Preclinical Weight Loss Efficacy of AM833 in Combination With Semaglutide in Rodent Models of Obesity

Abstract Weight management pharmacotherapies seldom induce body weight loss that is comparable to that produced by bariatric surgery. In this regard, combination therapies targeting multiple signaling pathways that regulate energy balance may provide a means to achieve greater weight loss efficacy while also allowing the use of lower doses of each drug, and thus mitigating potential gastrointestinal tolerability issues commonly observed with current therapeutics for weight management. Amylin and GLP-1 are peptide hormones that regulate appetite. Upon ingestion of a meal, amylin is co-secreted with insulin from pancreatic beta-cells, while GLP-1 is secreted from enteroendocrine cells in the intestine. Both native peptides have a short half-life and reduce food intake, delay gastric emptying and decrease glucagon levels. Amylin and GLP-1 analogues have been developed for the treatment of diabetes, as well as weight management. The long-acting once-weekly GLP-1 analogue, semaglutide is approved for the treatment of type 2 diabetes and is in clinical development for weight management. AM833 (NNC0174-0833) is a long-acting, once-weekly human amylin analogue that is also in clinical development for weight management. Here, we present the combined effect of AM833 and semaglutide on weight loss in rodent models of obesity. Diet-induced obese (DIO) rats and mice on a high energy diet were dosed subcutaneously once-daily for 24 or 28 days with sub-maximal doses of AM833, semaglutide or two modes of combination treatments. The first combination mode consisted of concurrent co-dosing of both drugs, while the second entailed add-on of AM833 after one week of treatment with semaglutide. Body weight and food intake were measured daily. Body composition was assessed by magnetic resonance scan pre- and post-treatment. In the DIO rat, both concurrent (-13.1% ± 0.7%) and add-on (-12.8% ± 1.2%) treatment modes induced equivalent weight loss that was greater than each monotherapy (-6.3% ± 0.7%, 2 nmol/kg semaglutide and -5.8% ± 0.9%, 2 nmol/kg AM833) relative to initial body weights. Both combination groups achieved normalization of body weight to that of lean age-matched control rats. Reductions in cumulative food intake corresponded with the extent of weight loss. In the DIO mouse, weight loss in the combination groups was not significantly different (-9.6% ± 1.5%, concurrent vs. -11.5% ± 1.2%, add-on) but was greater than that observed in each monotherapy group (-1.9% ±1.2%, 1 nmol/kg semaglutide and +1.5% ± 2.2%, 10 nmol/kg AM833). In the DIO mouse, body weight did not normalize to match that of lean controls with combination treatment. In both rodent models, combination therapy at submaximal doses of AM833 and semaglutide achieved significantly greater weight loss compared to the monotherapy groups highlighting the potential of this combination for further clinical development.