Trial Outcomes & Findings for DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway (NCT NCT04963231)

Last Updated: 2025-07-02

Results Overview

BMI was calculated using participant's weight and height assessments, using the following formula: BMI = Kilogram (kg)/ square meter (m\^2). A significant clinically meaningful response was defined as achieving a ≥5% reduction in BMI from Baseline. Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

164 participants

Primary outcome timeframe

Baseline to Week 16

Results posted on

2025-07-02

Participant Flow

A total of 218 participants were screened and 164 participants received at least one dose of trial medication in Stage 1.

Participant milestones

Participant milestones
Measure	Stage 1: Setmelanotide (Open-Label) Participants received once daily subcutaneous (SC) injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 milligrams (mg) once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.	Stage 2: Setmelanotide (Double-Blind) Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of setmelanotide 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).	Stage 2: Placebo (Double-Blind) Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of matching placebo 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).
Stage 1 (Open-Label, Duration: 16 Weeks) STARTED	164	0	0
Stage 1 (Open-Label, Duration: 16 Weeks) COMPLETED	100	0	0
Stage 1 (Open-Label, Duration: 16 Weeks) NOT COMPLETED	64	0	0
Stage 2 (Double-Blind, Duration:24 Week) STARTED	0	32	17
Stage 2 (Double-Blind, Duration:24 Week) Safety Analysis Set Enrolled in Stage 2	0	35	14
Stage 2 (Double-Blind, Duration:24 Week) COMPLETED	0	29	10
Stage 2 (Double-Blind, Duration:24 Week) NOT COMPLETED	0	3	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage 1: Setmelanotide (Open-Label) Participants received once daily subcutaneous (SC) injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 milligrams (mg) once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.	Stage 2: Setmelanotide (Double-Blind) Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of setmelanotide 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).	Stage 2: Placebo (Double-Blind) Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of matching placebo 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).
Stage 1 (Open-Label, Duration: 16 Weeks) Adverse Event	43	0	0
Stage 1 (Open-Label, Duration: 16 Weeks) Protocol Violation	3	0	0
Stage 1 (Open-Label, Duration: 16 Weeks) Withdrawal by Subject	16	0	0
Stage 1 (Open-Label, Duration: 16 Weeks) Lost to Follow-up	2	0	0
Stage 2 (Double-Blind, Duration:24 Week) Adverse Event	0	0	1
Stage 2 (Double-Blind, Duration:24 Week) Withdrawal by Subject	0	2	2
Stage 2 (Double-Blind, Duration:24 Week) Other than specified	0	1	4

Baseline Characteristics

DAYBREAK: A Study of Setmelanotide in Participants With Specific Gene Variants in the Melanocortin-4 Receptor (MC4R) Pathway

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=164 Participants Stage 1: All participants received once daily SC injection of setmelanotide for 16 weeks in an open-label treatment Stage. Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily. Stage 2: Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of setmelanotide 3.0 mg or matching placebo from Week 16 to Week 40 in a double-blind treatment Stage.
Age, Continuous	30.2 years STANDARD_DEVIATION 16.94 • n=5 Participants
Sex: Female, Male Female	110 Participants n=5 Participants
Sex: Female, Male Male	54 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	38 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	124 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	16 Participants n=5 Participants
Race (NIH/OMB) White	128 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	16 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=164 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: PLXNA2	3 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: PLXNA3	2 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: PLXNA4	5 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3A	2 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: MAGEL2	3 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: CREBBP	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: DNMT3A	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: HTR2C	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Overall	49 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: NRP1	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: NRP2	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: PLXNA1	2 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3B	1 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3C	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3D	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3E	3 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3F	2 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SEMA3G	8 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: PHIP	9 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: SIM1	5 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: KSR2	1 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: MRAP2	0 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: RPGRIP1L	1 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: TBX3	2 Participants
Stage 1: Number of Participants by Genotype Who Demonstrated a Significant Clinically Meaningful Response to Setmelanotide at the End of Stage 1 Gene: TRPC5	0 Participants

