Pfizer has decided to discontinue development of danugliprone, a small-molecule glucagon-like peptide-1 receptor agonist for oral administration, according to a company press release. The decision was prompted by serious liver side effects in one clinical trial participant.
Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, are highly effective for the treatment of diabetes and weight loss. Current commercially available medications are peptides, making them expensive to manufacture and administered by injection. Novo Nordisk has developed a tablet form of semaglutide that is bioavailable when taken orally (Rybelsus), which is approved for use in adults with diabetes, but it remains a complex peptide to manufacture. Therefore, the development of small-molecule orally administered medications is of great interest, and several pharmaceutical companies are pursuing this approach.
One such experimental drug is danuglipron (PF-06882961), which was being developed by Pfizer for weight management. Initially intended for twice-daily administration, it was reformulated for once-daily dosing, and its pharmacokinetic profile proved optimal for entering Phase III trials. Before commencing Phase III trials, the company reviewed the collected safety data from a database of over 1,400 participants in preliminary trials.
The overall incidence of liver enzyme elevations was comparable to that of licensed GLP-1 agonists. However, one patient experienced asymptomatic, significant liver injury, potentially related to the drug, which resolved after discontinuation. Taking these data into account, coupled with recently updated regulatory requirements, Pfizer decided to abandon further clinical development of this molecule.
This marks the company's second failure in the development of small-molecule GLP-1 agonists. Work on lotiglipron, which caused elevated transaminase levels in early clinical trials, was previously discontinued. Meanwhile, its competitor, Eli Lilly, has already advanced its once-daily drug in this class, orfoglipron, to Phase III trials. The company plans to publish the results of seven of these trials (five for diabetes and two for weight management) by the end of 2025. AstraZeneca, Roche, Structure Therapeutics, and Viking Therapeutics are also pursuing similar developments.
Novo Nordisk previously reported the success of a phase I trial of amicretin (NNC0487-0111), a tablet that acts as both a GLP-1 and amylin receptor agonist. It was more effective than semaglutide in reducing body weight in non-diabetic patients.
