A natural history study of patients with POMC or LEPR deficiency and medical histories collected during a Phase 2 trial of setmelanotide in patients with HO revealed that 1 of 8 patients with LEPR deficiency and 2 of 18 with HO had previously tried unsuccessfully to lose weight with metformin, and hyperphagia change with metformin was not reported [53, 71]. This evidence concerns the gene LEPR and obesity due to leptin receptor gene deficiency.