Setmelanotide to Treat Obesity in a Patient With Pseudohypoparathyroidism Type 1a (PHP1a)

Pseudohypoparathyroidism type 1A (PHP1a) is a rare genetic disorder caused by impaired G-protein signaling due to heterozygous mutations in the gene GNAS. Multiple abnormalities may result including hypocalcemia, hypothyroidism, hypogonadism, and developmental delay. Obesity also commonly occurs due to impaired signaling through the melanocortin-4 receptor (MC4R). The melanocortin-4 receptor agonist setmelanotide has been proposed as a potential yet untested treatment strategy for patients with pathogenic GNAS variants.

In the current study, the investigators plan to test effects of setmelanotide on body weight, body composition, and metabolic parameters in a single patient with PHP1a. GNAS is a paternally imprinted gene, and thus PHP1a results primarily when a mutation is inherited on the preferentially expressed maternal allele. However, detailed studies have shown that 1) GNAS is not imprinted in all areas of the brain, and 2) in regions where imprinting does occur, it is incomplete (e.g., low levels of paternally inherited protein remain expressed). As such, the investigators hypothesize that setmelanotide will augment MC4R signaling by maximally stimulating low levels of intact, paternally inherited GNAS in patients with PHP1a and milder GNAS disorders.

This project stands to identify a novel patient population with rare monogenic obesity who may benefit from setmelanotide therapy and who is classically resistant to mainstream obesity medications. Evidence of clinical benefit in this single patient would serve as proof of concept for a larger scale clinical study of patients with PHP1a and GNAS mutations.

Inclusion criteria

• Known patient with PHP1a (confirmed GNAS mutation)
• Optimized therapy for diabetes and dyslipidemia

Exclusion criteria

• Use of medications that may affect endpoints that are changed within 3 months prior to Baseline or that are likely to require a change in dose during the open-label treatment period