Clinical Trial Results:
Title: A 2-Stage (Open-Label Run-in followed by Randomized Withdrawal), Double-Blind, Placebo-Controlled, Phase 2 study of Setmelanotide in Patients with Specific Gene Defects in the Melanocortin-4 Receptor Pathway Trial design: This was a 2-stage, Phase 2 study of setmelanotide in patients with obesity with specific gene variants in the melanocortin 4 receptor (MC4R) pathway, with a 16-week open-label treatment stage followed by a 24-week randomized, double-blind, placebo-controlled stage. The primary objective was to evaluate the proportion of patients who achieved a clinically meaningful reduction in body weight in response to setmelanotide at the end of open-label treatment. During Stage 1, setmelanotide was administered subcutaneously once daily (QD). For patients >=12 years of age, the starting dose of setmelanotide was 2 mg QD for approximately 2 weeks then increased to 3 mg QD. For patients 6 to <12 years of age, the starting dose was 1 mg QD for approximately 1 week, increased to 2 mg QD for approximately 1 week, and then increased to 3 mg QD. To be eligible to enter Stage 2 of the study, a patient aged >=18 years had to achieve a body mass index (BMI) at least 3% less than at baseline at the end of Stage 1. A patient <18 years old had to achieve a BMI at least 3% less than at baseline or a decrease in BMI Z-score of at least 0.05 at the end of Stage 1. All patients eligible for Stage 2 were randomized 2:1 to either continue setmelanotide or receive matching placebo. Overall 164 patients were treated with study drug in Stage 1, with a mean duration of treatment of 86 days (range: 1 to 140 days). In Stage 2, a total of 49 patients received study drug with a mean duration of treatment of 140.6 days (range: 9 to 197 days).

