Hepion Pharmaceuticals, Inc. · OTC:HEPA
Hepion Pharmaceuticals — 2nd World Congress on Alcohol and Alcoholism 2022
19 slides from Hepion Pharmaceuticals's conference presentation, September 2022
Slide 1: Disclosure of interest
Disclosure of interest Una Rastovic I have nothing to declare.
Slide 2: Cyclophilin inhibitor Rencofilstat as a potential therapy for Alcohol-related Liver Disease
2nd World Congress on Alcohol and Alcoholism Cyclophilin inhibitor Rencofilstat as a potential therapy for Alcohol-related Liver Disease Elena Palma, Una Rastovic, Sara Campinoti, Nicola Harris, Omolola Ajayi, Bruna Almeida, Tsin Shue Koay, Sandra Phillips, Karoline Lackner, Daren Ure, Melissa Prezi
Slide 3: Alcohol-related Liver Disease
Alcohol-related Liver Disease • PROBLEM: 3 million deaths (5.3%) annually (WHO) • CURRENT TREATMENT: • alcohol abstinence • interventions following a decompensating event, acute liver failure, or HCC – late-stages of ALD • TREATMENT OPPORTUNITY: 30 years to intervene and prevent late-stage ALD! • CH
Slide 4: Cyclophilins
Cyclophilins • peptidyl-prolyl isomerase (PPIase) • facilitate protein folding and conformational changes -> function of the targeted proteins • ubiquitously expressed (nucleus, ER, secreted) • involved in different cellular processes • elevated expression and secretion in different pathologies (e.g
Slide 5: Cyclophilin network is highly dysregulated in liver biopsies from patients with Alcoholic Hepatitis
Cyclophilin network is highly dysregulated in liver biopsies from patients with Alcoholic Hepatitis DNA microarray in liver biopsies from patients with Alcoholic Hepatitis (AH, n=15) and compared to healthy controls (Ctrl, n=7)- GEO Dataset reference series GSE28619 (reanalysis of a publicly availab
Slide 6: Role of cyclophilins in liver disease
Role of cyclophilins in liver disease • Effects of cyclophilin inhibition in vitro and in animal models • suppressed HBV and HCV infection and replication • reduced inflammation • suppressed collagen production and enhanced collagenase activity • prevented mitochondrial dysfunction and cell death •
Slide 7: Cyclophilin inhibitors
Cyclophilin inhibitors • Cyclosporin A (CsA) • Sanglifehrins • fungus Tolypocladium inflatum, 1971. • soil Streptomyces • pancyclophilin inhibition • pancyclophilin inhibition • immunosupressive – therapy following • immunosuppresive transplantation • nonimmunosupressive derivative: • nonimmunosupre
Slide 8: Rencofilstat (CRV431)
Rencofilstat (CRV431) • nonimmunosupressive derivative of CsA • potently inhibited all cyclophilin isoforms tested—A, B, D and G • antiviral effect, decreased fibrosis and tumor development in chronic liver disease mouse models • beneficial effect in different stages of liver disease • Phase 2b clin
Slide 9: Aim
Aim • Efficacy of CRV431 in ALD: • 2D model of primary human HSC • 3D model of human PCLS • Fibrosis: HSC activation & ECM production • Hepatotoxicity • Inflammation
Slide 10: Methods: 2D culture of primary human HSC
Methods: 2D culture of primary human HSC 2.5ng/ml TGF-β1 Co-treatment 5µM CRV431 Post-treatment • TGF-β induces HSC to produce ECM in vitro Baseline characteristics of the liver tissue donors for the production of HSC. - TGFb + TGFb Background Fibronectin Demographics Tumour Alcohol liver Treatment
