Clinical Trial Results:
Title: A Phase 2, Open-Label 20-Week Study to Evaluate the Safety and Efficacy of Setmelanotide in Subjects with Hypothalamic Obesity. Trial design: This was a Phase 2, multicentre, open-label, proof of concept study designed to assess the effect of setmelanotide on weight in individuals affected by hypothalamic obesity (HO). It was planned to enrol approximately 15 patients with HO, aged 6 to 40 years, across 3-5 clinical sites in the US. HO is caused by hypothalamic insults (eg, tumours, tumour resections, radiotherapy treatment) that may result in defective leptin signalling (the MC3/4 receptor pathway). The study consisted of a 2-8 week screening period and a 16-week treatment period. After enrolment, patients entered the screening period when they completed a daily hunger questionnaire. During the treatment period, all patients initiated treatment with subcutaneous (SC) setmelanotide and the dose was to be escalated to a final dose of 3.0 mg once daily (QD) (the therapeutic dose). Patients were to continue dosing at 3.0 mg QD and return to the clinic every 4 weeks (at Visits 3-5) to complete all study assessments. Note, doses of <3.0 mg QD could be administered if needed due to an adverse event or other safety or tolerability concern. After 16 weeks, at Visit 6, the patient received the last setmelanotide injection and participation in the study concluded in one of the following 2 ways: • Completed Visit 6 and enrolled in a separate extension study, Rhythm Study RM-493-022. • Decided not to participate in the extension study and proceeded to the End-of-Study (EOS) visit (Visit 7) at Week 20 for a final safety review. The median duration of treatment was 16.14 weeks (range: 7.43 to 22.57 weeks). The primary endpoint was defined as the proportion of patients who achieved at least 5% body mass index (BMI) reduction from baseline at ~16 weeks of treatment with setmelanotide.

Trial information Top of page
Trial identification
Sponsor protocol code	RM-493-030
Additional study identifiers
ISRCTN number	-
US NCT number	NCT04725240
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Rhythm Pharmaceuticals, Inc,
Sponsor organisation address	222 Berkeley Street, 12th Floor, Boston, United States, MA 02116
Public contact	Clinical Trial Information Desk, Rhythm Pharmaceuticals, Inc., +1 857-264-4280, clinicaltrials@rhythmtx.com
Scientific contact	Clinical Trial Information Desk, Rhythm Pharmaceuticals, Inc., +1 857-264-4280, clinicaltrials@rhythmtx.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	31 Aug 2022
Is this the analysis of the primary completion data?	Yes
Primary completion date	28 Jun 2022
Global end of trial reached?	Yes
Global end of trial date	28 Jun 2022
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The primary objective was to evaluate the change in body weight in response to setmelanotide administered subcutaneously (SC) daily in patients with HO.
Protection of trial subjects	The Institutional Review Board (IRB) reviewed all appropriate study documentation in order to safeguard the rights, safety, and well-being of the patients. The study was only conducted at sites where IRB/IEC approval had been obtained. This study was conducted in accordance with: • Consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines • The International Council for Harmonisation (ICH) Good Clinical Practices (GCP) Guideline [E6] • Applicable laws and regulatory requirements. After the study had been fully explained, written informed consent was obtained from either the patient or his/her guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent complied with ICH-GCP and all applicable regulatory requirement(s).
Background therapy	Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) received at the time of enrolment or received during the study had to be recorded. The Medical Monitor was to be contacted with any questions regarding concomitant or prior therapy. However, patients were not permitted to enter the study if they have had weight gain >5% during the previous 3 months or >2% weight loss during the prior 3 months. Dietary and/or exercise regimens, with or without the use of medications, supplements or herbal treatments associated with weight loss (eg, orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, GLP1 receptor agonists, etc.) were allowed if: • the regimen and/or dose had been stable for at least 3 months prior to randomisation • the patient had not experienced weight loss ≥2% during the previous 3 months, AND • the patient intended to keep the regimen and/or dose stable throughout the course of the study. GLP 1 receptor agonists could be used up to the dose approved for the treatment of diabetes mellitus (eg, liraglutide up to a daily dose of 1.8 mg) as long as (1) it was not being prescribed for the treatment of obesity, (2) the dose had been stable for at least 3 months prior to enrolment, (3) the patient had not experienced >3% weight loss during the previous 3 months, AND (4) the patient intended to keep the dose stable throughout the course of the study. Other medications that could have caused weight loss were allowed as long as the patient (1) had used a stable dose for at least 3 months prior to enrolment, (2) had not lost weight during the previous 3 months, and (3) intended to keep the dose stable through the course of the study. All concomitant medications had to be kept at a stable dose throughout the course of the study, unless a dose change was necessary to treat an AE.
Evidence for comparator	Not applicable.
Actual start date of recruitment	06 Jun 2021
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	United States: 18
Worldwide total number of subjects	18
EEA total number of subjects	0
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	5
Adolescents (12-17 years)	8
Adults (18-64 years)	5
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	This study recruited 18 patients with HO in 5 clinical sites in the United States with the first patient enrolled on 06 June 2021 (first dosed 12 July 2021) and the last patient visit on 28 June 2022. Patients were included if they had documented evidence of HO.
Pre-assignment
Screening details	Screening assessments included medical history, physical exam, comprehensive skin examination, laboratory tests, blood pressure, hunger scale, body composition, Columbia-Suicide Severity Rating Scale (C-SSRS) form, and energy expenditure evaluation.
Period 1
Period 1 title	Baseline (overall period)
Is this the baseline period?	Yes
Allocation method	Not applicable
Blinding used	Not blinded
Blinding implementation details	This was an open-label, proof-of-concept study.
Arms
Arm title	All patients
Arm description	All patients with HO included in the study.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. The standard dose escalation was: Patients aged 6 to <16 years: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients aged >=16 years: 2.0 mg in Weeks 1-2, and 3.0 mg in Weeks 3-16.
Number of subjects in period 1 All patients Started 18 Completed 16 Not completed 2      Adverse event, non-fatal 2

