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NEW ORLEANS — Berobenatide, an investigational long-acting GLP-1 receptor agonist (RA) being investigated as a weekly or once monthly obesity and type 2 diabetes (T2D) therapy, showed favorable weight loss, A1c reductions, and tolerability in a series of phase 2 trials.

Results from the VESPER-1 open label extension (OLE) trial, the VESPER-2 trial, and the VESPER-3 trial were all presented here at the American Diabetes Association (ADA) 2026 Scientific Sessions.

“Berobenatide is a potentially important new option for people living with overweight or obesity, especially because a once-monthly dosing could offer a more manageable alternative to today’s more frequent injections,” said John Buse, MD, PhD, a professor of medicine at University of North Carolina School of Medicine, Chapel Hill, in a press statement at the meeting. 

Buse, who presented the findings from the VESPER-1 OLE and VESPER-3 trials, in which patients transitioned from weekly to monthly dosing of the drug, added that the “less frequent dosing may help ease the burden of ongoing treatment and support better long-term adherence in chronic conditions like obesity and [T2D].” 

Studies indicate that as many as 50% of patients discontinue GLP-1 RAs within the first year. Those who do remain on the drugs likely need to do so indefinitely to retain weight loss and cardiometabolic benefits, therefore interest in methods to improve retention is high. 

VESPER-1 OLE and VESPER-3: From Weekly to Monthly 

In the initial trial, VESPER-1, 239 adults with obesity or overweight with comorbidities were randomized to one of four weekly doses of subcutaneously injected berobenatide — 0.4 mg, 0.6 mg, 0.9 mg, or 1.2 mg — or to placebo. Top-line data from the trial, released in 2025, showed that berobenatide provided effective weight loss with no unexpected safety signals. 

The OLE trial defined a new maximum dose of 9.6 mg of berobenatide and demonstrated a transition from weekly to monthly dosing without significant added tolerability burden, Buse reported. 

The phase 2b VESPER-3 study, which focused primarily on the transition of weekly to monthly dosing, involved 268 patients with overweight or obesity without diabetes (mean BMI, 36.9; mean age, 46.2 years; 71% female).

The patients were randomized to one of the four different weekly dosing titrations or placebo, leading up to monthly dosing at week 12 of either 3.2 mg, 4.8 mg, or placebo. 

After week 28 of the ongoing 64-week trial, the placebo-adjusted weight loss was up to 12.3% in the 4.8 mg monthly dose group, with no plateaus in weight loss observed in the study.

“We found that weight loss continued after an early transition from weekly to monthly berobenatide dosing,” said Buse.

Adverse Events 

Overall discontinuations of treatment were 11.1% in the lowest monthly dosing group (3.2 mg), increasing to about 20% in the two weekly titration groups transitioning to the highest dose (4.8 mg monthly), for an average of 17.2%. 

The total discontinuations resulting from gastrointestinal treatment-emergent adverse events were 9.3% and 11.3% in the two differently titrated groups receiving 4.8 mg monthly.

In terms of specific gastrointestinal adverse events, rates of nausea were 37.7% in the overall berobenatide group vs 15.1% with placebo; vomiting occurred in 23.3% vs 1.9%, diarrhea in 14.4% vs 5.7%, and constipation in 20.9% vs 3.8%, respectively, with the highest rates occurring in the first weeks of treatment.

Each dosing group showed a reduction to very low adverse events by the end of the weekly titration, with notable increase upon transition to monthly, with some severe symptoms reported in those transitioning from 0.6 /1.2 mg weekly to 4.8 mg monthly at week 12.

“Upon switching to monthly dosing, a mild, transient increase in nausea and/or vomiting was observed, however, the symptoms improved rapidly with continued dosing,” Buse said. “The safety and tolerability of berobenatide were generally consistent with the GLP-1 RA class of drugs,” he said.

Based on these findings, the phase 3 monthly dosing trial (VESPER-6) will include the 4.8 mg monthly as the medium dose, with 9.6 mg to be tested as the highest dose.

VESPER-2: Effects in T2D 

Similar favorable safety and efficacy results were observed in the phase 2b VESPER-2 trial, which looked at weekly dosing of berobenatide in 133 patients with overweight/obesity as well as T2D.

In this study, patients had an average A1c of 8.2%, and the median duration of T2D was 8.5 years. The mean age was 56.4 years, and 42.1% were female. About 76.4% were on metformin and 12.3% were on SGLT2 inhibitors.

At 28 weeks, 90.6% of patients treated with berobenatide completed the study with dose-dependent reductions in A1c of up to 2.2% observed, along with reductions in body weight of up to 10.2%. Participants reported no or only mild gastrointestinal adverse events and overall safety and tolerability that were consistent with the broader class of GLP-1 RAs, with no increases in rates of hypoglycemia.

“These are the first efficacy and safety data for berobenatide in adults with [T2D] and obesity/overweight,” said first author Ildiko Lingvay, MD, a professor of medicine at UT Southwestern Medical Center, in Dallas, in presenting the findings.

“Gastrointestinal adverse events were mostly mild or moderate in severity and occurred early during dose escalation, and no new safety signals were identified.”

She noted that these results will inform the ongoing weekly phase 3 trial in individuals with T2D (VESPER-5), with 0.8 and 1.2 mg doses to be used as the low and medium maintenance doses, respectively, and 2.4 mg as the high dose.

