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

NCT03746522 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: RM-493-0232018-004058-11
• Study Type: interventional
• Target: 52
• Locations: 6 countries
• Sites: 12

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 participants with Bardet Biedl syndrome (BBS) or Alström syndrome (AS). The study's primary efficacy endpoint is to evaluate the proportion of participants (≥ 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.

Conditions

Bardet Biedl Syndrome (BBS); Alström Syndrome (AS)

Keywords

MC4R Pathway; Obesity; BBS; AS

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants (≥12 Years of Age at Baseline) Who Reached ≥10% Weight Loss Threshold After 1 Year (Period 2): Pivotal Cohort

  The percentage of participants (≥12 years of age at baseline) who achieved a ≥10% reduction from baseline in body weight at Period 2 or after 52 weeks of treatment with setmelanotide were analyzed. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of the placebo-controlled period, all participants from the placebo group switched to setmelanotide treatment. The placebo group was integrated into the 52-week analysis so that the participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of "active" treatment. Placebo participants were also included in this analysis.

  52 weeks

Secondary Outcomes (3)

• Mean Percent Change From Baseline in Body Weight (≥12 Years of Age) at Week 52 (Period 2): Pivotal Cohort

  Baseline, Week 52

• Mean Percent Change From Baseline in the Weekly Average of the Daily Hunger Score (≥12 Years of Age) at Week 52 (Period 2): Pivotal Cohort

  Baseline, Week 52

• Number of Participants (≥12 Years of Age With no Cognitive Impairment) Who Achieved a ≥ 25% Improvement in the Weekly Average of the Daily Hunger Score From Baseline at Week 52 (Period 2): Pivotal Cohort

  Baseline, Week 52

Study Arms (3)

Setmelanotide (Double-Blind)

EXPERIMENTAL

Participants received once daily SC injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). Participants ≥16 years of age started on setmelanotide 2.0 mg with dose escalation to 3.0 mg. Participants \<16 years of age started on setmelanotide 1.0 mg with dose escalation to 3.0 mg.

Drug: Setmelanotide

Placebo (Double-Blind)

PLACEBO COMPARATOR

Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1).

Drug: Placebo

Setmelanotide (Open-label)

EXPERIMENTAL

After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).

Drug: Setmelanotide

Interventions

Setmelanotide DRUG

SC injection of setmelanotide

Also known as: SET, RM-493

Setmelanotide (Double-Blind); Setmelanotide (Open-label)

Placebo DRUG

SC injection of placebo

Placebo (Double-Blind)

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• BBS clinical diagnosis or AS diagnosis
• Greater than or equal to (≥) 6 years of age.
• Obese, defined as BMI ≥30 kilograms/meters\^2 for participants ≥16 years of age or weight \>97th percentile for age and sex on growth chart assessment for participants 6 to 15 years of age.
• 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.
• 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.
• 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 participants must also not donate sperm during and for 90 days following their participation in the study.

You may not qualify if:

• 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 participants may be reconsidered approximately 1 month after cessation of such intensive regimens.
• 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 (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide). Participants 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.
• Prior gastric bypass surgery resulting in \>10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain. Specifically, participants 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 participants with a history of bariatric surgery must be discussed with, and receive approval from, the Sponsor prior to enrollment.
• 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.
• In participants with no significant neurocognitive deficits:
• A Patient Health Questionnaire-9 (PHQ-9) score of ≥15 and/or
• Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS), any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
• Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any participant with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
• Moderate to severe renal dysfunction defined as \<30 mL/min.
• History or close family history (parents or siblings) of skin cancer or melanoma (excluding non-invasive basal or squamous cell lesion), or participant history of ocular-cutaneous albinism.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion).
• Participant is, in the opinion of the Study Investigator, not suitable to participate in the study.
• Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
• Significant hypersensitivity to study drug.
• Inability to comply with once daily (QD) injection regimen.

Sponsors & Collaborators

• Rhythm Pharmaceuticals, Inc.: lead

Study Sites (12)

Wr-McCr, Llc

San Diego, California, 92108, United States

Location

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

Springfield, Massachusetts, 01199, United States

Location

Columbia University Center

New York, New York, 10032, United States

Location

M3 Wake Research

Raleigh, North Carolina, 27612, United States

Location

University of Tennessee Health Science Center

Memphis, Tennessee, 38103, United States

Location

Marshfield Clinic Research Foundation

Marshfield, Wisconsin, 54449, United States

Location

Alberta Health Services

Edmonton, Alberta, T6G 2E1, Canada

Location

Sorbonne University, Hôpital de la Pitié-Salpêtrière

Paris, 75013, France

Location

Centre Hospitalier Universitaire de Strasbourg

Strasbourg, 67091, France

Location

UPR Medical Sciences Campus

Rio Piedras, 00935, Puerto Rico

Location

Universidad Autónoma de Madrid University Hospital Niño

Madrid, 28009, Spain

Location

St. Thomas Hospital

London, SE1 7EH, United Kingdom

Location

Related Publications (4)

• Ervin C, Norcross L, Mallya UG, Fehnel S, Mittleman RS, Webster M, Haqq AM, Haws RM. Interview-Based Patient- and Caregiver-Reported Experiences of Hunger and Improved Quality of Life with Setmelanotide Treatment in Bardet-Biedl Syndrome. Adv Ther. 2023 May;40(5):2394-2411. doi: 10.1007/s12325-023-02443-y. Epub 2023 Mar 24.

  PMID: 36961653 DERIVED

• Forsythe E, Haws RM, Argente J, Beales P, Martos-Moreno GA, Dollfus H, Chirila C, Gnanasakthy A, Buckley BC, Mallya UG, Clement K, Haqq AM. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results. Orphanet J Rare Dis. 2023 Jan 16;18(1):12. doi: 10.1186/s13023-022-02602-4.

  PMID: 36647077 DERIVED

• 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.

  PMID: 36356613 DERIVED

• 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.

  PMID: 34013094 DERIVED

MeSH Terms

Conditions

Bardet-Biedl Syndrome; Alstrom Syndrome; Obesity

Interventions

setmelanotide

Condition Hierarchy (Ancestors)

Hypothalamic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Retinitis Pigmentosa; Eye Diseases, Hereditary; Eye Diseases; Ciliopathies; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and 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; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Rhythm Clinical Trials
• Organization: Rhythm Pharmaceuticals, Inc.

clinicaltrials@rhythmtx.com

857-264-4280

Study Officials

• David Meeker, MD

  Rhythm Pharmaceuticals, Inc.

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2018
• First Posted: November 19, 2018
• Study Start: November 23, 2018
• Primary Completion: November 16, 2020
• Study Completion: March 8, 2021
• Last Updated: December 1, 2023
• Results First Posted: December 1, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1); PR (1); CA (1); FR (2); GB (1); US (6)