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	All patients
Reporting group description	All patients with HO included in the study.
Reporting group values All patients Total Number of subjects 18 18 Age categorical Units: Subjects     < 18 13 13     >= 18 5 5 Age continuous Units: years     arithmetic mean (standard deviation) 15.0 ± 5.30 - Gender categorical Units: Subjects     Female 7 7     Male 11 11 Weight at baseline The most recent weight measurement prior to the first administration of study drug. Units: kilogram(s)     arithmetic mean (standard deviation) 102.76 ± 30.120 - BMI at baseline The most recent body mass index (BMI) measurement prior to the first administration of study drug. Units: kg/m2     arithmetic mean (standard deviation) 37.95 ± 6.532 - Waist circumference at baseline The most recent waist circumference measurement prior to the first administration of study drug. Units: centimetre     arithmetic mean (standard deviation) 114.07 ± 16.354 -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	All patients
Reporting group description	All patients with HO included in the study.
Subject analysis set title	Patients aged ≥6 to <18 years
Subject analysis set type	Full analysis
Subject analysis set description	Patients aged ≥6 to <18 years
Subject analysis set title	Patients aged ≥18 years
Subject analysis set type	Full analysis
Subject analysis set description	Patients aged ≥18 years
Subject analysis set title	Patients aged <12 years
Subject analysis set type	Full analysis
Subject analysis set description	Patients aged <12 years
Subject analysis set title	Patients aged ≥12 years
Subject analysis set type	Full analysis
Subject analysis set description	Patients aged ≥12 years

End points Top of page

Primary: Patients with ≥5% BMI reduction from baseline Top of page
End point title	Patients with ≥5% BMI reduction from baseline [1]
End point description	The proportion of patients with HO who achieved at least 5% reduction from baseline in BMI after 16 weekss of treatment with setmelanotide. The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided. A p-value of <0.0001 was calculated from a one-sided exact binomial test comparing to the null hypothesis proportion of 0.05 (which comes from a historical control rate of 5%).
End point type	Primary
End point timeframe	From baseline to Week 16.
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis of the primary endpoint was planned or performed because this was an open-label study with no comparator group. A comparison with a historical control group is described above.
End point values All patients Number of subjects analysed 18 Units: percent     number (confidence interval 90%) 88.9 (69.0 to 98.0)
No statistical analyses for this end point

