1668-P: Novel Once-Weekly Amylin Analog Petrelintide (ZP8396) Is Well Tolerated with Improved GI Tolerability after Multiple Dosing

Petrelintide (ZP8396) has demonstrated potential to reduce body weight after single and multiple dosing (SD and MD) in humans. The tolerability of doses, with similar exposure levels, was compared. SAD and MAD trials assessed safety, PK, and PD of petrelintide in healthy, lean and overweight males. 56 participants (mean BMI 25.6 kg/m2) were randomized to a SD of petrelintide or placebo (6:2) across seven dose cohorts (0.04 to 2.4 mg). 20 participants (mean BMI 25.4 kg/m2) were randomized to six once-weekly doses (MD) of petrelintide or placebo (7:3) across two dose cohorts (0.6 and 1.2 mg), without dose titration. Body weight reduction and adverse events (AEs) from Gastrointestinal (GI) and Metabolism and Nutrition SOC are compared descriptively. SD of 1.4 and 2.4 mg resulted in similar exposures in terms of Cmax and AUCtau as MD doses of 0.6 and 1.2 mg at steady state, respectively. All AEs were mild to moderate, with no serious or severe AEs reported, and no treatment discontinuations. No moderate GI AEs were seen after MD. The most frequently related AEs were decreased appetite, nausea and vomiting. A lower percentage of participants reported nausea or vomiting after MD compared to a SD. For 0.6 mg MD, 14% reported nausea vs 67% for 1.4 mg SD. For 1.2 mg MD, 29% reported nausea vs 83% for 2.4 mg SD. Reporting of vomiting was similarly low for 0.6 mg MD and 1.4 mg SD cohorts, 1 participant in each cohort. For 1.2 mg MD, none reported vomiting whilst 67% reported after 2.4 mg SD. The percentage of participants reporting either decreased appetite and/or early satiety were similar after SD and MD. The mean body weight reduction was 3.6% and 4.2% in SAD cohorts and 5.3% and 5.1% in MAD cohorts, after one or six weeks of dosing, respectively. Results indicate improved GI tolerability of petrelintide when exposure is gradually increased. AEs of decreased appetite and early satiety were similar after SD and MD. Higher doses are being explored to assess the potential for the management of obesity. Disclosure J. Griffin: Employee; Zealand Pharma A/S. U. Hövelmann: None. A.E. Melgaard: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. S. Macura: Employee; Novo Nordisk A/S, Zealand Pharma A/S. M. Hammer: Employee; Zealand Pharma A/S. T. Johansen: Employee; Zealand Pharma A/S. Stock/Shareholder; Zealand Pharma A/S. M.B. Olsen: None.