Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients with rare genetic disorders of obesity

Phase 1

• Conditions: Treatment of the obesity and hyperphagia of rare genetic disorders of obesity, including:? LepR Deficiency Obesity? POMC Heterozygous Deficiency Obesity? POMC Epigenetic Deficiency Obesity? Bardet-Biedl syndrome? Alström syndrome? LEPR Heterozygous Deficiency Obesity? Bi-allelic, homozygous or compound heterozygous genetic statusfor either the POMC, PCSK1, or LEPR genes, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype; Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

• Registration Number: EUCTR2017-000387-14-ES
• Lead Sponsor: Rhythm Pharmaceuticals, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-05-21
• Last Update Posted: 20 August 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Rare genetic disease patients genetically confirmed diagnoses (may be confirmed by test at Screening) of:
a. Homozygous or compound heterozygous (different gene mutation on both alleles) LepR mutations
b. Heterozygous POMC mutations
c. POMC hypermethylation (epigenetic) variants (>51.92 % POMC methylation intensity at the specific analyzed POMC region)
d. Bardet-Biedl Syndrome
e. Alström Syndrome
f. LEPR Heterozygous Deficiency Obesity
g. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic
status for either the POMC, PCSK1, or LEPR genes, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype.

2. Age 12 years and above.
3. If adult age =18 years, obesity with body mass index (BMI) = 30 kg/m2; if age 12 and above, obesity with weight > 97th percentile for age and sex on growth chart assessment.
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, and be able to understand and sign the written informed consent/assent.
5. Female participants of child-bearing potential must confirmed non-pregnant, and agree to use contraception as outlined in the protocol. Female participants of nonchildbearing 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 FSH level in the postmenopausal
lab range), or delayed pubertal development and failure to have achieved menarche,
do not require contraception during the study.
6. Male participants with female partners of childbearing potential must agree to a double barrier method if they become sexually active during the study. Male patients must not donate sperm during and for 90 days following their participation in the study.
Are the trial subjects under 18? yes
Number of subjects for this age range: 32
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 42
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 6

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 > 2% weight loss. Patients may be reconsidered approximately 1 month after cessation of such intensive regimens.
2. Recent (within 1 month) participation in another clinical trial that would confound the results of this study.
3. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain. Specifically, patients may be considered if surgery was not successful, or resulted in <10% weight loss compared to preoperative baseline weight or clear evidence of weight regain after an initial response to bariatric surgery. All patients with a history of bariatric surgery must be discussed with, and receive approval from Rhythm prior to enrollment.
4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes will interfere significantly with study compliance. Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an appropriate guardian able to give consent has been appointed.
5. A Patient Health Questionnaire-9 (PHQ-9) score of = 15 in subjects with no significant neurocognitive deficits.
6. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in the last month, again in patients without evidence of significant neurocognitive impairment.
7. Current, clinically significant pulmonary, cardiac, or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results. Any such patients should be discussed with the sponsor prior to inclusion.
8. History of significant liver disease or liver injury, or current liver assessment for a cause of abnormal liver tests [as indicated by abnormal liver function tests, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or serum bilirubin (> 1.5 x upper limit of normal (ULN) for any of these tests)] for an etiology other than non-alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis will be exclusionary, but the presence of NAFLD would not be exclusionary.
9. History or presence of impaired renal function as indicated by clinically significant abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockroft Gault equation < 30 mL/min (Appendix 11.10).
10. History or close family history (parents or siblings) of skin cancer or melanoma, or patient history of ocularcutaneous albinism.
11. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions, determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist. Any concerning lesions identified during the screening period 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.
12. Volunteer is, in the opinion of the Study Investigator, not suitable to participate in the s

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified