お知らせ • May 25
NGM Biopharmaceuticals, Inc. Reports Topline Results from 24-Week Phase 2B Alpine 2/3 Study of Aldafermin in NASH
NGM Biopharmaceuticals, Inc. reported results from the 24-week Phase 2b ALPINE 2/3 study evaluating aldafermin in 171 patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH) with stage 2 or 3 liver fibrosis (F2/F3). The trial was an equally randomized, double-blind, placebo-controlled study that assessed the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg doses of aldafermin once-daily subcutaneous injections compared to placebo. The study did not meet its primary endpoint evaluating a dose response showing improvement in liver fibrosis by >1 stage with no worsening of NASH at week 24 (p=0.55), analyzed using a dose response-driven statistical analysis plan (Multiple Comparison Procedure Modeling, or MCP-Mod). The study did achieve statistical significance versus placebo on certain secondary endpoints, including NASH resolution (at the 3 mg dose) and multiple non-invasive measures of NASH, including liver fat content reduction by MRI-PDFF, ALT, AST and Pro-C3 (at the 1 mg and 3 mg doses). NGM’s disclosed pipeline includes: NGM621, an anti-complement C3 antibody, currently in Phase 2 development for the treatment of geographic atrophy; NGM120, a GFRAL antagonistic antibody in Phase 2 development for the treatment of metastatic pancreatic cancer and cancer-related cachexia; and NGM707 and NGM438, anti-ILT2/ILT4 and LAIR1 myeloid checkpoint candidates, respectively, both of which are anticipated to begin Phase 1 studies for the treatment of advanced solid tumors this year. Additionally, Merck continues to progress a global Phase 2b study of MK-3655, an FGFR1c/KLB agonistic antibody for the treatment of NASH, which was discovered by NGM under its collaboration with Merck. In the 24-week study (n=171), the overall safety profile of aldafermin was consistent with prior studies and similar to that of placebo. Patients treated with aldafermin at all three doses studied in the trial demonstrated a comparable frequency of adverse events versus placebo: any treatment-emergent adverse events (TEAEs) for placebo, 0.3 mg, 1 mg and 3 mg aldafermin were 84%, 70%, 83% and 88%, respectively; serious adverse events (SAEs) for placebo, 0.3 mg, 1 mg and 3 mg aldafermin were 7%, 2%, 10% and 2%, respectively. None of the reported SAEs were deemed related to treatment by the site investigator; drug-related TEAEs leading to discontinuation for placebo, 0.3 mg, 1 mg and 3 mg aldafermin were 5%, 2%, 2% and 2%, respectively; and there was one fatal adverse event in the 1 mg aldafermin arm, which occurred 30 days after the last confirmed aldafermin dose and was determined unrelated to treatment by the site investigator. As expected, given aldafermin’s mechanism of action as a potent inhibitor of the classical bile acid synthesis pathway, a mean LDL-cholesterol increase was observed, which was fully mitigated by concomitant statin use. ALPINE 2/3 was a multi-center, double-blind, randomized, placebo-controlled Phase 2b study that evaluated the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg once-daily subcutaneous injections of aldafermin over 24 weeks of treatment. The study enrolled 171 patients with biopsy-confirmed NASH with F2-F3 liver fibrosis who were randomized 1:1:1:1 to receive aldafermin 0.3 mg (n=43), aldafermin 1 mg (n=42), aldafermin 3 mg (n=43) or placebo (n=43). The primary objective of the study was to evaluate a dose-response showing fibrosis improvement >1 stage with no worsening of NASH at week 24. Secondary endpoints included NASH resolution, fibrosis improvement and NASH resolution, and relative changes in LFC, ALT, AST and biomarkers of fibrosis at week 24. Patients were also evaluated at week 30 following six weeks off treatment for safety and non-invasive measures. The primary endpoint, improvement in liver fibrosis is greater than or equal to 1 stage and no worsening of steatohepatitis at week 24, was evaluated using the MCP-Mod (Multiple Comparison Procedure-Modeling) approach to assess the dose response relationship in the ITT population. All remaining analyses of the primary endpoint and of all secondary endpoints were evaluated using a pre-specified pairwise approach and used the Cochran-Mantel-Haenszel test. Continuous efficacy endpoints were analyzed using analysis of covariance. Per protocol, patient liver biopsies were performed at baseline screening and after 24 weeks of treatment (n=143) and were read using the NASH CRN criteria by one central, independent hepatopathologist who was blinded to patient and treatment assignment. ALPINE 4 is a multi-center, double-blind, randomized, placebo-controlled Phase 2b study evaluating the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg once-daily subcutaneous injections of aldafermin over 48 weeks of treatment. The study is designed to enroll 160 patients with biopsy-confirmed NASH with F4 liver fibrosis and compensated cirrhosis. The primary endpoint is to evaluate a dose-response showing fibrosis improvement >1 stage with no worsening of NASH at week 48. Secondary endpoints include relative changes in ALT, AST, biomarkers of fibrosis and Liver Stiffness Measure at week 48. Patients will also be evaluated at week 54 following six weeks off treatment for safety and non-invasive measures.
