Lilly's oral orforglipron led to up to 14.7% weight loss in phase 2 trial

Eli Lilly reported on June 23, 2023 that its experimental once-daily pill orforglipron produced average weight loss of up to 14.7% at 36 weeks in adults with obesity or overweight, in phase 2 results published in the New England Journal of Medicine and presented at the American Diabetes Association's 83rd Scientific Sessions ^[1]. Orforglipron is a nonpeptide GLP-1 receptor agonist, which Lilly describes as its first oral nonpeptide drug in this class ^[1].

The 36-week study enrolled adults with obesity or overweight who also had at least one weight-related health condition, not including type 2 diabetes ^[1]. Participants took one of four doses — 12 mg, 24 mg, 36 mg or 45 mg — or a placebo as a daily capsule in the morning, without food or water restrictions, alongside healthy eating and exercise education provided by study staff ^[1]. Their average starting weight was 240 pounds (109 kg) ^[1].

At the 26-week primary endpoint, weight fell by 8.6% (19.8 lb, or 9.0 kg) to 12.6% (29.3 lb, or 13.3 kg) depending on dose, compared with 2.0% (4.6 lb, or 2.1 kg) for placebo ^[1]. Weight continued to drop through 36 weeks, when reductions ranged from 9.4% (21.6 lb, or 9.8 kg) to 14.7% (34.0 lb, or 15.4 kg), compared with 2.3% (5.3 lb, or 2.4 kg) for placebo ^[1].

At 36 weeks, 72% to 92% of participants on orforglipron lost at least 5% of their body weight, versus 24% on placebo, and 47% to 75% lost at least 10%, versus 9% on placebo ^[1]. BMI fell by 3.4 to 5.5 kg/m2 across doses versus 0.9 kg/m2 with placebo, and waist circumference fell by 9.6 to 13.6 cm versus 4 cm ^[1].

Gastrointestinal side effects were the most commonly reported and were generally mild to moderate, usually occurring during the period when doses were increased, Lilly said, adding that the overall safety profile was similar to other incretin-based therapies ^[1]. Reuters described the side effects the same way ^[2].

A separate 26-week phase 2 trial tested orforglipron in adults with type 2 diabetes, comparing it with placebo and with injected dulaglutide (Trulicity) ^[1]. Average A1C fell by up to 2.1 percentage points from a starting average of 8.1%, compared with 0.4 points for placebo and 1.1 points for dulaglutide ^[1]. Weight fell by up to 10.1 kg (22.3 lb) from a starting average of 100.3 kg (221.1 lb), compared with 2.2 kg for placebo and 3.9 kg for dulaglutide ^[1]. Between 65% and 96% of orforglipron participants reached an A1C below 7.0%, versus 64% on dulaglutide and 24% on placebo ^[1]. Those results were published in The Lancet ^[1].

"These exciting results indicate that orforglipron may be an effective, once-daily oral that can be taken without food or water restrictions," said Dr. Sean Wharton, director at Wharton Medical Clinic, in Lilly's announcement ^[1].

Why it matters for patients

Oral GLP-1 options so far have meant timing rules — in this trial, orforglipron was taken in the morning with no food or water restrictions ^[1]. That is a practical difference for people who find injection devices or fasting schedules hard to manage, though how it compares with other oral products has not been reported from head-to-head studies.

The results are mid-stage. Orforglipron is experimental, and Lilly has not announced when phase 3 results are expected or when it might seek approval ^[1]. Phase 2 findings often do not carry over to larger trials.

Reuters placed the weight loss in context: in a phase 3 trial of 938 people with type 2 diabetes who were also obese or overweight, injected tirzepatide (Mounjaro) produced about 15% weight loss at 72 weeks, and Lilly previously reported 22.5% loss in people who were obese or overweight without diabetes ^[2]. Those trials used different drugs, populations and durations, so the numbers cannot be compared directly ^[2].

Gastrointestinal side effects were the main tolerability issue in the orforglipron study, as with other drugs in this class ^[1][2].

Orforglipron is not the only oral candidate. Novo Nordisk was scheduled to present results for its oral obesity drug candidate at the same diabetes meeting, and Pfizer is also developing obesity pills ^[2].

What happens next

Lilly has started phase 3 programs for orforglipron: ATTAIN, for obesity and overweight, and ACHIEVE, for type 2 diabetes ^[1]. No dates for phase 3 results or for a regulatory filing have been reported ^[1].

Novo Nordisk's oral obesity candidate results were expected at the diabetes meeting on the Sunday after the orforglipron announcement ^[2]. Lilly said it expects the U.S. Food and Drug Administration to decide as early as late 2023 whether to approve Mounjaro (tirzepatide) as an obesity treatment ^[2].

Orforglipron was discovered by Chugai Pharmaceutical and licensed to Lilly in 2018 ^[1].