The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on Oct. 15 recommended marketing authorization for Foundayo (orforglipron), Eli Lilly’s once-daily oral GLP-1 receptor agonist, for weight management and type 2 diabetes in adults. The European Commission must now make the final decision. The opinion landed in the same week that Viking Therapeutics began Phase 3 trials of a rival oral molecule and Nature Medicine published Phase 3 results for a third, underlining how crowded the race for an obesity pill has become.

According to the EMA summary, the applicant is Eli Lilly Nederland B.V. The recommended weight-management indication covers adults with a body mass index (BMI) of 30 or above, or of 27 to below 30 with at least one weight-related condition such as prediabetes, type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease, as an adjunct to diet and physical activity. For type 2 diabetes it can be used alone when metformin is considered inappropriate, or with other diabetes drugs. The most common side effects are nausea, vomiting and diarrhea.

Orforglipron is a small-molecule, nonpeptide drug, which allows it to be taken as a conventional tablet. The US Food and Drug Administration approved it on April 1 for adults with obesity or with overweight and a weight-related condition. Lilly’s announcement stressed that it can be taken at any time of day without food or water restrictions and said the company had filed in more than 40 countries. David A. Ricks, Lilly’s chair and chief executive, said in the release that “this is obesity care designed for the real world.”

The weight-loss evidence comes from ATTAIN-1, a 72-week, Lilly-funded Phase 3 trial of 3,127 adults with obesity but without diabetes, published in the New England Journal of Medicine. Under the trial’s primary analysis, the treatment-regimen estimand, which counts everyone regardless of whether they stayed on the drug, body weight fell by 7.5%, 8.4% and 11.2% at the 6 mg, 12 mg and 36 mg doses, against 2.1% with placebo. At the top dose, 54.6% of participants lost at least 10% of their body weight, versus 12.9% on placebo. Discontinuation because of adverse events ranged from 5.3% to 10.3% with orforglipron, compared with 2.7% with placebo, and the most common adverse events were gastrointestinal. Lilly’s release highlights a larger figure, 12.4% versus 0.9%, which comes from the efficacy estimand and applies to participants who stayed on treatment.

On Oct. 14, Viking Therapeutics announced the start of SUNRISE, a Phase 3 program for an oral tablet form of VK2735, a dual GLP-1 and GIP receptor agonist. SUNRISE-1 will enroll adults with obesity or overweight without type 2 diabetes, and SUNRISE-2 adults with type 2 diabetes. Each randomized, double-blind, placebo-controlled trial targets 560 adults taking 27.5 mg, 35 mg or 55 mg once daily, or placebo, for 68 weeks, with percent change in body weight versus placebo as the primary endpoint. The company said its Phase 2 VENTURE-Oral study showed mean weight reductions of up to 12.2% at 13 weeks. “Advancing the oral tablet formulation of VK2735 into Phase 3 is an exciting step toward expanding Viking’s portfolio of therapeutic treatments for obesity,” said Brian Lian, Viking’s chief executive.

Meanwhile, a Nature Medicine paper published Oct. 5 reported OUTSTAND-2, a Phase 3 trial of safiglipron, another oral small-molecule GLP-1 receptor agonist, sponsored by Jiangsu Hengrui Pharmaceuticals. The double-blind trial randomized 810 adults with type 2 diabetes inadequately controlled on metformin, at 98 sites in China, to 30 mg, 60 mg or 90 mg of safiglipron or 10 mg of dapagliflozin. All three doses met the non-inferiority margin for HbA1c change at 32 weeks, and the 90 mg dose was superior under the treatment policy estimand. Weight loss in this diabetes population was modest: 2.35%, 3.55% and 4.17% across the three doses on the efficacy estimand, compared with 3.60% on dapagliflozin. Gastrointestinal side effects were more frequent with safiglipron, and discontinuations for adverse events were about 4% versus 1.5%.

Why it matters

Injectable GLP-1 drugs have reshaped obesity treatment, and a daily tablet could reach patients who will not or cannot inject. Viking’s Lian said a once-daily oral option could support better long-term adherence and could be positioned either as an induction therapy or for maintenance.

The safiglipron data are a reminder that oral GLP-1 molecules are not interchangeable. In OUTSTAND-2, weight loss at 32 weeks was no greater than with the comparator, an SGLT2 inhibitor, even as glucose control improved.

The caveats

Cross-trial comparisons of percentages are unreliable. ATTAIN-1 ran 72 weeks in people with obesity and no diabetes; VENTURE-Oral was a 13-week Phase 2 study; OUTSTAND-2 was a 32-week diabetes trial with an active comparator. Each reports weight under different estimands, and the headline figure in Lilly’s release describes people who stayed on treatment rather than everyone enrolled. The Viking data come from a company press release, not a peer-reviewed publication, and its Phase 3 trials have only just begun. Both the NEJM and Nature Medicine papers were funded by the drugs’ manufacturers, and several authors are company employees. The CHMP opinion is a recommendation, not an approval.

What to watch

The European Commission’s decision on Foundayo, and the first readouts from Viking’s 68-week SUNRISE trials.

This article is for general information and does not replace advice from a qualified clinician. Corrections: email the editor using the address on the Contact page.