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Final analysis of a 24-week, randomized, double blind, placebo-controlled, multicenter study of aldafermin (NGM282) in patients with nonalcoholic steatohepatitis
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Aldafermin Lowers Liver Fat, Improves Fibrosis in 24-Week NASH Trial
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
In a 24-week, double-blind, placebo-controlled trial, the subcutaneous FGF19 analog aldafermin cut liver fat and improved fibrosis in people with nonalcoholic steatohepatitis (NASH) [1]. More than 1 in 5 participants receiving aldafermin, versus none receiving placebo, had both improved fibrosis and NASH resolution at week 24.
US researchers who conducted this 78-person trial reminded colleagues that no treatment has been licensed for NASH, which boosts risk of cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplant, and death. One of several medications now in clinical trials for NASH, aldafermin inhibits bile acid synthesis, promotes insulin sensitization, lowers toxic fatty acids, and decreases de novo lipogenesis. In a previous phase 2, double-blind, placebo-controlled trial involving 82 US and Australian participants with NASH, three quarters of participants randomized to 3 or 6 mg of aldafermin daily had at least a 5% drop in absolute liver fat content after 12 weeks versus 7% with placebo (P < 0.0001 for both doses) [2].
The new phase 2 trial enrolled adults with (1) biopsy-confirmed NASH with a NAFLD Activity Score at or above 4, (2) stage 2 or 3 liver fibrosis, (3) absolute liver fat content at or above 8% by MRI-PDFF,* and (4) alanine aminotransferase (ALT) at or above 19 IU/L in women or 30 IU/L in men. At 9 US sites, researchers randomized participants in a 2-to-1 ratio to 1 mg of subcutaneous aldafermin daily or placebo. These people had a liver biopsy before treatment began and after 24 weeks. The primary endpoint was 24-week change from baseline in absolute liver fat content measured by MRI-PDFF.
The 53 people randomized to aldafermin and the 25 randomized to placebo averaged 53 and 54.1 years in age, 35.8 and 36.8 kg/m2 in body mass index, 5.7 and 5.4 in NAFLD Activity Score, and 18.0% and 18.5% in liver fat content. Proportions of men were 51% in the aldafermin group and 36% in the placebo group, while 60% and 64% had diabetes.
At week 24 absolute change in liver fat content averaged -7.7% with aldafermin and -2.7% with placebo, a significant difference (P = 0.002). At the same point relative change in liver fat content averaged -39% with aldafermin and -13% with placebo (P = 0.008). Proportions of participants with at least a 5% absolute drop in liver fat content at week 24 were 68% with aldafermin versus 24% with placebo (P < 0.001), and respective proportions with at least a 30% relative drop were 66% versus 29% (P = 0.004).
Fibrosis improved at least 1 stage with no NASH worsening in 38% receiving aldafermin and 18% getting placebo. Respective proportions with resolution of NASH with no fibrosis worsening were 24% and 9%. Proportions of aldafermin and placebo recipients who achieved statistically significant fibrosis improvement and NASH resolution at week 24 were 22% versus 0% (P = 0.015). NAFLD Activity Score improved by 2 points or more in 62% on aldafermin and 9% on placebo (P < 0.001).
ALT, aspartate aminotransferase, and PRO-C3 (a fibrogenesis marker) all improved significantly with aldafermin (versus placebo) in the first 4 weeks of treatment and maintained that advantage through 24 weeks. Serum bile acids fell by almost 60% on average through 24 weeks with aldafermin, while rising more than 30% with placebo (P < 0.001).
No one randomized to aldafermin and 1 person randomized to placebo had a treatment-emergent adverse event leading to drug withdrawal. Numbers and proportions with any drug-related adverse event were 27 (50.9%) with aldafermin and 11 (44%) with placebo, and proportions with any serious adverse event 2 (3.8%) and 3 (12%). Diarrhea was the most frequent adverse event with aldafermin, affecting 15 people (28.3%) versus 6 (24%) receiving placebo. Nausea affected 5 (9.4%) in the aldafermin arm and 6 (24%) in the placebo group.
The researchers noted that these results "are consistent with our previous 12-week studies [see reference 2], demonstrating durable response and accumulation of histological benefit over time."
*MRI-PDFF, magnetic resonance imaging proton density fat fraction.
References
1. Harrison SA, Neff G, Guy CD, et al. Final analysis of a 24-week, randomized, double blind, placebo-controlled, multicenter study of aldafermin (NGM282) in patients with nonalcoholic steatohepatitis. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 72.
2. Harrison SA, Rinella ME, Abdelmalek MF, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2018;391:1174-1185. doi: 10.1016/S0140-6736(18)30474-4.
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