Obesity, Pseudohypoparathyroidism Type 1a
Conditions
Keywords
pseudohypoparathyroidism type 1a, obesity, setmelanotide
Brief summary
The investigators plan to test the efficacy and safey of 6-months of open-label setmelanotide to treat obesity in a single patient with pseudohypoparathyroidism type 1a due to a GNAS mutation.
Detailed description
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.
Interventions
DRUGSetmelanotide
Setmelanotide will be prescribed at the standard initial dose of 2 mg SC daily. The treatment will be uptitrated at the 2-Week visit to 3 mg SC daily if tolerated. We will continue this maximal dose for a period of 6 months.
Sponsors
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single patient open-label study
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Greater than or Equal to 5% Weight loss | Baseline to 6 Months | Greater than or equal to 5% weight loss from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Weight Loss | Baseline to 3 Months, Baseline to 6 Months | Percent change in weight from baseline |
| Trunk Fat Mass | Baseline to 6 Months | Trunk fat mass measured on dual-energy x-ray absorptiometry scan |
| Hemoglobin A1c | Baseline to 3 Months, Baseline to 6 Months | Hemoglobin A1c (%) measured on blood draw |
| Serum Triglycerides | Baseline to 3 Months, Baseline to 6 Months | Serum triglycerides (mg/dL) measured on blood draw |
Countries
United States
Outcome results
None listed