Eli Lilly has met its goal of achieving semaglutide-like efficacy with an oral GLP-1 drug. The phase 3 study linked the oral GLP-1 drug orforglipron to similar reductions in blood glucose and body weight to Novo Nordisk’s injectable blockbuster, although the figures are down on Lilly’s midphase data.
Speaking on an earnings call in February, Daniel Skovronsky, M.D., Ph.D., chief scientific officer at Lilly, was clear about the objectives for orforglipron. Lilly’s goal was to deliver an oral drug with an “efficacy, safety and tolerability profile that is similar to that of an injectable single-acting GLP-1.” Semaglutide, which Novo sells as Ozempic and Wegovy, is the leading injectable single-acting GLP-1.
Lilly reported the first phase 3 data on orforglipron Thursday. The study randomized people with Type 2 diabetes to receive one of three doses of orforglipron or placebo. After 40 weeks of once-daily dosing, A1C, a measure of blood sugar, fell between 1.3% and 1.6% in the orforglipron cohorts, compared to a 0.1% drop in the placebo group. The result caused the trial to meet its primary endpoint.
Novo reported (PDF) A1C reductions of 1.4% to 1.6% after 30 weeks of dosing with Ozempic in a previous phase 3 trial. Lilly saw a steeper drop in A1C in its phase 2 trial, when it linked orforglipron to reductions of up to 2.1% after 26 weeks of treatment. Lilly didn’t take the highest dose from phase 2 into phase 3.
Weight loss was a key secondary endpoint in Lilly’s phase 3 orforglipron trial. After 40 weeks, patients on the oral GLP-1 drug candidate had lost between 4.7% and 7.9% of their body weight, with participants on the highest dose losing the most weight. At the top dose, patients lost an average of 7.3 kg of the 90.2 kg they weighed at the start of the trial. In Novo's phase 3 trial, patients on Ozempic lost up to 4.7 kg from mean starting weights of up to 96.9 kg.
As with A1C, Lilly saw steeper reductions in body weight in its phase 2 trial, when the company posted mean weight loss of up to 10.1 kg after 26 weeks on orforglipron. Skovronsky has said Lilly expects weight loss seen in people with diabetes to be significantly less than in people living with obesity.
The drugmaker also shared a snapshot of safety and tolerability data. The most common adverse events were diarrhea, nausea and indigestion, which respectively affected up to 26%, 18% and 20% of patients on the oral GLP-1 drug. For comparison, Novo reported rates of nausea and diarrhea of 20% and 9%, respectively, in its phase 3 trial.
The readout marks the start of a wave of data drops for orforglipron. Skovronsky has previously said Lilly expects to see data from up to five studies in Type 2 diabetes and two trials in obesity, with two phase 3 obesity readouts scheduled for the third quarter. Lilly plans to use the data to seek approval in obesity this year, with submissions in Type 2 diabetes penciled in for 2026.
Citi analysts said in a note this morning that the readout exceeded market expectations of around 5-6% weight loss for orforglipron, while the lack of liver toxicity will be a "sigh of relief to many" after Pfizer discontinued its oral GLP-1 earlier this week for this reason. Lilly stock was up 15% to $844.69 in the opening hour of trading Thursday from a Wednesday closing price of $734.90.