Introduction and Objective: Petrelintide is an amylin analog in development for weight management. To explore how petrelintide drives weight loss as compared to GLP-1RA based therapy, the present study assessed the effects of petrelintide and semaglutide in rats with diet-induced obesity. Methods: Male Sprague Dawley rats were fed a high-fat diet (60% kcal from fat) for 14 weeks. Rats were then randomized into four groups, treated for three weeks with vehicle, semaglutide (8 nmol/kg, s.c. (subcutaneous) daily), petrelintide (10 nmol/kg, s.c. every other day) or weight-matched to petrelintide and semaglutide by caloric restriction (n=6/group). Body weight, food intake, locomotor activity, VO2 and CO2 (by indirect calorimetry) were continuously measured. Results: Petrelintide, semaglutide and weight-matched reduced body weight (6.1-7.0% weight reduction vs. 4.9% increase in vehicle group), cumulative food intake and the respiratory exchange ratio. Semaglutide initially decreased dark phase locomotor activity vs. vehicle. Petrelintide and semaglutide both decreased food intake during the dark phase. However, only petrelintide significantly decreased food intake during the light phase (59.9 ± 16.5 g, 96.6 ± 8.5 g vs. 138 ± 17.9 g for petrelintide, semaglutide vs. vehicle; cumulative food intake ± SEM). Both petrelintide and semaglutide initially decreased meal size and frequency. However, compared to semaglutide, the sustained decrease in food intake with petrelintide was to a higher degree driven by a reduction in meal size (in light phase 1.5 ± 0.16 g, 2.52 ± 0.2 g vs. 3.3 ± 0.4 g, and in dark phase 2.2 ± 0.3 g, 2.6 ± 0.3 g vs. 3.2 ± 0.1 g for petrelintide, semaglutide and vehicle; mean meal size ± SEM). Conclusion: These results suggest that petrelintide vs. semaglutide elicits different effects on eating pattern and increases satiation. Initial reduced locomotor activity in rats dosed with semaglutide could indicate lower tolerability vs. petrelintide. Disclosure A.J. Gradel: Employee; Current; Zealand Pharma A/S. B. Vestergaard: Employee; Current; Zealand Pharma A/S. J. Griffin: Employee; Current; Zealand Pharma A/S. L. Torz Pedersen: Employee; Current; Zealand Pharma A/S. Funding Zealand Pharma A/S funded study
GRADEL et al. (Fri,) studied this question.