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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.

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