Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Patients With Moderate to Severe Obesity

• ClinicalTrials.gov Identifier: NCT03746522
• Recruitment Status: Completed
• First Posted: November 19, 2018
• Last Update Posted: July 20, 2021
• Sponsor: Rhythm Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Rhythm Pharmaceuticals, Inc.

Study Description

Brief Summary:

This pivotal, phase 3 study is designed to confirm the efficacy and safety of setmelanotide, a potent melanocortin receptor type 4 (MC4R) agonist, for the treatment of obesity and hyperphagia in patients with Bardet Biedl syndrome (BBS) or Alström syndrome (AS). The study's primary efficacy endpoint will evaluate the proportion of patients (≥12 years of age at baseline) who lose ≥10% of their baseline body weight following approximately (~) 52 weeks of treatment with setmelanotide compared to a historical control rate. The study will consist of 3 treatment periods. Eligible patients will enter a 14 week, randomized, double-blind, placebo-controlled treatment period (Period 1) that will be followed by a 38 week open label treatment period (Period 2) in which all patients will receive setmelanotide. The primary analysis will be performed after Period 2. Following Period 2, patients will continue open-label treatment for 14 weeks (Period 3) after which they may be enrolled into a separate treatment extension study.

Condition or disease	Intervention/treatment	Phase
Bardet Biedl Syndrome (BBS); Alström Syndrome (AS)	Drug: Setmelanotide; Drug: Placebos	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Patients With Moderate to Severe Obesity
• Actual Study Start Date: December 10, 2018
• Actual Primary Completion Date: November 16, 2020
• Actual Study Completion Date: March 8, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Setmelanotide; Dosage form: Subcutaneous injection Dosage: 3 mg Frequency: daily	Drug: Setmelanotide; Setmelanotide is a peptide that binds to the human MC4 receptor.; Other Name: SET
Placebo Comparator: Placebo; Dosage form: Subcutaneous injection Dosage: 3 mg equivalent volume Frequency: daily	Drug: Placebos; Matching placebo at equivalent volume to 3 mg setmelanotide.

Outcome Measures

Primary Outcome Measures :

1. Effect of Setmelanotide [ Time Frame: 52 weeks ]
   The proportion of patients (greater than or equal to 12 years of age at baseline) who achieve a greater than or equal to 10% reduction from baseline in body weight (ie, are 'responders') after ~52 weeks of treatment with setmelanotide.

Eligibility Criteria

• Ages Eligible for Study: 6 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. BBS clinical diagnosis as per Beales, 1999 (with either 4 primary features or 3 primary and 2 secondary features) Or AS diagnosis as per Marshall, 2007 (using major and minor age adjusted criteria).
2. Greater than or equal to ≥6 years of age.
3. Obese, defined as BMI ≥30 kg/m2 for patients ≥16 years of age or weight >97th percentile for age and sex on growth chart assessment for patients 6 to 15 years of age.
4. Study participant and/or parent or guardian is able to communicate well with the Investigator, to understand and comply with the requirements of the study, and is able to understand and sign the written informed consent/assent.
5. Female participants of child-bearing potential must be confirmed non-pregnant and agree to use contraception as outlined in the protocol. Female participants of non-childbearing potential, defined as: surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a screening follicle stimulating hormone (FSH) level in the post-menopausal lab range), or failure to have progressed to Tanner Stage V and/or failure to have achieved menarche, do not require contraception during the study.
6. Male participants with female partners of childbearing potential must agree to use a double barrier method contraception if they become sexually active during the study or within 90 days following their participation in the study. Male patients must also not donate sperm during and for 90 days following their participation in the study.

Exclusion Criteria:

1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents (including herbal medications) that has resulted in >2% weight loss. These patients may be reconsidered approximately 1 month after cessation of such intensive regimens.
2. Current or prior (within prior 2 months) use of any medication, including those approved to treat obesity, that could impact the efficacy results of this study (eg, orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide). Patients on a stable dose and regimen (for at least 2 months) of medication to treat attention deficit hyperactivity disorder (ADHD) may be enrolled in the study as long as they agree to remain on the same dose and regimen during the study.
3. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain. Specifically, patients may be considered if surgery was not successful, resulted in <10% weight loss compared to pre-operative baseline weight, or there is clear evidence of weight regain after an initial response to bariatric surgery. All patients with a history of bariatric surgery must be discussed with, and receive approval from, the Sponsor prior to enrollment.
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-V) disorders that the Investigator believes will interfere significantly with study compliance. Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an appropriate guardian able to give consent has been appointed.

