LB54640 for Obesity

Not currently recruiting at 14 trial locations

Overseen By Lisa Burke

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: LG Chem

Must not be taking: MC4R agonists

Disqualifiers: Prader-Willi, ROHHADNET, severe psychiatric, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 14 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called LB54640, an oral melanocortin 4 receptor agonist, to evaluate its effectiveness and safety in promoting weight loss for individuals with Hypothalamic Obesity (HO). This condition can cause significant weight gain due to damage in the hypothalamus. Participants will receive either varying doses of LB54640 or a placebo (a pill with no active medicine) and will be monitored for changes in weight, hunger, and overall quality of life. The trial seeks individuals aged 12 and older who have gained weight due to hypothalamic injury and have a BMI of 30 or more, or are in the top 5% for BMI for their age and sex if under 18. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

The trial protocol does not specify whether you need to stop taking your current medications. Please consult with the study team for guidance.

Will I have to stop taking my current medications?

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

Is there any evidence suggesting that LB54640 is likely to be safe for humans?

Research has shown that LB54640 has been safe in past studies. These studies found no changes in blood pressure or heart rate, common concerns in obesity treatments. This indicates that patients generally tolerate the treatment well. Additionally, the data revealed no major side effects, which is encouraging for potential trial participants. Although the treatment remains under investigation, its safety record so far appears reassuring. ^{1 2 3 4 5}

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

Researchers are excited about LB54640 for obesity because it offers a fresh approach compared to most current treatments, which often involve lifestyle changes or medications like phentermine and orlistat. LB54640 is unique in its potential mechanism of action, targeting pathways that may directly influence metabolism and fat storage more effectively. Unlike many existing options that require significant lifestyle adjustments or have various side effects, this treatment could offer a more targeted and potentially safer alternative. Additionally, the study explores multiple dosing options to maximize efficacy and minimize side effects, allowing researchers to fine-tune how best to use it in practice.

What evidence suggests that LB54640 might be an effective treatment for Hypothalamic Obesity?

Research shows that LB54640 is a promising treatment for obesity. Animal studies found that it effectively reduces weight by targeting a specific brain area that controls hunger and energy use. In these studies, LB54640 performed well compared to similar treatments. Although research in humans continues, its mechanism suggests it could help manage weight by controlling appetite and boosting metabolism. This trial will evaluate different doses of LB54640 and a placebo to determine its effectiveness and safety in treating obesity. This approach offers hope for treating a type of obesity linked to brain function. ^{1 2 3 4 6}

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 individuals aged 12 and older with Hypothalamic Obesity, marked by weight gain after hypothalamic injury. Adults must have a BMI of ≥30 kg/m2, while those under 18 should be at or above the 95th percentile for their age and sex. Participants must agree to use effective contraception during the study and for three months after.

Inclusion Criteria

Male and female participants agree to follow study contraception requirements and use a highly effective form of contraception throughout the study and for 90 days after the study

I have been diagnosed with hypothalamic obesity.

I am 12 years old or older.

Exclusion Criteria

I have been diagnosed with Prader-Willi syndrome or ROHHADNET.

HbA1c >10.9%

Fasting glucose level >270 mg/dL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an oral daily dose of LB54640 or placebo through Week 14

14 weeks

Open-label extension

Eligible participants who consent continue to receive an oral daily dose of LB54640 through Week 56

42 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• LB54640

Trial Overview The study tests LB54640's effectiveness in reducing weight, hunger, and improving quality of life in patients with Hypothalamic Obesity compared to a placebo. It involves taking an oral dose daily up to Week 14, with an option to continue until Week 56.

How Is the Trial Designed?

Group I: Open-label LB54640 Experimental Treatment 1 Intervention

Eligible participants who provide consent to continue into the open-label portion of the study will receive open-label LB54640.

Group II: LB54640 Middle dose Experimental Treatment 1 Intervention

Participants will be randomized to receive LB54640 low dose, middle dose, or high dose, or placebo by oral administration in a 1:1:1:1 ratio.

Group III: LB54640 Low dose Experimental Treatment 1 Intervention

Participants will be randomized to receive LB54640 low dose, middle dose, or high dose, or placebo by oral administration in a 1:1:1:1 ratio.

Group IV: LB54640 High dose Experimental Treatment 1 Intervention

Participants will be randomized to receive LB54640 low dose, middle dose, or high dose, or placebo by oral administration in a 1:1:1:1 ratio.

Group V: Placebo Placebo Group 1 Intervention

Participants will be randomized to receive LB54640 low dose, middle dose, or high dose, or placebo by oral administration in a 1:1:1:1 ratio.

Who Is Running the Clinical Trial?

LG Chem

Lead Sponsor

Trials

66

Recruited

33,800+

Shin Hak-Cheol

LG Chem

Chief Executive Officer since 2022

Bachelor's degree in Mechanical Engineering from Seoul National University

Ko Yoon-joo

LG Chem

Chief Medical Officer

MD from Yonsei University

Rhythm Pharmaceuticals, Inc.

Lead Sponsor

Trials

31

Recruited

10,400+

Published Research Related to This Trial

The study identifies that the amino acid leucine 133 in the third transmembrane region of the melanocortin-4 receptor (MC4R) is crucial for the selective antagonism of the synthetic melanocortin analog SHU9119, which is important for understanding its role in body weight regulation.

