Oral GLP-1 Drug Danuglipron to Move Forward, but With Tweaks to Dose

About half of patients with obesity but not diabetes who were enrolled in a phase IIb trial of danuglipron, an oral glucagon-like peptide-1 (GLP-1) receptor agonist, dropped out due to side effects, Pfizer announced today. But the manufacturer says it will go forward with a different formulation—once daily rather than twice daily—since the drug was effective at inducing weight loss.

In top-line results from the trial, danuglipron met the primary endpoint of a statistically significant change in body weight from baseline. However, 75% of patients experienced nausea, nearly half reported vomiting, and one-quarter had diarrhea when taking the drug twice daily. Discontinuation rates for those on the drug were greater than 50%, as compared to around 40% with placebo.

Thus, the company is curious what will happen with a switch to once-daily dosing.

“We believe an improved once-daily formulation of danuglipron could play an important role in the obesity treatment paradigm, and we will focus our efforts on gathering the data to understand its potential profile,” Pfizer said in a press release, noting that at least for now it does not plan to advance twice-daily danuglipron into phase III studies.

Mean reductions in bodyweight on danuglipron in the newly released data ranged from 6.9% to 11.7% at 32 weeks, compared with a weight gain of 1.4% for placebo patients, and 4.8% to 9.4% at 26 week compared with a gain of 0.17% for placebo patients. In an earlier study of patients with diabetes, published in JAMA Network Open, danuglipron showed dose-dependent placebo-adjusted reductions in HbA1c of up to 1.16% at 16 weeks and mean reductions in bodyweight of 4.17 kg.

As reported by TCTMD, drugs targeting GLP-1 for weight loss are having a moment, with the recent SELECT trial results cementing a role in cardiovascular disease prevention. To date, the FDA-approved agents in weight management—semaglutide, liraglutide and as of last month, tirzepatide (Zepbound; Eli Lilly)—are injectables, though the race is on to find a successful oral formulation.