Clinical Trials Register

Summary
EudraCT Number:	2021-002855-12
Sponsor's Protocol Code Number:	RM-493-034
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-09-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2021-002855-12

A.3

Full title of the trial

A 2-Stage (Open-Label Run-in followed by Randomized Withdrawal),
Double-Blind, Placebo-Controlled, Phase 2 study of Setmelanotide in
Patients with Specific Gene Defects in the Melanocortin-4 Receptor
Pathway

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of setmelanotide in obese patients with specific genetic defects

A.3.2

Name or abbreviated title of the trial where available

Setmelanotide in patients with specific gene defects

A.4.1

Sponsor's protocol code number

RM-493-034

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04963231

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Rhythm Pharmaceuticals Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Rhythm Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Rhythm Pharmaceuticals Inc.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	222 Berkeley Street, Suite 1200
B.5.3.2	Town/ city	Boston
B.5.3.3	Post code	MA02116
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 857 264 4280
B.5.5	Fax number	+1 857 264 4299
B.5.6	E-mail	oohayon@rhythmtx.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2101
D.3 Description of the IMP
D.3.1	Product name	Setmelanotide
D.3.2	Product code	RM-493
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Setmelanotide
D.3.9.1	CAS number	920014-72-8
D.3.9.2	Current sponsor code	RM-493
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Specific Gene Defects in the Melanocortin-4 Receptor Pathway, responsible for improper functions of certain
messenger materials in the body. E.g Melanocyte-Stimulating Hormone (MSH)

E.1.1.1

Medical condition in easily understood language

Improper function of certain messenger materials in the body that control body weight and hunger in people
Identify the therapeutic area

E.1.1.2

Therapeutic area

Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the proportion of obese patients with genetic defects in the melanocortin-4 receptor (MC4R) pathway who
achieve a clinically meaningful reduction in body weight in response to setmelanotide after an initial response to
open-label treatment

E.2.2

Secondary objectives of the trial

To evaluate the initial response to open-label treatment with setmelanotide in patients with genetic defects in the
MC4R pathway
To evaluate change in weight, waist circumference, hunger and quality of life in response to setmelanotide in patients
with genetic defects in the MC4R pathway
To evaluate the safety and tolerability of setmelanotide in patients with genetic defects in the MC4R pathway

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients must have a pre-identified genetic variant in an established MC4R pathway gene that contributes to obesity.
For a gene variant to be eligible for inclusion in the study, the variant must be categorized by a CLIA/CAP/ISO15189
certified laboratory using American College of Medical Genetics (ACMG) criteria as (1) Pathogenic, (2) Likely
Pathogenic, or (3) a Variant of Uncertain Significance (VUS). In the case where an investigator has genetic results on a
patient who may be eligible for the study, but the genetics have not yet been categorized by a CLIA/CAP/ISO15189
certified laboratory, then the Sponsor may provide testing and/or categorization through a third-party laboratory.
2. Patients between the ages of 6 and 65, inclusive, at the time of signing Informed Consent or Assent are eligible for
the study.
3. Obese, defined as BMI ≥40 kg/m2 for patients ≥18 years of age or BMI ≥97th percentile for age and gender for
patients 6 up to <18 years of age based on the United States (US) Centers for Disease Control and Prevention criteria.
4. Study participant and/or parent or guardian is able to communicate well with the Investigator, to understand and
comply with the requirements of the study (including QD injection regimen and all other study procedures) and is able
to understand and sign the written informed consent/assent. Patients who are unable to comply with all study
procedures due to cognitive limitations or any other reason should not be enrolled into the study.
5. If male or a childbearing female, including pre-pubertal females if relevant, agrees to use a highly reliable form of
contraception throughout the study and for 90 days following the study.
Highly reliable acceptable forms of contraception include hormonal (i.e., oral, implantable, or injectable) AND singlebarrier
method (i.e., condom), or an intrauterine device (IUD) AND single-barrier method (i.e., condom) or
vasectomy/vasectomized partner. True abstinence is acceptable only if it is the preferred and usual lifestyle of the
patient. Female participants of non-childbearing potential, defined as surgically sterile (status post hysterectomy,
bilateral oophorectomy, or bilateral tubal ligation), post-menopausal for at least 12 months (and confirmed with a
screening follicle-stimulating hormone [FSH] level in the post-menopausal lab range), and failure to have achieved
menarche, do not require contraception during the study. Female patients must not become pregnant and male
patients must not donate sperm during and for 90 days following their participation in the study.