Transition Point a ‘Concern’ 

In an overview/commentary of the research in the session, Donna Ryan, MD, a professor emerita with the Pennington Biomedical Research Center, Louisiana State University, in Baton Rouge, noted that “the overall tolerability is encouraging.”

Monthly dosing can be pursued, she said, however, “we really need more information about that transition from weekly to monthly because when they went up to those higher monthly doses, that’s when the tolerability signal occurred.”

She added: “If they can solve that problem, this could end up [being] very good.”

Further commenting to Medscape Medical News, W. Timothy Garvey, MD, a professor of medicine at the University of Alabama at Birmingham, agreed that the transition is a point of concern.

“Some patients were having significant symptoms, and it’s quite a jump [from the weekly to monthly dose], so I think that needs to be worked on tolerability a little more,” he said.

“They have some work to do in terms of optimizing dosing to minimize the side effects, but I think they’ll get there,” he added.

The potential benefits in terms of T2D are especially exciting, said Garvey. “Just think if a person with [T2D] could take just one injection a month and the injection is also sufficient to achieve some weight loss and address some of the obesity-related complications as well as obtain good hemoglobin A1c targets without hypoglycemia — that could improve the lives of people with [T2D] immensely,” he said. 

Of note, the reductions in A1c down to target levels in the normal range, without hypoglycemia, was “remarkable,” he added. “I never thought I’d see that in my career.” 

More Options Needed 

Noting that other once monthly incretin-based therapies, such as MariTide, are also in development, Josh Neumiller, PharmD, senior vice president of medical affairs at the ADA and the Allen I. White distinguished professor in the College of Pharmacy and Pharmaceutical Sciences at Washington State University, in Spokane, agreed that “having additional options available for people living with obesity and diabetes that can better fit into their lifestyles is important when tailoring the individualized treatment approach for the person.”

Regarding the VESPER-3 results, he added that “because a plateau in weight loss was not seen at 28 weeks, the observed weight loss at 64 weeks will be informative about the weight loss potential of this agent beyond 28 weeks when administered once monthly.” 

Addressing the broader need for more options in the treatment of obesity during the session, Louis J. Aronne, MD, a professor of metabolic research at Weill Cornell Medicine, New York, noted that “we regularly see patients who don’t respond to even the highly effective medicines we have [for obesity] right now, so we need multiple options for patients.”

“There are over 100 drugs to treat hypertension in 10 therapeutic categories, [as opposed to] fewer than 10 for obesity, and only two that are widely used,” he pointed out. 

“We need more options that work in different ways so that clinicians and patients have options to keep them on treatment, [and] to reduce side effects.” 

Aronne agreed that the “very robust” effect of berobenatide on A1c was especially remarkable. “Think about having a monthly treatment to prevent diabetes and treat early diabetes — that would be a game changer,” he said.

The VESPER trials were sponsored by Pfizer. 

Buse’s disclosures include consulting and/or other relationships with Aardvark Therapeutics, Altimmune, Alveus Therapeutics, Amgen, Antag, Aqua Medical, AstraZeneca, Corcept Therapeutics, Eli Lilly, General Medicines Inc, Kayothera, Metsera, Novo Nordisk, Pfizer, Recordati, Roche, Sparrow Pharmaceuticals, Vertex, vTv Therapeutics, Zealand, and GentiBio. 

Lingvay’s disclosures include consulting, research or other relationships with Novo Nordisk, Dexcom, Roche, Pfizer, Lilly, Aardvark Therapeutics, AbbVie, Adarx, Altasciences, Alveus Therapeutics, Amgen, Antag Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Baim Institute, Bain Capital, Bayer, Betagenon AB, Bioio Inc., Biomea, Boehringer Ingelheim, Boston Scientific, Carmot, Corxel, Cytoki Pharma, Genentech, Janssen/J&J, Juvena, Kailera Therapeutics, Keros Therapeutic, Inc, Mediflix, Metsera, Neurocrine, Penguin Bio, Regeneron, Response Pharmaceutical, Sanofi, Shionogi, Sparrow, Skye Bioscience, Source Bio, Structure Therapeutics, SUMMIT, Tenvie, TERNS Pharma, Verdiva Bio, Viking Therapeutics, and Zealand Pharma. 

Ryan’s disclosures include consulting and/or other relationships with AbbVie, Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Calibrate, Carmot/Roche, CINRX, Currax, eMed, Epitomee, Fractyl, Kailera, Lilly, Nestle, Novo Nordisk, Pfizer, Regeneron, Scientific Intake, Source Bio, Structure Therapeutics, Tenvie, Viking, Wondr Health, and Zealand. 

Garvey’s disclosures include consulting and/or other relationships with Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Zealand, Genentech/Roche, Terns Pharmaceuticals, Neurocrine, Keros
Therapeutics, Gan & Lee, Corcept, Graviton Bioscience, AbbVie, Madrigal, i2o Therapeutics, and Regeneron. 

Neumiller had no disclosures to report. 

Aronne’s disclosures include consulting and/or other relationships with Altimmune, Amgen, Boehringer Ingelheim, Currax Pharmaceuticals, Eli Lilly and Company, Janssen, Jazz Pharmaceuticals, Novo Nordisk, Pfizer, Veru Pharma, Zealand Pharmaceuticals, Jamieson Wellness, and Skye Bioscience.