Clinical Trials & Endpoints in NASH Cirrhosis April 25, 2018 Peter G. Traber, MD CEO & CMO, Galectin Therapeutics 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Chronic Liver Disease, Cirrhosis and its Progression Compensated Decompensated Chronic Cirrhosis Cirrhosis Liver ↑ Liver Fibrosis Disease • NASH • Viral Hepatitis • Alcohol • Variceal Bleeding • Other • Ascites • Encephalopathy • Jaundice/Liver Failure • Hepatocellular Carcinoma 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Survival Between Compensated and Decompensated Cirrhosis Percent Alive Months D’Aminco et. Al., J Hepatol 2006;44:217 (Graphic borrowed from Dr. Guadalupe Garcia-Tso) 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Portal Hypertension is the Main Driver of Decompensation Portal Pressure Decompensated Compensated Cirrhosis Cirrhosis D’Aminco et. Al., J Hepatol 2006;44:217 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Portal Hypertension is Initiated by Increased Intrahepatic Resistance Increased Resistance Portal Hypertension 5 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Multiple Contributors to Increased Intrahepatic Blood Flow Resistance in Cirrhosis Normal Liver Acinar Unit Distorted Architecture in Cirrhosis Structural Components Scar tissue Stellate cells Regenerative nodules Neoangiogenesis Micro thrombosis Non-Structural Components Nitric Oxide Endothelin Eiconsanoids CO/others “Endothelial Dysfunction” 6 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Cirrhosis Complications Center Around Increased Portal Vein Blood Pressure Encephalopathy Increased Resistance Shunting Hepatic Insufficiency Portal Hypertension Splanchnic vasodilatation Increased Flow Increased Effective Cardiac Output Hypovolemia Neurohormonal Na/H2O Ascites Activation Retention 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Critical Importance of Esophageal Varices in Cirrhosis An important goal of treatment of patients with compensated cirrhosis without esophageal varices is to prevent progression to varices and complications Esophagus: No Varices Esophageal Varices Bleeding Esophageal Varices 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
In Compensated HCV Cirrhosis, the Presence of Varices is Associated with Greater Probabilities of Decompensation and Death Cirrhosis Decompensation Liver-Related Death Bruno et. al., Am J Gastro 2009;104:1147 (Graphic borrowed from Dr. Guadalupe Garcia-Tso) 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
In Compensated HCV Cirrhosis, the Presence of Varices Prior to HCV Treatment Determines Decompensation Post-SVR No Varices Varices DiMarco et. al., Gastroenterology 2016;151:131 (Graphic borrowed from Dr. Guadalupe Garcia-Tso) 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Targeting NASH Cirrhosis Compensated Cirrhosis Decompensated Cirrhosis NASH: Stage 1 Stage 2 Stage 3 and 4 Cell Death Fatty Liver Inflammation No Varices Varices Develop Bleeding, Ascites, Encephalopathy Fibrosis ≥6 >10 >12 Portal Pressure (mmHg) Estimated US Prevalence 1.5-2.5M 24 - 30M 1.5-2.5M 80 - 100M 1 Garcia-Tsao, G., Friedman, S., Iredale, J., Prinzani, M. Hepatology. 2010;51:14451449 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Potential Clinical Trial Endpoints in NASH Cirrhosis Feels, functions, and survival Patient Outcomes Decompensation events: bleeding varices, ascites, hepatic encephalopathy, transplant, death HCC; Patient reported quality of life (?) Hepatic Venous Pressure Gradient Portal Pressure Crossing thresholds Absolute or percent change Responder definitions Reversal of cirrhosis (NASH-CRN stage 4 to a lower stage) Liver Biopsy Reduction in the percent of collagen (morphometry) Measures of liver stiffness: US (e.g. FibroScan, ARFI); MRE Imaging/Structure Multiparametric MRI (e.g. Perspectum LiverMultiScan); PDFF MELD Score Composite Scores Child-Turcotte-Pugh Score; ELF and others Metabolism: 13 C methacetin breath