Trial information Top of page
Trial identification
Sponsor protocol code	RM-493-034
Additional study identifiers
ISRCTN number	-
US NCT number	NCT04963231
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Rhythm Pharmaceuticals, Inc
Sponsor organisation address	222 Berkeley Street, 12th Floor, Boston, United States, MA 02116
Public contact	Rhythm Clinical Trials, Rhythm Pharmaceuticals Inc., +1 857 264 4280, clinicaltrials@rhythmtx.com
Scientific contact	Rhythm Clinical Trials, Rhythm Pharmaceuticals Inc., +1 857 264 4280, clinicaltrials@rhythmtx.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	Yes
EMA paediatric investigation plan number(s)	EMEA-002209-PIP01-17
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	30 Jul 2024
Is this the analysis of the primary completion data?	Yes
Primary completion date	14 Feb 2024
Global end of trial reached?	Yes
Global end of trial date	30 Sep 2024
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the proportion of obese patients with genetic defects in the melanocortin-4 receptor (MC4R) pathway who achieve a clinically meaningful reduction in body weight in response to setmelanotide after an initial response to open-label treatment.
Protection of trial subjects	The Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) reviewed all appropriate study documentation in order to safeguard the rights, safety, and well-being of the patients. The study was only conducted at sites where IRB/IEC approval had been obtained. This study was conducted in accordance with: • Consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines • The International Council for Harmonisation (ICH) Good Clinical Practices (GCP) Guideline [E6] • Applicable laws and regulatory requirements. After the study had been fully explained, written informed consent/assent was obtained from either the patient or his/her guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent complied with ICH-GCP and all applicable regulatory requirement(s).
Background therapy	Medication that was considered necessary for the patient’s safety and wellbeing was given during the study at the discretion of the treating physician after discussion with the Medical Monitor. All concomitant medications were kept at a stable dose throughout the course of the study, unless a dose change was necessary due to an AE. Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the patient was receiving at the time of enrolment or received during the study was recorded along with the: • Reason for use • Dates of administration including start and end dates • Dosage information including dose and frequency GLP 1 receptor agonists and anti-obesity medications were permitted as long as: • the regimen and/or dose had been stable for at least 3 months prior to randomization • the patient had not experienced weight loss ≥2% during the previous 3 months, AND • the patient intended to keep the regimen and/or dose stable throughout the course of the study. The Sponsor was contacted if there were any questions regarding concomitant or prior therapy.
Evidence for comparator	-
Actual start date of recruitment	29 Nov 2021
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	United States: 100
Country: Number of subjects enrolled	Germany: 30
Country: Number of subjects enrolled	Greece: 10
Country: Number of subjects enrolled	Israel: 10
Country: Number of subjects enrolled	Netherlands: 5
Country: Number of subjects enrolled	Spain: 5
Country: Number of subjects enrolled	United Kingdom: 3
Country: Number of subjects enrolled	Canada: 1
Worldwide total number of subjects	164
EEA total number of subjects	50
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	23
Adolescents (12-17 years)	32
Adults (18-64 years)	109
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	164 patients with rare genetic disorders of obesity (RGDO) were recruited in Canada, Europe, Israel, and the USA from 29 Nov 2021 (first dose 13 Jan 2022). Patients were between 6 - 65 years with a genetically confirmed variant in an established MC4R pathway gene contributing to obesity. The last patient last visit for the analysis was 14 Feb 2024.
Pre-assignment
Screening details	Screening assessments included medical history, physical exam, comprehensive skin examination, laboratory tests, blood pressure, hunger scale, body composition, Columbia-Suicide Severity Rating Scale (C-SSRS) form, and energy expenditure evaluation.
Period 1
Period 1 title	Stage 1 - Open Label
Is this the baseline period?	Yes
Allocation method	Not applicable
Blinding used	Not blinded
Blinding implementation details	Not applicable; Stage 1 was open-label.
Arms
Arm title	Stage 1 - Setmelanotide
Arm description	This was a 16 week open-label treatment stage in which all patients with RGDO were treated with setmelanotide.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	For patients 12 years or older, the starting dose was 2 mg QD for approximately 2 weeks after which it was increased to 3 mg QD. Dose escalation occurred at the study visit planned for Day 14 (±3 days) and occurred on the day of that visit. If the starting dose was not tolerated, the dose was reduced to 1 mg QD, which was the lowest target dose in patients ≥12 years of age; however, in consultation with the medical monitor, the dose could be lowered to 0.5 mg QD if not tolerated. For patients 6 to <12 years old, the starting dose was 1 mg QD for approximately 1 week, then increased to 2 mg QD for approximately 1 week, and then increased to 3 mg QD. Dose escalation occurred during the phone call planned for Day 7 (±2 days) and on the day of the study visit planned for Day 14 (±3 days). If the starting dose was not tolerated, the dose was reduced to 0.5 mg QD, the lowest target dose in patients 6 - 12 years old. All study patients received study drug by SC injection QD.
Number of subjects in period 1 Stage 1 - Setmelanotide Started 164 Completed 100 Not completed 64      Consent withdrawn by subject 16      Adverse event, non-fatal 43      Lost to follow-up 2      Protocol deviation 3
Period 2
Period 2 title	Stage 2
Is this the baseline period?	No
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Carer
Blinding implementation details	Stage 1 of the trial is open-label. Patients who are eligible to enter Stage 2 of the trial will be randomized in a blinded manner at the Stage 2 Entry Visit in a 2:1 ratio to receive either setmelanotide (2) or placebo (1). Stratification by gene cohort occurred for specific genes being enrolled into this trial.
Arms
Are arms mutually exclusive	Yes
Arm title	Placebo
Arm description	Eligible patients who entered Stage 2 continued in the study for an additional 24 weeks. Eligible patients were randomized 2:1 to either continue QD setmelanotide or receive matching placebo. Patients in this arm received placebo.
Arm type	Placebo
Investigational medicinal product name	Placebo
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	All study patients received study drug by SC injection QD (administered in the morning).
Arm title	Setmelanotide
Arm description	Eligible patients who entered Stage 2 continued in the study for an additional 24 weeks. Eligible patients were randomized 2:1 to either continue QD setmelanotide or receive matching placebo. Patients in this arm received QD setmelanotide.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	For patients 12 years or older, the starting dose was 2 mg QD for approximately 2 weeks after which it was increased to 3 mg QD. Dose escalation occurred at the study visit planned for Day 14 (±3 days) and occurred on the day of that visit. If the starting dose was not tolerated, the dose was reduced to 1 mg QD, which was the lowest target dose in patients ≥12 years of age; however, in consultation with the medical monitor, the dose could be lowered to 0.5 mg QD if not tolerated. For patients 6 to <12 years old, the starting dose was 1 mg QD for approximately 1 week, then increased to 2 mg QD for approximately 1 week, and then increased to 3 mg QD. Dose escalation occurred during the phone call planned for Day 7 (±2 days) and on the day of the study visit planned for Day 14 (±3 days). If the starting dose was not tolerated, the dose was reduced to 0.5 mg QD, the lowest target dose in patients 6 - 12 years old. All study patients received study drug by SC injection QD.
Number of subjects in period 2 [1] Placebo Setmelanotide Started 17 32 Completed 10 29 Not completed 7 3      Other than specified above - 1      Consent withdrawn by subject 2 2      Other than reasons specified above 4 -      Adverse event, non-fatal 1 -
Notes [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period. Justification: Eligibility for participation in Stage 2 was dependent on achieving a pre-specified reduction in BMI or BMI Z-score at the end of Stage 1.

