NGM Biopharmaceuticals announced positive preliminary results from a pre-specified interim analysis of the aldafermin 1 mg 24-week Cohort 4, which is the final cohort of an adaptive Phase 2 study evaluating the efficacy, safety and tolerability of aldafermin (formerly NGM282) in patients with biopsy-confirmed non-alcoholic steatohepatitis (NASH).
The Cohort 4 interim analysis demonstrated that once-daily treatment with 1 mg of aldafermin for 24 weeks in patients with stage 2 or 3 (F2-F3) liver fibrosis resulted in a statistically significant change in the absolute liver fat content (LFC) of -7.9% (measured by magnetic resonance imaging-estimated proton density fat fraction, or MRI-PDFF), as compared to -2.0% in the placebo arm (p<0.05), and a statistically significant change in relative LFC of -39.6%, as compared to -5.9% in the placebo arm (p<0.05). As per the study protocol, results were calculated using least square (LS) mean, which is a statistical approach that adjusts for observed baseline differences. 72% of patients treated with aldafermin achieved a ≥5% absolute reduction in LFC versus 17% for placebo. Similarly, 72% of patients treated with aldafermin achieved a ≥30% relative reduction in LFC versus 17% for placebo. Of the patients treated with aldafermin, 28% achieved a normal LFC after 24 weeks, defined as ≤5% absolute LFC, versus none in the placebo arm. In addition, in assessing biomarkers of liver inflammation and injury, treatment with aldafermin resulted in clinically meaningful reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Treatment with aldafermin also resulted in a statistically significant reduction in PRO-C3, an exploratory biomarker of liver fibrogenesis, as compared to placebo.
“These 24-week findings are highly consistent with the profound impact on liver fat and key biomarkers of NASH that were reported from the three prior 12-week cohorts of this Phase 2 study,” said Stephen A. Harrison, M.D., Medical Director at Pinnacle Clinical Research, Visiting Professor of Hepatology at University of Oxford, UK and principal investigator on the study. “This interim analysis demonstrated that extended exposure to aldafermin was well tolerated with no withdrawals during the 24-week treatment period. The magnitude of effect on LFC reduction and normalization, combined with the improvement in liver enzymes, reinforce aldafermin’s potential to potently and rapidly reverse multiple aspects of NASH.”
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As observed in the prior Phase 2 cohorts, patients treated with aldafermin in the Cohort 4 interim analysis experienced a mean increase of 47.6 mg/dL LDL cholesterol (LDL-C) at week 2 of treatment relative to baseline (103.5 mg/dL), which is consistent with the drug’s mechanism of action and potent FGFR4-mediated CYP7A1 inhibition. As per protocol, when elevation of LDL-C of at least 10 mg/dL was recorded, patients were directed to take an appropriate dose of rosuvastatin daily for the remainder of the study. Concomitant statin use mitigated the drug-induced LDL cholesterol rise, and the mean LDL-C level was below baseline at 24 weeks. In an assessment of other lipid biomarkers, the concurrent use of aldafermin with this statin protocol resulted in a slight increase in HDL-C and a statistically significant decrease in serum triglycerides relative to baseline.
There were no study withdrawals and no serious adverse events in the aldafermin arm of the Cohort 4 interim analysis, as compared to one withdrawal due to an adverse event and two serious adverse events in the placebo arm. The most common adverse events in the aldafermin arm, which were generally mild to moderate, were diarrhea, headache, nausea and arthralgia (joint pain).
“Aldafermin continues to be differentiated with what we believe is an industry-leading profile as a monotherapy for the potential treatment of NASH, as few drugs in development for this disease have shown meaningful metabolic, anti-inflammatory and anti-fibrotic activity,” said Hsiao D. Lieu, M.D., Senior Vice President, Chief Medical Officer of NGM. “Throughout our Phase 2 program, we’ve seen a relationship between aldafermin’s impact on biomarkers of disease and subsequent histology results. To that end, we look forward to the biopsy data readout for Cohort 4, which will further inform planning activities for our Phase 3 study.”
Topline results of the full Cohort 4, which will include an assessment of 24 weeks of treatment on liver histology, are anticipated in the first quarter of 2020.
“We’re pleased with these interim findings, as they represent another milestone in our advancement of aldafermin as an important potential treatment option to address the unmet needs of patients suffering from NASH,” said David J. Woodhouse, Ph.D., Chief Executive Officer of NGM. “This new data set adds to the comprehensive body of clinical evidence supporting the potential commercial profile of aldafermin and its promise as a cornerstone treatment for advanced NASH patients.”
Cohort 4 is an ongoing multi-center, double-blind, randomized, placebo-controlled Phase 2 study evaluating the efficacy, safety and tolerability of 1 mg daily subcutaneous injections of aldafermin over 24 weeks of treatment. The study enrolled 78 patients with biopsy-confirmed NASH with F2-F3 liver fibrosis. The primary endpoint is the treatment effect on absolute changes in LFC as measured by MRI-PDFF compared to placebo. Secondary and exploratory endpoints include relative changes in LFC, biomarkers of liver function and effect on liver histology. The interim analysis of non-invasive measures of efficacy, including LFC, liver transaminases and exploratory fibrosis biomarkers, was conducted when 38 patients completed 24 weeks of treatment.
Aldafermin is an engineered variant of the human hormone FGF19 that is dosed once daily as a subcutaneous injection and is being developed to reduce liver fat content, improve liver function and reverse fibrosis by targeting multiple pathogenic pathways of liver disease. NGM has generated robust preclinical and clinical evidence supporting the ability of aldafermin to resolve disease and reverse fibrosis in NASH patients. This wholly owned therapeutic has been evaluated in multiple Phase 2 studies in primary biliary cholangitis, primary sclerosing cholangitis, type 2 diabetes and NASH.