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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Pseudohypoparathyroidism Type 1a
• Intervention / Treatment: Drug: Setmelanotide

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.

• Study Type: Interventional
• Enrollment (Estimated): 1
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lindsay T. Fourman, MD; Phone Number: 617-643-4590; Email: lfourman@mgb.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
      • Contact: Lindsay T. Fourman, MD; Phone Number: 6176434590; Email: lfourman@mgb.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Patient with pseudohypoparathyroidism type 1a; A preselected patient with obesity related to pseudohypoparathyroidism type 1a.	Drug: Setmelanotide; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Greater than or Equal to 5% Weight loss	Greater than or equal to 5% weight loss from baseline	Baseline to 6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Weight Loss	Percent change in weight from baseline	Baseline to 3 Months, Baseline to 6 Months
Trunk Fat Mass	Trunk fat mass measured on dual-energy x-ray absorptiometry scan	Baseline to 6 Months
Hemoglobin A1c	Hemoglobin A1c (%) measured on blood draw	Baseline to 3 Months, Baseline to 6 Months
Serum Triglycerides	Serum triglycerides (mg/dL) measured on blood draw	Baseline to 3 Months, Baseline to 6 Months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Daily Calorie Intake	Average total daily calorie intake as measured by four-day food record	Baseline to 3 Months, Baseline to 6 Months
Daily Step Count	Average step count per day as measured by FitBit	Baseline to 3 Months, Baseline to 6 Months
Eating Behaviors	Three-Factor Eating Questionnaire, scored from 0 to 100 with higher scores indicating greater levels of select eating behaviors	Baseline to 3 Months, Baseline to 6 Months
Quality of Life	36-Item Short Form Health Survey (SF-36), scored from 0 to 100 with higher indicating better	Baseline to 3 Months, Baseline to 6 Months
Daytime Sleepiness	Epworth Sleepiness Scale, scored from 0 to 24 with higher scores indicating greater daytime sleepiness	Baseline to 3 Months, Baseline to 6 Months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: March 22, 2026
• First Submitted That Met QC Criteria: March 22, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): April 1, 2026
• Last Update Submitted That Met QC Criteria: March 26, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: obesity; setmelanotide; pseudohypoparathyroidism type 1a
• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Nutrition Disorders; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Overnutrition; Body Weight; Bone Diseases, Metabolic; Overweight; Metal Metabolism, Inborn Errors; Calcium Metabolism Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Pseudohypoparathyroidism; setmelanotide
• Other Study ID Numbers: 2026P000332

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data and biospecimens may be shared.
• IPD Sharing Time Frame: IPD and supporting information will be available upon completion of the study for at least 3 years.
• IPD Sharing Access Criteria: IPD and supporting information may be requested from the study PI. Each request will be considered on a case-by-case basis and granted if appropriately justified.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No