Setmelanotide for Obesity

Not currently recruiting at 58 trial locations

Overseen By Daniel Mogford

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Rhythm Pharmaceuticals, Inc.

Disqualifiers: Psychiatric disorders, Suicidal ideation, Pulmonary, Cardiac, Endocrine, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called setmelanotide to determine its effectiveness for people with obesity linked to specific genetic conditions. Researchers focus on individuals with obesity and specific gene variants in the Melanocortin-4 Receptor pathway, such as POMC, PCSK1, LEPR, SRC1, or SH2B1. The goal is to assess whether setmelanotide can effectively manage weight in people with these genetic profiles. Ideal candidates for this trial are those who have been obese since childhood and have one of these specific genetic variants. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for obesity.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, it excludes participants with certain health conditions and those who have recently participated in other clinical studies, which might imply some restrictions. Please consult with the trial coordinators for specific guidance.

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that setmelanotide is generally safe for people. In studies involving patients with specific genetic types of obesity, such as POMC, PCSK1, and LEPR deficiencies, setmelanotide helped them lose a significant amount of weight, proving its effectiveness. Two long-term studies, each lasting a year with 27 patients, tested the safety of setmelanotide and found it to be safe.

Setmelanotide has already received approval for treating obesity caused by specific genetic conditions, which supports its safety. Common side effects include skin darkening and reactions at the injection site, but these are usually mild. Past studies reported no serious safety issues, making it a promising option for those considering joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for obesity?

Setmelanotide is unique because it specifically targets rare genetic variants linked to obesity, such as NCOA1 (SRC1), POMC, PCSK1, LEPR, and SH2B1. Most treatments for obesity, like lifestyle changes and medications such as orlistat and phentermine, focus on reducing appetite or increasing metabolism generally. However, setmelanotide works by activating the melanocortin-4 receptor (MC4R) pathway, a critical regulator of hunger and energy expenditure. This targeted approach could lead to more effective weight loss for individuals with these specific genetic variants, which is why researchers are excited about its potential.

What evidence suggests that this trial's treatments could be effective for obesity?

Research has shown that setmelanotide yields promising results for weight loss in individuals with certain genetic conditions related to obesity. Studies have found significant weight loss and improvements in body size and hunger levels. For example, one study reported a 14.8% drop in BMI for a patient with a specific type of obesity after six months of treatment. In this trial, participants will be assigned to different arms based on their genetic variants, such as NCOA1 (SRC1), POMC or PCSK1, LEPR, and SH2B1. Other research consistently shows that setmelanotide helps with weight issues, particularly in patients with LEPR-deficiency obesity. This suggests that setmelanotide could be effective for individuals with certain gene changes affecting the Melanocortin-4 Receptor pathway, which plays a key role in controlling weight. ^{6 7 8 9 10}

Who Is on the Research Team?

David Meeker, MD

Principal Investigator

Rhythm Pharmaceuticals, Inc.

Are You a Good Fit for This Trial?

This trial is for people aged 6-65 with obesity and specific genetic variants affecting the MC4R pathway. They should have tried diet and exercise, experienced childhood obesity, and not be pregnant or breastfeeding. Exclusions include recent bariatric surgery, severe psychiatric or medical conditions, a history of melanoma or certain skin lesions, significant weight loss recently, or participation in other drug trials within the last three months.

Inclusion Criteria

Patient and/or parent or guardian must be able to understand and comply with the requirements of the study and must be able to understand and sign the written informed consent/assent

My genetic test shows a variant in the NCOA1 gene.

I have a genetic variant in the POMC or PCSK1 gene.

Exclusion Criteria

I or my immediate family have a history of melanoma, or I have oculocutaneous albinism.

I have had weight loss surgery recently.

Patients with glycated hemoglobin (HbA1C) >10% at Screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive setmelanotide or placebo in a double-blind, randomized manner

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Setmelanotide

Trial Overview The EMANATE trial is testing Setmelanotide against a placebo to see if it helps with weight loss in patients who have certain gene variants linked to obesity. It's randomized (participants are put into groups by chance), double-blind (neither participants nor researchers know who gets what treatment), and has identical goals across different sub-studies focusing on various genes.

How Is the Trial Designed?

Group I: SH2B1 variant Experimental Treatment 2 Interventions

1:1 Randomization

Group II: POMC or PCSK1 variant Experimental Treatment 2 Interventions

1:1 Randomization

Group III: NCOA1 (SRC1) variant Experimental Treatment 2 Interventions

1:1 Randomization

Group IV: LEPR variant Experimental Treatment 2 Interventions

1:1 Randomization

Setmelanotide is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Imcivree for:

• Chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

Approved in European Union as Imcivree for:

• Chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

Approved in Canada as Imcivree for:

• Chronic weight management in adult and pediatric patients 6 years of age and older with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS).

Who Is Running the Clinical Trial?

Rhythm Pharmaceuticals, Inc.

Lead Sponsor

Trials

31

Recruited

10,400+

Published Research Related to This Trial

Setmelanotide is an MC4 receptor agonist approved in the USA for chronic weight management in patients aged 6 and older with obesity due to POMC, PCSK1, or LEPR deficiencies, highlighting its targeted efficacy for specific genetic causes of obesity.

