Structure Therapeutics said its oral GLP-1 receptor agonist showed a relatively clean safety profile and low discontinuation rates in a mid-stage trial.

However, efficacy among patients with type 2 diabetes fell below that of a rival pill being developed by Eli Lilly, which could have contributed to a Monday stock purge.

The agent, dubbed GSBR-1290, led to a roughly 1% reduction in blood glucose and weight loss of just over 3% versus placebo in the 12-week Phase 2a study involving participants with type 2 diabetes, Structure said. 

Management had been targeting HbA1c reduction in the range of 1.01% to 1.02% and 5% weight loss.

GSBR-1290 is one of a slew of oral monotherapy assets that are seen to be the next innovation in the GLP-1 agonist space. 

The current market leaders in this class of diabetes and obesity treatments – Novo Nordisk’s Wegovy and Ozempic and Lilly’s Mounjaro and Zepbound – are bringing in billions in revenue but are all injections. 

Structure’s Phase 2 study included 94 patients, split into one cohort with obesity and a second group with type 2 diabetes.

“Our data demonstrated that once-daily GSBR-1290 has the potential to be a best-in-class compound and a backbone for future combinations that could address large cardiometabolic indications,” noted Structure CEO Raymond Stevens in a statement Monday. 

However, the preliminary results – specifically its efficacy in diabetes – didn’t quite equal the performance of Lilly’s own experimental GLP-1 pill orforglipron, wrote Leerink analyst David Risinger in an investor note. 

Lilly’s drug was shown to reduce HbA1c levels by about 1.25% to 1.75% and weight by 5% to 6% after 12 weeks when adjusted for a placebo in a Phase 2 trial involving patients with diabetes, Risinger said. 

In a Phase 1b trial involving similar subjects, with a 12-week endpoint, orforglipron demonstrated HbA1c reduction of 1.37% and weight reduction of up to 7.1% versus placebo.

Read-across between trials is known to be an apples-to-oranges exercise, confounded by various factors. Nevertheless, the unflattering efficacy comparison to orforglipron may have been the reason behind Structure’s 45% premarket plunge Monday. 

Structure’s pill might have an edge when it comes to tolerability, though. 

Over 12 weeks, GSBR-1290 posted a 2.8% study discontinuation rate due to adverse events in diabetes and a 0% rate in the nondiabetic obese. Those figures easily bested orforglipron’s maximum dropout rate of 35.7% in type 2 diabetes patients participating in a Phase 1b study that also had a 12-week endpoint.

In addition, GSBR-1290 looked more comparable to orforglipron among subjects in the nondiabetic obesity cohort. Those patients showed average weight loss of 4.74% versus those who received a placebo after eight weeks. Orforglipron, for its part, demonstrated 5% to 6% weight loss at eight weeks in a Phase 2 trial of nondiabetic patients. 

Given the compound appears to be less efficacious in type 2 diabetes, Risinger lowered his 2035 estimate for GSBR-1290’s unadjusted end-market sales by 34% to $6.9 billion, from an earlier forecast of $10.4 billion.

“On the positive side, we expect ‘1290 to deliver greater weight loss with longer duration dosing, and management disclosed that it plans to evaluate higher dosing in subsequent trials,” Risinger wrote in an investor note Monday.

Structure is planning to disclose 12-week data among the nondiabetic obese in next year’s second quarter and analysts are expecting greater weight loss than demonstrated at the eight-week mark. 

“At 12 weeks, we feel like we will be very comparable in terms of efficacy” to orfoglipron, Stevens told Reuters.

Originally developed for diabetes, GLP-1 drugs mimic the action of the GLP-1 hormone to manage blood sugar, slow digestion and suppress appetite. Given global demand, calls have been building for a more convenient, cheap and widely available formulation.

While efficacy results for oral versions have been on par with injectables, many patients experience gastrointestinal side effects. Pfizer recently dropped plans to pursue a twice-daily version of obesity pill danuglipron due to an over 50% discontinuation rate in a Phase 2b trial. That came after the drugmaker was forced to punt on another oral GLP-1 candidate, lotiglipron, because of a safety signal.

Still, the desire for a piece of the megablockbuster returns seen by Novo and Lilly has stoked M&A interest in the “diabesity” space. Swiss drugmaker Roche recently paid $2.7 billion upfront for Carmot Therapeutics, which is developing a small-molecule GLP-1 drug, and AstraZeneca bought rights to a GLP-1 candidate from Eccogene for $185 million upfront.

Stevens, whose company is also evaluating four oral combination GLP-1R programs with different mechanisms, has also signaled openness to partnering for Phase 3 and commercialization of GSBR-1290.