Primary: Patients with ≥5% BMI reduction from baseline Top of page

Secondary: Composite reduction in BMI Z-score and change in body weight Top of page
End point title	Composite reduction in BMI Z-score and change in body weight
End point description	Composite proportion of patients aged ≥6 to <18 years with ≥0.2 reduction of BMI Z-score and patients aged ≥18 years with ≥5% reduction of body weight from baseline after 16 weeks of setmelanotide. The summary of the endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided. A p-value of <0.0001 was calculated from a one-sided exact binomial test comparing to the null hypothesis proportion of 0.05 (which comes from a historical control rate of 5%).
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values All patients Number of subjects analysed 18 Units: percent     number (confidence interval 90%) 88.9 (69.0 to 98.0)
No statistical analyses for this end point

Secondary: Composite reduction in BMI Z-score and change in body weight Top of page

Secondary: Reduction in BMI Z-score in patients aged ≥6 to <18 years Top of page
End point title	Reduction in BMI Z-score in patients aged ≥6 to <18 years
End point description	The proportion of patients aged ≥6 to <18 years with HO with ≥0.2 reduction of BMI Z-score from baseline at 16 weeks of treatment with setmelanotide. The summary of the endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided. A p-value of <0.0001 was calculated from a one-sided exact binomial test comparing to the null hypothesis proportion of 0.05 (which comes from a historical control rate of 5%).
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values Patients aged ≥6 to <18 years Number of subjects analysed 13 Units: percent     number (confidence interval 90%) 92.3 (68.4 to 99.6)
No statistical analyses for this end point

Secondary: Reduction in BMI Z-score in patients aged ≥6 to <18 years Top of page

Secondary: Reduction in body weight in patients aged ≥18 years Top of page
End point title	Reduction in body weight in patients aged ≥18 years
End point description	The proportion of patients aged ≥18 years with HO with ≥5% reduction of body weight from baseline at 16 weeks of treatment with setmelanotide. The summary of the endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided. A p-value of <0.0001 was calculated from a one-sided exact binomial test comparing to the null hypothesis proportion of 0.05 (which comes from a historical control rate of 5%).
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values Patients aged ≥18 years Number of subjects analysed 5 Units: percent     number (confidence interval 90%) 80.0 (34.3 to 99.0)
No statistical analyses for this end point

Secondary: Reduction in body weight in patients aged ≥18 years Top of page

Secondary: Change in waist circumference - ≥18 years of age Top of page
End point title	Change in waist circumference - ≥18 years of age
End point description	The change in waist circumference from baseline in patients aged ≥18 years at 16 weeks of treatment with setmelanotide. The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values Patients aged ≥18 years Number of subjects analysed 4 Units: percent     arithmetic mean (confidence interval 90%) -8.13 (-11.832 to -4.419)
No statistical analyses for this end point

Secondary: Change in waist circumference - ≥18 years of age Top of page

Secondary: Change in waist circumference - <18 years of age Top of page
End point title	Change in waist circumference - <18 years of age
End point description	The change in waist circumference from baseline in patients aged <18 years at 16 weeks of treatment with setmelanotide. The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values Patients aged ≥6 to <18 years Number of subjects analysed 12 Units: percent     arithmetic mean (confidence interval 90%) -11.14 (-14.050 to -8.233)
No statistical analyses for this end point

Secondary: Change in waist circumference - <18 years of age Top of page

Secondary: Change in hunger score - <12 years of age Top of page
End point title	Change in hunger score - <12 years of age
End point description	The change in daily hunger score from baseline in patients aged <12 years at 16 weeks of treatment with setmelanotide. The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values Patients aged <12 years Number of subjects analysed 5 Units: percent     arithmetic mean (confidence interval 90%) -62.02 (-84.741 to -39.307)
No statistical analyses for this end point