test (Exalenz) Liver Function Bile acid handling: HepQuant Shunt/Stat FDA Agreement FDA: May Be Surrogate Endpoint 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Liver Function Should be Area of Future Focus, as in Other Organ Failure Feels, functions, and survival Patient Outcomes Decompensation events: bleeding varices, ascites, hepatic encephalopathy, transplant, death HCC; Patient reported quality of life (?) Metabolism: 13 C methacetin breath test Liver Function Others & Combinations Bile acid handling: HepQuant Shunt/Stat Hepatic Venous Pressure Gradient Portal Pressure Crossing thresholds Absolute or percent change Responder definitions Reversal of cirrhosis (NASH-CRN stage 4 to a lower stage) Liver Biopsy Reduction in the percent of collagen (morphometry) Measures of liver stiffness: US; MRE Imaging/Structure Multiparametric MR; PDFF MELD Score Composite Scores Child-Turcotte-Pugh Score; ELF and others 2018 Galectin Therapeutics | NASDAQ: GALT 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com For more information, see galectintherapeutics.com
Rationale for Galectin-3 Inhibition in NASH Ø Gal-3 is a lectin protein that binds to galactose residues Stellate Macrophage on glycoproteins and is increased in NASH and liver Cell fibrosis/cirrhosis Ø Gal-3 null mice are resistant to NASH and fibrosis Gal-3 + + Ø Gal-3 involved in multiple pathophysiologic processes in NASH and liver fibrosis Ø GR-MD-02 is a complex carbohydrate drug that inhibits Myofibroblast Macrophage gal-3 and improves pathology of NASH and reverses Subsets fibrosis/cirrhosis in animal models 1,2 + Ø Safe and well tolerated in normal and NASH patients with Hepatocyte advanced fibrosis in Phase 1 studies Scavenger 1 Traber PG and Zomer E.PLOS ONE 2013;8:e83481 Receptor 2 Traber PG, Chou H, Zomer E, Hong F, Klyosov A Fiel M-I, Friedman, SL. PLOS ONE 2013;8:e75361. 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
NASH-CX Clinical Trial Design AIM: Evaluate Safety and Efficacy of GR-MD-02 in Compensated NASH Cirrhosis NASH cirrhosis (biopsy) No decompensating event Major Inclusion Criteria HVPG ≥ 6 mmHg No or small varices Week 1 Week 54 Placebo (PLB) n = 54 GR-MD-02 2 mg/kg (GR2) n = 54 GR-MD-02 8 mg/kg (GR8) n = 54 Every other week intravenous infusion X 26 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Study Endpoints & Assessment Methods Ø Primary Endpoint (baseline and week 54) § Change in Hepatic Venous Pressure Gradient (HVPG) • Standardized Procedure and Central Blinded Reading Ø Secondary Endpoints (baseline and week 54) § Change in Liver Histology • NAFLD Activity Score and Fibrosis Staging • Quantitative Morphometry for Collagen • Central Blinded Reading § Endoscopy to Evaluate for Varices § 13 C Methacetin Breath Test (Exalenz) § FibroScan § Complications of Cirrhosis 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Study Disposition (36 US Sites) N = 290 Patients Screened N = 128 Screening Failures N = 162 No Varices = 81 Patients Randomized (1 withdrew before 1 st dose) N = 53 N = 54 N = 54 2 mg/kg GR-MD-02 (GR2) 8 mg/kg GR-MD-02 (GR8) Placebo (PLB) Discontinued Treatment = 3 Discontinued Treatment = 1 Discontinued Treatment = 6 Lost to Follow-Up (1) Adverse Event (1) Adverse Event (3) Withdrew consent (1) Lost to Follow-Up (2) Physician decision (1) Physician decision (1) 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
HVPG Primary Endpoint (Pre-Specified Analyses) Total Patient Population Mild Portal Hypertension mean ± SEM mean ± SEM mean ± SEM ITT with LOCF (last observation carried forward); ANOVA with LSD (least squared difference) 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
No Esophageal Varices at Baseline (Post Hoc Analysis) 50% of patients (81) did not have varices at baseline mean ± SEM ITT with LOCF; ANOVA with LSD 2018 Galectin Therapeutics | NASDAQ: GALT For more information, see galectintherapeutics.com
Recommend
More recommend
