NCT03746522

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

Completed Phase 3 Results posted Last updated 1 December 2023

What this trial tests

Phase 3 trial testing Setmelanotide in Bardet Biedl Syndrome (BBS) in 52 participants. Completed in 8 March 2021.

Timeline

23 November 2018

Primary endpoint
16 November 2020

8 March 2021

Quick facts

Lead sponsor	Rhythm Pharmaceuticals, Inc.
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	52
Start date	23 November 2018
Primary completion	16 November 2020
Estimated completion	8 March 2021
Sites	12 locations across France, United Kingdom, Canada, Puerto Rico, United States, Spain

Drugs / interventions tested

• Setmelanotide (SETMELANOTIDE) — full drug profile →
• Placebo

Conditions studied

• Bardet Biedl Syndrome (BBS) — all drugs for Bardet Biedl Syndrome (BBS) →
• Alström Syndrome (AS) — all drugs for Alström Syndrome (AS) →

Sponsor

Rhythm Pharmaceuticals, Inc. — full company profile →

Who can join

6 and older, any sex, with Bardet Biedl Syndrome (BBS) or Alström Syndrome (AS). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants (≥12 Years of Age at Baseline) Who Reached ≥10% Weight Loss Threshold After 1 Year (Period 2): Pivotal Cohort Primary · 52 weeks

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

Group	Value	95% CI
Pivotal Cohort	32.3	16.7 – 51.4

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

The mean percent change from baseline in body weight at 52 weeks was 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.

Group	Value	95% CI
Pivotal Cohort	-5.21	± 7.895

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 Secondary · Baseline, Week 52

Mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0= "not hungry at all" to 10= "hungriest possible" on Likert-type scale. On Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on weekly basis. Weekly average hunger score of daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. There was a 14-week placebo-controlled period a

Group	Value	95% CI
Pivotal Cohort	-30.91	± 24.733

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 Secondary · Baseline, Week 52

Number of participants (≥12 years of age with no cognitive impairment) achieving ≥25% improvement from baseline in hunger score at Week 52 was assessed. Hunger score ranged from 0= "not hungry at all" to 10= "hungriest possible" on Likert-type scale. On Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on weekly basis. Weekly average hunger score of daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. There was a 14-week placebo-controlled period at the beginn

Group	Value	95% CI
Pivotal Cohort	10

Adverse events — posted to ClinicalTrials.gov

Time frame: Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Setmelanotide (Double-Blind Period)

Serious: 1/27 (4%)

Deaths: 0/27

Placebo (Double-Blind Period)

Serious: 2/25 (8%)

Deaths: 0/25

Setmelanotide (Open-label)

Serious: 0/50 (0%)

Deaths: 0/50

Serious adverse events (4 terms)

Reaction	System	Setmelanotide (Double-Blin…	Placebo (Double-Blind Peri…	Setmelanotide (Open-label)
Anaemia	Blood and lymphatic system disorders	—	—	—
Blindness	Eye disorders	—	—	—
Anaphylactic reaction	Immune system disorders	—	—	—
Suicidal ideation	Psychiatric disorders	—	—	—

Other adverse events (30 terms — click to expand)

Reaction	System	Setmelanotide (Double-Blin…	Placebo (Double-Blind Peri…	Setmelanotide (Open-label)
Skin hyperpigmentation	Skin and subcutaneous tissue disorders	—	—	—
Injection site erythema	General disorders	—	—	—
Injection site pruritus	General disorders	—	—	—
Injection site bruising	General disorders	—	—	—
Injection site pain	General disorders	—	—	—
Nausea	Gastrointestinal disorders	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—
Headache	Nervous system disorders	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—
Injection site induration	General disorders	—	—	—
Melanocytic naevus	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—
High density lipoprotein decreased	Investigations	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—
Spontaneous penile erection	Reproductive system and breast disorders	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—	—
Fatigue	General disorders	—	—	—
Injection site haemorrhage	General disorders	—	—	—
Injection site oedema	General disorders	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	—	—	—
Dizziness	Nervous system disorders	—	—	—
Injection site reaction	General disorders	—	—	—
Dermatitis atopic	Skin and subcutaneous tissue disorders	—	—	—
Dry skin	Skin and subcutaneous tissue disorders	—	—	—
Glucose tolerance impaired	Metabolism and nutrition disorders	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—
Pharyngitis streptococcal	Infections and infestations	—	—	—

Most-reported serious reactions: Anaemia, Blindness, Anaphylactic reaction, Suicidal ideation.

Data from ClinicalTrials.gov NCT03746522 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alström syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period.
   Haqq AM, Chung WK, Dollfus H, Haws RM, et al · · 2022 · cited 122× · PMID 36356613 · DOI 10.1016/s2213-8587(22)00277-7
2. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.
   Haws R, Brady S, Davis E, Fletty K, et al · · 2020 · cited 102× · PMID 32627316 · DOI 10.1111/dom.14133
3. Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please.
   Smith CEL, Lake AVR, Johnson CA. · · 2020 · cited 82× · PMID 33392209 · DOI 10.3389/fcell.2020.622822
4. Cilia signaling and obesity.
   Engle SE, Bansal R, Antonellis PJ, Berbari NF. · · 2021 · cited 56× · PMID 32466971 · DOI 10.1016/j.semcdb.2020.05.006
5. Bardet-Biedl syndrome: Weight patterns and genetics in a rare obesity syndrome.
   Pomeroy J, Krentz AD, Richardson JG, Berg RL, et al · · 2021 · cited 54× · PMID 32700463 · DOI 10.1111/ijpo.12703
6. Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice?
   Ryan DH. · · 2021 · cited 38× · PMID 34518444 · DOI 10.7570/jomes21033
7. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results.
   Forsythe E, Haws RM, Argente J, Beales P, et al · · 2023 · cited 32× · PMID 36647077 · DOI 10.1186/s13023-022-02602-4
8. The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design.
   Haws RM, Gordon G, Han JC, Yanovski JA, et al · · 2021 · cited 31× · PMID 34013094 · DOI 10.1016/j.conctc.2021.100780