Danuglipron

Pfizer's PF-06882961, an oral small-molecule GLP-1 receptor agonist that lowered HbA1c and body weight in phase 2 trials but was discontinued on April 14, 2025 after high gastrointestinal dropout and a potential drug-induced liver injury case.

Also referenced as: PF-06882961, PF 06882961, PF06882961

Also appears in: Metabolic

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What is Danuglipron?

Danuglipron, developed by Pfizer as PF-06882961, is a small molecule, not a peptide. It is a synthetic benzimidazole carboxylic acid with the molecular formula C31H30FN5O4 and a molecular weight of about 555.6 Da, roughly one-seventh the mass of semaglutide, and it has no amino-acid sequence. It activates the same glucagon-like peptide-1 receptor (GLP-1R) as the native hormone GLP-1 and the injectable peptide drugs, from a tablet taken with food. Pfizer’s chemists found the series in a sensitized high-throughput screen for 5-fluoropyrimidine-based agonists; adding a carboxylic acid group produced large gains in receptor potency while reducing off-target activity and metabolic clearance (Griffith et al., Journal of Medicinal Chemistry, 2022;65(12):8208–8226).

The molecule mattered because it was one of the first oral small-molecule GLP-1R agonists to reach phase 2b testing, developed in parallel with Lilly’s orforglipron. Its program ended in two steps. In December 2023 Pfizer stopped advancing the twice-daily formulation after a phase 2b obesity trial recorded gastrointestinal adverse events and discontinuations well above expectations, and on April 14, 2025 the company ended the once-daily modified-release program after a potential drug-induced liver injury was detected in a dose-optimization study. Drugs@FDA lists no danuglipron application, and as of November 2026 no sponsor has an active development program for the molecule.

How it works

• Orthosteric GLP-1R agonism that mimics the peptide. Cryo-electron microscopy structures of the active GLP-1R show that the binding site of PF 06882961 substantially overlaps the site occupied by GLP-1 itself, whereas the non-peptide agonist CHU-128 adopts a distinct binding mode with a more open extracellular face. Water-mediated hydrogen-bond networks in the danuglipron-bound structure explain why the compound closely reproduces the signaling and receptor-regulation profile of the natural peptide and CHU-128 does not (Zhang et al., Molecular Cell, 2020;80(3):485–500.e7).
• A primate-specific binding pocket. Danuglipron increased insulin secretion in primates but not in rodents. Receptor mutagenesis and a cryo-EM structure traced this to a binding pocket that requires tryptophan 33 of the receptor, a residue present in primates but not in rodent GLP-1R, which is why Pfizer’s preclinical efficacy work relied on a humanized-receptor mouse model (Griffith et al., Journal of Medicinal Chemistry, 2022;65(12):8208–8226; Saxena et al., Nature Medicine, 2021;27(6):1079–1087).
• Incretin pharmacodynamics in people. In the 28-day multiple ascending-dose study in type 2 diabetes, danuglipron produced the physiological signature expected of GLP-1R agonism: a modest rise in heart rate at day 28 without heart-rate adverse events, slightly lower systolic blood pressure, and nausea, dyspepsia and vomiting as the most common adverse events (Saxena et al., Nature Medicine, 2021;27(6):1079–1087). In 37 Japanese adults with type 2 diabetes, 8 weeks of dosing titrated to 40, 80 or 120 mg produced dose-proportional steady-state exposure and placebo-adjusted reductions of up to −67.89 mg/dL in mean daily glucose, −1.41% in HbA1c and −1.87 kg in body weight (Ono et al., Diabetes, Obesity and Metabolism, 2023;25(3):805–814).
• Oral absorption without a fasting window. Unlike oral semaglutide, which must be taken on an empty stomach with strict timing, danuglipron was dosed with food throughout its phase 2 program (Saxena et al., JAMA Network Open, 2023;6(5):e2314493). Renal clearance of unchanged drug is below 1%, and exposure did not change meaningfully across mild, moderate or severe renal impairment in participants with type 2 diabetes (Fediuk et al., Journal of Clinical Pharmacology, 2024;64(4):449–460).

