BMS’s Cardiac Myosin Allosteric Modulator Mavacamten Granted Breakthrough Therapy Designation by CDE for Obstructive Hypertrophic Cardiomyopathy

Text | Sunshine

On February 7, the CDE website showed that Bristol-Myers Squibb's (BMS) Mavacamten capsule was proposed to be included in the breakthrough therapy category for the treatment of adult patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) to improve exercise capacity, New York Heart Association (NYHA) cardiac function classification, and symptoms.

In August 2020, LianBio partnered with MyoKardia, a wholly-owned subsidiary of Bristol-Myers Squibb, to obtain the license for the development and commercialization of mavacamten in mainland China, Hong Kong, Macau, Taiwan, Thailand, and Singapore. The total deal value was $187.5 million, including a $40 million upfront payment, $147.5 million in milestone payments, and sales royalties.

Hypertrophic cardiomyopathy is a chronic progressive disease caused by excessive myocardial contraction and obstruction of left ventricular blood filling, which can lead to debilitating symptoms and cardiac dysfunction. The most common cause of the disease is mutations in myocardial sarcomeric proteins. In patients with obstructive or non-obstructive hypertrophic cardiomyopathy, exertion can lead to fatigue or shortness of breath, affecting daily life. Hypertrophic cardiomyopathy is also associated with an increased risk of atrial fibrillation, stroke, heart failure, and sudden cardiac death. Currently, it is estimated that there are approximately 1.1 to 2.8 million patients with hypertrophic cardiomyopathy in China, with limited treatment options available for symptom relief and no effective drug treatments.

Mavacamten is a potential first-in-class, oral, myocardial myosin allosteric modulator for the treatment of diseases where excessive cardiac contraction and impaired diastolic filling are intrinsic factors. It reduces myocardial contractility by inhibiting the over-formation of myosin-actin cross-bridges. Excessive formation of these cross-bridges can lead to hypercontractility, left ventricular hypertrophy, and reduced compliance. In both clinical and preclinical studies, mavacamten has consistently demonstrated biomarkers indicating reduced ventricular wall stress, alleviated excessive myocardial contraction, and improved diastolic compliance.

MyoKardia reported in May 2020 on the pivotal Phase III clinical trial data of mavacamten for symptomatic obstructive HCM patients. The results showed that both the primary and all secondary endpoints achieved high statistical significance (p<0.0006), effectively improving patients' exercise capacity, left ventricular outflow tract gradient (LVOTG), NYHA class, etc. Based on this, BMS submitted a marketing application to the FDA in March 2021, with the latest PDUFA date set for April 28, 2022.

In addition, in January this year, mavacamten completed the first dosing of a Chinese patient in the Phase III clinical trial EXPLORER-CN for the treatment of oHCM.