Lilly ends two mid-stage trials of oral GLP-1 drug naperiglipron

Eli Lilly has ended two of three mid-stage trials of naperiglipron, an experimental once-daily oral GLP-1 pill the company had been developing behind its lead oral candidate, orforglipron. The Phase 2 studies were terminated for "strategic business reasons," according to updates to their federal trial database entries, and Lilly declined to explain further ^[1][2].

Both stopped studies had barely begun enrolling. One was designed to test naperiglipron against placebo in 150 people with overweight or obesity and type 2 diabetes, and had enrolled one patient ^[2]. The other aimed to enroll 220 adults aged 55 to 80 with a body mass index between 22 and 25 kg/m2, which Fierce Biotech described as a "healthy body mass index" group. It also enrolled one patient ^[1][2]. Both studies started over the summer and were originally expected to run about a year ^[1].

The third Phase 2 trial is still open to enrollment and aims for 275 patients with overweight or obesity, who take naperiglipron or placebo once daily ^[1][2]. That study began in November 2024 ^[2]. The two reports disagree on when it will finish: one lists a primary completion date of April 2026 ^[2], the other September 2026 ^[1]. "The results will inform the next steps for this program," a Lilly spokesperson said ^[1][2].

Naperiglipron is an oral small molecule that activates the GLP-1 receptor, the same target as the injected drugs semaglutide (sold as Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound). Like other drugs in the class, it is designed to promote insulin release from the pancreas in response to blood sugar and to suppress appetite ^[2]. Analysts at BMO Capital Markets wrote in a June 23 note that naperiglipron uses a similar chemical scaffold to Pfizer's danuglipron and lotiglipron, both of which Pfizer discontinued over safety issues. "While history for the scaffold has been challenging, we are interested to learn more why Lilly believes it can evade these past pitfalls," the analysts wrote ^[2].

The pullback comes as Lilly reports late-stage results for orforglipron, which the company says is on track for a regulatory filing this year ^[2]. In the Phase 3 ATTAIN-1 trial, a 36-milligram dose produced average weight loss of 12.4%, or 27.3 pounds, in people with obesity or overweight who did not have diabetes ^[1][2]. That was below the 13.4% analysts had expected based on Novo Nordisk's injectable semaglutide ^[2] and below the 15.7% reported for Novo's CagriSema ^[1]. Lilly's chief scientific officer, Daniel Skovronsky, defended the result at the time as "as good as it gets for GLP-1 monotherapy here in the once-a-day small molecule [space]" ^[1].

A second Phase 3 trial, ATTAIN-2, reported last week that orforglipron produced 10.5% average weight loss in people with overweight or obesity and type 2 diabetes, along with reductions in average blood sugar and cardiometabolic risk factors at the 72-week mark ^[1][2]. Analysts at Truist Securities called those results "in-line" with expectations but said they leave "room for competition" ^[2]. The two reports give different figures for how Lilly's shares reacted to the ATTAIN-1 results: a 13% drop on the day of the release ^[1] and a 7% slide in the aftermath ^[2].

Why it matters for patients

Naperiglipron is not approved and is not available to patients, so the trial shutdowns do not change anything for people already taking an approved GLP-1. But they do narrow the field of oral options that could reach the market in the next few years. With naperiglipron reduced to a single ongoing study, orforglipron is now the only Lilly oral GLP-1 candidate with late-stage data and a stated filing plan ^[1][2].

Whether naperiglipron shares any of the safety problems seen with Pfizer's danuglipron and lotiglipron has not been disclosed, and Lilly has not said why it ended the two studies. The remaining trial's results, which the company says will guide next steps, are the main pending source of information on the drug ^[1][2].

Trial results are averages. The 12.4% and 10.5% weight reductions reported for orforglipron describe group outcomes, not what any individual can expect. Whether an oral GLP-1 would cost less than current injectables, or how insurers would cover it, has not been reported.

What happens next

Lilly has said it plans to file orforglipron for regulatory review this year; a filing is not an approval, and the FDA's review timeline has not been disclosed ^[2]. The remaining Phase 2 naperiglipron study is listed with a primary completion date of April 2026 in one report ^[2] and September 2026 in another ^[1].