58-OR: The Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide Transiently Delays Gastric Emptying Similarly to a Selective Long-Acting GLP-1 Receptor Agonist

Abstract

A long-acting GLP-1 receptor agonist (RA) transiently delays gastric emptying (GE). We investigated the GE effect of a novel dual GIP and GLP-1 RA, tirzepatide (TZP), compared to that of a selective GLP-1 RA in nonclinical and clinical studies. No effect on GE was seen with GIP RA alone in mice. Combination of GIP RA with GLP-1 RA or a dual agonist, TZP, did not delay GE more than GLP-1 RA alone. The effect of TZP on GE was evaluated in a Phase 1 study, comprising 4 week multiple ascending dose (MAD; N=35) QW in healthy subjects and 4-week proof of concept (PoC) (N=53) in patients with T2DM. In MAD, TZP was administered QW at fixed doses of 0.5, 1.5, 4.5 mg, and a titration dose of 5-5-8-10 mg. A selective GLP-1 RA, dulaglutide (dula), 1.5 mg QW was also included. In PoC, TZP was administered QW at fixed doses of 0.5 mg and 5 mg, and at titration doses of 5-5-10-10 mg and 5-5-10-15 mg. Acetaminophen (APAP) was administered on Day -1 (prior to TZP or dula), at 24 hours after the first (Day 2) and fourth (Day 23) doses to coincide with peak TZP or dula exposure. Impact of TZP on GE was evaluated using APAP Cmax, AUC, and tmax, compared to placebo (PL). Baseline adjusted Cmax of APAP (ratio to Day -1) was used to compare the GE effect of TZP with that of dula. APAP Cmax decreased by approximately 50% and tmax was delayed by an hour after the first TZP dose (doses >1.5 mg), suggesting a delay in GE while AUC was not notably altered. Evaluation of APAP PK after the first and fourth doses of the fixed dose regimen of TZP showed that impact of TZP on GE was maximized after first dose (Day 2 vs. PL), and showed complete tachyphylaxis after repeated dosing (Day 23 vs. PL). Similarly, in the titration cohort, impact of TZP on GE was significant after the first dose. However, incomplete tachyphylaxis was observed after 4 weeks of TZP administration due to the titration regimen. Impact of the fixed doses of TZP on GE was comparable to that of a selective GLP 1 RA (dula). Disclosure S. Urva: None. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sun Pharma. T. Coskun: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. C. Benson: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.