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Stage 1 - Open Label
Reporting group description	-
Reporting group values Stage 1 - Open Label Total Number of subjects 164 164 Age categorical Units: Subjects     Children (2-11 years) 23 23     Adolescents (12-17 years) 32 32     Adults (18-64 years) 109 109 Age continuous Units: years     arithmetic mean (standard deviation) 30.2 ( 16.94 ) - Gender categorical Units: Subjects     Female 110 110     Male 54 54 Baseline BMI Units: kg/m2     arithmetic mean (standard deviation) 45.3 ( 9.55 ) - Baseline waist circumference Units: centimetre     arithmetic mean (standard deviation) 126.8 ( 22.04 ) -
Subject analysis sets
Subject analysis set title	SEMA3 Path
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in the SEMA3 Path
Subject analysis set title	PHIP
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in PHIP
Subject analysis set title	SIM1
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in SIM1
Subject analysis set title	MAGEL2
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in MAGEL2
Subject analysis set title	Other
Subject analysis set type	Safety analysis
Subject analysis set description	Note that there is also a genetic cohort identified as “other”; however, efficacy data were not pooled across the genes within this cohort.
Subject analysis sets values SEMA3 Path PHIP SIM1 MAGEL2 Other Number of subjects 90 16 20 10 28 Age categorical Units: Subjects     Children (2-11 years)     Adolescents (12-17 years)     Adults (18-64 years) Age continuous Units: years     arithmetic mean (standard deviation) 31.1 ( 17.69 ) 26.6 ( 16.59 ) 28.5 ( 13.45 ) 32.4 ( 19.01 ) 29.8 ( 16.87 ) Gender categorical Units: Subjects     Female 60 8 15 8 19     Male 30 8 5 2 9 Baseline BMI Units: kg/m2     arithmetic mean (standard deviation) 45.52 ( 8.76 ) 40.8 ( 10.02 ) 47.7 ( 9.73 ) 42.1 ( 8.26 ) 46.8 ( 11.39 ) Baseline waist circumference Units: centimetre     arithmetic mean (standard deviation) 127.5 ( 20.23 ) 119.7 ( 25.44 ) 128.5 ( 23.47 ) 125.9 ( 26.81 ) 127.8 ( 23.71 )

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Stage 1 - Setmelanotide
Reporting group description	This was a 16 week open-label treatment stage in which all patients with RGDO were treated with setmelanotide.
Reporting group title	Placebo
Reporting group description	Eligible patients who entered Stage 2 continued in the study for an additional 24 weeks. Eligible patients were randomized 2:1 to either continue QD setmelanotide or receive matching placebo. Patients in this arm received placebo.
Reporting group title	Setmelanotide
Reporting group description	Eligible patients who entered Stage 2 continued in the study for an additional 24 weeks. Eligible patients were randomized 2:1 to either continue QD setmelanotide or receive matching placebo. Patients in this arm received QD setmelanotide.
Subject analysis set title	SEMA3 Path
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in the SEMA3 Path
Subject analysis set title	PHIP
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in PHIP
Subject analysis set title	SIM1
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in SIM1
Subject analysis set title	MAGEL2
Subject analysis set type	Safety analysis
Subject analysis set description	Genetic cohort including patients with mutations in MAGEL2
Subject analysis set title	Other
Subject analysis set type	Safety analysis
Subject analysis set description	Note that there is also a genetic cohort identified as “other”; however, efficacy data were not pooled across the genes within this cohort.