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m\^2. Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=164 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: DNMT3A, At Baseline	44.138 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: DNMT3A, Change at Week 16	-1.080 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: HTR2C, At Baseline	52.105 Kg/m^2 Standard Deviation 3.0212
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: HTR2C, Change at Week 16	-1.381 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: MRAP2, Change at Week 16	-1.470 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: RPGRIP1L, At Baseline	43.442 Kg/m^2 Standard Deviation 2.6778
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: RPGRIP1L, Change at Week 16	-3.603 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: TBX3, At Baseline	40.170 Kg/m^2 Standard Deviation 10.5867
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: TRPC5, At Baseline	49.974 Kg/m^2 Standard Deviation 24.5155
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: TRPC5, Change at Week 16	0.161 Kg/m^2 Standard Deviation 1.2979
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3B, Change at Week 16	-2.557 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3C, At Baseline	47.543 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3C, Change at Week 16	-2.334 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SIM1, At Baseline	47.729 Kg/m^2 Standard Deviation 9.7294
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SIM1, Change at Week 16	-1.698 Kg/m^2 Standard Deviation 1.8931
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: MAGEL2, At Baseline	42.047 Kg/m^2 Standard Deviation 8.2605
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: MAGEL2, Change at Week 16	-1.637 Kg/m^2 Standard Deviation 1.3549
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: CREBBP, At Baseline	47.490 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: CREBBP, Change at Week 16	0.165 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: KSR2, At Baseline	47.624 Kg/m^2 Standard Deviation 11.4457
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: KSR2, Change at Week 16	-1.073 Kg/m^2 Standard Deviation 1.4410
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3D, At Baseline	45.814 Kg/m^2 Standard Deviation 5.7690
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3D, Change at Week 16	-1.638 Kg/m^2 Standard Deviation 0.6445
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3E, At Baseline	43.005 Kg/m^2 Standard Deviation 1.6275
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3E, Change at Week 16	-3.132 Kg/m^2 Standard Deviation 2.4180
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3F, At Baseline	54.979 Kg/m^2 Standard Deviation 15.1825
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3F, Change at Week 16	-3.556 Kg/m^2 Standard Deviation 1.1758
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3G, At Baseline	44.464 Kg/m^2 Standard Deviation 8.4848
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3G, Change at Week 16	-2.124 Kg/m^2 Standard Deviation 1.5203
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PHIP, At Baseline	40.808 Kg/m^2 Standard Deviation 10.0222
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PHIP, Change at Week 16	-2.120 Kg/m^2 Standard Deviation 1.0108
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Overall: At Baseline	45.338 Kg/m^2 Standard Deviation 9.5526
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Overall: Change at Week 16	-1.916 Kg/m^2 Standard Deviation 1.7971
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: NRP1, At Baseline	48.601 Kg/m^2 Standard Deviation 2.7893
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: NRP1, Change at Week 16	0.229 Kg/m^2 Standard Deviation 1.6024
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: NRP2, At Baseline	46.568 Kg/m^2 Standard Deviation 10.6754
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: NRP2, Change at Week 16	-1.040 Kg/m^2 Standard Deviation 0.8650
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA1, At Baseline	45.576 Kg/m^2 Standard Deviation 5.5644
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA1, Change at Week 16	-1.884 Kg/m^2 Standard Deviation 1.8912
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA2, At Baseline	48.577 Kg/m^2 Standard Deviation 12.1795
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA2, Change at Week 16	-2.492 Kg/m^2 Standard Deviation 2.0273
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA3, At Baseline	34.083 Kg/m^2 Standard Deviation 6.4705
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA3, Change at Week 16	-3.333 Kg/m^2 Standard Deviation 0.5166
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA4, At Baseline	46.634 Kg/m^2 Standard Deviation 8.5714
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA4, Change at Week 16	-2.218 Kg/m^2 Standard Deviation 2.9947
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3A, At Baseline	39.405 Kg/m^2 Standard Deviation 7.8242
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3A, Change at Week 16	-2.328 Kg/m^2 Standard Deviation 0.2612
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3B, At Baseline	42.890 Kg/m^2 Standard Deviation 5.0100
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: MRAP2, At Baseline	58.100 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: TBX3, Change at Week 16	-1.951 Kg/m^2 Standard Deviation 1.3582