Research status

Phase 1. The first-in-human single ascending-dose study (NCT03309241) ran in 25 healthy adults from October 17, 2017 to February 21, 2018 and showed dose-proportional increases in systemic exposure (Griffith et al., Journal of Medicinal Chemistry, 2022;65(12):8208–8226). The multiple ascending-dose trial (NCT03538743) enrolled 98 patients with type 2 diabetes on background metformin across eight cohorts, dosed for 28 days between June 25, 2018 and May 23, 2019; most adverse events were mild, with no clinically meaningful laboratory or electrocardiogram findings (Saxena et al., Nature Medicine, 2021;27(6):1079–1087). Further phase 1 studies covered Japanese participants, renal impairment and drug interactions.

Phase 2a dose-escalation study (NCT04617275). A 12-week trial in 123 adults with type 2 diabetes on metformin and 28 adults with obesity without diabetes, run from January 6, 2021 to November 17, 2021, compared two starting doses and two escalation speeds up to targets of 80, 120 or 200 mg twice daily. Discontinuation ranged from 27.3% to 72.7% across danuglipron groups versus 16.7% to 18.8% on placebo, mostly because of adverse events; nausea affected 20.0% to 47.6% of treated participants and vomiting 18.2% to 40.9%. Gastrointestinal events tracked the target dose and were not substantially changed by the starting dose. HbA1c fell 1.04% to 1.57% across danuglipron groups versus 0.32% on placebo, and body weight fell 1.93 to 5.38 kg versus 0.42 kg (Saxena et al., Diabetes, Obesity and Metabolism, 2023;25(10):2805–2814).

Phase 2b in type 2 diabetes (NCT03985293). The pivotal mid-stage diabetes trial enrolled 411 treated adults at 97 sites in 8 countries or regions between July 7, 2020 and July 7, 2021, randomized to placebo or danuglipron 2.5, 10, 40, 80 or 120 mg twice daily with food for 16 weeks; 316 (77%) completed treatment. Every danuglipron dose reduced HbA1c and fasting plasma glucose significantly versus placebo, with a placebo-adjusted HbA1c reduction of −1.16% (90% CI −1.47 to −0.86) and a fasting glucose reduction of −33.24 mg/dL at 120 mg; body weight fell significantly only in the 80 mg (−2.04 kg) and 120 mg (−4.17 kg) groups. Nausea, diarrhea and vomiting were the commonest adverse events (Saxena et al., JAMA Network Open, 2023;6(5):e2314493).

Phase 2b in obesity (NCT04707313). The dose-ranging obesity trial ran from January 29, 2021 to a primary completion date of September 13, 2023 and randomized 628 adults with obesity and without diabetes, aged 18 to 75, to placebo or danuglipron escalated to 40 to 200 mg twice daily in 1-, 2- or 4-week intervals for 26 or 32 weeks. Of 626 treated participants (90 placebo, 536 danuglipron), only 39.3% completed treatment: about 38% stopped because of adverse events and 22% for other reasons, with high discontinuation seen in every arm including placebo. All danuglipron groups still produced statistically significant weight loss, with placebo-adjusted least-squares mean reductions ranging from −5.0% (90% CI −6.8 to −3.2) to −12.9% (90% CI −16.1 to −9.5). Nausea and vomiting led, and gastrointestinal adverse events rose with dose; no other dose-related safety trends were observed (Buckeridge et al., Diabetes, Obesity and Metabolism, 2025;27(9):4915–4926). When Pfizer reported the topline results in December 2023, it cited nausea in up to 73% of treated participants, vomiting in about 47%, diarrhea in about 25% and adverse-event discontinuation above 50% across danuglipron doses, and said it would no longer test the twice-daily formulation.