E.4

Principal exclusion criteria

1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents
including herbal medications that has resulted in >3% weight loss.
2. Use of any medication that is approved to treat obesity within 3 months of first dose of study drug (e.g., orlistat,
lorcaserin, phentermine-topiramate, naltrexone-bupropion).
3. Bariatric surgery within the previous 6 months.
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder, major depressive disorder, or other psychiatric
disorder(s) that the Investigator believes will interfere significantly with study compliance.
5. Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, any
suicide attempt in the past 20 years or any suicidal behavior in the last month.
6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with
the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed
with the Sponsor to determine eligibility.
7. Has significant features of (or meets the diagnostic criteria for) a genetic syndrome that is associated with obesity,
such as Tatton-Brown-Rahman syndrome (DNMT3A), Rett Syndrome (MECP2), Chung-Jansen syndrome (PHIP),
Schaaf-Yang syndrome (MAGEL2), ulnar mammary syndrome (TBX3), or Rubinstein-Taybi syndrome (CREBBP).
Note: Although some of the genetic variants that are eligible to be enrolled into this study are associated with specific
syndromes, the intent of this study is not to enroll children with significant cognitive impairment or other significant comorbidities.
Patients with the correct genetic variants, but who otherwise do not exhibit the syndrome, are eligible for
enrollment.
8. Glycated hemoglobin (HbA1C) >10.0% at Screening.
9. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic
steatohepatitis (NASH).
10. Glomerular filtration rate (GFR) <60 mL/min at Screening.
11. History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
Note: If the type of skin cancer is not known, then the patient should not be enrolled into the study.
12. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive
basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator
during Screening. Any concerning lesions identified during Screening will be biopsied and results known to be benign
prior to enrollment. If the pretreatment biopsy results are of concern, the patient may need to be excluded from the
study.
13. Patient is, in the opinion of the Investigator, not suitable to participate in the study.
14. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
15. Patients previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
16. Significant hypersensitivity to any excipient in the study drug.
17. Females who are breastfeeding or nursing.

E.5 End points

E.5.1

Primary end point(s)

To evaluate the proportion of obese patients with genetic defects in the MC4R pathway who achieve a clinically
meaningful reduction in body weight in response to setmelanotide after an initial response to open-label treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

The proportion of patients who enter Stage 2 who are Responders to active treatment compared to placebo, where
Responders are defined as:
− for patients ≥18 years old at the time of enrollment: achieving a ≥10% reduction in body weight from Baseline
− for patients <18 years old at the time of enrollment: achieving a reduction of BMI Z-score of ≥0.3 from Baseline

E.5.2

Secondary end point(s)

To evaluate the initial response to open-label treatment with setmelanotide in patients with genetic defects in the
MC4R pathway
To evaluate change in body weight, waist circumference, hunger and quality of life in response to setmelanotide in
patients with genetic defects in the MC4R pathway
To evaluate the safety and tolerability of setmelanotide in patients with genetic defects in the MC4R pathway

E.5.2.1

Timepoint(s) of evaluation of this end point

The proportion of enrolled patients who meet the criteria to enter Stage 2 of the study compared to a historic rate of 5%
Mean change and percent change in body weight from Baseline in patients ≥18 years old on active treatment
compared to placebo
Mean change in BMI Z-score from Baseline in patients <18 years old on active treatment compared to placebo
Mean percent change in waist circumference from Baseline in patients ≥12 years of age compared to placebo
Mean percent change in the weekly average hunger score from Baseline.
Change from Baseline in The 5-level EQ-5D (EQ-5D-5L) and the Impact of Weight on Quality of Life-Lite (IWQOL-Lite)
Safety and tolerability assessed by the frequency and severity of AEs, vital signs, ECGs, and laboratory evaluations

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Israel

Saudi Arabia

Turkey

United States

Belgium

Denmark

France

Germany

Italy

Netherlands

Spain

United Kingdom

Greece

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1