Pfizer drops oral obesity drug after seeing liver safety concern, focuses on less-convenient candidate

Pfizer is dropping one of its oral obesity drug candidates after seeing elevated liver enzymes in clinical trials. The setback leaves the Big Pharma’s near-term prospects resting on a candidate that is given twice as often as rival weight loss medicines in development at Eli Lilly and Novo Nordisk.

Last year, Pfizer presented midphase data on its GLP-1 receptor agonist danuglipron. The data suggested that the oral obesity drug is competitive in terms of weight loss but needs to be given twice a day at the highest dose to have the biggest effect. As the recent full publication of the data showed, the rates of gastrointestinal side effects and discontinuations because of adverse events increased as the dose rose.

With Lilly and Novo advancing once-daily drugs, Pfizer held off on deciding whether to start a phase 3 trial of danuglipron until it got a better look at its other GLP-1 receptor agonist lotiglipron. Given once a day, lotiglipron could have fixed the limitations of danuglipron and been a bigger threat to Lilly and Novo. 

However, lotiglipron has its own problems, as Pfizer revealed Monday. Analyses of data from a pair of phase 1 drug-drug-interaction studies and a phase 2 trial led Pfizer to stop clinical development of the obesity candidate. Pfizer attributed the decision to pharmacokinetic data and elevated transaminases, a type of enzyme that can be an indicator of liver dysfunction.

None of the patients reported liver related symptoms or side effects, and there was no evidence of liver failure. Pfizer sought to distance danuglipron from the lotiglipron findings, noting that no transaminase elevations have been seen in clinical trials that have enrolled more than 1,400 people.

Even so, the termination of lotiglipron development is a blow to Pfizer. Lotiglipron offered Pfizer a chance to match the dosing regimen of Lilly’s orforglipron, which triggered 14.7% weight loss at 36 weeks, and Novo’s oral semaglutide. Novo’s molecule has its own convenience challenges as a drug that is taken on an empty stomach with a sip of water, but, of the three, danuglipron is the only twice-daily candidate.

Pfizer, alert to the convenience advantage that is being ceded to its rivals, will work on a once-daily modified-release version of danuglipron while advancing the current formulation into a pivotal program. The Big Pharma expects to finalize a late-phase program for the current formulation by the end of the year, although the final decision on whether to forge ahead will depend on pending phase 2b results.