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Once-daily oral nonpeptide GLP-1-RA achieved up to 14.7% mean weight reduction at 36 weeks

Phase 2 data for orforglipron (12 mg, 24 mg, 36 mg or 45 mg), a nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, has showed statistically significant dose-dependent body weight reductions for all doses ranging from 8.6% (19.8 lb. or 9.0 kg) to 12.6% (29.3 lb. or 13.3 kg) compared to 2.0% (4.6 lb. or 2.1 kg) for placebo. For those taking orforglipron, body weight continued to decrease at 36 weeks where all doses achieved body weight reductions ranging from 9.4% (21.6 lb. or 9.8 kg) to 14.7% (34.0 lb. or 15.4 kg) compared to 2.3% (5.3 lb. or 2.4 kg) for placebo. The mean baseline body weight of participants was 240 lb. (109 kg). The results were shared during an oral presentation at the American Diabetes Association's 83rd Scientific Sessions and were simultaneously published in the New England Journal of Medicine.

(Photo credit: Wharton Medical Clinic)

"We recognise that obesity is a global epidemic and there is a need for a variety of effective medications and administration routes," said Dr Sean Wharton, Director at Wharton Medical Clinic. "We are working to address these needs by researching different options, including a daily oral pill called orforglipron. In a phase 2 study, orforglipron demonstrated an average of up to 14.7% weight reduction. These exciting results indicate that orforglipron may be an effective, once-daily oral that can be taken without food or water restrictions."

Eli Lilly’s Orforglipron met both primary and secondary endpoints for the efficacy estimand and demonstrated clinically significant weight reductions in adults with obesity or overweight, with at least one weight-related comorbidity (not including type 2 diabetes).

All four tested doses of orforglipron achieved all key secondary endpoints at 36 weeks of treatment for the efficacy estimand, including participants achieving:

  • Body weight reductions of ≥5%: 72% (12 mg), 90% (24 mg), 92% (36 mg) and 90% (45 mg) compared to 24% with placebo

  • Body weight reductions of ≥10%: 47% (12 mg), 62% (24 mg), 75% (36 mg) and 69% (45 mg) compared to 9% with placebo

  • BMI reduction from baseline: 3.4 kg/m2 (12 mg), 4.7 kg/m2 (24 mg), 5.0 kg/m2 (36 mg) and 5.5 kg/m2 (45 mg) compared to 0.9 kg/m2 with placebo

  • Waist circumference reduction from baseline: 9.6 cm (12 mg), 11.2 cm (24 mg), 10.6 cm (36 mg) and 13.6 cm (45 mg) compared to 4 cm with placebo

The safety profile of orforglipron was similar to other incretin-based therapies. Gastrointestinal side effects were the most commonly reported adverse events, were generally mild-to-moderate in severity, and usually occurred during the dose escalation period.

An additional phase 2 study evaluated orforglipron for the treatment of type 2 diabetes compared to placebo and dulaglutide. Data were presented at the American Diabetes Association's 83rd Scientific Sessions and simultaneously published in The Lancet. The study met its primary and secondary endpoints, demonstrating orforglipron achieved meaningful reductions in A1C and body weight at 26 weeks with an adverse events profile consistent with other GLP-1 receptor agonists. In that study, for the efficacy estimand, mean reduction in A1C (from a mean baseline of 8.1%) with orforglipron at 26 weeks was up to 2.1% compared to 0.4% with placebo and 1.1% with dulaglutide.

Orforglipron (3 mg, 12 mg, 24 mg, 36 mg or 45 mg) also demonstrated weight reductions up to 10.1 kg (or 22.3 lb.) in adults with type 2 diabetes (from a mean baseline of 100.3 kg or 221.1 lb.) compared to 2.2 kg (or 4.9 lb.) with placebo and 3.9 kg (or 8.6 lb.) for dulaglutide. With orforglipron, 65% to 96% of participants achieved an A1C of less than 7.0% at 26 weeks versus 64% in the dulaglutide group and 24% in the placebo group. An A1C of less than 5.7% was demonstrated with orforglipron doses greater than 3 mg in 18% to 34% of participants.

"People living with chronic diseases such as type 2 diabetes and obesity deserve options – including oral treatments – to meet their treatment needs. In two phase 2 studies, orforglipron demonstrated the ability to lower weight and A1C in both patient populations," said Dr Jeff Emmick, senior vice president, product development, Lilly. "These study results support the continued development of orforglipron in phase 3. We look forward to those results and the continued development of our pipeline assets that explore novel treatments for type 2 diabetes and obesity."

Lilly has initiated phase 3 development programs to further study the efficacy and safety of orforglipron for the treatment of obesity and overweight (ATTAIN trials) and type 2 diabetes (ACHIEVE trials).


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