A Structure Therapeutics obesity pill helped patients lose an average of nearly 40 pounds in a mid-stage clinical trial, keeping the drug competitive in the growing crowd of oral medications pursuing the obesity market.
Structure’s once-daily pill, aleniglipron, is an oral small molecule designed to target and activate the GLP-1 receptor. While the first obesity drugs for this target were medications administered as weekly injections, Novo Nordisk recently launched an oral version of its GLP-1 peptide obesity drug, the FDA-approved Wegovy pill. Eli Lilly has an oral small molecule GLP-1 agonist currently under regulatory review. Based on aleniglipron’s mid-stage results, San Francisco-based Structure said it is now preparing aleniglipron for its Phase 3 study.
The Phase 2 program for aleniglipron was split into two parts. Last December, Structure reported preliminary results showing the 120 mg dose achieved up to 11.3% weight loss measured at 36 weeks. Participants in this cohort were permitted to roll over to an open-label extension study. Updated results reported Monday show an average 16.2% weight loss measured at 56 weeks for this cohort with no evidence of a plateauing of aleniglipron’s effect, suggesting patients will lose more weight if they keep taking the drug.
On Monday, Structure reported data for two higher doses tested in 85 adults participants with obesity or overweight and at least one weight-related condition. In this part of the Phase 2 program, participants who received the study drug started at 5 mg and titrated up to the 120 mg dose level. At week 28, all participants in the active arms were randomly assigned again to receive either the 120 mg, 180 mg, or 240 mg doses for the remainder of the study. At 44 weeks, the 180 mg dose led to an average 15.3% weight loss (about 39 pounds); the 240 mg dose achieved an average 15% weight loss (about 37 pounds). By comparison, the placebo arm showed a 1.1% average gain in weight. Aleniglipron’s results were clinically meaningful and statistically significant.
The most common adverse events were gastrointestinal, which is consistent with the entire GLP-1 agonist drug class. Structure said vomiting reports for study participants were low and classified as mild or moderate, and there were no cases of diarrhea or constipation. Across all arms that received the study drug from 28 to 44 weeks at doses of 120 mg or higher, only one adverse event-related treatment discontinuation was reported.
One of the problems with GLP-1 drugs is that patients lose muscle in addition to fat. Structure is running a placebo-controlled body composition study that enrolled 71 adults to assess the 120 mg dose over 40 weeks. Participants started at 2.5 mg then titrated up to the 120 mg dose level. In a pre-specified interim data analysis at 20 weeks, Structure said results showed that starting at the 2.5 mg dose for the first four weeks supported a manageable tolerability profile with meaningful improvements in adverse-event discontinuations compared to the higher 5 mg dose starting point in Phase 2.
Structure plans to schedule a meeting with the FDA to discuss the clinical data and finalize the Phase 3 design with a goal of starting this pivotal study in the second half of the year. The company said this study is currently designed with starting dose of 2.5 mg and will evaluate multiple doses up to 240 mg.
“The consistent weight loss observed across multiple studies to date reaffirms aleniglipron’s potential to be a best-in-class oral GLP-1, with injectable-like efficacy that could become a backbone oral small molecule therapy for obesity,” Structure CEO Raymond Stevens said in a prepared statement.
In a Monday research note, Leerink Partners analysts called the aleniglipron results best in class, noting that they top the data posted by Lilly’s oral GLP-1 agonist orforglipron, which is expected to receive an FDA decision in the second quarter of this year. At the 44-week mark, this Lilly pill showed a 12.4% average placebo-adjusted weight loss.
William Blair analyst Andy Hsieh has a more measured view of the Structure drug. It’s premature to claim aleniglipron is best in class or even differentiated from Lilly’s oral GLP-1 pill, he wrote in a research note. There are always caveats with cross-trial comparisons, but the design of Structure’s study makes comparisons particularly difficult. Specifically, Hsieh pointed to the Structure trial’s design, which added two higher doses toward the later part of the study as well as the lack of statistical analysis for the open-label portion of the trial.
While the weight loss achieved for the Structure drug is numerically higher the 12.4% average reported in orforglipron’s pivotal study, it’s close to the results for that drug’s Phase 2 program, which achieved an average 14.2% placebo-adjusted reduction in weight for the 36 mg dose, the highest dose went on to Phase 3 testing. That said, Hsieh acknowledged the need for oral small molecule GLP-1 drugs, particularly in middle- or lower-income countries where it could be challenging to commercialize a pricey injectable obesity medication. In an investor presentation, Structure said only oral small molecules can achieve the scale to meet the global need for obesity medications. Hsieh said William Blair believes Structure’s drug is well positioned to address that market.
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