Pfizer Discontinues Development of Danuglipron for Chronic Weight Management
Despite meeting key pharmacokinetic goals, a potential case of drug-induced liver injury led Pfizer to conclude that danuglipron’s risk-benefit profile did not support further development for chronic weight management.
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Pfizer has announced it will discontinue development of danuglipron (PF-06882961), an oral GLP-1 receptor agonist previously under investigation for chronic weight management. The decision follows recent dose-optimization studies of a once-daily formulation that achieved key pharmacokinetic goals and demonstrated promising efficacy and tolerability based on prior twice-daily results; however, an asymptomatic but potentially drug-induced liver injury occurred in a single participant. Though liver enzyme elevations across the program aligned with those reported with other approved GLP-1 agents, the overall clinical profile, combined with regulatory feedback, led the company to decide to end the program.
“While we are disappointed to discontinue the development of danuglipron, we remain committed to evaluating and advancing promising programs in an effort to bring innovative new medicines to patients,” said Chris Boshoff, MD, PhD, chief scientific officer, president, research and development, Pfizer, in a press release.1
In December 2023, Pfizer shared data from a Phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial analyzing the efficacy of danuglipron in 626 participants with obesity but without type 2 diabetes. The study evaluated twice-daily danuglipron administered over 26 to 32 weeks across three cohorts with varying titration schedules and dose levels ranging from 40 mg to 200 mg.
Results showed statistically significant reductions in body weight from baseline across all doses. At 32 weeks, mean weight loss ranged from 6.9% to 11.7%, compared to a 1.4% gain in the placebo group. At 26 weeks, danuglipron-treated patients saw reductions between 4.8% and 9.4%, versus 0.17% for placebo. When adjusted for placebo, mean weight reductions ranged from 8% to 13% at 32 weeks and 5% to 9.5% at 26 weeks. Time on target doses ranged from six to 24 weeks, depending on the titration schedule.1
Despite these favorable outcomes, more than half of participants discontinued treatment, driven by high rates of gastrointestinal adverse effects, such as nausea (73%), vomiting (47%), and diarrhea (25%). Citing this high discontinuation rate, Pfizer confirmed it would not pursue the twice-daily regimen in future Phase III trials.2
In July 2024, the company reported progress on a once-daily modified release formulation, supported by data from an ongoing pharmacokinetic study. That formulation demonstrated a profile suitable for once-daily dosing and a safety profile consistent with earlier danuglipron studies, with no liver enzyme elevations observed among more than 1,400 participants.3
This isn’t the first setback that Pfizer has faced regarding its GLP-1 pipeline. In June 2023, the company announced its decision to halt clinical development of lotiglipron, primarily based on pharmacokinetic data from Phase I drug-drug interaction studies. Elevated levels of transaminase were detected in the aforementioned Phase I studies as well as a Phase II study. While none of the participants experienced liver-related symptoms, liver failure, or required treatment, the biomarker elevations were significant enough to raise concern.4
Despite the decision to discontinue development of danuglipron for chronic weight management, Pfizer reiterated its commitment to the obesity space, highlighting ongoing development of its oral GIPR antagonist and other early-stage candidates.1
“Cardiovascular and metabolic diseases including obesity remain important areas of unmet medical need, and we plan to continue applying our global capabilities to advance a pipeline of investigational treatments that have the potential to fill critical gaps in patient care, including continued development of our oral GIPR antagonist candidate and other earlier obesity programs,” Boshoff said in the release.
References
1. Pfizer Provides Update on Oral GLP-1 Receptor Agonist Danuglipron. Pfizer. April 14, 2025. Accessed April 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-oral-glp-1-receptor-agonist
2. Pfizer Announces Topline Phase 2b Results of Oral GLP-1R Agonist, Danuglipron, in Adults with Obesity. BusinessWire. December 1, 2023. Accessed April 14, 2025. https://www.businesswire.com/news/home/20231130108413/en/Pfizer-Announces-Topline-Phase-2b-Results-of-Oral-GLP-1R-Agonist-Danuglipron-in-Adults-with-Obesity
3. Pfizer Advances Development of Once-Daily Formulation of Oral GLP-1 Receptor Agonist Danuglipron. BusinessWire. July 11, 2024. Accessed April 14, 2025. https://www.businesswire.com/news/home/20240710971928/en/Pfizer-Advances-Development-of-Once-Daily-Formulation-of-Oral-GLP-1-Receptor-Agonist-Danuglipron
4. Pfizer Provides Update on GLP-1-RA Clinical Development Program for Adults with Obesity and Type 2 Diabetes Mellitus. Pfizer. June 26, 2023. Accessed April 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-provides-update-glp-1-ra-clinical-development
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