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m\^2 Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=109 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: RPGRIP1L, Change at Week 16	-3.603 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TBX3, At Baseline	44.494 Kg/m^2 Standard Deviation 4.3444
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Overall: At Baseline	48.464 Kg/m^2 Standard Deviation 8.0877
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA1, Change at Week 16	-0.678 Kg/m^2 Standard Deviation 0.8796
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA2, At Baseline	50.335 Kg/m^2 Standard Deviation 12.3004
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA2, Change at Week 16	-2.324 Kg/m^2 Standard Deviation 0.6565
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: KSR2, At Baseline	51.397 Kg/m^2 Standard Deviation 9.2011
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: KSR2, Change at Week 16	-0.792 Kg/m^2 Standard Deviation 1.5759
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: RPGRIP1L, At Baseline	43.442 Kg/m^2 Standard Deviation 2.6778
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Overall: Change at Week 16	-1.872 Kg/m^2 Standard Deviation 1.8963
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: NRP2, At Baseline	51.640 Kg/m^2 Standard Deviation 8.5762
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: NRP2, Change at Week 16	-0.783 Kg/m^2 Standard Deviation 1.0489
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA1, At Baseline	46.959 Kg/m^2 Standard Deviation 6.2279
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA3, At Baseline	40.801 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA3, Change at Week 16	-3.698 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA4, At Baseline	48.420 Kg/m^2 Standard Deviation 7.4340
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA4, Change at Week 16	-2.532 Kg/m^2 Standard Deviation 3.1514
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3A, At Baseline	47.366 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3A, Change at Week 16	-2.513 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3B, At Baseline	43.320 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3D, At Baseline	47.296 Kg/m^2 Standard Deviation 6.0613
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3D, Change at Week 16	-1.638 Kg/m^2 Standard Deviation 0.6445
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3E, At Baseline	42.004 Kg/m^2 Standard Deviation 1.1954
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3E, Change at Week 16	-4.716 Kg/m^2 Standard Deviation 0.0565
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3F, At Baseline	64.964 Kg/m^2 Standard Deviation 9.9946
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3F, Change at Week 16	-4.388 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3G, At Baseline	46.762 Kg/m^2 Standard Deviation 6.5047
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3G, Change at Week 16	-2.302 Kg/m^2 Standard Deviation 1.6478
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PHIP, At Baseline	45.343 Kg/m^2 Standard Deviation 7.0089
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PHIP, Change at Week 16	-2.110 Kg/m^2 Standard Deviation 1.1464
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SIM1, At Baseline	50.790 Kg/m^2 Standard Deviation 8.9593
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SIM1, Change at Week 16	-1.465 Kg/m^2 Standard Deviation 1.7916
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: MAGEL2, At Baseline	46.198 Kg/m^2 Standard Deviation 5.0997
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: MAGEL2, Change at Week 16	-1.191 Kg/m^2 Standard Deviation 1.0137
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: CREBBP, At Baseline	47.490 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: CREBBP, Change at Week 16	0.165 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: DNMT3A, At Baseline	44.138 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: DNMT3A, Change at Week 16	-1.080 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: HTR2C, At Baseline	52.105 Kg/m^2 Standard Deviation 3.0212
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: HTR2C, Change at Week 16	-1.381 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TBX3, Change at Week 16	-0.705 Kg/m^2
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TRPC5, At Baseline	62.246 Kg/m^2 Standard Deviation 17.2758
Mean Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TRPC5, Change at Week 16	0.161 Kg/m^2 Standard Deviation 1.2979