The drug has also received PRIME designation from the European Medicines Agency, indicating its potential for treating obesity and hunger control in various rare genetic disorders linked to the MC4 receptor pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Setmelanotide: First Approval. Markham, A.[2021]

Setmelanotide significantly aids in weight loss for patients with severe obesity linked to MC4R deficiency, with an average weight loss of 6.91% over a mean follow-up of 52 weeks among 328 patients.

While effective for weight loss, setmelanotide is associated with an increased risk of skin hyperpigmentation, indicating a need for monitoring side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Setmelanotide, a Melanocortin-4 Receptor Agonist, for Obese Patients: A Systematic Review and Meta-Analysis. Ferraz Barbosa, B., Aquino de Moraes, FC., Bordignon Barbosa, C., et al.[2023]

Setmelanotide is an FDA-approved injectable drug that significantly aids in weight loss, showing at least a 10% decrease in body weight after one year in patients with specific genetic forms of obesity, based on data from multiple clinical trials.

Common side effects include injection site reactions, skin hyperpigmentation, nausea, headache, and diarrhea, indicating that while effective, patients may experience notable adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Setmelanotide: A Novel Targeted Treatment for Monogenic Obesity. Pressley, H., Cornelio, CK., Adams, EN.[2023]

Setmelanotide, a melanocortin-4 receptor activator, has led to significant weight loss in two patients with pro-opiomelanocortin deficiency, a rare condition causing severe obesity.

While setmelanotide shows promise for treating obesity, caution is advised due to its potential effects on other melanocortin receptors, which could lead to unintended consequences.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic Precision Medicines: Curing POMC Deficiency. Müller, TD., Tschöp, MH., O'Rahilly, S.[2022]

Setmelanotide has been approved for treating specific genetic conditions that cause obesity, representing a significant step in personalized medicine for obesity management.

Semaglutide, which has shown to produce approximately twice the weight loss compared to older antiobesity medications, is under regulatory review for treating obesity and is already used for diabetes, highlighting its dual efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next Generation Antiobesity Medications: Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab: What do They Mean for Clinical Practice? Ryan, DH.[2021]

Setmelanotide is a potent MC4R agonist that effectively promotes weight loss in obese individuals with MC4R deficiency, as demonstrated in a 28-day Phase 1b clinical trial.

The drug showed greater efficacy in patients with POMC defects compared to those with MC4R mutations, indicating that while Setmelanotide can aid weight loss in MC4R deficiency, further research is needed to determine its effectiveness across different genetic backgrounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Collet, TH., Dubern, B., Mokrosinski, J., et al.[2022]

Setmelanotide, a melanocortin-4 receptor agonist, led to significant weight loss of 30 kg (36% of body weight) in a 5-year-old child with obesity due to POMC deficiency after 12 months of treatment, demonstrating its efficacy in managing genetic obesity.

The treatment not only improved the child's hyperphagia and metabolic status but also positively impacted the quality of life for the parents, highlighting the broader benefits of early intervention with setmelanotide in young children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial Effects of Setmelanotide in a 5-Year-Old Boy With POMC Deficiency and on His Caregivers. Dubern, B., Lourdelle, A., Clément, K.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10608339/

Efficacy and Safety of Setmelanotide, a Melanocortin-4 ... Our results show that setmelanotide (MC4R agonist) is associated with significant weight loss, body measurement, and hunger improvements in individuals who ...

2. ir.rhythmtx.com ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-new-data-presentations-patients

Release Details One adult patient with congenital hypothalamic obesity achieved a -14.8% BMI reduction baseline at month 6 of setmelanotide therapy.

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK599840/

Clinical Review - Setmelanotide (Imcivree) - NCBI - NIH Overall, the results of Study 023 and Study 022 were consistent with setmelanotide improving important weight-related outcomes for patients with BBS, but the ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03287960?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BInterventionSearch%5D(BIM-22493)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)))&rank=7

Setmelanotide for the Treatment of Leptin Receptor (LEPR) ... A group of independent scientists who monitor the safety and scientific integrity of a clinical trial. The DMC can recommend to the sponsor that the trial be ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2020/213793Orig1s000MedR.pdf

213793Orig1s000 - accessdata.fda.gov LEPR-deficiency obesity, demonstrated that setmelanotide was effective on the primary endpoint in adults and children 6 years of age and ...

6. imcivree.com imcivree.com/hcp/bbs/safety-profile/

Safety Profile | IMCIVREE® (setmelanotide) injection | For ... IMCIVREE is indicated to reduce excess body weight and maintain weight reduction long term in adults and pediatric patients aged 2 years and older.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/213793s001lbl.pdf

IMCIVREE® (setmelanotide) injection, for subcutaneous use The safety of IMCIVREE was evaluated in two 52-week, open-label clinical studies of. 27 patients with obesity due to POMC, PCSK1, or LEPR deficiency with POMC, ...

8. imcivree.com imcivree.com/hcp/ppl/safety-profile/

Safety Profile | IMCIVREE® (setmelanotide) injection | For ... Clinical safety summary of setmelanotide in healthy volunteers with obesity and patients with rare genetic diseases of obesity. Poster ...

9. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK589641/

Setmelanotide - StatPearls - NCBI Bookshelf - NIH Setmelanotide is a medication that acts on the melanocortin-4 receptor (MC4R) for the treatment of severe obesity caused by genetic disorders.

10. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/imcivree

Imcivree | European Medicines Agency (EMA) In 2 main studies, Imcivree was shown to be effective at reducing body weight by at least 10% in people with POMC and LEPR deficiency. The first study was ...