Once-Monthly GLP-1 Injection Shows Significant Weight Loss Without Plateau in non diabetics in Phase 2 trial
Pfizer reported that its ultra-long-acting, once-monthly GLP-1 injectable achieved up to 12.3% placebo-adjusted weight loss by week 28, with no weight-loss plateau, in adults with obesity or overweight without type 2 diabetes.
The study had two objectives:
(1) to demonstrate PF’3944 could achieve continued weight loss when switching from weekly to monthly subcutaneous injections and maintain its efficacy while reducing the dosing frequency four-fold; and
(2) to demonstrate PF’3944 could switch to a four-fold equivalent monthly dose while maintaining a well-tolerated and favorable safety profile.
The study demonstrated statistically significant weight reduction with up to 12.3% mean placebo-adjusted weight loss at week 28 (efficacy estimand*). The study included up to two titration steps and weekly dosing with PF’3944 until week 12, followed by monthly dosing to week 28. The primary endpoint of weight reduction from randomization to week 28 was superior to placebo in all four dose regimens tested (P < 0.001). The detailed results from VESPER-3 will be presented on June 6, 2026, at the 86th Scientific Sessions of the American Diabetes Association.
VESPER-3 is an ongoing 64-week, randomized, double-blind, placebo-controlled study in participants with obesity or overweight without type 2 diabetes. The study is designed to evaluate weekly (QW) titration phase to monthly (QM) dosing of PF’3944 in four different titration and QM dose arms, compared to placebo (five arms, ~n=54 per arm). Participants were randomized across four titration protocols: Arm 1 (0.4 mg QW/ 0.8 mg QW/ 3.2 mg QM); Arm 2 (0.8 mg QW/ 3.2 mg QM); Arm 3 (0.4 mg QW/ 0.8 mg QW/ 1.2 mg QW / 4.8 mg QM); Arm 4 (0.6 mg QW/ 1.2 mg QW/ 4.8 mg QM); or Arm 5 (placebo). Interim tolerability results were previously reported after 12 weeks of weekly dosing by Metsera; these topline results reflect efficacy and tolerability data from an additional 16 weeks with monthly dosing.
At week 28, 10% and 12.3% placebo-adjusted weight loss* was achieved in Arms 1 and 3 respectively, which are the low and medium monthly maintenance dosing regimens planned for inclusion in Phase 3. These data show robust and continuous weight loss after switching to monthly dosing, with no plateau observed at week 28, suggesting continued weight loss is expected as the study continues through week 64.
PF’3944 also maintained a well-tolerated and favorable safety profile through week 28 that is consistent with the GLP-1 RA class. Observed gastrointestinal treatment-emergent adverse events (TEAEs) were predominantly 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. Across Arms 1 and 3, five total participants discontinued from treatment due to adverse events (AEs) in the weekly phase and five total participants discontinued from treatment due to AEs in the monthly phase. There were zero discontinuations from treatment due to AEs in the placebo group.
“These topline results from the Phase 2b VESPER-3 study reinforce the potential of PF’3944 as a monthly treatment with competitive efficacy,” said Jim List, MD, PhD, Chief Internal Medicine Officer. “Based on the monthly dosing efficacy and tolerability demonstrated in this trial, we remain confident in our plan to include a higher 9.6 mg monthly maintenance dose of PF’3944 in Phase 3. With PF’3944 as an anchor of Pfizer’s obesity pipeline, we are positioned to address critical gaps in obesity care and meet the diverse needs of patients.”
Following its recent acquisition of Metsera and exclusive global collaboration and license agreement with YaoPharma, Pfizer now has a diverse pipeline of clinical stage injectable and oral obesity candidates targeting GLP-1 receptor as well as glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists and antagonists, and amylin analogs. Pfizer is planning an expansive obesity development program across its robust pipeline, with plans to advance 20+ trials in 2026. This includes 10 Phase 3 trials of PF’3944, including the recently initiated Phase 3 VESPER-4 pivotal study investigating once-weekly PF’3944 in people with obesity or overweight and without type 2 diabetes; the planned Phase 3 VESPER-5 study investigating once-weekly PF’3944 in people with obesity or overweight with type 2 diabetes; the planned Phase 3 VESPER-6 study with once-monthly PF’3944 in obesity or overweight; and at least seven additional planned Phase 3 studies of PF’3944 designed to target comorbidities and increase patient optionality and access.
About PF-08653944 (PF’3944; previously called MET-097i)
PF’3944 is an ultra-long-acting fully biased GLP-1 receptor agonist (RA). It is being developed as a single agent weekly and as a monthly therapy, and in combination with various peptides including an amylin analog PF-08653945 (PF’3945; MET-233i) and a GIPR agonist PF-08654696 (MET-034i).