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=112 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA1, Change at Week 16	-4.00 percent change Standard Deviation 4.296
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3A, Change at Week 16	-5.39 percent change Standard Deviation 0.123
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3G, Change at Week 16	-5.09 percent change Standard Deviation 3.284
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PHIP, Change at Week 16	-6.12 percent change Standard Deviation 3.623
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SIM1, Change at Week 16	-4.02 percent change Standard Deviation 5.310
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Overall: Change at Week 16	-4.62 percent change Standard Deviation 4.394
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: NRP1, Change at Week 16	0.57 percent change Standard Deviation 3.329
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: NRP2, Change at Week 16	-2.33 percent change Standard Deviation 2.105
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA2, Change at Week 16	-4.90 percent change Standard Deviation 3.909
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA3, Change at Week 16	-8.95 percent change Standard Deviation 0.156
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: PLXNA4, Change at Week 16	-5.00 percent change Standard Deviation 6.577
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3B, Change at Week 16	-6.79 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3C, Change at Week 16	-4.91 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3D, Change at Week 16	-3.57 percent change Standard Deviation 1.960
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3E, Change at Week 16	-7.39 percent change Standard Deviation 5.752
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: SEMA3F, Change at Week 16	-7.66 percent change Standard Deviation 0.119
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: MAGEL2, Change at Week 16	-4.60 percent change Standard Deviation 4.288
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: CREBBP, Change at Week 16	0.35 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: DNMT3A, Change at Week 16	-2.45 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: HTR2C, Change at Week 16	-2.49 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: KSR2, Change at Week 16	-2.15 percent change Standard Deviation 2.928
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: MRAP2, Change at Week 16	-2.53 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: RPGRIP1L, Change at Week 16	-8.64 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: TBX3, Change at Week 16	-6.41 percent change Standard Deviation 5.011
Percent Change in BMI From Baseline to the End of Stage 1 in All Participants, Per Genotype Gene: TRPC5, Change at Week 16	-0.03 percent change Standard Deviation 2.094

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=69 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: NRP2, Change at Week 16	-1.37 percent change Standard Deviation 1.804
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA1, Change at Week 16	-1.22 percent change Standard Deviation 1.576
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA2, Change at Week 16	-4.69 percent change Standard Deviation 0.913
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Overall: Change at Week 16	-3.95 percent change Standard Deviation 4.057
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA3, Change at Week 16	-9.06 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA4, Change at Week 16	-5.34 percent change Standard Deviation 6.682
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3A, Change at Week 16	-5.31 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3D, Change at Week 16	-3.57 percent change Standard Deviation 1.960
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3E, Change at Week 16	-11.23 percent change Standard Deviation 0.185
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3F, Change at Week 16	-7.58 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3G, Change at Week 16	-4.80 percent change Standard Deviation 2.810
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PHIP, Change at Week 16	-5.11 percent change Standard Deviation 2.770
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SIM1, Change at Week 16	-2.63 percent change Standard Deviation 3.720
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: MAGEL2, Change at Week 16	-2.67 percent change Standard Deviation 2.227
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: CREBBP, Change at Week 16	0.35 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: DNMT3A, Change at Week 16	-2.45 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: HTR2C, Change at Week 16	-2.49 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: KSR2, Change at Week 16	-1.23 percent change Standard Deviation 3.189
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: RPGRIP1L, Change at Week 16	-8.64 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TBX3, Change at Week 16	-1.70 percent change
Percent Change in BMI From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TRPC5, Change at Week 16	-0.03 percent change Standard Deviation 2.094

