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

Introduction&nbsp; Alström&nbsp;syndrome (AS) is an autosomal recessive ciliopathy caused by mutations in&nbsp;ALMS1, which encodes a protein that localizes to centrosomes and basal bodies of primary cilia. Early emergence of obesity in&nbsp;patients with&nbsp;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&nbsp;Alms1-/-&nbsp;mice.&nbsp;&nbsp; Methods&nbsp; Dose-response for the selective melanocortin 1/4 receptor agonist RM-493 (Setmelanotide) in suppressing food intake was determined in 19-wk-old female&nbsp;Alms1-/-&nbsp;mice&nbsp;(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)&nbsp;Alms1-/-&nbsp;mice had food intake measured continuously in metabolic cages&nbsp;(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.&nbsp; Results&nbsp; In the dose-response study,&nbsp;Alms-/-&nbsp;and&nbsp;WT&nbsp;had&nbsp;food intake responses that were&nbsp;similar&nbsp;for&nbsp;40&nbsp;(p=0.72),&nbsp;but different&nbsp;for&nbsp;100, 250, and 1000 nmol/kg/d (p’s<0.05). We selected&nbsp;250&nbsp;nmol/kg/d&nbsp;as the dose for further investigation&nbsp;as&nbsp;food intake&nbsp;was unchanged&nbsp;in WT&nbsp;(p=0.23)&nbsp;but reduced&nbsp;in&nbsp;Alms1-/-&nbsp;(p=0.04). In&nbsp;the&nbsp;second cohort,&nbsp;food intake&nbsp;and&nbsp;body weight&nbsp;were&nbsp;similar&nbsp;at&nbsp;baseline&nbsp;compared to&nbsp;vehicle&nbsp;for&nbsp;both&nbsp;male and female&nbsp;Alms1-/-&nbsp;(p’s>0.84).&nbsp;RM-493&nbsp;(250 nmol/kg/d)&nbsp;reduced food intake&nbsp;in male&nbsp;Alms1-/- compared to vehicle (-46.4%;&nbsp;p=0.003), causing&nbsp;a&nbsp;nonsignificant&nbsp;reduction in body weight&nbsp;(-13.1%;&nbsp;p=0.33),&nbsp;whereas&nbsp;food intake&nbsp;in female&nbsp;Alms1-/-&nbsp;was&nbsp;reduced by 28.5%,&nbsp;and body weight by 6.5%,&nbsp;although&nbsp;neither difference was significant (p’s&nbsp;>0.61).&nbsp;During the washout period, male&nbsp;Alms1-/-&nbsp;ate 62.8% more food than during the vehicle period&nbsp;(p<0.0001),&nbsp;resulting in body weight regain&nbsp;of&nbsp;5.0 ± 0.7 g. Female&nbsp;Alms1-/-&nbsp;ate 24.8% more food&nbsp;during the washout period compared to&nbsp;vehicle&nbsp;(p=0.056),&nbsp;regaining&nbsp;2.4 ± 0.6 g of body weight.&nbsp;&nbsp;&nbsp; Conclusion&nbsp; RM-493&nbsp;acutely&nbsp;reduces food intake&nbsp;in&nbsp;Alms1-/-&nbsp;mice&nbsp;with a greater effect in males than females.&nbsp;Withdrawal of RM-493 results in compensatory overeating&nbsp;and&nbsp;rapid weight regain back to pre-treatment values. These findings identify RM-493 as a promising drug&nbsp;candidate&nbsp;for&nbsp;treating&nbsp;obesity in AS.&nbsp;The impact of RM-493 on long-term body weight will be determined in ongoing chronic treatment studies in&nbsp;Alms1-/-&nbsp;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. Abstracts 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.