Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity

NCT03287960 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: RM-493-0152017-002005-36
• Study Type: interventional
• Target: 15
• Locations: 6 countries
• Sites: 6

Brief Summary

To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.

Conditions

Leptin Receptor Deficiency Obesity

Keywords

LEPR deficiency obesity; setmelanotide; RM-493; Leptin receptor; Obesity; Melanocortin 4 receptor

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)

  The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (\~1 year) of treatment were analyzed.

  Week 52

Secondary Outcomes (9)

• Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)

  Week 52

• Mean Percent Change From Baseline in Body Weight

  Baseline and Week 52

• Mean Percent Change From Baseline in Hunger Score ('Most Hunger')

  Baseline and Week 52

• Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline

  Baseline and Week 52

• Absolute Change From Baseline in Waist Circumference

  Baseline and Week 52

Study Arms (1)

Setmelanotide

EXPERIMENTAL

Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was \<100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (\~1 year) of treatment at a therapeutic dose.

Drug: Setmelanotide; Drug: Placebo

Interventions

Setmelanotide DRUG

Once daily subcutaneous injection

Also known as: RM-493

Setmelanotide

Placebo DRUG

Once daily subcutaneous injection

Setmelanotide

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:

• Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic status for the LEPR gene, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype.
• Age 6 years and above. 6+: Germany, Netherlands, UK. 12+: France
• If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kilograms per meters squared (kg/m\^2); if child or adolescent (\< 18 years of age), obesity with weight \> 97th percentile for age on growth chart assessment.
• 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, after being informed about the study.
• Female participants of child-bearing potential must 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 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 a double barrier method if they become sexually active during the study. Male participants must 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 weight loss or weight stabilization.
• Prior gastric bypass surgery resulting in \>10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain.
• Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes will interfere significantly with study compliance.
• A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
• 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, severe stable restrictive or obstructive lung disease arising because of extreme obesity, evidence of significant heart failure (New York Heart Association \[NYHA\] Class 3 or greater), or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results.
• History of significant liver disease or liver injury, or current liver assessment for a cause of abnormal liver tests \[as indicated by abnormal liver function tests, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or serum bilirubin (\> 2.0 x upper limit of normal (ULN) for any of these tests)\] for an etiology other than non-alcoholic fatty liver disease (NAFLD).
• History or presence of impaired renal function as indicated by clinically significant abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft Gault equation \< 30 milliliter/minute (mL/min).
• History or close family history (parents or siblings) of skin cancer or melanoma, or participant history of ocular-cutaneous albinism.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions, determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist.
• Volunteer 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 every day (QD) injection regimen.
• Participants who have been placed in an institution through an official or court order, as well as those who are dependent on the sponsor, Investigator or study site.

Sponsors & Collaborators

• Rhythm Pharmaceuticals, Inc.: lead

Study Sites (6)

Markham Stouffville Hospital

Markham, Ontario, L3P 7P3, Canada

Location

Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital

Paris, 75013, France

Location

University of Ulm

Ulm, Germany

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

Hôpital Félix GUYON

Saint-Denis, 97405, Reunion

Location

University of Cambridge Metabolic Research Laboratories

Cambridge, CB2 0QQ, United Kingdom

Location

Related Publications (1)

• Clement K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kuhnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020 Dec;8(12):960-970. doi: 10.1016/S2213-8587(20)30364-8. Epub 2020 Oct 30.

  PMID: 33137293 DERIVED

MeSH Terms

Conditions

Obesity

Interventions

setmelanotide

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

Based on meetings with the Federal Drug Administration (FDA), the structure of the endpoints was slightly different in the statistical analysis plan (SAP) and the protocol. In addition, there was no planned comparison to a randomized placebo group given the rarity of monogenic LEPR deficiency obesity.

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: NA
• Masking: NONE
• Masking Details: During the 8 week double-blind placebo-controlled withdrawal period, participants received 4 weeks of daily setmelanotide and 4 weeks of daily placebo. Participants, investigators, and sites remained blinded as to when placebo treatment was administered.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period

Study Record Dates

• First Submitted: September 14, 2017
• First Posted: September 19, 2017
• Study Start: January 30, 2018
• Primary Completion: September 25, 2020
• Study Completion: September 25, 2020
• Last Updated: May 23, 2023
• Results First Posted: May 23, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); CA (1); DE (1); RE (1); GB (1); FR (1)