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Data are provided for overall and according to participants with specified primary gene. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=109 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3D, At Baseline	128.09 Kg Standard Deviation 49.981
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3D, Change at Week 16	-4.48 Kg Standard Deviation 0.589
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3E, At Baseline	115.77 Kg Standard Deviation 19.328
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3E, Change at Week 16	-12.98 Kg Standard Deviation 1.956
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3F, At Baseline	176.65 Kg Standard Deviation 10.960
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3F, Change at Week 16	-12.80 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3G, At Baseline	129.41 Kg Standard Deviation 21.874
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3G, Change at Week 16	-6.59 Kg Standard Deviation 4.622
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: KSR2, At Baseline	150.16 Kg Standard Deviation 19.630
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: KSR2, Change at Week 16	-2.13 Kg Standard Deviation 4.721
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: RPGRIP1L, At Baseline	103.47 Kg Standard Deviation 11.193
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: RPGRIP1L, Change at Week 16	-8.63 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TRPC5, At Baseline	203.00 Kg Standard Deviation 25.173
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TRPC5, Change at Week 16	0.20 Kg Standard Deviation 4.243
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Overall, At Baseline	136.01 Kg Standard Deviation 29.815
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Overall: Change at Week 16	-5.33 Kg Standard Deviation 5.315
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: NRP2, At Baseline	147.35 Kg Standard Deviation 2.098
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: NRP2, Change at Week 16	-2.03 Kg Standard Deviation 2.687
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA1, At Baseline	145.30 Kg Standard Deviation 33.751
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA1, Change at Week 16	-2.33 Kg Standard Deviation 3.144
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA2, At Baseline	137.94 Kg Standard Deviation 37.878
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA2, Change at Week 16	-6.50 Kg Standard Deviation 2.234
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA3, At Baseline	89.73 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA3, Change at Week 16	-8.13 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA4, At Baseline	135.87 Kg Standard Deviation 24.052
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA4, Change at Week 16	-7.55 Kg Standard Deviation 8.772
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3A, At Baseline	157.07 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3A, Change at Week 16	-8.33 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3B, At Baseline	97.60 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PHIP, At Baseline	134.11 Kg Standard Deviation 36.996
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PHIP, Change at Week 16	-5.77 Kg Standard Deviation 3.504
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SIM1, At Baseline	141.25 Kg Standard Deviation 35.591
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SIM1, Change at Week 16	-4.13 Kg Standard Deviation 4.720
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: MAGEL2, At Baseline	134.41 Kg Standard Deviation 20.544
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: MAGEL2, Change at Week 16	-3.88 Kg Standard Deviation 3.681
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: CREBBP, At Baseline	103.60 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: CREBBP, Change at Week 16	0.36 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: DNMT3A, At Baseline	129.37 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: DNMT3A, Change at Week 16	-3.17 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: HTR2C, At Baseline	126.23 Kg Standard Deviation 9.780
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: HTR2C, Change at Week 16	-3.40 Kg
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TBX3, At Baseline	119.00 Kg Standard Deviation 11.644
Mean Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TBX3, Change at Week 16	-2.17 Kg

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=69 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3D, Change at Week 16	-3.57 percent change Standard Deviation 1.960
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3E, Change at Week 16	-11.23 percent change Standard Deviation 0.185
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: CREBBP, Change at Week 16	0.35 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: DNMT3A, Change at Week 16	-2.45 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: HTR2C, Change at Week 16	-2.49 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: KSR2, Change at Week 16	-1.23 percent change Standard Deviation 3.189
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: RPGRIP1L, Change at Week 16	-8.64 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TBX3, Change at Week 16	-1.70 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: TRPC5, Change at Week 16	-0.03 percent change Standard Deviation 2.094
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Overall: Change at Week 16	-3.94 percent change Standard Deviation 4.052
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: NRP2, Change at Week 16	-1.37 percent change Standard Deviation 1.804
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA1, Change at Week 16	-1.22 percent change Standard Deviation 1.576
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA2, Change at Week 16	-4.69 percent change Standard Deviation 0.913
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA3, Change at Week 16	-9.06 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PLXNA4, Change at Week 16	-5.34 percent change Standard Deviation 6.682
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3A, Change at Week 16	-5.31 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3F, Change at Week 16	-7.58 percent change
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SEMA3G, Change at Week 16	-4.80 percent change Standard Deviation 2.810
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: PHIP, Change at Week 16	-5.00 percent change Standard Deviation 2.749
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: SIM1, Change at Week 16	-2.63 percent change Standard Deviation 3.720
Percent Change in Body Weight From Baseline to the End of Stage 1 in Participants ≥18 Years Old, Per Genotype Gene: MAGEL2, Change at Week 16	-2.67 percent change Standard Deviation 2.227