Secondary: Change in hunger score - <12 years of age Top of page

Secondary: Change in hunger score - ≥12 years of age Top of page
End point title	Change in hunger score - ≥12 years of age
End point description	The change in daily hunger score from baseline in patients aged ≥12 years at 16 weeks of treatment with setmelanotide. The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to Week 16.
End point values Patients aged ≥12 years Number of subjects analysed 11 Units: percent     arithmetic mean (confidence interval 90%) -65.26 (-84.512 to -46.017)
No statistical analyses for this end point

Secondary: Change in hunger score - ≥12 years of age Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From baseline to Week 16 of treatment.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	24.0
Reporting groups
Reporting group title	All patients
Reporting group description	All patients with HO included in the study.
Serious adverse events All patients Total subjects affected by serious adverse events      subjects affected / exposed 1 / 18 (5.56%)      number of deaths (all causes) 0      number of deaths resulting from adverse events 0 Infections and infestations Clostridium difficile colitis      subjects affected / exposed 1 / 18 (5.56%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events All patients Total subjects affected by non serious adverse events      subjects affected / exposed 18 / 18 (100.00%) General disorders and administration site conditions Fatigue      subjects affected / exposed 3 / 18 (16.67%)      occurrences all number 4 Injection site pain      subjects affected / exposed 3 / 18 (16.67%)      occurrences all number 3 Injection site pruritus      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Pain      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Pyrexia      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Injection site erythema      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Injection site induration      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Injection site swelling      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Reproductive system and breast disorders Erection increased      subjects affected / exposed [1] 3 / 11 (27.27%)      occurrences all number 3 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Epistaxis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Nasal congestion      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Psychiatric disorders Conversion disorder      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Investigations Alanine aminotransferase increased      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Blood creatine phosphokinase increased      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Blood uric acid increased      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Hepatic enzyme increased      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 2 Weight decreased      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Injury, poisoning and procedural complications Contusion      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Radius fracture      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Congenital, familial and genetic disorders Type V hyperlipidaemia      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Nervous system disorders Headache      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Balance disorder      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Seizure      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Speech disorder      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Blood and lymphatic system disorders Anaemia      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Gastrointestinal disorders Nausea      subjects affected / exposed 11 / 18 (61.11%)      occurrences all number 15 Vomiting      subjects affected / exposed 6 / 18 (33.33%)      occurrences all number 8 Diarrhoea      subjects affected / exposed 4 / 18 (22.22%)      occurrences all number 4 Abdominal pain      subjects affected / exposed 3 / 18 (16.67%)      occurrences all number 3 Abdominal pain upper      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 2 Gastritis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Portal hypertensive gastropathy      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Hepatobiliary disorders Hypertransaminasaemia      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Hepatic steatosis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Skin and subcutaneous tissue disorders Skin hyperpigmentation      subjects affected / exposed 6 / 18 (33.33%)      occurrences all number 6 Acne      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Rash      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Rash erythematous      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Musculoskeletal and connective tissue disorders Back pain      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Myalgia      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Pain in extremity      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Scoliosis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Infections and infestations COVID-19      subjects affected / exposed 4 / 18 (22.22%)      occurrences all number 5 Upper respiratory tract infection      subjects affected / exposed 2 / 18 (11.11%)      occurrences all number 2 Administration site cellulitis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Gastroenteritis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Sinusitis      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Staphylococcal abscess      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1 Metabolism and nutrition disorders Dehydration      subjects affected / exposed 1 / 18 (5.56%)      occurrences all number 1
Notes [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: This denominator includes only the male subjects in the group (N = 11).

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
09 Sep 2021	There was one protocol amendment. In this amendment, in addition to some clarifications or minor changes to inclusion and exclusion criteria, and administrative updates, the patient population was revised to allow older patients to be included (due to the rare nature of the disease under investigation) and the number of patients aged 6-10 years was restricted to a maximum of 10. Additionally, the primary endpoint was changed from an evaluation of weight loss to a reduction in BMI. Also, secondary endpoints were revised to define key secondary endpoints.
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

More information Top of page