Pfizer halts development of oral GLP-1 agonist danuglipron
Safety concerns prompt Pfizer to terminate development of once-daily oral GLP-1 receptor agonist for weight management, despite promising pharmacokinetic data from recent dose-optimisation studies.
Pfizer Inc. has announced the discontinuation of its oral glucagon-like peptide-1 (GLP-1) receptor agonist danuglipron (PF-06882961), a candidate that was under investigation for chronic weight management. The decision follows the identification of a case of potential drug-induced liver injury in a recent clinical trial participant, despite the compound showing promising pharmacokinetic profiles in dose-optimisation studies.
Safety signal prompts programme termination
The pharmaceutical giant revealed that its dose-optimisation studies of once-daily formulations of danuglipron (NCT06567327 and NCT06568731) successfully met key pharmacokinetic objectives. These studies had established a formulation and dose with the potential to deliver competitive efficacy and tolerability in Phase 3 testing, based on earlier studies of twice-daily danuglipron.
However, whilst the overall frequency of liver enzyme elevations across danuglipron’s safety database of more than 1,400 participants was reported to be consistent with approved agents in the GLP-1 class, a single asymptomatic participant in one of the dose-optimisation studies experienced potential drug-induced liver injury. This adverse event resolved after discontinuation of the investigational compound.
After comprehensive review of all clinical data generated to date for danuglipron, alongside recent regulatory input, Pfizer made the decision to terminate development of the molecule entirely, rather than attempt to advance it to Phase 3 trials.
Implications for the oral GLP-1 market
The termination of danuglipron represents a significant setback in the race to develop orally administered GLP-1 receptor agonists for weight management. Oral formulations are widely considered to be potential game-changers in the rapidly expanding obesity therapeutics market, offering the prospect of improved patient convenience compared to injectable GLP-1 analogues.
Chris Boshoff, MD, PhD, Chief Scientific Officer and President, Research and Development at Pfizer, commented: “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 programmes.”
Future directions in metabolic disease
Despite this setback, Pfizer confirmed its ongoing commitment to metabolic disease research, with particular focus on its oral gastric inhibitory polypeptide receptor (GIPR) antagonist candidate and other earlier-stage obesity programmes. The company indicated that data from the danuglipron clinical development programme will be presented at a scientific forum or submitted for publication in a peer-reviewed journal in the future.
The announcement follows Pfizer’s earlier decision in December 2023 to discontinue development of twice-daily danuglipron, when higher rates of gastrointestinal adverse events including nausea, vomiting and diarrhoea led the company to focus exclusively on once-daily formulations.
Scientific context
GLP-1 receptor agonists have demonstrated significant efficacy in both type 2 diabetes management and weight reduction. Injectable formulations such as semaglutide (Wegovy/Ozempic) and tirzepatide (Mounjaro/Zepbound) have shown remarkable weight loss results in clinical trials, driving unprecedented demand.
However, the development of oral GLP-1 receptor agonists has proven challenging, with only Novo Nordisk’s semaglutide (Rybelsus) currently approved, and solely for type 2 diabetes rather than weight management. Pfizer’s danuglipron had been one of the most advanced oral GLP-1 candidates specifically targeting obesity.
