Timing of Onset of Adverse Events With Setmelanotide, an MC4R Agonist, in Patients With Severe Obesity Due to LEPR or POMC Deficiency

Introduction: Setmelanotide is a melanocortin 4 receptor agonist indicated for chronic weight management in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. This analysis aimed to assess the timing of the onset of adverse events (AEs) of special interest in patients with POMC/PCSK1 or LEPR deficiency obesity treated with setmelanotide. Methods: The timing of AE onset with setmelanotide was evaluated in a pooled set of patients with POMC/PCSK1 or LEPR deficiency who received setmelanotide in Phase 2 (RM-493-011 [NCT02507492]) or Phase 3 (RM-493-012 [NCT02896192] and RM-493-015 [NCT03287960]) clinical trials. Patients in the Phase 2 investigator-initiated trial (Charité Universitätsmedizin Berlin) received open-label setmelanotide for 12 to 13 weeks followed by an extension study for eligible patients. The Phase 3 trials included a 12-week open-label phase, an 8-week placebo-controlled phase, and a subsequent 32-week open-label phase, for a total treatment length of at least 1 year. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). AEs of special interest were defined as those related to treatment-emergent AEs (TEAEs) commonly occurring with setmelanotide (hyperpigmentation disorders, disturbances in sexual arousal, nausea, vomiting, injection site reactions [ISRs]). Results: As of November 10, 2020, 35 patients (15 POMC, 2 PCSK1, 18 LEPR) were enrolled and included across the 3 trials; 2 patients in the Phase 2 trial were ongoing treatment as of the cutoff. Daily setmelanotide dose ranged from 0.25 to 3.0 mg. All patients experienced ≥1 TEAE, the most common being skin hyperpigmentation (85.7%), injection site erythema (68.6%), nausea (57.1%), and headache (51.4%). For AEs of special interest, hyperpigmentation disorders occurred in 85.7% of patients (30/35), disturbances in sexual arousal in 17.1% (6/35), nausea in 57.1% (20/35), vomiting in 28.6% (10/35), and ISRs in 88.6% (31/35). The onset of most hyperpigmentation disorder (34/53 events; 64.2%) and disturbances in sexual arousal (6/11 events; 54.6%) AEs were during Month 1 after starting setmelanotide. Onset of nausea and vomiting were most frequent during Month 1 of treatment (nausea: 12/34 events [35.3%]; vomiting: 6/19 events [31.6%]). ISRs occurred throughout the trial, with 41.6% (91/219 events) having an onset within Month 1 of treatment. Eighteen serious AEs occurred, none were interpreted as related to the study drug. Conclusions: In patients with POMC/PCSK1 or LEPR deficiency obesity who received setmelanotide treatment, the onset of AEs of special interest in any month was generally highest during Month 1 of treatment, with fewer events occurring during subsequent months. Apart from hyperpigmentation, all AEs occurred intermittently.