Ultra-long-acting GLP-1 induces weight loss at 28 weeks for adults with obesity

Key takeaways:

• Adults receiving once-weekly 1.2 mg MET-097 lost 12.5% of their body weight at 28 weeks.
• An interim analysis of VESPER-3 revealed that slower dose titration may reduce gastrointestinal adverse events.

ATLANTA — An ultra-long-acting GLP-1 was tied to weight loss of up to 12.5% at 28 weeks among adults with overweight or obesity with no plateau observed, according to data from the VESPER-1 trial presented at ObesityWeek.

MET-097 (Metsera) is a fully biased, long-acting injectable GLP-1 designed to reduce body weight for people with overweight or obesity. In data from the phase 2b VESPER-1 trial, researchers found four different doses of the agent conferred significant weight reductions at 28 weeks compared with placebo.

“The body weight loss is consistent with that that has been observed with dual agonists, highlighting the advantage of full receptor bias,” John B. Buse, MD, PhD, distinguished professor of medicine at the University of North Carolina at Chapel Hill, and director of the UNC Diabetes Care Center, said during a presentation.

In VESPER-1, 225 adults with obesity or overweight with weight-related comorbidities (mean age, 40.3 years; 63.2% women) were randomly assigned, 1:1:1:1:1, to once-weekly 0.4 mg, 0.6 mg, 0.9 mg or 1.2 mg MET-097 or placebo for 28 weeks. The primary efficacy endpoint was percentage change in body weight from baseline to 28 weeks.

All four MET-097 groups had a reduction in weight at 28 weeks, with the 0.4 mg group losing 6.4% of body weight, the 0.6 mg group achieving an 8.4% weight loss, the 0.9 mg group losing 11.3% of body weight and the 1.2 mg group having a 12.5% weight reduction. The placebo group had an increase of 1.7% in body weight from baseline to 28 weeks.

Buse said the weight loss observed in the MET-097 groups did not appear to plateau at 28 weeks. Additionally, he noted preliminary data from an extension study showed continued weight loss up to 36 weeks among adults receiving MET-097.

“This can possibly be explained by the design of the molecule, which is characterized by full GLP-1 receptor bias to maximize [cyclic adenosine monophosphate] signaling,” Buse said.

In VESPER-1, there were three serious treatment-emergent adverse events, with two occurring in the 0.4 mg group and one in the 0.6 mg group. Gastrointestinal adverse events occurred in 60.4% of the 0.4 mg and 0.6 mg MET-097 groups, 55.3% of the 0.9 mg group and 62.5% of the 1.2 mg group compared with 41.7% of placebo participants. Buse said most cases of nausea and vomiting occurred in the first 3 days after a participant began the study drug.

Buse also presented interim safety data from the VESPER-3 trial, a randomized, double-blind, phase 2 trial with a planned enrollment of 250 adults with overweight or obesity. The trial is designed to assess the efficacy of once-monthly doses of MET-097. The interim analysis presented by Buse examined the tolerability of the study drug during a 12-week dose titration phase. Participants were randomly assigned to 0.4 mg of MET-097 titrated up to 0.8 mg, 0.4 mg with a dose increase to 0.8 mg and then 1.2 mg, 0.6 mg with a dose increase to 1.2 mg, 0.8 mg with no dose titration, or placebo.

At 12 weeks, adults who started with 0.4 mg of MET-097 and titrated up to 0.8 mg and later 1.2 mg in VESPER-3 had 44% less nausea, 11% less vomiting and 101% less diarrhea than adults who received 1.2 mg of MET-097 in VESPER-1.

“This further supports the hypothesis that the smooth pharmacokinetics associated with long half-life can improve tolerability,” Buse said.

Buse said the findings from VESPER-1 support the initiation of phase 3 trials for MET-097.

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