Berobenatide had a favourable benefit–risk profile for chronic weight management in the VESPER-2 trial.In the phase II VESPER-2 trial, the investigational injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA) berobenatide shows robust reductions in weight and HbA1c in adults with obesity/overweight and type 2 diabetes (T2D).
“At 28 weeks, berobenatide demonstrated dose-dependent reductions in HbA1c of up to 2.2 percent and in body weight of up to 10.2 percent, with a slope that continued to decrease weekly,” said Dr Ildiko Lingvay from The University of Texas Southwestern Medical Center, Dallas, Texas, US, at ADA 2026.
Weight reductions
The 10.2-percent weight loss (WL) was observed with the highest berobenatide dose (1.6 mg); the placebo-corrected least-squares mean (LSM) change was –9.5 percent. With berobenatide 0.4, 0.8, and 1.2 mg, the LSM changes from baseline were –2.5, –6, and –7.2 percent, respectively. [Lingvay, et al, AAD 2026]
The proportions of participants who achieved ≥5, ≥10, and ≥15 percent WL with berobenatide 1.6 mg were 84.2, 47.4, and 15.8 percent, respectively.
With the 0.8- and 1.2-mg doses, 56.5 percent and 55.5 percent, respectively, achieved ≥5 percent WL. The corresponding rates in the ≥10-percent WL category were 30.4 and 22.2 percent; in the ≥15-percent WL category, 13 percent and 5.6 percent.
With berobenatide 0.4 mg, 10.5 percent of participants lost ≥5 percent of their body weight, 5.3 percent lost ≥10 percent, but none lost ≥15 percent. Only 4.3 percent of placebo-treated patients achieved WL in any category.
HbA1c reductions
Berobenatide 1.6 mg also yielded the greatest reduction in HbA1c from baseline to week 28 (LSM change, –2.2 percent; placebo-corrected LSM change, –2 percent). The corresponding LSM changes with berobenatide 0.4, 0.8, and 1.2 mg were –1.7, –1.9, and –2.1 percent, respectively. Lingvay noted that the reduction achieved with the lowest berobenatide dose was quite impressive.
With berobenatide 1.6 mg, the proportions of participants who achieved HbA1c <7, <6.5, and <5.7 percent were 89.5, 89.5, and 21.1 percent, respectively. With the 0.8-mg dose, the corresponding rates were 82.6, 78.3, and 26.1 percent.
The berobenatide 1.2 mg group had the greatest proportion of participants who achieved HbA1c <7 percent (93.8 percent). Nearly 90 percent achieved HbA1c <6.5 percent, and about a third achieved HbA1c <5.7 percent.
Even with berobenatide 0.4 mg, two-thirds of participants achieved HbA1c <7 percent, 55.6 percent achieved HbA1c <6.5 percent, and 5.6 percent achieved <5.7 percent.
With placebo, 17.6 percent of participants achieved HbA1c <7 percent. None were able to achieve the other HbA1c outcomes.
Safety profile
More berobenatide- vs placebo-treated patients had drug-related treatment-emergent adverse events (TEAEs; 59.4 percent vs 42.3 percent), but both groups had few serious AEs (6.6 percent and 3.8 percent) and treatment discontinuations due to AEs (7.5 percent and 0 percent).
Looking at gastrointestinal AEs, the berobenatide group had higher rates of nausea (23.6 percent vs 11.5 percent), vomiting (17.9 percent vs 3.8 percent), diarrhoea (26.4 percent vs 23.1 percent), and constipation (19.8 percent vs 7.7 percent) than the placebo group. Nonetheless, most were mild or moderate in severity, with no severe cases, and occurred early during dose escalation.
“The safety profile of berobenatide was quite impressive overall and consistent with the GLP-1 RA class; there were no new safety signals, and no increase in hypoglycaemia rates,” Lingvay said.
Favourable benefit–risk profile
VESPER-2 included 132 participants (mean age 56.4 years, 58 percent men) on a background regimen of metformin and/or sodium-glucose transport 2 inhibitors. The mean weight was 104.3 kg, mean BMI 36.2 kg/m2, and mean HbA1c 8.2 percent.
Participants were randomized 1:1:1:1:1 to four berobenatide doses or placebo QW. For the two berobenatide groups, participants received 0.4 or 0.8 mg until week 28; for the other two groups, participants started with 0.4 mg for 4 weeks, uptitrated to 0.8 mg over the next 4 weeks, and then to 1.2 or 1.6 mg until week 28.
“[Taken together,] weekly berobenatide had a favourable benefit–risk profile for chronic weight management in individuals with T2D,” Lingvay said.