Introduction and Objective: AT7687 is a first-in-class peptide GIPR antagonist validated as anti-obesity therapy in obese monkeys, as monotherapy and in combination with liraglutide and cagrilintide. This randomized, double-blind, placebo-controlled study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of AT7687 (AT).Methods: In the single ascending dose (SAD) part, 60 participants randomized 6:2 by cohort received a single dose of AT (range: 12.5 mg – 380 mg) or placebo (PL). In the multiple ascending dose (MAD) part, 42 participants randomized 10:2 by cohort received 4 doses of AT (range: 17 mg – 150 mg) or PL once weekly. BMI range was 20·0−39·9 kg/m². The primary endpoint was treatment-emergent adverse events (TEAEs); secondary endpoints were PK parameters; exploratory endpoints included changes in oral glucose tolerance test (OGTT) response, body weight, lipids and hemodynamics.Results: All doses were safe and well-tolerated. 36/79 (46%) subjects on AT and 9/23 subjects (39%) on PL experienced only mild TEAEs; moderate TEAEs occurred in 7/79 (9%) and 0/23 subjects (0%), respectively. There were no severe or serious AEs and no discontinuations. Gastrointestinal AEs were mild and occurred in similar proportions (19% AT; 17% PL). Cmax and AUC exposure were dose proportional. AT led to statistically significant change in post- minus pre-dose Insulinogenic Index in both SAD (p=0.009) and MAD (p=0.029), with no difference in PL. In MAD, the placebo-adjusted mean change in LDL-C was up to -9.1% at Day 29 and up to 5.3 bpm reduction in resting heart rate at Day 22. There were no significant changes in weight at Day 29.Conclusion: AT7687 was well-tolerated, showed clinical evidence of potent GIPR antagonism, and encouraging trends of cardiometabolic benefits, justifying advancement into longer trials to assess its efficacy as monotherapy and as an ideal combination partner in obesity management.
A. Baladi Nejad: Employee; Current; Antag Therapeutics. Employee; Ended; Novo Nordisk A/S. J. Boland: None. A.H. Hand: None. K.M. Knudsen: Consultant; Current; Antag Therapeutics, Breye Therapeutics. L.S. Gasbjerg: Stock/Shareholder; Current; Antag Therapeutics. Consultant; Current; Antag Therapeutics. Advisory Panel; Ended; Novo Nordisk. Other – Speaker honorarium; Ended; Novo Nordisk. A.H. Sparre-Ulrich: None. R. Nkulikiyinka: Employee; Current; Antag Therapeutics.
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