Mutating leucine 133 to methionine changes SHU9119 from an antagonist to an agonist at MC4R, highlighting the specific molecular interactions that determine receptor activity and selectivity between different melanocortin receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity. Yang, Y., Chen, M., Lai, Y., et al.[2021]

Melanocortin receptors, particularly MC4R, play a crucial role in regulating food intake and body weight, with evidence from rodent models showing that activating these receptors can decrease appetite and promote weight loss.

Despite challenges in developing effective small molecule agonists for MC4R, selective peptide agonists have shown promise in reducing food intake and body weight in animal studies, indicating potential for future obesity treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanocortin-4 receptor agonists for the treatment of obesity. Emmerson, PJ., Fisher, MJ., Yan, LZ., et al.[2019]

The study identified a specific mutation (L250Q) in the human Melanocortin-4 Receptor that leads to constitutive activation of the receptor, which is paradoxical since such activation is expected to promote a lean phenotype rather than obesity.

Agouti-related protein was found to act as an inverse agonist at this mutated receptor, suggesting a potential mechanism by which it may contribute to obesity in individuals with the L250Q mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular mechanism of the constitutive activation of the L250Q human melanocortin-4 receptor polymorphism. Proneth, B., Xiang, Z., Pogozheva, ID., et al.[2013]

Out of 10 novel melanocortin-4 receptor (MC4R) mutants studied, 6 showed decreased expression on the cell surface, which could contribute to obesity by impairing receptor function.

The MC4R inverse agonist ML00253764 was found to act as a pharmacological chaperone, helping to rescue certain mutant receptors to the cell surface, thereby restoring their function and increasing cAMP production in response to stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. Fan, ZC., Tao, YX.[2021]

In a study of 120 unrelated obese patients, a novel mutation (Glu(308)Lys) in the MC4-R gene was identified, which reduces the receptor's ability to stimulate cAMP production, indicating a potential mechanism for obesity.

The study found a 1.7% prevalence of potentially pathogenic mutations in the MC4-R gene among the obese population, but no significant association between these mutations and the obese phenotype was established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation. Santini, F., Maffei, M., Ceccarini, G., et al.[2022]

Two novel melanocortin agonists, IRC-022493 and IRC-022511, were found to effectively activate mutated human melanocortin 4 receptors (hMC4R) associated with severe obesity in vitro, suggesting their potential as targeted treatments for obesity linked to these genetic mutations.

The study involved 11 obese French patients with specific hMC4R mutations, and the agonists showed similar activation levels as the natural hormone α-MSH, indicating they could be promising candidates for developing anti-obesity drugs for individuals with these mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. Roubert, P., Dubern, B., Plas, P., et al.[2013]

A new series of compounds derived from tert-butyl pyrrolidine have been developed that selectively target the melanocortin receptor subtype-4 (MC4R).

These compounds are potent and can be taken orally, suggesting they may be effective and convenient options for therapeutic use involving MC4R modulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and SAR of potent and orally bioavailable tert-butylpyrrolidine archetype derived melanocortin subtype-4 receptor modulators. Guo, L., Ye, Z., Ujjainwalla, F., et al.[2008]

Setmelanotide, an MC4R agonist, shows higher potency for stimulating cAMP formation compared to the natural agonist α-MSH, indicating its potential for targeted weight loss therapies.

The study reveals that setmelanotide has a stronger binding affinity to the MC4R receptor than α-MSH, and that certain genetic variants of MC4R can alter how these ligands interact with the receptor, which may inform personalized obesity treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structural analysis of setmelanotide binding to MC4R variants in comparison to wild-type receptor. Hammad, MM., Mohammad, A., Alam-Eldin, N., et al.[2022]

Citations

1. ir.rhythmtx.com ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-first-patients-dosed-phase-2

Release Details The Phase 2 trial is a randomized, placebo-controlled, double-blind study to assess the effect of LB54640 on safety, weight reduction, hunger, and quality of ...

2. innovation.lgchem.com innovation.lgchem.com/upload/P/b668cfebe3c34561bc84d342aa1ff15b.pdf

First Oral MC4R Agonist for the Treatment of Rare Genetic ... - Efficacy of LB54640 has been evaluated in rodent models of obesity compared to in-class competitor. - Pharmacokinetic profiles of LB54640 have been examined ...

3. ir.rhythmtx.com ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announce-topline-results-phase-2-trial

Release Details The Phase 2 trial is a randomized, placebo-controlled, double-blind study to assess the effect of bivamelagon (LB54640) on safety, weight reduction, hunger, ...

4. globalgenes.org globalgenes.org/raredaily/rhythm-acquires-global-rights-to-lg-chems-oral-mc4r-agonist-for-rare-obesities/

Rhythm Acquires Global Rights to LG Chem's Oral MC4R ... Rhythm Pharmaceuticals has entered into a global licensing agreement with LG Chem for LB54640, an investigational oral small molecule melanocortin-4 receptor ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8526285/

Setmelanotide, Semaglutide, Tirzepatide and Bimagrumab ... The purpose of this review is to examine these four compounds and to speculate on how these tools will transform the practice of obesity medicine.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06046443

NCT06046443 | A Study to Assess Efficacy and Safety of ... The study will evaluate the effect of LB54640 on safety, weight reduction, hunger, and quality of life in patients 12 years of age and older with HO.