Bristol Myers Squibb Presents Phase 3 Data Showing Sustained Health Status Improvements with Mavacamten in Obstructive Hypertrophic Cardiomyopathy

May 16, 2021 /BioonBIOON/ -- Bristol-Myers Squibb (BMS) recently at the 70th Annual Scientific Session of the American College of CardiologyMeeting(ACC.21) New analysis data from the Phase 3 EXPLORER-HCM study (NCT03470545) on mavacamten for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) were presented: at 30 weeks of treatment,Compared with the placebo group, patients in the mavacamten group showed sustained improvement in health status.This analysis confirmed the benefits of mavacamten for the health status of patients with oHCM. The relevant data have also been concurrently published in the international medical journal *The Lancet*, under the title:Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial。

Mavacamten is a first-in-class, oral cardiac myosin inhibitor., developed for the treatment of patients with symptomatic oHCM.oHCM is a chronic heart disease with a high incidence., mavacamten can address the intrinsic molecular defect of this disease. Currently, mavacamten is under review by the U.S. FDA, with a Prescription Drug User Fee Act (PDUFA) target date of January 28, 2022. In July 2020,FDABreakthrough Therapy Designation (BTD) was granted to mavacamten for the treatment of oHCM.

EXPLORER-HCM is a phase 3, double-blind, placebo-controlled study conducted in symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM) (LVOT gradient ≥50 mmHg, NYHA functional class II-III). In the study, patients were randomized in a 1:1 ratio to mavacamten (n=123) or placebo (n=128) for 30 weeks of continuous treatment, followed by an 8-week washout period. Previously published results demonstrated that mavacamten exhibited robust therapeutic efficacy, with clinically meaningful improvements in symptoms, functional status, and quality of life, while also demonstrating the ability to relieve left ventricular outflow tract obstruction. In the EXPLORER-HCM study, all primary and secondary endpoints achieved statistical significance.

The latest analysis released involves the Kansas City Cardiomyopathy Questionnaire (KCCQ; range 0–100, with higher scores indicating better health status), a disease-specific questionnaire comprising 23 items that quantifies various aspects of patients' daily lives, including symptoms, physical function, social function, and quality of life. KCCQ assessments were conducted at baseline and at weeks 6, 12, 18, 30, and 38. Changes in KCCQ scores from baseline were analyzed using a mixed model for repeated measures (MMRM) and responder analysis methods. A total of 92 patients in the mavacamten group and 88 patients in the placebo group completed both the baseline and week 30 (end of treatment) KCCQ questionnaires.

The analysis results showed that: (1) at Week 30 of treatment,The change in the KCCQ overall summary score (KCCQ-OSS) was significantly greater in the mavacamten group than in the placebo group.(Mean ± SD: 14.9 ± 16 vs 5.4 ± 14; difference = 9.1 [95% CI: 5.5-12.8]; p < 0.001),Similar benefits across all KCCQ subscales. (2) Compared with the placebo group,A higher proportion of patients in the mavacamten group achieved a substantial, clinically meaningful improvement.(KCCQ-OSS change ≥20 points: 36% [33/92] vs 15% [13/88]), a change of ≥5 points is considered clinically meaningful, and these benefits returned to baseline levels following treatment discontinuation. (3) A higher proportion of patients in the placebo group experienced worsened or unchanged health status at week 30.

New Analysis Data from the EXPLORER-HCM Study (Click image to view full size)

John A. Spertus, Professor of Medicine at the University of Missouri-Kansas City and Principal Investigator of the EXPLORER-HCM study, stated: "The KCCQ is a 23-item disease-specific questionnaire that quantifies symptoms, physical function, social function, and quality of life. By using this tool, we were able to demonstrate substantial clinical benefits in patients receiving mavacamten during the trial, with these benefits diminishing upon treatment discontinuation. This new analysis of data from the EXPLORER-HCM study provides important insights into the benefits of myosin inhibition in improving the health status of patients with severe obstructive hypertrophic cardiomyopathy (oHCM), a chronic and often debilitating condition."

Jay Edelberg, M.D., Head of Development, Heart Failure and Cardiomyopathies, Bristol-Myers Squibb, said: “mavacamten represents Bristol-Myers Squibb's ongoing commitment to improving patients' lives through scientific discovery, particularly for those with chronic cardiovascular diseases such as oHCM. This new analysis of the Phase 3 EXPLORER-HCM study data further supports the scientific evidence demonstrating the benefits of mavacamten in improving health status, symptoms, and quality of life for patients with symptomatic oHCM, and we look forward to the possibility of bringing this important new therapy to patients next year.”

Hypertrophic Cardiomyopathy (Image source: urmc.rochester.edu)

Hypertrophic cardiomyopathy (HCM) is the most common monogenicGeneticsHeart disease is a chronic, debilitating, progressive disease. Patients may experience symptoms such as shortness of breath, dizziness, and fatigue, as well as severe, life-altering complications, including heart failure, arrhythmias,Strokeand sudden cardiac death.

Mavacamten is a first-in-class, oral, cardiac myosin allosteric inhibitor for the treatment of diseases intrinsically driven by cardiac hypercontractility and impaired diastolic filling. Mavacamten is believed to reduce myocardial contractility by inhibiting the formation of excessive myosin-actin cross-bridges. The formation of excessive myosin-actin cross-bridges can lead to myocardial hypercontractility, left ventricular hypertrophy, and reduced compliance. In clinical and preclinical studies, mavacamten has consistently demonstrated a reduction in wall stress`Biomarker`、reduce excessive myocardial contraction、increase diastolic compliance。

In July 2020, the United StatesFDAMavacamten was granted Breakthrough Therapy Designation for the treatment of oHCM. Mavacamten was initially developed for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Based on its mechanism of action and evidence of therapeutic activity, mavacamten is also under clinical investigation for the treatment of symptomatic non-obstructive hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF).

Chemical structure of mavacamten (Image source: chemsrc.com)

mavacamten (MYK-461) was developed by MyoKardia. On October 5, 2020, Bristol-Myers Squibb announced the acquisition of MyoKardia for $13.1 billion in cash, at a 60% premium. On November 17, 2020, Bristol-Myers Squibb announced that the acquisition of MyoKardia had been successfully completed. This acquisition marks Bristol-Myers Squibb's second-largest deal following its $74 billion acquisition of Celgene in 2019.

Notably, on August 11, 2020, byInvestment CompanyLianBio, incubated by Perceptive Advisors, was officially established and announced two major partnerships on the same day: one to in-license BridgeBio Pharma's product pipeline into China, and the other to in-license MyoKardia's mavacamten into China.

Bristol-Myers Squibb has high expectations for mavacamten. Upon the acquisition of MyoKardia, the company announced that mavacamten would become a first-in-class drug for the treatment of HCM. The industry is also highly optimistic about the commercial prospects of mavacamten. In December 2020, the pharmaceutical market research firm Evaluate Vantage released the "Top 10 New Drugs with the Greatest Commercial Potential in 2021," on which mavacamten ranked third. Evaluate Vantage projected that,Global sales of mavacamten are projected to reach $2 billion in 2026..(Bioon.com)

Original Source: Bristol-Myers Squibb Presents Late-Breaking Phase 3 Data Demonstrating Health Status Benefits of Mavacamten in Patients with Obstructive Hypertrophic Cardiomyopathy at American College of Cardiology’s 70th Annual Scientific Session