyclophilin participation in several disease processes CD147 pro-inflammatory receptors Cyclophilin A (cytosol and secreted) x x INFLAMMATION Secreted from injured cells and Cyp A acts as proinflammatory cytokine by binding to CD147 Procollagen Cyclophilin B (end
Slide 6: MetaCore Biological Systems Database (2.6M+ curated interactions)
MetaCore Biological Systems Database (2.6M+ curated interactions) CRV431 predicted to inhibit diversity of cyclophilin-protein interactions Transcription Regulates expression Total protein and Protein binding Target Type regulated by “#” transcription of “#” gene interactions interactions genes/prot
Slide 7: CRV431 – Pan-Cyclophilin Inhibitor
CRV431 – Pan-Cyclophilin Inhibitor • Cyclophilin inhibitor (Ki ≈ 1 nM) CRV431: Novel, high-potency, cyclophilin inhibitor that •targets Non-immunosuppressive analog multiple stages of liver disease, ofNASH including cyclosporine A • Oral, once daily • Concentrates in liver • Completed Phase 1 (SAD,
Slide 8: Anti-Fibrotic and Additional CRV431 Effects in Diverse Preclinical Models
Anti-Fibrotic and Additional CRV431 Effects in Diverse Preclinical Models Human Cell Cultures CRV431 Effects Hepatic stellate cells, fibroblasts TGFβ or endogenous stimulation ▼fibrotic gene expression (multiple organs) ▼procollagen and fibronectin secretion CRV431: Novel, high-potency, cyclophilin
Slide 9: Preclinical Models: Diet and Toxin Induced Liver Fibrosis in Rodents
Preclinical Models: Diet and Toxin Induced Liver Fibrosis in Rodents Western Diet + CCl4 (Mice) Thioacetamide (Rats) 12 weeks diet + CCl4 9 weeks thioacetamide 6 weeks vehicle, CRV431, or OCA 9 weeks vehicle or CRV431 Fibrosis (% Sirius Red) Fibrosis (% Sirius Red) Fibrosis score P0.0001 15 P=0.008
Slide 10: CRV431 Effects on Human Precision Cut Liver Slices
CRV431 on Human Precision Cut Liver Slices (FibroFind, UK) Summary Fibrosis: Picrosirius Red ▪ Precision cut liver slices from 4 human donors % Normalized to Nonstimulated and Stimulated ▪ Sirius red baseline (1.3 - 9.5%) increased with TGFβ + PDGF-BB stimulation for 3 days to 6.6 - 11.5% Sirius Red
Slide 11: CRV431 Effects on Human Precision Cut Liver Slices: Gene Expression and Secreted Proteins
CRV431 on Human Precision Cut Liver Slices (FibroFind, UK) Gene Expression Secreted Protein Markers (Daily Average Change) 150 25 Col11 Col11 % change vs vehicle SMA 0 Fibronectin % vs vehicle 100 Timp1 Timp1 -25 IL-6 Hyaluronic Acid MCP-1 IL-6 -50 50 MCP-1 -75 0 -47% -8% -24% -8% -17% 6% 0% (6-m
Slide 12: Bioinformatics Analyses - Transcriptomics
Bioinformatics Analyses - Transcriptomics Clarivate Metacore and Key Pathway Advisor Platforms P0.0001 10 Sirius Red (% of area) 8 Western Diet/CCl4 6 4 Mice 2 CRV431 effects on liver transcriptome: 0 • differentially expressed genes (DEGs) Normal Vehicle CRV431 OCA CRV431 50 mg/kg 10 mg/kg + OCA W
Slide 13: Processes Regulated by NASH and by CRV431 in Preclinical Models
Processes Regulated by NASH and by CRV431 in Preclinical Models CRV431 effects on gene expression consistent with human NASH reversal METABOLISM SAMPLE OF GENE EXPRESSION CHANGES IN HUMAN Development: Insulin, IGF-1 and TNF-alpha in brown adipocyte differentiation NASH and BY CRV431 IN PRECLINICAL M
Slide 14: CRV431 Effects on Liver Gene Expression in Preclinical Models
CRV431 Effects on Liver Gene Expression in Preclinical Models Cell-matrix interactions Gene downregulation Gene upregulation
Slide 15: CRV431 Effects on Liver Gene Expression in Preclinical Models
CRV431 Effects on Liver Gene Expression in Preclinical Models ECM remodeling Gene downregulation Gene upregulation
Slide 16: CRV431 Effects on Liver Gene Expression in Preclinical Models
CRV431 Effects on Liver Gene Expression in Preclinical Models Bile acid regulation of lipid metabolism Gene downregulation Gene upregulation
Slide 17: Causal Analysis of CRV431 Effects in Western Diet/CCl4 Model
Causal Analysis of CRV431 Effects in Western Diet/CCl4 Model SREBP Transcriptional Control of Cholesterol and Fatty Acid Biosynthesis Gene upregulation Gene downregulation CRV431 downregulated several enzymes involved in fatty acid biosynthesis and cholesterol biosynthesis
Slide 18: Human Liver Slices: CRV431 Effects on Transcriptome
Human Liver Slices: CRV431 Effects on Transcriptome Predicted key hub genes include multiple, familiar NASH drug targets CRV431 effects consistent with model RNA upregulated by CRV431 RNA downregulated by CRV431 THRβ CRV431 effects PPARα inconsistent with model PPARδ FGF1
Slide 19: Bioinformatics Analyses - Metabolomics
Bioinformatics Analyses - Metabolomics OWL Metabolomics Fibrosis (% Sirius Red) 15 P=0.008 CRV431 effects on liver metabolome: • altered expression of 14% of metabolites Sirius red (% of area) Thioacetamide 10 • majority of changes consistent with Rats 5 attenuation of thioacetamide effects 0 Vehicl
Slide 20: Metabolomics in Thioacetamide Rats
Metabolomics in Thioacetamide Rats CRV431 attenuated many changes induced by 9 weeks thioacetamide Liver Metabolites Metabolomics Summary Statistically Significant Δ: CRV431 vs Vehicle 21 Plasma TAA Vehicle vs. Control CRV431 by CRV431 and TAA 5 61 Liver TAA CRV431 vs. Control 4 Log2 expression vs C
Slide 21: Metabolomics in Thioacetamide Rats
Metabolomics in Thioacetamide Rats CRV431 attenuated many changes induced by 9 weeks thioacetamide Liver Metabolites Log2-fold change vs Control Plasma Metabolites Log2-fold change vs Control 6 TAA Vehicle vs. Control 5 TAA Vehicle vs. Control 5 4 4 TAA CRV431 vs. Control TAA CRV431 vs. Control 3 Lo
Slide 22: CRV431 Summary
CRV431 • Multiple therapeutic actions in diverse liver injury models • Therapeutic activities consistent across several analytical platforms SUMMARY • Phase 2 clinical trials: • DATA-RICH: histopathology, multi-omics, biomarkers, clinical labs, imaging • AI-POWR™: in-house, AI/deep learning platform