End points Top of page

Primary: Proportion of Patients who Achieved a ≥5% Reduction in BMI from Baseline at Week 16 (End of Stage 1) Top of page
End point title	Proportion of Patients who Achieved a ≥5% Reduction in BMI from Baseline at Week 16 (End of Stage 1) [1]
End point description	To evaluate the proportion of patients with obesity and genetic variants in the MC4R pathway who achieve a clinically meaningful reduction in body weight in response to setmelanotide
End point type	Primary
End point timeframe	Baseline to End of Stage 1 (16 weeks)
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This was not a comparator study. For the analysis of Proportion of Patients who Achieved a ≥5% Reduction in BMI from Baseline, percent changes in BMI from baseline over time were summarized using descriptive statistics.
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 164 90 16 20 10 Units: percent     number (confidence interval 95%) 29.9 (23.0 to 37.5) 31.1 (21.8 to 41.7) 56.3 (29.9 to 80.2) 25.0 (8.7 to 49.1) 30.0 (6.7 to 65.2)
No statistical analyses for this end point

Primary: Proportion of Patients who Achieved a ≥5% Reduction in BMI from Baseline at Week 16 (End of Stage 1) Top of page

Secondary: Mean Change in BMI from Baseline to the End of Stage 1 - All Patients Top of page
End point title	Mean Change in BMI from Baseline to the End of Stage 1 - All Patients
End point description	To evaluate change in weight parameters in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 112 58 13 16 7 Units: kg/m2     arithmetic mean (standard deviation) -1.92 ( 1.79 ) -2.19 ( 2.02 ) -2.12 ( 1.01 ) -1.70 ( 1.89 ) -1.64 ( 1.35 )
No statistical analyses for this end point

Secondary: Mean Change in BMI from Baseline to the End of Stage 1 - All Patients Top of page

Secondary: Percent Change in BMI from Baseline to the End of Stage 1 - All patients Top of page
End point title	Percent Change in BMI from Baseline to the End of Stage 1 - All patients
End point description	To evaluate change in weight parameters in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 112 58 13 16 7 Units: percent     arithmetic mean (standard deviation) -4.62 ( 4.39 ) -4.98 ( 4.47 ) -6.12 ( 3.62 ) -4.02 ( 5.31 ) -4.60 ( 4.28 )
No statistical analyses for this end point

Secondary: Percent Change in BMI from Baseline to the End of Stage 1 - All patients Top of page

Secondary: Mean Change in BMI from Baseline to the End of Stage 1; Patients ≥18 Years Top of page
End point title	Mean Change in BMI from Baseline to the End of Stage 1; Patients ≥18 Years
End point description	To evaluate change in weight parameters in response to setmelanotide in patients ≥18 years old with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 69 36 7 10 4 Units: kg/m2     arithmetic mean (standard deviation) -1.87 ( 1.89 ) -2.36 ( 2.12 ) -2.11 ( 1.14 ) -1.47 ( 1.79 ) -1.19 ( 1.01 )
No statistical analyses for this end point

Secondary: Mean Change in BMI from Baseline to the End of Stage 1; Patients ≥18 Years Top of page

Secondary: Percent Change in BMI from Baseline to the End of Stage 1; Patients ≥18 Years Top of page
End point title	Percent Change in BMI from Baseline to the End of Stage 1; Patients ≥18 Years
End point description	To evaluate change in weight parameters in response to setmelanotide in patients ≥18 years old with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 69 36 7 10 4 Units: percent     arithmetic mean (standard deviation) -3.95 ( 4.05 ) -4.96 ( 4.47 ) -5.11 ( 2.77 ) -2.63 ( 3.72 ) -2.67 ( 2.22 )
No statistical analyses for this end point

Secondary: Percent Change in BMI from Baseline to the End of Stage 1; Patients ≥18 Years Top of page

Secondary: Mean Change in Body Weight from Baseline to the End of Stage 1; Patients ≥18 Years Top of page
End point title	Mean Change in Body Weight from Baseline to the End of Stage 1; Patients ≥18 Years
End point description
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks(
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 69 36 7 10 4 Units: kilogram(s)     arithmetic mean (standard deviation) -5.33 ( 5.31 ) -6.77 ( 5.91 ) -5.77 ( 3.50 ) -4.13 ( 4.72 ) -3.88 ( 3.68 )
No statistical analyses for this end point

