Orforglipron's phase 2 results put an oral GLP-1 pill on the map

Eli Lilly said on June 23, 2023 that its experimental once-daily pill orforglipron produced average weight reductions of up to 14.7% at 36 weeks in adults with obesity or overweight, according to phase 2 results presented at the American Diabetes Association's 83rd Scientific Sessions and published simultaneously in the New England Journal of Medicine ^[1]. Orforglipron is a nonpeptide GLP-1 receptor agonist, a small molecule taken by mouth rather than an injected or peptide-based drug ^[1].

The 36-week study (NCT05051579) randomly assigned adults with obesity, or overweight with at least one weight-related health problem other than type 2 diabetes, to orforglipron at 12 mg, 24 mg, 36 mg or 45 mg, or to placebo ^[1]. Participants started at a mean body weight of 240 pounds (109 kg) ^[1]. At the 26-week primary endpoint, average weight reductions ranged from 8.6% (19.8 lb. or 9.0 kg) to 12.6% (29.3 lb. or 13.3 kg), compared with 2.0% (4.6 lb.) on placebo ^[1]. Reuters reported the 8.6% figure corresponded to the 12 mg dose and 12.6% to the 45 mg dose ^[2].

Weight continued to fall through 36 weeks, with reductions across the doses ranging from 9.4% (21.6 lb. or 9.8 kg) to 14.7% (34.0 lb. or 15.4 kg), versus 2.3% (5.3 lb.) for placebo ^[1]. Reuters attributed the 14.7% result to the highest dose tested ^[2]. All four doses met the key secondary endpoints at 36 weeks: 72% to 92% of participants lost at least 5% of body weight compared with 24% on placebo, and 47% to 75% lost at least 10% compared with 9% on placebo ^[1]. Waist circumference fell 9.6 cm to 13.6 cm across the orforglipron groups versus 4 cm with placebo ^[1].

Lilly said the safety profile was similar to other incretin-based drugs, with gastrointestinal side effects the most common adverse events, generally mild to moderate, and usually occurring during dose escalation ^[1]. The release did not give specific rates of nausea, vomiting or study discontinuation.

A separate phase 2 trial in type 2 diabetes (NCT05048719), published in The Lancet, tested orforglipron at 3 mg through 45 mg against placebo and injected dulaglutide over 26 weeks ^[1]. Average A1C fell by up to 2.1% from a baseline of 8.1%, compared with 0.4% for placebo and 1.1% for dulaglutide, and weight fell by up to 10.1 kg (22.3 lb.) versus 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].

Why it matters for patients

The practical headline is how the pill was taken. In the obesity trial, orforglipron or placebo was given daily as an oral capsule in the morning "without food or water restrictions" ^[1]. Dr. Sean Wharton, an investigator quoted in Lilly's release, said the results suggest orforglipron "may be an effective, once-daily oral that can be taken without food or water restrictions" ^[1]. That matters because the current oral GLP-1 option is a peptide with dosing rules; the sources here do not spell out those rules, so any direct comparison with Rybelsus (oral semaglutide) is not addressed in this data.

It is also worth keeping the stage of research in mind. These are phase 2 results in a mid-size trial over 26 to 36 weeks. They do not establish long-term safety, durability of weight loss, effects on heart attacks or strokes, or how orforglipron compares head-to-head with semaglutide or tirzepatide. Pricing, insurance coverage and manufacturing capacity for a small-molecule pill are not discussed in the sources.

What happens next

Lilly said it has started phase 3 programs: ATTAIN for chronic weight management and ACHIEVE for type 2 diabetes ^[1][2]. No filing or approval dates for orforglipron were given.

At the same meeting, phase 3 results in 938 people with type 2 diabetes and obesity or overweight showed the injected drug Mounjaro (tirzepatide) produced average weight loss of 15%, or 33 pounds (14.8 kg), over 72 weeks ^[2]. Lilly said it expected an FDA decision on tirzepatide for obesity as early as late 2023 ^[2]. Novo Nordisk was scheduled to present results for its own oral obesity candidate at the meeting two days later, and Pfizer is also developing obesity pills ^[2].