Pharmaceutical company Pfizer has decided to stop work on developing the small-molecule agonist of receptors to glucagon-like peptide-1 for oral administration danuglipron, the company said in a press release. The reason for this was serious side effects from the liver in one of the participants in clinical trials.
Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide are highly effective for the treatment of diabetes and weight loss. Current drugs are peptides, making them expensive to produce 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 difficult-to-produce peptide. Therefore, there is great interest in developing small-molecule drugs for oral administration, and several pharmaceutical companies are pursuing this goal.
One such experimental drug is danuglipron (PF-06882961), which Pfizer was developing for weight management. It was originally intended to be taken twice daily but was reformulated for once-daily dosing, and its pharmacokinetic profile was found to be optimal for entering phase 3 trials. Before entering phase 3, the company reviewed safety data from a database of more than 1,400 participants in preliminary trials.
The overall incidence of liver enzyme elevations was comparable to licensed GLP-1 agonists. However, one patient experienced asymptomatic significant liver injury potentially related to the drug, which resolved after discontinuation of the drug. Pfizer, in conjunction with recently updated regulatory requirements, decided to abandon further clinical development of the molecule.
This was the company's second failure in the development of small-molecule GLP-1 agonists - work on the drug lotiglipron, which caused an increase in transaminase levels in the early stages of clinical trials, was previously stopped. At the same time, its competitor Eli Lilly has already brought its drug in this group, orfoglyprone, taken once a day, to phase III trials - the company plans to publish the results of seven of them (five for the treatment of diabetes and two for weight control) by the end of 2025. AstraZeneca, Roche, Structure Therapeutics and Viking Therapeutics are also developing in a similar direction.
Novo Nordisk previously reported success in a phase I trial of a tablet formulation of amicretin (NNC0487-0111), which is both a GLP-1 receptor agonist and an amylin receptor agonist. It was more effective than semaglutide in reducing body weight in patients without diabetes.