Secondary: Mean Change in Body Weight from Baseline to the End of Stage 1; Patients ≥18 Years Top of page

Secondary: Percent Change in Body Weight from Baseline to the End of Stage 1; Patients ≥18 Years Top of page
End point title	Percent Change in Body Weight from Baseline to the End of Stage 1; Patients ≥18 Years
End point description
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 69 36 7 10 4 Units: percent     arithmetic mean (standard deviation) -3.94 ( 4.05 ) -4.96 ( 4.47 ) -5.00 ( 2.74 ) -2.63 ( 3.72 ) -2.67 ( 2.22 )
No statistical analyses for this end point

Secondary: Percent Change in Body Weight from Baseline to the End of Stage 1; Patients ≥18 Years Top of page

Secondary: Mean Change in BMI Z-score from Baseline to the End of Stage 1; Patients <18 Years Top of page
End point title	Mean Change in BMI Z-score from Baseline to the End of Stage 1; Patients <18 Years
End point description	To evaluate change in weight parameters in patients less than 18 years of age in response to setmelanotide in patients with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 43 22 6 6 3 Units: Z-score     arithmetic mean (standard deviation) -0.13 ( 0.14 ) -0.09 ( 0.08 ) -0.20 ( 0.19 ) -0.18 ( 0.23 ) -0.18 ( 0.16 )
No statistical analyses for this end point

Secondary: Mean Change in BMI Z-score from Baseline to the End of Stage 1; Patients <18 Years Top of page

Secondary: Mean Change in Weekly Average of the daily Maximal Hunger Score from Baseline to the End of Stage 1; Patients ≥12 Years Top of page
End point title	Mean Change in Weekly Average of the daily Maximal Hunger Score from Baseline to the End of Stage 1; Patients ≥12 Years
End point description	To evaluate change in hunger in response to setmelanotide in patients ≥12 years old with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 78 38 8 14 6 Units: Hunger Score     arithmetic mean (standard deviation) -2.56 ( 2.26 ) -2.35 ( 2.43 ) -3.87 ( 1.41 ) -1.91 ( 2.38 ) -3.28 ( 2.52 )
No statistical analyses for this end point

Secondary: Mean Change in Weekly Average of the daily Maximal Hunger Score from Baseline to the End of Stage 1; Patients ≥12 Years Top of page

Secondary: Percent Change in Weekly Average of the daily Maximal Hunger Score from Baseline to the End of Stage 1; Patients ≥12 Years Top of page
End point title	Percent Change in Weekly Average of the daily Maximal Hunger Score from Baseline to the End of Stage 1; Patients ≥12 Years
End point description	To evaluate change in hunger in response to setmelanotide in patients ≥12 years old with genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 78 38 8 14 6 Units: percent     arithmetic mean (standard deviation) -31.13 ( 63.27 ) -23.70 ( 81.93 ) -56.87 ( 19.46 ) -25.60 ( 51.69 ) -39.44 ( 30.21 )
No statistical analyses for this end point

Secondary: Percent Change in Weekly Average of the daily Maximal Hunger Score from Baseline to the End of Stage 1; Patients ≥12 Years Top of page

Secondary: The Proportion of Patients ≥12 Years Old, Per Gene, Who Achieve a ≥2 Point Reduction in the Weekly Average of the Daily Maximal Hunger Score Top of page
End point title	The Proportion of Patients ≥12 Years Old, Per Gene, Who Achieve a ≥2 Point Reduction in the Weekly Average of the Daily Maximal Hunger Score
End point description	The proportion of patients ≥12 years old, per gene, who achieve a ≥2 point reduction (improvement) in the weekly average of the daily maximal hunger score.
End point type	Secondary
End point timeframe	Baseline to end of Stage 1 (16 weeks)
End point values Stage 1 - Setmelanotide SEMA3 Path PHIP SIM1 MAGEL2 Number of subjects analysed 141 77 12 20 8 Units: Patients     Patients Achieving a ≥2 Point Reduction 49 22 7 7 5     Patients Not Achieving a ≥2 Point Reduction 92 55 5 13 3
No statistical analyses for this end point

