LB54640 for Obesity

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

28 Participants Needed

Trial Summary

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.

What data supports the idea that LB54640 for Obesity is an effective drug?

The available research shows that melanocortin 4 receptor (MC4R) agonists, like LB54640, can help reduce food intake and body weight. Studies on similar drugs have shown that activating MC4R can lead to weight loss in rodent models. This suggests that LB54640, which is a small molecule MC4R agonist, might also be effective in treating obesity by reducing appetite and promoting weight loss. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug LB54640 for obesity?

Research shows that activating the melanocortin 4 receptor (MC4R) can help reduce food intake and body weight, which is important for treating obesity. Similar drugs that target MC4R have been shown to decrease food intake and body weight in animal studies, suggesting that LB54640, as an MC4R agonist, may have similar effects. ^{1 2 3 4 5}

What safety data exists for LB54640 for obesity?

The provided research does not directly mention safety data for LB54640 or its other names. The studies focus on the efficacy of melanocortin 4 receptor (MC4R) agonists in activating mutated receptors associated with obesity, but do not provide specific safety data for LB54640. ^{1 3 4 6 7}

Is LB54640 safe for humans?

The research articles provided do not contain specific safety data for LB54640 or its related compounds in humans. ^{1 3 4 6 7}

Is the drug LB54640 a promising treatment for obesity?

Yes, LB54640 is a promising drug for obesity because it targets the melanocortin 4 receptor (MC4R), which plays a key role in controlling appetite and body weight. Similar drugs have shown success in activating MC4R, even in cases where genetic mutations make it hard for the body to respond to natural signals. This suggests that LB54640 could help people with obesity, especially those with specific genetic conditions. ^{1 2 3 4 8}

What makes the drug LB54640 unique for treating obesity?

LB54640 is unique because it is an oral small molecule that acts as a melanocortin 4 receptor (MC4R) agonist, which means it helps activate a specific receptor involved in regulating appetite and energy balance. This mechanism is similar to setmelanotide, another MC4R agonist, but LB54640's oral administration could offer a more convenient option compared to other treatments that might require injections. ^{1 2 3 4 8}

What is the purpose of this trial?

The goal of this study is to determine how well LB54640 works and how safe it is in patients with Hypothalamic Obesity (HO). 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. Patients will take an oral daily dose of either LB54640 (low, middle, or high dose) or placebo through Week 14. Eligible patients who consent to continue in the study after Week 14 will take an oral daily dose of LB54640 through Week 56.

Research Team

David Meeker, MD

Principal Investigator

Rhythm Pharmaceuticals, Inc.

Eligibility Criteria

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 gained weight due to a brain injury and my BMI is over 30 if I'm an adult, or over the 95th percentile for my age and sex if I'm under 18.

I have been diagnosed with hypothalamic obesity.

Exclusion Criteria

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

Fasting glucose level >270 mg/dL

I have lost more than 2% of my weight in the last 3 months.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Synthesis and SAR of potent and orally bioavailable tert-butylpyrrolidine archetype derived melanocortin subtype-4 receptor modulators. [2008]

2. United States pubmed.ncbi.nlm.nih.gov

Molecular determinants of human melanocortin-4 receptor responsible for antagonist SHU9119 selective activity. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Novel pharmacological MC4R agonists can efficiently activate mutated MC4R from obese patient with impaired endogenous agonist response. [2013]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Structural analysis of setmelanotide binding to MC4R variants in comparison to wild-type receptor. [2022]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Melanocortin-4 receptor agonists for the treatment of obesity. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Molecular mechanism of the constitutive activation of the L250Q human melanocortin-4 receptor polymorphism. [2013]

7. United States 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. [2021]