What Comes Next for Berobenatide? VESPER-3 and Phase 3 Expectations, With John Buse, MD, PhD

With VESPER-3's 28-week interim results showing placebo-adjusted weight loss of up to 12.3% with once-monthly berobenatide dosing, attention is now turning to what the 64-week final analysis will add and how phase 2b findings should inform expectations for the upcoming phase 3 program.¹

In an interview at the 2026 Scientific Sessions of the American Diabetes Association (ADA), John Buse, MD, PhD, offered his perspective on how clinicians and researchers should contextualize the current data.

The phase 3 VESPER-4 and VESPER-6 trials will test a 9.6 mg monthly maintenance dose, a threshold not directly evaluated in VESPER-3. How the drug performs at higher doses, in larger and more diverse populations, and under real-world self-administration conditions remains to be established.

Berobenatide Efficacy Benchmarking and Future Directions

Buse noted the investment community is focused on whether berobenatide will match or exceed tirzepatide, semaglutide, or orforglipfron in weight reduction. His assessment: the drug will likely fall within a competitive range, and the 64-week readout will clarify the ceiling of achievable weight loss.

He cautioned, however, against drawing firm comparative conclusions from phase 2 data. Phase 2 programs involve modest patient numbers and limited site counts, and in the VESPER trials specifically, drug administration was conducted in-clinic rather than by patients at home.

"It's sort of an estimate and challenging to compare from one drug to another how they perform in phase 2," Buse said. "And then we'll have to see whether they can duplicate that performance in phase 3."

He added the phase 3 program incorporates dosing modifications designed to improve on what was tested in VESPER-1 and VESPER-3, suggesting the efficacy signal seen in phase 2 may not represent the drug's full potential.

Buse also addressed the absence of a weight loss plateau at week 28, a finding he described as directionally informative but not definitive. The 28-week data appear on par with the most active agents currently available, he said, but the precise landing point in phase 3 remains uncertain. Regarding head-to-head comparisons, he noted that only a proper comparative trial will settle differences between agents.

Berobenatide 9.6 mg Monthly Dose Rationale and Tolerability Expectations

The 9.6 mg monthly maintenance dose for phase 3 was derived from VESPER-1 OLE data, where 2.4 mg weekly was administered, and 9.6 mg represents the monthly equivalent of 4 such weekly doses.¹ VESPER-1 did not directly test 9.6 mg once monthly, and a different titration scheme was used, but the data suggest 9.6 mg will be both tolerable and associated with additional efficacy relative to lower doses.

Buse estimated the phase 3 dose could yield weight loss approximating 20%, while characterizing this as a reasoned projection rather than an established finding. Tolerability across the berobenatide phase 2 program has been favorable, with Buse noting berobenatide appeared surprisingly well tolerated in some studies. He added adverse event assessment methodology differs between phase 2 and phase 3, meaning the full safety picture will come into sharper focus only with the larger trial.¹

Editors’ note: Buse reports relevant disclosures with Corcept, Dexcom, GentiBio, Novo Nordisk, Amgen, AstraZeneca, Boehringer-Ingelheim, Corcept Therapeutics, and others.

References

1. Buse J. Long-Term Treatment with the Ultra-Long-Acting GLP-1 Receptor Agonist MET-097 (PF-08653944) in Adults with Obesity or Overweight: The VESPER-1 Open-Label Extension. Presented at: American Diabetes Association 2026 Scientific Sessions; June 6, 2026; New Orleans, LA.

2. Buse J. Monthly Dosing of MET-097 (PF-08653944) for Weight Management: Primary Outcomes of the VESPER-3 Phase 2 Trial. Presented at: American Diabetes Association 2026 Scientific Sessions; June 6, 2026; New Orleans, LA.

3. ADA. Ultra-long-acting injectable GLP-1 RA shows promise for supporting weight management in individuals with and without type 2 diabetes. Published June 6, 2026. https://www.prnewswire.com/news-releases/ultra-long-acting-injectable-glp-1-ra-shows-promise-for-supporting-weight-management-in-individuals-with-and-without-type-2-diabetes-302793181.html