Slide 11: Antifibrotic in human HSC: CRV431 decreased expression of profibrogenic markers
Antifibrotic in human HSC: CRV431 decreased expression of profibrogenic markers in TGFβ stimulated HSC Co-treatment: aSMA Post-treatment: aSMA Co-treatment: a-SMA percentage of positive cells% 30 untreated 20 Post-treatment +TGFβ +CRV vs +TGFβ 10 TIMP1 3 0 ACTA2 -TGFb-CRV +TGFb-CRV +TGFb+CRV 2 COL1A
Slide 12: CRV431 reduced ECM production and altered orientation of ECM fibers
Antifibrotic in human HSC: CRV431 reduced ECM production and significantly altered the orientation of ECM fibers produced by HSC Post-treatment: Pan Collagen Co-treatment: Pan Collagen Co-treatment: Co-treatment: Post-treatment: a’ a’’ a’’’ Pan Collagen Fibronectin Pan Collagen +TGFβ +TGFβ Mean: 0.9
Slide 13: Methods: 3D culture of human PCLS
Methods: 3D culture of human PCLS 5µM CRV431 250mM EtOH 0.1mM FA 10µg/ml LPS Baseline characteristics of the liver tissue donors for the production of PCLS. Demographics Background liver Tumour Alcohol • Alcohol-induced fibrosis Treatment current/ Units/ SUBJECT ID Gender Age Ethnicity BMI Fibrosis
Slide 14: Antifibrotic in ALD: CRV431 reduced profibrogenic markers in PCLS
Antifibrotic in ALD: Addition of CRV431 reduced expression and secretion of profibrogenic markers in PCLS Gene expression Secretion in culture supernatant CRV431 vs no drug TIMP-1 Day 5 ✱✱✱ no insult EtOH EtOH+FA EtOH+FA+LPS 1000 TIMP-1 3 no drug Day 3 TIMP-1 (ng/ml) COL1A1 CRV431 2 ACTA2 100 PDGFRB
Slide 15: CRV431 treatment was not hepatotoxic in PCLS culture
CRV431 treatment was not hepatotoxic in PCLS culture Total hepatocyte death Release of cytokeratin-18 (M65) 100000 no drug CRV431 M65 (U/l) 10000 p=0.423 1000 Day 1 Day 3 Day 5 Total hepatocyte death in PCLS measured as a release of cytokeratin-18 (M65 epitope) n≥9, statistical analysis: 2-way ANOVA
Slide 16: CRV431 restored a balanced cytokine profile in alcohol induced liver damage
CRV431 restored a balanced cytokine profile in alcohol induced liver damage no drug CRV431 TNFα Day 3 IL-6 Day 3 IL-8 Day 3 IL-1β Day 3 p<0.024 p<0.001 ns 100000 p<0.001 100000 ns p<0.001 100000 p=0.024 p<0.001 100000 p<0.001 p=0.001 TNFα (pg/ml) p=0.065 IL-1β (pg/ml) 10000 10000 10000 IL-6 (pg/ml)
Slide 17: Rencofilstat (CRV431) in NASH Patients: The Phase 2a AMBITION Study
Rencofilstat (CRV431) in NASH Patients: The Phase 2a AMBITION Study • Safe and well tolerated • Reduction of ALT & PRO-C3: antifibrotic Harrison S, Hobbs T, Mayo PR, et al. NASH-TAG 2022
Slide 18: Conclusions
Conclusions • Cyclophilin inhibition is a promising treatment for liver diseases including ALD • Cyclophilin inhibitor Rencofilstat (CRV431) currently in clinical development for NASH and HCC has a potential to be used as a treatment in ALD: • Reduced expression and secretion of profibrotic markers
Slide 19: Acknowledgements
Acknowledgements Prof. Nigel Heaton Liver Immunology Liver Regeneration & Prof. Yoh Zen Tissue Engineering Dr Rosa Miquel Dr Elena Palma Mr Andreas Prachalias Dr Shilpa Chokshi Dr Luca Urbani Mr Krishna Menon Dr Sara Campinoti Nicola Harris Ane Zamalloa Bruna Almedia Ravi Jagatia Lai Wei Farooq Mali
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