Secondary: The Proportion of Patients ≥12 Years Old, Per Gene, Who Achieve a ≥2 Point Reduction in the Weekly Average of the Daily Maximal Hunger Score Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From baseline to end of Stage 2
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	26.0
Reporting groups
Reporting group title	Stage 1 - All patients
Reporting group description	All 164 patients received at least 1 dose of setmelanotide in Stage 1, and therefore, comprise the Safety Analysis Set.
Reporting group title	Stage 2 - Setmelanotide
Reporting group description	Note, 3 patients randomised to placebo were rescued with open-label setmelanotide during Stage 2. They were analysed for safety with the setmelanotide group.
Reporting group title	Stage 2 - Placebo
Reporting group description	Note, 3 patients randomised to placebo were rescued with open-label setmelanotide during Stage 2. They were analysed for safety with the setmelanotide group.
Serious adverse events Stage 1 - All patients Stage 2 - Setmelanotide Stage 2 - Placebo Total subjects affected by serious adverse events      subjects affected / exposed 6 / 164 (3.66%) 0 / 35 (0.00%) 0 / 14 (0.00%)      number of deaths (all causes) 0 0 0      number of deaths resulting from adverse events 0 0 0 Nervous system disorders Headache      subjects affected / exposed 1 / 164 (0.61%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Gastrointestinal disorders Gastritis      subjects affected / exposed 1 / 164 (0.61%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Vomiting      subjects affected / exposed 1 / 164 (0.61%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders Asthma      subjects affected / exposed 1 / 164 (0.61%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Skin and subcutaneous tissue disorders Angioedema      subjects affected / exposed 1 / 164 (0.61%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0 Psychiatric disorders Depression      subjects affected / exposed 2 / 164 (1.22%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences causally related to treatment / all 2 / 2 0 / 0 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Stage 1 - All patients Stage 2 - Setmelanotide Stage 2 - Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 160 / 164 (97.56%) 25 / 35 (71.43%) 10 / 14 (71.43%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus      subjects affected / exposed 52 / 164 (31.71%) 7 / 35 (20.00%) 2 / 14 (14.29%)      occurrences all number 100 10 5 Nervous system disorders Headache      subjects affected / exposed 43 / 164 (26.22%) 4 / 35 (11.43%) 0 / 14 (0.00%)      occurrences all number 60 6 0 Dizziness      subjects affected / exposed 8 / 164 (4.88%) 1 / 35 (2.86%) 0 / 14 (0.00%)      occurrences all number 11 1 0 General disorders and administration site conditions Injection site erythema      subjects affected / exposed 62 / 164 (37.80%) 1 / 35 (2.86%) 2 / 14 (14.29%)      occurrences all number 164 4 2 Injection site pain      subjects affected / exposed 46 / 164 (28.05%) 0 / 35 (0.00%) 1 / 14 (7.14%)      occurrences all number 99 0 1 Injection site induration      subjects affected / exposed 47 / 164 (28.66%) 1 / 35 (2.86%) 2 / 14 (14.29%)      occurrences all number 90 1 2 Injection site pruritus      subjects affected / exposed 49 / 164 (29.88%) 1 / 35 (2.86%) 0 / 14 (0.00%)      occurrences all number 62 1 0 Fatigue      subjects affected / exposed 29 / 164 (17.68%) 0 / 35 (0.00%) 1 / 14 (7.14%)      occurrences all number 35 0 1 Injection site oedema      subjects affected / exposed 20 / 164 (12.20%) 1 / 35 (2.86%) 0 / 14 (0.00%)      occurrences all number 35 1 0 Injection site bruising      subjects affected / exposed 22 / 164 (13.41%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 25 0 0 Injection site reaction      subjects affected / exposed 9 / 164 (5.49%) 1 / 35 (2.86%) 0 / 14 (0.00%)      occurrences all number 16 1 0 Injection site discolouration      subjects affected / exposed 10 / 164 (6.10%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 10 0 0 Gastrointestinal disorders Nausea      subjects affected / exposed 75 / 164 (45.73%) 4 / 35 (11.43%) 0 / 14 (0.00%)      occurrences all number 89 4 0 Vomiting      subjects affected / exposed 41 / 164 (25.00%) 3 / 35 (8.57%) 0 / 14 (0.00%)      occurrences all number 48 3 0 Diarrhoea      subjects affected / exposed 22 / 164 (13.41%) 2 / 35 (5.71%) 0 / 14 (0.00%)      occurrences all number 25 2 0 Abdominal pain      subjects affected / exposed 13 / 164 (7.93%) 2 / 35 (5.71%) 2 / 14 (14.29%)      occurrences all number 14 2 2 Pigmentation lip      subjects affected / exposed 9 / 164 (5.49%) 1 / 35 (2.86%) 0 / 14 (0.00%)      occurrences all number 9 1 0 Constipation      subjects affected / exposed 4 / 164 (2.44%) 2 / 35 (5.71%) 2 / 14 (14.29%)      occurrences all number 4 3 2 Reproductive system and breast disorders Vulvovaginal discomfort      subjects affected / exposed 10 / 164 (6.10%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 10 0 0 Spontaneous penile erection      subjects affected / exposed 6 / 164 (3.66%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 7 0 0 Erection increased      subjects affected / exposed 4 / 164 (2.44%) 1 / 35 (2.86%) 0 / 14 (0.00%)      occurrences all number 5 2 0 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 13 / 164 (7.93%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 16 0 0 Skin and subcutaneous tissue disorders Skin hyperpigmentation      subjects affected / exposed 130 / 164 (79.27%) 7 / 35 (20.00%) 1 / 14 (7.14%)      occurrences all number 286 8 2 Pruritus      subjects affected / exposed 11 / 164 (6.71%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 11 0 0 Rash      subjects affected / exposed 10 / 164 (6.10%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 10 0 0 Skin discolouration      subjects affected / exposed 1 / 164 (0.61%) 1 / 35 (2.86%) 2 / 14 (14.29%)      occurrences all number 1 1 2 Psychiatric disorders Libido increased      subjects affected / exposed 15 / 164 (9.15%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 15 0 0 Disturbance in sexual arousal      subjects affected / exposed 11 / 164 (6.71%) 0 / 35 (0.00%) 0 / 14 (0.00%)      occurrences all number 12 0 0 Infections and infestations Nasopharyngitis      subjects affected / exposed 14 / 164 (8.54%) 4 / 35 (11.43%) 1 / 14 (7.14%)      occurrences all number 15 4 2

