Effectiveness and Safety of Setmelanotide in a Patient With a Heterozygous PCSK1 Deficiency

Setmelanotide, a melanocortin 4 receptor (MC4R) agonist, is a promising pharmacological treatment option for people with rare monogenic obesity conditions affecting the leptin-melanocortin signaling pathway, including proprotein convertase subtilisin/kexin type 1 (PCSK1) gene mutations. It has been studied in people with homozygous mutations causing a complete deficiency of PCSK1. We report the first case of a 40-year-old female with a heterozygous PCSK1 N221D (c.661 A>G) variant mutation leading to severe early-onset treatment-resistant obesity with previous suboptimal response to bariatric surgery and conventional obesity medications, who achieved a total weight loss of 11.8% with setmelanotide treatment over the course of 3 months. Although her mutation confers a loss of 10% to 30% enzymatic function in in vitro studies, setmelanotide was highly effective in treating her obesity. It is also the first reported case of a cutaneous adverse effect of setmelanotide in the form of severe skin hyperpigmentation in a patient with a pathogenic PCSK1 variant. This case underscores the effectiveness and safety of setmelanotide in a heterozygous PCSK1 mutation.