Once-daily modified-release program. Pfizer instead reformulated the molecule. A four-part phase 1 crossover study in 33 healthy adults (NCT06153758, November 27, 2023 to September 30, 2024) compared the single-dose pharmacokinetics of immediate-release and modified-release formulations, and in July 2024 the company said it would continue development as a once-daily pill. Two multiple-dose studies in otherwise healthy adults with overweight or obesity followed: a 23-participant pharmacokinetic study (NCT06568731, August 23, 2024 to December 18, 2024) and an 82-participant study of multiple-dose pharmacokinetics and statin interactions (NCT06567327, August 28, 2024 to a primary completion date of March 16, 2025). Neither has posted results.

Discontinuation. On April 14, 2025 Pfizer announced that it would no longer invest in danuglipron. The trigger was a potential case of drug-induced liver injury detected during the dose-optimization studies; the participant was asymptomatic and the abnormality resolved after the drug was stopped. The company stated that across more than 1,400 treated participants the overall frequency of liver enzyme elevations was in line with approved drugs in the class, and that the decision followed a review of all clinical data together with recent input from regulators. A phase 1 interaction study between danuglipron and Pfizer’s oral GIP-pathway candidate PF-07976016 (NCT06910839), started March 13, 2025, was terminated before any danuglipron was administered, the registry entry citing the sponsor’s decision to discontinue development. The decision followed Pfizer’s June 2023 discontinuation of its other oral GLP-1R agonist, lotiglipron, over elevated transaminases.

Secondary literature. Meta-analyses have pooled the danuglipron trials with orforglipron. A 2023 review of seven randomized trials (1,037 patients) found significant HbA1c and weight reductions with higher odds of gastrointestinal adverse events (OR 2.57) and of discontinuation for adverse events (OR 2.89) than control (Karakasis et al., Metabolism, 2023;149:155710); a 2025 review of eight trials (1,454 participants) put danuglipron’s pooled effects at −0.90% HbA1c and −2.17 kg body weight with the same gastrointestinal penalty (Zhou et al., Frontiers in Endocrinology, 2025;16:1646956).

Common dosage forms

• Immediate-release oral tablets (investigational). The phase 1 and phase 2 program used immediate-release tablets supplied only to clinical-trial sites.
• Modified-release oral tablet (investigational). A modified-release tablet was supplied only to the 2023 to 2025 phase 1 pharmacokinetic studies.
• No marketed presentation. No danuglipron product has been approved or sold in any country, and no injectable, compounded or pediatric presentation exists.

Key considerations

• Regulatory status. The Research Market status reflects the absence of any FDA application for danuglipron and Pfizer’s April 14, 2025 decision to end its development. Drugs@FDA lists no danuglipron application, no marketing application has been reported in any other jurisdiction, and the molecule never advanced beyond phase 2.
• A tolerability wall, not an efficacy failure. Danuglipron delivered up to −1.16% placebo-adjusted HbA1c in diabetes and up to −12.9% placebo-adjusted weight loss in obesity. The program failed on retention, with fewer than 40% of participants completing the obesity phase 2b trial, and the reformulation intended to fix this never reached efficacy testing.
• The liver signal is a single case against a class-level background. One asymptomatic, reversible potential drug-induced liver injury ended the program, while Pfizer reported liver enzyme elevations across more than 1,400 participants at rates consistent with approved GLP-1R agonists. Pfizer’s small-molecule GLP-1R program has now produced two discontinuations with a hepatic component, lotiglipron in 2023 and danuglipron in 2025.
• Not a peptide, and species-restricted. Danuglipron is a 555.6 Da benzimidazole acid whose binding pocket depends on tryptophan 33, a residue found in primate but not rodent GLP-1R, so rodent studies do not read across to human receptor pharmacology without a humanized model. Its relationship to the peptide GLP-1R agonists is pharmacological, not structural.
• Naming. PF-06882961 and danuglipron denote the same molecule; danuglipron is the nonproprietary name. It is distinct from orforglipron (Lilly) and from Pfizer’s earlier lotiglipron (PF-07081532), and it is not a form of any peptide GLP-1R agonist.