Monthly GLP-1 for Obesity Promising as More Manageable Alternative

NEW ORLEANS — Injections of an ultra-long-acting investigational GLP-1 agonist led to significant weight loss in people with overweight or obesity, with reductions continuing after a switch to once-monthly dosing, according to the ongoing VESPER clinical program.

After an initial 12-week titration period with weekly dosing, average body weight with the 4.8-mg monthly dose level of berobenatide declined 12.1% by week 28 — and without reaching a plateau — as compared with a 0.2% increase with placebo, interim findings from the dose-finding phase IIb VESPER-3 study showed.

“The transition to monthly dosing was well-tolerated,” said John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill, at the American Diabetes Association (ADA) annual meeting.

Safety and tolerability were consistent with the GLP-1 receptor agonist class, Buse noted, and the study “is informing the phase III program, where the highest dose will be 9.6 mg monthly — the 2.4-mg dose from VESPER-1 multiplied by four.”

Main results from the phase IIb VESPER-1 trial, presented earlier this year, reported a 16% weight loss by week 32 with 2.4 mg of berobenatide once-weekly. During an extension phase presented at ADA also by Buse, participants who switched from placebo to 4.8 mg once monthly achieved a 14.9% body-weight reduction by week 60.

Previously dubbed MET-097, berobenatide is an ultra-long-acting GLP-1 receptor agonist that is fully biased toward beneficial receptor signaling pathways. According to drugmaker Pfizer, berobenatide is being developed as a weekly and monthly single-agent therapy, as well as in combination with various peptides, including an amylin and a glucose-dependent insulinotropic polypeptide receptor agonist.

“Once-monthly dosing could offer a more manageable alternative to today’s more frequent injections,” Buse noted in a statement. “For patients, this less frequent dosing may help ease the burden of ongoing treatment and support better long-term adherence in chronic conditions like obesity and type 2 diabetes.”

Both randomized VESPER studies enrolled adults with obesity or overweight with comorbid hypertension, dyslipidemia, or both. The ongoing VESPER-3 study will evaluate its final endpoint at 64 weeks to provide long-term data. Roughly 54 participants were included in each of the five trial arms.

Gastrointestinal treatment-emergent adverse events (TEAEs) in VESPER-3 were mostly mild or moderate, with no more than one instance of severe nausea or vomiting observed in any dose group, and no instances of severe diarrhea.

Five participants discontinued berobenatide due to adverse events during the weekly phase, and another five discontinued during the monthly phase. No participants on placebo discontinued treatment.

Also reported at the ADA meeting were findings from VESPER-2, which evaluated berobenatide in adults with obesity or overweight and comorbid type 2 diabetes.

By week 28, patients on the highest dose (1.6 mg once weekly) achieved a 10.2% body-weight reduction from baseline compared with a 0.7% reduction in the placebo group. Participants on the highest dose also saw a 2.2% HbA1c reduction compared with a 0.2% reduction with placebo.

Pooling together the dose groups, berobenatide led to more TEAEs (73.6% vs 57.7%) and serious adverse events (6.6% vs 3.8%). Eight participants on the active drug (7.5%) discontinued due to adverse events. The TEAE profile was consistent with the GLP-1 drug class, with gastrointestinal side effects being the most common. These included nausea (23.6% vs 11.5%), vomiting (17.9% vs 3.8%), diarrhea (26.4% vs 23.1%), and constipation (19.8% vs 7.7%).

“This is the very first study that evaluated berobenatide in people with type 2 diabetes and overweight or obesity,” said presenter Ildiko Lingvay, MD, MPH, of UT Southwestern Medical Center in Dallas.

“This was a very important study to plan the phase III program,” she continued. The next trial will have 0.8-mg and 1.2-mg doses as the low and medium maintenance doses, with 2.4 mg as the high dose.

The phase III VESPER-4 study will test once-weekly berobenatide in patients without type 2 diabetes, while VESPER-5 will test it in those with comorbid diabetes. The VESPER-6 study will evaluate the drug as a once-monthly therapy for obesity or overweight.

At least seven additional phase III studies are planned to target specific comorbidities.