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m\^2. The BMI Z-score indicated the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease of BMI Z-score indicates a reduction in BMI from Baseline whereas an increase of BMI-Z score indicates an increase in BMI from Baseline. Baseline was defined as the last available measurement taken prior to the start of treatment Stage 1 administration.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=55 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: NRP1, Change at Week 16	-0.000 z-score Standard Deviation 0.0124
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: NRP2, At Baseline	2.386 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: NRP2, Change at Week 16	-0.086 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA1, Change at Week 16	-0.112 z-score Standard Deviation 0.0671
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA2, At Baseline	2.955 z-score Standard Deviation 0.0601
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA2, Change at Week 16	-0.043 z-score Standard Deviation 0.0707
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA4, Change at Week 16	-0.063 z-score Standard Deviation 0.1110
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3B, Change at Week 16	-0.140 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3C, At Baseline	2.828 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3D, At Baseline	2.454 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3E, At Baseline	2.913 z-score Standard Deviation 0.4705
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3E, Change at Week 16	-0.053 z-score Standard Deviation 0.0808
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3F, At Baseline	2.847 z-score Standard Deviation 0.5676
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3F, Change at Week 16	-0.192 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SIM1, Change at Week 16	-0.182 z-score Standard Deviation 0.2355
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: KSR2, Change at Week 16	-0.037 z-score Standard Deviation 0.0131
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: TBX3, At Baseline	2.471 z-score Standard Deviation 0.4419
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: TBX3, Change at Week 16	-0.254 z-score Standard Deviation 0.1661
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: TRPC5, At Baseline	2.078 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Overall, At Baseline	2.649 z-score Standard Deviation 0.3708
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Overall: Change at Week 16	-0.126 z-score Standard Deviation 0.1425
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: NRP1, At Baseline	2.919 z-score Standard Deviation 0.0848
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA1, At Baseline	2.729 z-score Standard Deviation 0.1250
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA3, At Baseline	2.485 z-score Standard Deviation 0.4970
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA3, Change at Week 16	-0.234 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PLXNA4, At Baseline	2.693 z-score Standard Deviation 0.3653
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3A, At Baseline	2.498 z-score Standard Deviation 0.2057
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3A, Change at Week 16	-0.078 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3B, At Baseline	2.595 z-score Standard Deviation 0.5201
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3C, Change at Week 16	-0.037 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3G, At Baseline	2.826 z-score Standard Deviation 0.4890
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SEMA3G, Change at Week 16	-0.115 z-score Standard Deviation 0.1020
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PHIP, At Baseline	2.457 z-score Standard Deviation 0.4515
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: PHIP, Change at Week 16	-0.201 z-score Standard Deviation 0.1923
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: SIM1, At Baseline	2.510 z-score Standard Deviation 0.3107
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: MAGEL2, At Baseline	2.503 z-score Standard Deviation 0.3034
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: MAGEL2, Change at Week 16	-0.184 z-score Standard Deviation 0.1615
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: MRAP2, At Baseline	2.738 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: MRAP2, Change at Week 16	-0.019 z-score
Mean Change in BMI Z-score From Baseline to the End of Stage 1 in Participants <18 Years Old, Per Genotype Gene: KSR2, At Baseline	2.831 z-score Standard Deviation 0.2260

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Daily Hunger Questionnaire for participants ≥12 years of age is self-administered questionnaire and comprises three items. For the assessment of this endpoint, maximal hunger was corresponding to the following question: In the last 24 hours, how hungry did you feel when you were the most hungry? The response was scored separately and averaged on weekly basis. Participants rated their hunger on an 11-point numeric rating scale ranging from 0 to 10 (0 = not hungry at all, and 10 = hungriest possible). Weekly average at Week 16 was defined as average of the available score values within 7 days in Week 16. Baseline was defined as the average of the available score values within 7 days before or on the stage 1 open-label treatment. Results are reported by overall participant results and by specific gene cohort.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=139 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3F, Change at Week 16	-48.16 percent change Standard Deviation 24.821
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: DNMT3A, Change at Week 16	-23.00 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: KSR2, Change at Week 16	-42.17 percent change Standard Deviation 30.842
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: TRPC5, Change at Week 16	-16.82 percent change Standard Deviation 28.427
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Overall: Change at Week 16	-31.13 percent change Standard Deviation 63.273
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: NRP2, Change at Week 16	-39.63 percent change Standard Deviation 1.203
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: PLXNA1, Change at Week 16	-21.04 percent change Standard Deviation 10.064
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: PLXNA2, Change at Week 16	-44.12 percent change Standard Deviation 37.973
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: PLXNA3, Change at Week 16	-49.25 percent change Standard Deviation 4.785
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: PLXNA4, Change at Week 16	-54.61 percent change Standard Deviation 31.759
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3A, Change at Week 16	-15.35 percent change Standard Deviation 5.880
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3B, Change at Week 16	-15.79 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3C, Change at Week 16	0.00 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3D, Change at Week 16	36.36 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3E, Change at Week 16	-37.37 percent change Standard Deviation 23.609
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SEMA3G, Change at Week 16	38.70 percent change Standard Deviation 176.373
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: PHIP, Change at Week 16	-56.87 percent change Standard Deviation 19.460
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: SIM1, Change at Week 16	-25.60 percent change Standard Deviation 51.690
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: MAGEL2, Change at Week 16	-39.44 percent change Standard Deviation 30.215
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: HTR2C, Change at Week 16	-37.29 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: MRAP2, Change at Week 16	-47.83 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: RPGRIP1L, Change at Week 16	-100.00 percent change
Percent Change in the Weekly Average of the Daily Maximal Hunger Score From Baseline to the End of Stage 1 in Participants ≥12 Years Old, Per Genotype Gene: TBX3, Change at Week 16	-33.67 percent change Standard Deviation 2.720

