Easl 2023 – GLP-1 combos take on a milder form of Nash

Similarly acting agents from Merck & Co and Altimmune aim to improve NAFLD, with mixed results.

Merck & Co’s GLP-1/glucagon agonist efinopegdutide beat Novo Nordisk’s semaglutide in a mid-stage head to head non-alcoholic fatty liver disease trial, the Easl meeting heard this morning. But this success might not be all it appears: the study used a low dose of Novo’s GLP-1, prompting suggestions that the comparison was not strictly fair. 

Another GLP-1/glucagon agonist, Altimmune’s pemvidutide, also hit in NAFLD, this time in a phase 1 trial. Fortunately for the company the side effects that plagued the same project’s obesity study do not seem to have manifested themselves – but the lack of a dose response is curious. 

Merck licensed efinopegdutide from Hanmi in 2020 for $10m up front. The project’s open-label phase 2a trial was designed to show its effect on liver fat content, with weight loss examined as a secondary endpoint. It hit the former measure with significance at six months, and more participants had relative reductions in hepatic fat of at least 30%, 50% and 70% with efinopegdutide than with semaglutide, though no claims of significance were made here.

Source: Easl presentation, abstract OS-060.

Merck’s asset also allowed a numerically greater weight loss figure: 8.5% against semaglutides’s 7.1%. However the difference was not statistically significant, with p=0.085.

An Easl delegate attending the presentation raised an obvious point: the dose of semaglutide in the trial, 1mg once weekly, was arguably too low. This was the dose used in Novo’s own phase 2 Nash trial of semaglutide, which hit only the primary endpoint but missed a key secondary when it reported in 2020.

The ongoing phase 3 Nash trial of semaglutide, Essence, is testing 2.4mg once-weekly, the same dose that is approved in obesity. Essence will not yield data for some years.

In response to the suggestion that the head-to-head NAFLD trial might not have been a fair comparison, Dr Manuel Romero Gomez of the University of Seville, presenting the data, said the lower dose also kept semaglutide’s side effects low. And it is true that efinopegdutide did lose out on safety, with 64% of efinopegdutide patients having drug-related adverse events versus 48% of those on semaglutide. Three efinopegdutide patients discontinued owing to a drug-related AE, versus none in the control arm. 

Perhaps a more robust test will come in the shape of efinopegdutide’s ongoing phase 2 trial in Nash, an indication for which it has fast-track status. Again it is being tested against semaglutide, but this time Novo’s drug is being dosed at 2.4mg. Results could appear in 2025.

Safer in NAFLD

Altimmune is also pursuing GLP-1/glucagon agonism in NAFLD. Pemvidutide has already proven itself effective in obesity, but at the price of intolerable toxicity. In NAFLD it appears to be safer, according to phase 1 results presented at Easl. 

As in the phase 2 obesity study, the new trial, which enrolled NAFLD patients who were also obese or overweight, used pemvidutide doses of 1.2mg, 1.8mg, and 2.4mg. All doses showed statistically significant reduction in liver fat against placebo.

Source: Easl presentation, abstract OS-063.

Pemvidutide also beat placebo on weight loss, though not to the degree seen in the obesity trial. There the highest dose enabled placebo-adjusted weight loss of 9.7%, whereas in the obese or overweight NAFLD patients in the new trial the middle dose was the most effective, allowing 6% weight loss among non-diabetic patients and 1.9% in those with diabetes.

But perhaps the most interesting findings were on safety data presented at Easl from 66 subjects who participated in a 12-week extension study. Serious or severe adverse events were seen in 5% of placebo subjects and 6-7% of those given the lower two doses, but were absent entirely in the high-dose group. 

Two patients in the 1.2mg dose group and one in the 1.8mg group discontinued owing to adverse events. There were no AE-related dropouts from the high-dose group, naturally, because there were no AEs. 

The lack of a dose response in both weight loss and on toxicity could raise questions. Perhaps the phase 2 paired liver biopsy Nash study Altimmune intends to begin in the next couple of months will help answer them.

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