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GLP-1-RA: Pfizer to continue danuglipron but discontinue lotiglipron

Pfizer will continue to progress its first full agonist oral glucagon-like peptide-1 receptor agonist (GLP-1-RA) candidate - danuglipron - towards further clinical development for the potential treatment of adults with obesity and Type 2 diabetes mellitus (T2DM), subject to results from the ongoing Phase 2 trial.

Results previously published in the Journal of the American Medical Association Network Open from the Phase 2 study of danuglipron in T2DM showed dose-dependent placebo-adjusted reductions (doses ranging from 2.5 mg through 120 mg for 16 weeks) in HbA1c of up to -1.16%; fasting plasma glucose of -33.24 mg/dL; and body weight of -4.17 kg over 16 weeks. The most common adverse events were nausea, vomiting and diarrhea. The Phase 2b study of danuglipron in non-diabetic obesity participants is currently ongoing (doses ranging from 40 mg through 200 mg for up to 32 weeks) and expected to complete by end of year. The safety profile of danuglipron to date, including transaminase changes, appears to be similar to the peptidic GLP-1R agonist class.

“Building on Pfizer’s small molecule design expertise, we were developing two promising GLP-1-RAs that have shown proof of concept, with the intent of selecting one to advance into further clinical studies. We look forward to analyzing the danuglipron Phase 2 results and selecting the dose and titration schedule that will maximize the therapeutic benefit and safety and tolerability,” said Dr William Sessa, Senior Vice President and Chief Scientific Officer, Internal Medicine, Pfizer. “If successful in clinical trials and approved, danuglipron could be in a prime position to differentiate based on profile, including full receptor agonism, which we believe has the potential to translate to robust efficacy.”


However, the company has also announced it will discontinue the clinical development of another GLP-1-RA candidate, lotiglipron, after pharmacokinetic data from Phase 1 drug-drug-interaction studies and laboratory measurements showed elevated transaminases in these Phase 1 studies as well as the ongoing Phase 2 study. None of these participants reported liver related symptoms or side effects, there was no evidence of liver failure, and none needed treatment. Such transaminase elevations have not been observed in the over 1,400 patients enrolled in the danuglipron programme.


The company expects to finalise plans for the danuglipron late-stage programme by the end of 2023 and also is developing a once-daily modified release version.

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