SECONDARY outcome

Timeframe: Baseline, Week 16

Population: Participants in the Safety Analysis Set with available data were analyzed.

Outcome measures

Outcome measures
Measure	Stage 1: Setmelanotide (Open-Label) n=141 Participants Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3A	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3B	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: CREBBP	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: MRAP2	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Overall	49 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: NRP2	2 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: PLXNA1	1 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: PLXNA2	3 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: PLXNA3	2 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: PLXNA4	6 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3C	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3D	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3E	2 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3F	2 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SEMA3G	4 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: PHIP	7 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: SIM1	7 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: MAGEL2	5 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: DNMT3A	0 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: HTR2C	1 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: KSR2	3 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: RPGRIP1L	1 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: TBX3	2 Participants
Number of Participants ≥12 Years Old, Who Achieved a ≥2 Point Reduction From Baseline to the End of Stage 1 in the Weekly Average of the Daily Maximal Hunger Score, Per Genotype Gene: TRPC5	1 Participants

Adverse Events

Stage 1: Setmelanotide (Open-Label)

Serious events: 6 serious events

Other events: 160 other events

Deaths: 0 deaths

Stage 2: Setmelanotide (Double-Blind)

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Stage 2: Placebo (Double-Blind)

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Stage 1: Setmelanotide (Open-Label) n=164 participants at risk Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 mg once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily.	Stage 2: Setmelanotide (Double-Blind) n=35 participants at risk Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of setmelanotide 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).	Stage 2: Placebo (Double-Blind) n=14 participants at risk Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of matching placebo 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).
Gastrointestinal disorders Gastritis	0.61% 1/164 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/35 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/14 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.
Gastrointestinal disorders Vomiting	0.61% 1/164 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/35 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/14 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.
Psychiatric disorders Depression	1.2% 2/164 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/35 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/14 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.
Nervous system disorders Headache	0.61% 1/164 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/35 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/14 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.
Respiratory, thoracic and mediastinal disorders Asthma	0.61% 1/164 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/35 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/14 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.
Skin and subcutaneous tissue disorders Angioedema	0.61% 1/164 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/35 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.	0.00% 0/14 • Stage 1 : Baseline to Week 16 Stage 2 : Week 16 to Week 44 Stage 1: Safety Analysis Set included all participants who received at least one dose of trial medication. Stage 2: Safety Analysis Set Enrolled in Stage 2 included all participants who were enrolled in Stage 2 and received at least one dose of trial medication in Stage 2. Three participants in the placebo group were rescued with setmelanotide open-label during Stage 2. They were classified to setmelanotide group.

Other adverse events

Additional Information

Rhythm Pharmaceuticals, Inc.

Rhythm Clinical Trials

Phone: 857-264-4280

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All information regarding setmelanotide supplied by Rhythm to the investigator is privileged and confidential information. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from Rhythm. The information obtained from the clinical study will be used towards the development of setmelanotide and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required.
Publication restrictions are in place

Restriction type: OTHER