#4061 PHARMACOKINETICS OF SETMELANOTIDE IN INDIVIDUALS WITH RENAL IMPAIRMENT: RESULTS FROM A PHASE 1, OPEN-LABEL, SINGLE-DOSE STUDY

Abstract

Abstract Background and Aims Setmelanotide is an approved treatment for chronic weight management and control of hunger in patients aged ≥6 years with specific forms of obesity including Bardet-Biedl syndrome (BBS). Setmelanotide may be considered for patients with renal impairment, including those with BBS, who often experience impaired renal function as a primary feature of the syndrome. This study evaluated the pharmacokinetics (PK) and safety of a single dose of setmelanotide in individuals without BBS who have renal impairment. Method This Phase 1, open-label study (NCT04348175) was conducted in 3 centers in the United States. Eligible individuals were aged 18-83 years and had general obesity with a body mass index (BMI) of 22-40 kg/m2. Individuals were assigned to a study cohort according to renal function, determined by estimated glomerular filtration rate (normal renal function [healthy volunteers]: ≥90 mL/min/1.73 m2; mild renal impairment: 60-89 mL/min/1.73 m2; moderate renal impairment: 30-59 mL/min/1.73 m2; severe renal impairment: 15-29 mL/min/1.73 m2). A single dose of 2.0 mg of setmelanotide was administered subcutaneously; however, 1.0 or 0.5 mg was administered to most patients with severe renal impairment following safety review of the patient cohorts with mild and moderate renal impairment because of the potential impacts of nausea and vomiting, and consequential dehydration, on renal function. Blood samples were collected for PK analysis from hour 0 up to hour 96 after setmelanotide administration. Patients with renal impairment and healthy volunteers were matched according to sex, age, and BMI. PK parameters in individuals who received <2.0 mg setmelanotide were dose normalized for comparisons across renal function groups. Safety and tolerability were monitored and evaluated. Results In total, 32 individuals were included. Age, sex, and BMI were generally similar across cohorts. Setmelanotide PK parameters were comparable regardless of renal function (Table 1). Mean area under the concentration-time curve was higher in individuals with renal impairment compared with healthy volunteers and increased with worsening renal function. Mean clearance was lower in individuals with renal impairment compared with healthy volunteers and decreased with worsening renal function. Thirty individuals (94%) experienced a treatment-emergent adverse event (TEAE), with gastrointestinal disorders (n=22; 69%) having the highest incidence. There were no severe, serious, or fatal TEAEs and no TEAEs leading to withdrawal. There were no meaningful differences in incidence of the most common TEAEs across cohorts. Conclusion Minimal differences in PK parameters were observed in individuals with mild and moderate renal impairment compared with healthy volunteers. Findings from this study are consistent with current setmelanotide dosing recommendations, which suggest a modified dosing regimen in patients with severe renal impairment.