MON-LB019 Setmelanotide (RM-493) Reduces Food Intake and Rapidly Induces Weight Loss in a Mouse Model of Alström Syndrome

Abstract

Introduction Alström syndrome (AS) is an autosomal recessive ciliopathy caused by mutations in ALMS1, which encodes a protein that localizes to centrosomes and basal bodies of primary cilia. Early emergence of obesity in patients with AS suggests a key role for ALMS1 in body weight regulation. Mice with non-functional Alms1 develop normal hypothalamic cilia, but these are not maintained postnatally. This suggests involvement of the central pathways regulating energy balance in the development of obesity in AS. Since leptin signaling has been shown to be impaired in the related ciliopathy Bardet-Biedl syndrome, we hypothesized that targeting central pathways downstream of leptin signaling would reduce food intake and body weight in Alms1-/- mice. Methods Dose-response for the selective melanocortin 1/4 receptor agonist RM-493 (Setmelanotide) in suppressing food intake was determined in 19-wk-old female Alms1-/- mice (n=3) and wild-type (WT) littermates (n=3), individually housed and receiving daily intraperitoneal injections of vehicle (3 d) followed by RM-493 (3 d). A separate cohort of 17-wk-old male (n=4) and female (n=4) Alms1-/- mice had food intake measured continuously in metabolic cages (CLAMS, Columbus Instruments). After determining baseline food intake, mice received vehicle (2 d), followed by RM-493 (3 d), then 3d of washout (no treatment). Repeated measures ANOVA was performed. Mean ± SE and nominal p-values are shown. Results In the dose-response study, Alms-/- and WT had food intake responses that were similar for 40 (p=0.72), but different for 100, 250, and 1000 nmol/kg/d (p’s<0.05). We selected 250 nmol/kg/d as the dose for further investigation as food intake was unchanged in WT (p=0.23) but reduced in Alms1-/- (p=0.04). In the second cohort, food intake and body weight were similar at baseline compared to vehicle for both male and female Alms1-/- (p’s>0.84). RM-493 (250 nmol/kg/d) reduced food intake in male Alms1-/- compared to vehicle (-46.4%; p=0.003), causing a nonsignificant reduction in body weight (-13.1%; p=0.33), whereas food intake in female Alms1-/- was reduced by 28.5%, and body weight by 6.5%, although neither difference was significant (p’s >0.61). During the washout period, male Alms1-/- ate 62.8% more food than during the vehicle period (p<0.0001), resulting in body weight regain of 5.0 ± 0.7 g. Female Alms1-/- ate 24.8% more food during the washout period compared to vehicle (p=0.056), regaining 2.4 ± 0.6 g of body weight. Conclusion RM-493 acutely reduces food intake in Alms1-/- mice with a greater effect in males than females. Withdrawal of RM-493 results in compensatory overeating and rapid weight regain back to pre-treatment values. These findings identify RM-493 as a promising drug candidate for treating obesity in AS. The impact of RM-493 on long-term body weight will be determined in ongoing chronic treatment studies in Alms1-/- and WT mice. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.