Pfizer’s oral obesity ambitions take a blow

Pfizer’s discontinuation of once-daily lotiglipron hands the advantage back to Lilly.

Pfizer had always said it was going to take only one of its oral GLP-1 contenders into phase 3. But the group gave investors an unpleasant surprise this morning by plumping for twice-daily danuglipron rather than once-daily lotiglipron, putting the group at a convenience disadvantage to rivals such as Lilly.

True, Pfizer said it was going to develop a once-daily modified release version of danuglipron, but this would presumably result in a delay to this programme. And the bad news for the group coincided with Lilly showing impressive weight loss with its once-daily contender orforglipron at the ADA meeting on Saturday.

Pfizer’s shares opened down 3% this morning, with the news compounding concerns about its pipeline generally, as well as GLP-1s specifically. The company has previously said this class could be worth $90bn in sales by 2030.

Liver enzyme elevations

Pfizer made its decision after seeing elevated liver enzymes in trials of lotiglipron. The group added that such elevations had not been observed with danuglipron, which has completed phase 2 in type 2 diabetes and is in a mid-stage obesity study.

However, Evercore ISI’s Umer Raffat asked: “Are we sure danuglipron won’t suffer lotiglipron’s fate?” He highlighted a number of cases of alanine aminotransferase increases with the highest dose of danuglipron in a phase 1 diabetes trial. He also raised the potential for heart rhythm issues with danuglipron following QT interval increases seen in the phase 2 diabetes trial.

Pfizer will need to assuage side-effect worries when it reports data from the obesity trial of danuglipron later this year. The group will also need to show at least 15% weight loss versus baseline – the bar that has now been set by Lilly.

15% weight loss

The ADA abstract for the Lilly project had detailed 12.6% weight loss with the highest dose of orforglipron at 26 weeks – the phase 2 study’s primary endpoint.

Full data, presented on Saturday and published simultaneously in the NEJM, showed that this increased to 14.7% at 36 weeks. And weight loss had not plateaued by this time point, raising the possibility of even greater improvement over time, the authors noted.

Orforglipron still looks short of Lilly's injected GIP/GLP-1 dual agonist Mounjaro, which remains the project to beat.

As with other GLP-1s, the rate of gastrointestinal effects was high. Notably, 58% of patients receiving 24mg, one of the middle doses of orforglipron, experienced nausea. The investigators put this down to a different dose-escalation schedule than was used in the other cohorts, with a higher starting dose and faster escalation.

They hope to improve orforglipron’s tolerability profile by starting lower and going slower; as such, adjustments are planned for the ongoing phase 3 programme.

Lilly is not the most advanced oral GLP-1 player: Novo Nordisk already has a product approved for diabetes, Rybelsus, and is ahead with an obesity pill. However, Lilly and Pfizer reckon they can avoid the strict food and water requirements needed with Novo’s drug.

Another contender in the oral GLP-1 race, Structure Therapeutics, had early data on its project GSBR-1290 at ADA and rose 5% this morning. But Astrazeneca recently discontinued an early trial of its oral GLP-1 AZD0186, saying the asset was not sufficiently differentiated versus standard of care.

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