お知らせ • May 23
Hepion Pharmaceuticals, Inc. Announces Positive Topline Results from Its Recently Completed Phase 2 Altitude-Nash Clinical Trial
Hepion Pharmaceuticals, Inc. announced positive topline results from its recently completed Phase 2ALTITUDE-NASH clinical trial. ALTITUDE-NASH met its primary endpoint by demonstrating improved physiologic liver function and was well tolerated after four months of treatment in subjects with stage 3 or greater fibrosis based on the AGILE 3+ criteria. All additional secondary endpoints were also met, including reductions in the liver injury biomarkers, alanine and aspartate transaminases; and multiple fibrosis-associated biomarkers, including ProC3 (procollagen 3 C-terminal peptide), PIIINP (procollagen 3 N-terminal peptide), TIMP1 (tissue inhibitor of metalloproteinase-1), hyaluronic acid, and enhanced liver fibrosis (ELF) scores (composite of PIIINP, TIMP1, and hyaluronic acid). These observations build on similar findings from a shorter Phase 2a trial and reinforce rencofilstat’s direct antifibrotic mode of action and increase the confidence for reductions in fibrosis in Hepion’s ongoing Phase 2b ASCEND-NASH paired biopsy trial. Primary Endpoint: Four Measures of Liver Impairment Significantly Improved Compared to Baseline with Four Months Rencofilstat 225 mg Treatment: The HepQuant SHUNT Test was used in this study under an U.S. Food and Drug Administration (“FDA”)-issued Investigational Device Exemption (IDE). The SHUNT Test is a minimally invasive test that tracks changes in the degree of liver function impairment and was used to determine four key measures: HepQuant DSI™ (Disease Severity Index) score, which primarily reflects hepatocyte function; SHUNT, which reflects the impact of micro-architectural changes, such as fibrosis on blood flow through the liver; HepQuant HR™ (Hepatic Reserve); and RISK ACE, which reflects the annual risk of a patient developing an adverse clinical outcome. Rencofilstat met the primary endpoint and lowered mean DSI score in all doses, with rencofilstat 225 mg treatment over 4 months resulting in statistically significant decreases in DSI (mean ? = -1.62 units; p<0.05), SHUNT% (mean ? = -2.8%; p<0.05), HR% (mean ? = 3.9%; p<0.01), and RISK ACE (mean ? = -1.2 events per 100 patient-years; p<0.001) compared to baseline; and 61% of subjects in the 225 mg rencofilstat arm had a DSI improvement of >2.0 points (p<0.05). In HepQuant’s research, improvements from baseline, especially for high DSI scores that decrease by 2.0 points or more, are associated with clinically significant reductions in risk for liver related complications, including esophageal varices and encephalopathy. To address the potential of rencofilstat for patients with the most advanced functional impairment and greatest risk of disease progression, an analysis was conducted on the 34 subjects with DSI>17 or SHUNT%>25 as research indicates these subjects are at high risk for hepatic complications (Table 2). In this subgroup, independent of rencofilstat dose, statistically significant decreases at Day 120 compared to baseline were again observed for DSI score (mean ? = -1.30 units; p<0.05), SHUNT% (mean ? = -3.4%; p<0.01), HR% (mean ? = 2.9%; p<0.05), and RISK ACE (mean ? = -1.6 events per 100 patient-years; p<0.01). The large reduction in SHUNT% suggests alleviation of micro-architectural defects as anticipated from an antifibrotic agent and suggests that rencofilstat may be most effective in patients with more severe liver impairment. Multiple biomarkers related to fibrosis were improved following four months of treatment with rencofilstat: ProC3, PIIINP, TIMP1, and hyaluronic acid. ELF scores were similarly improved by rencofilstat. Robust reductions in ALT and AST were also observed with all doses of rencofilstat, with the greatest reductions seen in the 225 mg rencofilstat dosing arm. Incremental dose-response patterns were observed for most of the biomarkers, and in all cases the largest reductions from baseline for each of the biomarkers occurred in the 225 mg rencofilstat group. Additional analyses were performed on the approximate one-third of subjects with elevated baseline ProC3, which assesses the formation of type III collagen and indicates both severity and activity of disease. Because Pro-C3 is a measure of collagen cleavage during active fibrinogenesis, subjects with high ProC3 levels represent a NASH population with more active disease, therefore representing an important target population for many NASH drug candidates. In ALTITUDE-NASH, the greatest magnitude of effects was observed with 225 mg rencofilstat (Table 4), and most frequent dose-dependencies were observed in subjects with baseline ProC3>37.5 ng/ml (Roche, Elecsys). Rencofilstat 225 mg, and often the 150 mg dose, led to greater improvements than with 75 mg rencofilstat for all the NASH biomarkers in this high-risk population as well as in the entire study population. Primary Safety and Tolerability Endpoints Met with No Serious Adverse Events Attributed to Rencofilstat: Of the 70 subjects enrolled in the study, 67 completed all study procedures including 120 days oral dosing of rencofilstat with a 14-day routine safety follow up period. Rencofilstat was well tolerated, with no trends in adverse events or safety signals identified. There were no deaths or hepatic decompensation events recorded in the trial, and a total of five serious adverse events (SAEs) occurred with four unrelated to study drug (COVID-19, headache, fibula fracture, COPD) and a single SAE (biliary acute pancreatitis) classified as possibly related to study drug in a subject diagnosed with a pancreatic stone as the likely source for the pancreatitis. Other safety labs, EKGs, and physical exams did not reveal any safety signals or concerns over the course of the study. Study Design and Objectives: ALTITUDE-NASH was designed as a Phase 2, multi-center, randomized, open label study. F3 NASH subjects were identified by having a baseline AGILE 3+ screening score of =0.53 or historical biopsy obtained within the preceding 6 months. The AGILE 3+ score is calculated using FibroScan fibrosis score, laboratory values (AST, ALT, platelets), and clinical parameters (age, sex, diabetes status). Subjects were randomized to one of three rencofilstat treatment groups receiving either 75 mg, 150 mg, or 225 mg soft gelatin capsules once daily for a period of 4 months. The HepQuant Shunt test was administered at baseline, Day 60, and Day 120 of treatment in addition to serum analyses for safety and efficacy markers at each study visit. End-of-study liver biopsies or other measures of structural extracellular matrix changes were not collected due to the relatively short duration of treatment.