Shares in NGM Biopharmaceuticals jumped as much as 24% on Monday after the company reported top-line results from a Phase II study showing that aldafermin, an engineered variant of the human hormone FGF19, significantly reduced absolute liver fat content (LFC) versus placebo in patients with non-alcoholic steatohepatitis (NASH). Preliminary findings also demonstrated that statistical significance was achieved on the composite endpoint of both fibrosis and resolution of NASH, compared with placebo.
"To my knowledge, aldafermin is the first drug to demonstrate a robust, statistically significant effect of greater than 20% of patients achieving the FDA composite regulatory endpoint of fibrosis improvement and resolution of NASH versus placebo, as well as show an impressive impact on both of these endpoints independently," commented principal investigator Stephen Harrison. He added "these data further strengthen aldafermin's potential as a transformative monotherapy for NASH patients with established fibrosis."
Cohort 4, the final cohort of an adaptive Phase II study evaluating aldafermin, formerly known as NGM282, as a potential treatment for NASH, enrolled 78 biopsy-confirmed NASH patients with stage 2 or 3 liver fibrosis. Participants were randomly assigned once-daily subcutaneous injections of aldafermin over 24 weeks of treatment, or placebo. The main goal was absolute LFC as measured by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) compared to placebo at 24 weeks, with an absolute LFC reduction of at least 5% considered to be clinically meaningful. Secondary and exploratory endpoints looked at relative changes in LFC, biomarkers of liver function and effect on liver histology.
The study achieved its primary endpoint, demonstrating an absolute least square (LS) mean reduction in LFC of 8% and a significant LS mean relative reduction in LFC of 39% in the treatment arm, versus reductions of 3% and 13%, respectively, for placebo. NGM said a significant 68% of aldafermin-treated patients achieved an absolute LFC decrease of at least 5%, while a significant 66% achieved a relative reduction in LFC of 30% or more. In the placebo group, the reductions were 24% and 29%, respectively.
Further, preliminary histology data revealed that treatment with aldafermin led to fibrosis improvement of at least one stage, with no worsening of NASH, in 38% of patients compared to 18% in the placebo arm. In addition, 24% of aldafermin-treated patients achieved the endpoint of NASH resolution, with no worsening of liver fibrosis, versus 9% for placebo. "Of note, 22% of patients in the aldafermin treatment arm versus 0% in the placebo arm achieved the composite endpoint of both fibrosis improvement and resolution of NASH, which was statistically significant," NGM said.
In terms of side effects, the company noted that "as observed in the prior Phase II cohorts," the Cohort 4 findings revealed that patients treated with aldafermin saw their mean LDL cholesterol levels rise 45 mg/dL at the second week relative to baseline, which it said is "consistent with the drug's mechanism of action and potent FGFR4-mediated CYP7A1 inhibition." However, NGM stated that LDL cholesterol "was effectively managed with concomitant statin use," and levels for both groups were "nearly identical" at approximately 77 mg/dL at the end of the 24-week study period. The company said that additional Cohort 4 data will be presented at an upcoming medical meeting.
The Cohort 1, Cohort 2 and Cohort 3 portions of the trial assessed various doses of aldafermin over a period of 12 weeks. For related analysis, see ViewPoints: NGM's interim Phase II look in NASH fails to engender confidence.
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