Effect of oral non-peptide GLP-1 receptor agonist orforglipron (LY3502970) in participants with obesity or overweight: a phase 2 study

Orforglipron (OFG) is a novel once daily oral non-peptide GLP-1 receptor agonist (RA) which can be taken with or without food, in development for chronic weight management. The objective of this Phase 2 study was to assess the efficacy, safety, and tolerability of OFG in patients with obesity or overweight with ≥1 weight-related comorbidity. Participants (N=272) were randomized to placebo or OFG (12, 24, 36, or 45 mg) treatment. OFG doses were increased to target using different dose escalation schemes in each arm. The primary endpoint was to compare percent body weight (BW) change from baseline in OFG vs placebo at Week 26, while the study continued to 36 weeks. Secondary endpoints included change from baseline in waist circumference (WC) and BMI, and the percentage of participants achieving ≥5 or ≥10% weight loss. At baseline, mean BW was 108.7 kg, BMI was 37.9 kg/m2, and 94% of participants had a BMI ≥30 kg/m2. Mean percentage BW loss, mean change in BMI and WC, and the percentage of participants achieving ≥5% or ≥10% weight loss were significantly greater with all OFG doses vs placebo (Figure). The AE profile was similar to other GLP-1 RAs; most were GI-related and mild to moderate in severity. The novel non-peptide GLP-1 RA OFG led to greater reductions in BW, BMI, and WC compared with placebo. These promising data support continued development of OFG as an oral treatment for obesity. Disclosure S.Wharton: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Boehringer Ingelheim International GmbH, Bausch Health, Canada, Research Support; Novo Nordisk, Eli Lilly and Company, Speaker's Bureau; Novo Nordisk, Eli Lilly and Company, Bausch Health, Canada. C.M.Kazda: Employee; Eli Lilly and Company. M.Konig: None. T.Blevins: Other Relationship; Medtronic, Research Support; Lilly Diabetes, Novo Nordisk, Dexcom, Inc., Abbott Diabetes, Tandem Diabetes Care, Inc., Medtronic, Speaker's Bureau; Lilly Diabetes, Novo Nordisk A/S. L.B.Connery: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. S.Raha: Employee; Eli Lilly and Company. K.J.Mather: Employee; Eli Lilly and Company. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. D.A.Robins: None. E.J.Pratt: Employee; Eli Lilly and Company. Funding Eli Lilly and Company