5. In patients with no significant neurocognitive deficits:

   • A PHQ-9 score of ≥15 and/or
   • Any suicidal ideation of type 4 or 5 on the C-SSRS, any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
7. History of significant liver disease or liver injury, or a current liver assessment due to abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin >1.5x the upper limit of normal [ULN] for any of these tests) for an etiology other than non-alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis is exclusionary, but the presence of NAFLD is not be exclusionary.
8. Moderate to severe renal dysfunction defined as <30 mL/min (Appendix 11.6).
9. History or close family history (parents or siblings) of skin cancer or melanoma (excluding non-invasive basal or squamous cell lesion), or patient history of ocular-cutaneous albinism.
10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of comprehensive skin evaluation performed by a qualified dermatologist during screening. Any concerning lesions identified during the screening period will be biopsied and results must be known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient should be excluded from the study.
11. Patient is, in the opinion of the Study Investigator, not suitable to participate in the study.
12. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
13. Significant hypersensitivity to study drug.
14. Inability to comply with QD injection regimen.

Contacts and Locations

Locations

United States, California

Wr-McCr, Llc

San Diego, California, United States, 92108

United States, Massachusetts

UMMS Baystate Health; BAYSTATE MEDICAL CENTER; Baystate Children's Specialty Center

Springfield, Massachusetts, United States, 01199

United States, New York

Columbia University Center

New York, New York, United States, 10032

United States, North Carolina

M3 Wake Research

Raleigh, North Carolina, United States, 27612

United States, Tennessee

University of Tennessee Health Science Center

Memphis, Tennessee, United States, 38103

United States, Wisconsin

Marshfield Clinic Research Foundation

Marshfield, Wisconsin, United States, 54449

Canada, Alberta

Alberta Health Services

Edmonton, Alberta, Canada, T6G 2E1

France

Sorbonne University Pitié-Salpêtrière Hospital

Paris, France, 75013

Hôpital Civil

Strasbourg, France, 67091

Puerto Rico

UPR Medical Sciences Campus

Rio Piedras, Puerto Rico, 00935

Spain

Universidad Autónoma de Madrid University Hospital Niño

Madrid, Spain, 28009

United Kingdom

St. Thomas Hospital

London, United Kingdom, SE1 7EH

Sponsors and Collaborators

Rhythm Pharmaceuticals, Inc.

Investigators

• Study Chair: Murray Stewart, MD; Rhythm Pharmceuticals, Inc

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Haqq AM, Chung WK, Dollfus H, Haws RM, Martos-Moreno GA, Poitou C, Yanovski JA, Mittleman RS, Yuan G, Forsythe E, Clement K, Argente J. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022 Dec;10(12):859-868. doi: 10.1016/S2213-8587(22)00277-7. Epub 2022 Nov 7. Erratum In: Lancet Diabetes Endocrinol. 2023 Feb;11(2):e2.

Haws RM, Gordon G, Han JC, Yanovski JA, Yuan G, Stewart MW. The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alstrom syndrome: Phase 3 trial design. Contemp Clin Trials Commun. 2021 May 3;22:100780. doi: 10.1016/j.conctc.2021.100780. eCollection 2021 Jun.

• Responsible Party: Rhythm Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03746522
• Other Study ID Numbers: RM-493-023
• First Posted: November 19, 2018
• Last Update Posted: July 20, 2021
• Last Verified: July 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rhythm Pharmaceuticals, Inc.:

MC4R Pathway; Obesity; BBS; AS

Additional relevant MeSH terms:

Bardet-Biedl Syndrome; Laurence-Moon Syndrome; Alstrom Syndrome; Obesity; Obesity, Morbid; Syndrome; Disease; Pathologic Processes; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Retinitis Pigmentosa; Eye Diseases, Hereditary; Eye Diseases; Ciliopathies; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn; Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases