Trial Outcomes & Findings for Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity (NCT NCT03746522)

Last Updated: 2023-12-01

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

52 participants

Primary outcome timeframe

52 weeks

Results posted on

2023-12-01

Participant Flow

Participants were enrolled in pivotal cohort (38 participants) or supplemental cohort (14 participants) and received setmelanotide/placebo for the 14-week double-blind period (Period 1) followed by setmelanotide in the open-label period (Period 2 and 3).

As planned, the analysis of the primary and secondary endpoints were done only in the pivotal cohort. Pivotal cohort: All the enrolled Bardet-Biedl syndrome (BBS)/Alström Syndrome (AS) participants at the time of the planned sixth AS participant enrollment. Supplemental cohort: Any additional participants enrolled were included in supplemental cohort.

Participant milestones

Participant milestones
Measure	Setmelanotide (Double-Blind) Participants received once daily subcutaneous (SC) injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). Participants ≥16 years of age started on setmelanotide 2.0 mg with dose escalation to 3.0 mg. Participants \<16 years of age started on setmelanotide 1.0 mg with dose escalation to 3.0 mg.	Placebo (Double-Blind) Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1).	Setmelanotide (Open-label) After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).
Period 1: Double-Blind (14 Weeks) STARTED	27	25	0
Period 1: Double-Blind (14 Weeks) COMPLETED	27	23	0
Period 1: Double-Blind (14 Weeks) NOT COMPLETED	0	2	0
Period 2: Open-Label (38 Weeks) STARTED	0	0	50
Period 2: Open-Label (38 Weeks) COMPLETED	0	0	41
Period 2: Open-Label (38 Weeks) NOT COMPLETED	0	0	9
Period 3: Open-Label (14 Weeks) STARTED	0	0	41
Period 3: Open-Label (14 Weeks) COMPLETED	0	0	41
Period 3: Open-Label (14 Weeks) NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo (Double-Blind) Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1).	Setmelanotide (Open-label) After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).
Period 1: Double-Blind (14 Weeks) Adverse Event	1	0
Period 1: Double-Blind (14 Weeks) Withdrawal by Subject	1	0
Period 2: Open-Label (38 Weeks) Withdrawal by Subject	0	3
Period 2: Open-Label (38 Weeks) Adverse Event	0	4
Period 2: Open-Label (38 Weeks) Other than specified	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Setmelanotide n=27 Participants Participants received once daily SC injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). Participants ≥16 years of age started on setmelanotide 2.0 mg with dose escalation to 3.0 mg. Participants \<16 years of age started on setmelanotide 1.0 mg with dose escalation to 3.0 mg. After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).	Placebo n=25 Participants Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).	Total n=52 Participants Total of all reporting groups
Age, Continuous	18.3 years STANDARD_DEVIATION 9.95 • n=5 Participants	20.7 years STANDARD_DEVIATION 12.05 • n=7 Participants	19.5 years STANDARD_DEVIATION 10.96 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	18 Participants n=7 Participants	31 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	7 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants n=5 Participants	22 Participants n=7 Participants	44 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants	21 Participants n=7 Participants	38 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	7 Participants n=5 Participants	1 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment Canada	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment United States	16 Participants n=5 Participants	17 Participants n=7 Participants	33 Participants n=5 Participants
Region of Enrollment United Kingdom	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Region of Enrollment France	4 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants
Region of Enrollment Spain	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: 52 weeks

Population: Participants in the Full Analysis Set (defined as randomized participants who received at least 1 dose of study drug and had active treatment baseline \[ATB\] data) with available data were analyzed. Participants in the pivotal cohort who received setmelanotide (and were ≥12 years of age) were included in the analysis.

Outcome measures

Outcome measures
Measure	Pivotal Cohort n=31 Participants Participants received once daily SC injection of setmelanotide/placebo for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2).
Percentage of Participants (≥12 Years of Age at Baseline) Who Reached ≥10% Weight Loss Threshold After 1 Year (Period 2): Pivotal Cohort	32.3 percentage of participants Interval 16.7 to 51.4

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Participants in the Full Analysis Set with available data were analyzed. Participants in pivotal cohort who received setmelanotide (and were ≥12 years of age) were included in the analysis.

The mean percent change from baseline in body weight at 52 weeks was analyzed. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of the placebo-controlled period, all participants from the placebo group switched to setmelanotide treatment. The placebo group was integrated into the 52-week analysis so that the participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of "active" treatment. Placebo participants were also included in this analysis.

Outcome measures

Outcome measures
Measure	Pivotal Cohort n=31 Participants Participants received once daily SC injection of setmelanotide/placebo for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2).
Mean Percent Change From Baseline in Body Weight (≥12 Years of Age) at Week 52 (Period 2): Pivotal Cohort	-5.21 percent change Standard Deviation 7.895

SECONDARY outcome

Timeframe: Baseline, Week 52

Mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0= "not hungry at all" to 10= "hungriest possible" on Likert-type scale. On Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on weekly basis. Weekly average hunger score of daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of the placebo-controlled period, all participants from the placebo group switched to setmelanotide treatment. Placebo group was integrated into the 52-week analysis so that participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of "active" treatment. Placebo participants were also included in this analysis.

Outcome measures

Outcome measures
Measure	Pivotal Cohort n=16 Participants Participants received once daily SC injection of setmelanotide/placebo for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2).
Mean Percent Change From Baseline in the Weekly Average of the Daily Hunger Score (≥12 Years of Age) at Week 52 (Period 2): Pivotal Cohort	-30.91 percent change Standard Deviation 24.733

SECONDARY outcome

Timeframe: Baseline, Week 52

Population: Participants in Full Analysis Set with available data were analyzed. Participants in pivotal cohort who received setmelanotide (and were ≥12 years of age) were included in the analysis.

Number of participants (≥12 years of age with no cognitive impairment) achieving ≥25% improvement from baseline in hunger score at Week 52 was assessed. Hunger score ranged from 0= "not hungry at all" to 10= "hungriest possible" on Likert-type scale. On Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on weekly basis. Weekly average hunger score of daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. There was a 14-week placebo-controlled period at the beginning of the trial. After completion of placebo-controlled period, all participants from placebo group switched to setmelanotide treatment. Placebo group was integrated into the 52-week analysis so that participants who received placebo, had 52 weeks of setmelanotide treatment after the first dose of "active" treatment. Placebo participants were also included in this analysis.

Outcome measures

Outcome measures
Measure	Pivotal Cohort n=16 Participants Participants received once daily SC injection of setmelanotide/placebo for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2).
Number of Participants (≥12 Years of Age With no Cognitive Impairment) Who Achieved a ≥ 25% Improvement in the Weekly Average of the Daily Hunger Score From Baseline at Week 52 (Period 2): Pivotal Cohort	10 Participants

Adverse Events

Setmelanotide (Double-Blind Period)

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

Placebo (Double-Blind Period)

Serious events: 2 serious events

Other events: 24 other events

Deaths: 0 deaths

Setmelanotide (Open-label)

Serious events: 0 serious events

Other events: 45 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Setmelanotide (Double-Blind Period) n=27 participants at risk Participants received once daily SC injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1).	Placebo (Double-Blind Period) n=25 participants at risk Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1).	Setmelanotide (Open-label) n=50 participants at risk After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).
Blood and lymphatic system disorders Anaemia	3.7% 1/27 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	0.00% 0/25 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	0.00% 0/50 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.
Eye disorders Blindness	0.00% 0/27 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	4.0% 1/25 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	0.00% 0/50 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.
Immune system disorders Anaphylactic reaction	0.00% 0/27 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	4.0% 1/25 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	0.00% 0/50 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.
Psychiatric disorders Suicidal ideation	0.00% 0/27 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	0.00% 0/25 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.	0.00% 0/50 • Double-blind: From first dose up to Week 14 Open-label: From Week 14 up to Week 66 Safety Analysis Set was defined as participants who received at least 1 dose of study drug (placebo or setmelanotide). Participants in the pivotal and supplemental cohorts were included.

Other adverse events

Additional Information

Rhythm Clinical Trials

Rhythm Pharmaceuticals, Inc.

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.
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Restriction type: OTHER