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
27 Jul 2022	Protocol Version 2.0: • Reduced sample size and target number of patients per gene • Changed primary endpoint to proportion of patients who were responders following open-label treatment with setmelanotide at the end of Stage 1; revised primary objective, accordingly. • Moved safety objective and endpoint from secondary to its own safety section. • Changed the weight- and hunger-related secondary objective and endpoints to be determined per gene.
27 Jul 2022	Protocol Version 2.0 continued (1): • Changed criterion to enter Stage 2 of the trial. • Changed criterion to receive “rescue” treatment with open-label setmelanotide in Stage 2 and changed rescue treatment to be provided as part of either a LTE study or through BVs. • Added the following inclusion criterion: Symptoms or behaviours of hyperphagia persistent during the patient’s life, including manifestations in childhood, as determined by the Investigator at screening • Changed the exclusion criterion to weight loss >2% within the previous 3 months and permitted the use of stable dietary and/or exercise regimens, or medications, supplements or herbal treatment used for weight maintenance or to prevent weight gain (including GLP 1 receptor agonists) • Added an exclusion criterion regarding the following genetic variants: biallelic BBS; biallelic ALMS1; homozygous, heterozygous, or compound heterozygous variants in MC4R, POMC, PCSK1, LEPR, NCOA1; SRC1 or SH2B1 genes as well as 16p11.2 chromosomal deletions that include the SH2B1 gene
27 Jul 2022	Protocol Version 2.0 continued (2): • Changed GFR exclusion criterion to eGFR <30 mL/min/1.73 m2 (per the MDRD equation in patients ≥18 years of age and per the bedside Schwartz equation in patients <18 years of age) • Permitted treatment discontinuation without withdrawal from the study • Added sections for “lost to follow-up,” “skin protection,” “drug interruption and stopping rules,” “biomarkers,” and “ADA” • Permitted dose reductions in the event the drug was not well-tolerated • Added fasting glucose to metabolic parameters • Updated analysis of the primary efficacy endpoint (based on revised endpoint)
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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