Pfizer Halts Development of Oral GLP-1 Agonist Danuglipron Amid Liver Safety Signal
Pfizer halts once-daily oral GLP-1 program danuglipron after liver safety concerns, shifting focus to alternative obesity targets including a GIPR antagonist in Phase 2.
Pfizer Inc. (NYSE: PFE) has discontinued development of its oral GLP-1 receptor agonist, danuglipron (PF-06882961), following a clinical finding of potential drug-induced liver injury during Phase 2 dose-optimization studies. The decision marks a strategic retreat from one of the few oral GLP-1 assets positioned to challenge the current dominance of injectable incretin therapies in the obesity market.
Danuglipron, a small-molecule GLP-1R agonist administered once daily, had been in development as an oral alternative to GLP-1 peptide injectables such as semaglutide (Novo Nordisk’s Wegovy) and tirzepatide (Eli Lilly’s Zepbound). Pfizer reported that while the pharmacokinetic and tolerability profiles in its latest once-daily formulation study met key objectives, a single case of elevated liver enzymes consistent with potential drug-induced liver injury prompted an internal risk-benefit reassessment.
“Although the formulation achieved desired PK exposure and early indicators of efficacy, we observed an adverse hepatic event that, while reversible upon discontinuation, raised enough concern to halt development,” said Mikael Dolsten, MD, PhD, Chief Scientific Officer and President, Pfizer R&D.
This decision follows an earlier discontinuation in 2023 of danuglipron’s twice-daily formulation, which suffered from dose-limiting GI tolerability issues including nausea and vomiting. The once-daily version was expected to mitigate these adverse effects while preserving weight loss efficacy.
Implications for GLP-1 Drug Development and Competitive Landscape
Pfizer’s exit from danuglipron development underscores the complexities of formulating safe, orally bioavailable GLP-1R agonists. Despite its promising preclinical and early clinical data, danuglipron faced increasing safety scrutiny given the class-wide regulatory sensitivity to hepatotoxicity and long-term tolerability in a chronic disease context.
With obesity positioned as a multi-billion-dollar therapeutic area projected to exceed $100B globally by 2030, Pfizer’s withdrawal leaves a narrower field of oral GLP-1 contenders. Eli Lilly’s orforglipron and Viking Therapeutics’ VK2735, among others, continue to progress in clinical development, each aiming to deliver oral or small-molecule alternatives to peptide-based therapies.
Market reaction to Pfizer’s move was swift. Shares of Novo Nordisk and Eli Lilly rose modestly on Monday, with investors viewing the decision as a de-risking of their market share in obesity and type 2 diabetes. Meanwhile, Pfizer reaffirmed its commitment to the space through other mechanisms.
Strategic Refocus: GIPR Antagonist in the Pipeline
While terminating danuglipron, Pfizer highlighted ongoing development of an oral glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist candidate, currently in Phase 2. GIP modulation is being explored both as monotherapy and in combination with GLP-1 agents for synergistic metabolic effects.
“We remain committed to advancing next-generation metabolic therapies and are reallocating our internal resources toward novel mechanisms, including oral GIPR antagonists and other first-in-class approaches,” Dolsten said.
Pfizer did not disclose timelines for GIPR candidate readouts but indicated continued focus on cardiometabolic disease as a core strategic priority. The company is expected to provide pipeline updates in upcoming earnings calls and at scientific congresses later this year.
Outlook
Pfizer’s withdrawal from danuglipron reflects both the regulatory and scientific headwinds facing oral GLP-1 drug development. The hepatic safety signal, even in a single subject, proved incompatible with chronic use in a preventive population — a reminder of the high safety bar required for obesity pharmacotherapies.
With major pharma consolidating around either peptide injectables or next-generation dual/triple agonist platforms, the search for safe, effective, and convenient oral agents continues — and remains a highly competitive frontier for innovation.
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BioFocus Newsroom