A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-Controlled Stage), Phase 2 Trial of Setmelanotide in Patients with Specific Gene Variants in the Melanocortin-4 Receptor Pathway

Phase 2

Recruiting

Conditions: Gene defects
obesity
10027424

Registration Number: NL-OMON54472

Lead Sponsor: Rhythm Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 11

Inclusion Criteria

1. Patients must have a pre-identified genetic variant in an established MC4R
pathway gene that contributes to obesity
Note: Genetic testing requirements and a list of genes which have variants that
are eligible for enrollment into the trial are provided in Appendix 1 of the
protocol.
2. Patients between the ages of 6 and 65, inclusive, at the time of signing
Informed Consent or Assent.
3. Patients with obesity, defined as BMI >=40 kg/m2 for patients >=18 years of
age or BMI >=97th percentile for age and gender for patients 6 to <18 years of
age based on the US Centers for Disease Control and Prevention criteria.
4. Patient and/or parent or guardian is able to communicate well with the
Investigator, to understand and comply with the requirements of the trial
(including the QD injection regimen and all other trial procedures) and is able
to understand and sign the written informed consent/assent. Patients who are
unable to comply with all trial procedures due to cognitive limitations or any
other reason should not be enrolled.
5. Patient must meet one of the following requirements:
Female participants of childbearing potential, defined as fertile, following
menarche and until becoming post-menopausal unless permanently sterile
(hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must be
confirmed non-pregnant and agree to use a highly effective form of
contraception throughout the trial and for 90 days following the trial.
Highly effective forms of contraception are detailed below and in Section 8.9.7
of the protocol:
• Combined (estrogen and progestin) hormonal contraception associated with
inhibition of ovulation (i.e., oral, intravaginal, or transdermal)
• Progestin-only hormonal contraception associated with inhibition of ovulation
(oral, implantable, or injectable)
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomy/vasectomized partner (provided that the vasectomized partner is the
sole sexual partner of the female participant, and the vasectomized partner has
received medical assessment of surgical success)
• Sexual abstinence, only if it is the preferred and usual lifestyle of the
patient
Female participants of non-childbearing potential, defined as: permanently
sterile (status post hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy), or post-menopausal for at least 12 months (and confirmed with a
screening follicle-stimulating hormone level in the post-menopausal lab range)
and do not require contraception during the trial.
Younger female patients who have not achieved sexual maturity at trial entry
will be assessed for Tanner staging and required to comply with contraception
requirements at first menarche.
Male participants with female partners of childbearing potential must agree to
use a highly effective method contraception if they become sexually active
during the trial or within 90 days following their participation in the trial.
Male patients must also not donate sperm during and for 90 days following their
participation in the trial.
6. Symptoms or behaviors of hyperphagia persistent during the patient*s life,
including manifestations in childhood, as determined by the Investigator at
screening.

Exclusion Criteria

1. Patients with the following genetic variants: biallelic Bardet-Biedl
Syndrome (BBS); biallelic Alström Syndrome 1 (ALMS1); homozygous, heterozygous,
or compound heterozygous variants in MC4R, POMC, PCSK1, LEPR, nuclear receptor
coactivator 1 (NCOA1; steroid receptor coactivator-1 [SRC1]) or SRC homology 2
B adapter protein 1 (SH2B1) genes as well as 16p11.2 chromosomal deletions that
include the SH2B1 gene.
2. Weight loss >2% in the previous 3 months.
Patients will not be excluded for using regimens for weight maintenance or to
prevent weight gain, such as dietary and/or exercise regimens, or medications,
supplements or herbal treatments (e.g., orlistat, lorcaserin, phentermine,
topiramate, naltrexone, bupropion, glucagon-like peptide-1 [GLP-1] receptor
agonists, etc.), provided:
• the regimen and/or dose has been stable for at least 3 months prior to
randomization
• the patient has not experienced weight loss >2% during the previous 3 months,
AND
• the patient intends to keep the regimen and/or dose stable throughout the
course of the trial.
3. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal
switch, gastric balloon, intestinal barrier, etc.) within the last 6 months.
All patients with a history of bariatric surgery or procedures must be
discussed with, and receive approval from, the Sponsor prior to enrollment.
4. Documented diagnosis of current unstable major psychiatric disorder(s)
(e.g., major depressive disorder, bipolar disorder, schizophrenia, etc.) or
documented worsening psychiatric condition that required changes in treatment
regimen within the previous 2 years, or other psychiatric related risks that
the Investigator believes may interfere with trial compliance or patient safety.
5. Clinically significant depression or suicidality, as defined by: any
suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale
(C-SSRS) during Screening, any suicide attempt during the patient*s lifetime,
any suicidal behavior in the last month, or a Patient Health Questionnaire-9
(PHQ-9) score of >=15 during Screening process.
Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to
significant neurocognitive impairment may be enrolled in the trial provided
that there are no clinical signs or symptoms of significant depression or
suicidal behavior in the opinion of the Investigator.
6. Current, clinically significant pulmonary, cardiac, endocrine/metabolic,
hepatic, or oncologic disease considered severe enough to interfere with the
trial and/or confound the results. Any patient with a potentially clinically
significant disease should be reviewed with the Sponsor to determine
eligibility.
7. Significant features of, or meeting the diagnostic criteria for, a genetic
syndrome that is associated with obesity.
Note: Although some of the genetic variants that are eligible to be enrolled
into this trial are associated with specific syndromes, the intent of this
trial is not to enroll children with significant cognitive impairment or other
significant co-morbidities. Patients with eligible genetic variants, but who
otherwise do not exhibit the syndrome, are eligible for enrollment.
8. HbA1C >10.0% at Screening.
9. History of significant liver disease other than non-alcoholic fatty liver
disease (NAFLD) or

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>• The proportion of patients by genotype who demonstrate a significant<br /><br>clinically meaningful response (defined below) to setmelanotide at the end of<br /><br>Stage 1:<br /><br>* For all patients: achieving a >=5% reduction in BMI from Baseline</p><br>

Secondary Outcome Measures