51-OR: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of BI 456906 in People with Overweight/Obesity

Abstract

Glucagon receptor (GCGR) agonism increases energy expenditure and glucagon-like peptide 1 receptor (GLP-1R) agonism reduces energy intake; thus, dual GCGR/GLP-1R agonists, such as BI 456906, may be more effective at treating obesity than mono GLP-1R agonists. This dose-finding study tested efficacy and safety of BI 456906 in participants (pts) with overweight/obesity. This double-blind, placebo (PBO)-controlled study (NCT04667377) randomised adults with BMI ≥27 kg/m2 to weekly subcutaneous BI 456906 (0.6, 2.4, 3.6, 4.8 mg) or PBO for 46 weeks (thereof 20-week (W) rapid, bi-weekly dose escalation; 26-W maintenance). Primary endpoint was bodyweight (BW) change (%) from baseline (BL) at W46. Secondary endpoints included proportion of pts reaching ≥5, ≥10 or ≥15% BW loss from BL at W46. In total, 387 pts were randomised (treated set [TS], N=386; full analysis set [FAS], N=384; n≈77 per arm). At BL (FAS) mean age was 49.1 years, BW 105.7 kg and BMI 37.1 kg/m2; 31.8% of pts were male. BI 456906 therapeutic benefit vs PBO was shown by a non-flat dose response curve of BW change (%) from BL at W46. Mean BW reduced with dose over 46 weeks (FAS; 0.6 mg, −6.2%; 2.4 mg, −12.5%; 3.6 mg, −13.2%; 4.8 mg, −14.9%; vs PBO, −2.8%). At W46, BW loss (FAS) of ≥5, ≥10 and ≥15% was reached by 82.8%, 68.8% and 54.7% of 4.8 mg BI 456906 pts and 25.9%, 11.1% and 5.6% of PBO pts, respectively. Pts reaching and staying on 4.8 mg BI 456906 achieved BW loss of 18.7% at W46. Adverse events (AEs) were reported by 90.9% of BI 456906 pts (TS; 0.6 mg, 90.9%; 2.4 mg, 89.7%; 3.6 mg, 92.2%; 4.8 mg, 90.9%) and 75.3% of PBO pts, mainly gastrointestinal (TS; 0.6 mg, 57.1%; 2.4 mg, 85.9%; 3.6 mg, 75.3%; 4.8 mg, 81.8%; PBO, 41.6%); 24.6% of BI 456906 pts and 3.9% of PBO pts stopped treatment, mainly during dose escalation. Serious AE incidence was similar in BI 456906 and PBO pts (TS; 0.6 mg, 1.3%; 2.4 mg, 2.6%; 3.6 mg, 7.8%; 4.8 mg, 5.2%; vs PBO, 6.5%). Over 46 weeks, BI 456906 showed substantial BW loss efficacy with no unexpected safety concerns. Disclosure C.Le roux: Advisory Panel; Novo Nordisk, Boehringer Ingelheim Inc., Lilly, Herbalife International of America, Inc., Johnson & Johnson, Medtronic, GI Dynamics, Keyron Ltd. O.Steen: None. K.J.Lucas: None. E.Startseva: Employee; Boehringer Ingelheim International GmbH. A.Unseld: None. A.M.Hennige: Employee; Boehringer Ingelheim International GmbH. Funding Zealand Pharma A/S; Boehringer Ingelheim