BMS-986435 for Heart Failure

(AURORA-HFpEF Trial)

Recruiting at 111 trial locations

Overseen By BMS Clinical Trials Contact Center www.BMSClinicalTrials.com

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Bristol-Myers Squibb

Disqualifiers: Obstructive cardiomyopathy, Cardiac amyloidosis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-12 weeks

208 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

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

What makes the drug BMS-986435 unique for treating heart failure?

BMS-986435 is unique because it targets specific pathways involved in heart muscle cell protection and function, potentially offering a novel approach compared to existing treatments that may not address these specific mechanisms. ^{1 2 3 4 5}

What is the purpose of this trial?

This trial is testing a new drug called BMS-986435/MYK-224 in people with a specific type of heart failure (HFpEF). The goal is to see if the drug is safe and if it can help improve heart function and reduce symptoms.

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults with stable, symptomatic heart failure but whose hearts can still pump normally (HFpEF). People with obstructive or genetic heart muscle issues, storage disorders like cardiac amyloidosis, or any serious condition that could affect the study or be risky can't join.

Inclusion Criteria

I have stable heart failure with preserved ejection fraction.

Exclusion Criteria

Participants must not have any other acute or serious condition that could interfere with assessments during the study or may pose a risk to the participant

I do not have a known heart condition involving thickened heart muscles.

I do not have a condition like cardiac amyloidosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BMS-986435/MYK-224 or placebo to evaluate safety, tolerability, and exposure-response

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BMS-986435/MYK-224

Trial Overview The study tests BMS-986435/MYK-224's safety and how well it's tolerated in people with HFpEF. It also looks at how drug levels relate to its effects. Participants will either receive this new drug or a placebo for comparison.

Participant Groups

Group I: BMS-986435 Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) were used to demonstrate that selective MAP4K4 inhibitors can protect heart muscle cells from death caused by the chemotherapy drug doxorubicin (DOX), enhancing cell viability and reducing apoptosis.

The MAP4K4 inhibitors did not affect the effectiveness of DOX on cancer cells, suggesting that targeting MAP4K4 could provide a safe therapeutic strategy to prevent heart damage during cancer treatment without compromising anti-cancer efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4. Golforoush, PA., Narasimhan, P., Chaves-Guerrero, PP., et al.[2022]

Transgenic mice with a cardiac-specific active form of MEK5alpha showed a significant increase in BMK1 activation, which is linked to improved heart function after ischemic injury.

The study suggests that BMK1 plays a protective role in the heart during ischemia/reperfusion events, indicating its potential as a therapeutic target for cardiac injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. Cameron, SJ., Itoh, S., Baines, CP., et al.[2009]

In a study comparing 4 donor hearts and 12 failing hearts from patients with heart failure, it was found that the activities of JNKs and p38-MAPKs were significantly higher in the failing hearts, suggesting their involvement in heart disease pathology.

While the total amounts of certain MAPKs were similar between donor and failing hearts, the reduced levels of the 46-kDa JNK in failing hearts indicate a potential alteration in MAPK signaling that could contribute to heart failure mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease. Cook, SA., Sugden, PH., Clerk, A.[2009]

The pro-drug DMX-10001, designed to inhibit cardiomyocyte death in myocardial infarction, was tested in a study involving 36 swine, but it did not significantly reduce infarct size despite achieving drug concentrations that were effective in mouse models and human stem cell-derived cardiomyocytes.

Although DMX-10001 showed a 27% reduction in infarct size when measured in grams or as a percentage of left ventricular mass, it ultimately failed to demonstrate efficacy in the large-mammal model, highlighting the challenges of translating results from smaller models to larger ones.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals? Te Lintel Hekkert, M., Newton, G., Chapman, K., et al.[2022]

Beta II protein kinase C (βIIPKC) is found to accumulate on the mitochondrial outer membrane in failing hearts, where it phosphorylates mitofusin 1 (Mfn1), leading to mitochondrial dysfunction and cell death.

The peptide SAMβA, which disrupts the interaction between Mfn1 and βIIPKC, has been shown to restore mitochondrial function and improve heart contractility in rats with heart failure, indicating its potential as a treatment for heart failure in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats. Ferreira, JCB., Campos, JC., Qvit, N., et al.[2020]

References

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

Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. [2009]

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

Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease. [2009]

4. Germany pubmed.ncbi.nlm.nih.gov

Preclinical trial of a MAP4K4 inhibitor to reduce infarct size in the pig: does cardioprotection in human stem cell-derived myocytes predict success in large mammals? [2022]

5. England pubmed.ncbi.nlm.nih.gov

A selective inhibitor of mitofusin 1-βIIPKC association improves heart failure outcome in rats. [2020]