FDA Accepts New Drug Application for Mavacamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy

The FDA has accepted a supplemental drug application (sNDA) for an expanded indication for mavacamten (Camzyos; Bristol Myers Squibb) to reduce the need for septal reduction therapy (SRT).

In April, the FDA approved mavacamten to treat adults with symptomatic New York Association (NYHA) class 2-3 obstructive hypertrophic cardiomyopathy (oHCM) to improve functional capacity and symptoms. The treatment modulates the number of myosin heads that can enter “on actin” states and lowers the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation.

“Currently, it is recommended that many patients with severe symptomatic obstructive hypertrophic cardiomyopathy undergo SRT. This often requires either an open-heart surgical procedure or septal ablation procedure—both specialized care options,” said Roland Chen, MD, senior vice president and head of cardiovascular development, Global Drug Development at Bristol Myers Squibb, in a press release. “The approval of Camzyos earlier this year marked a significant milestone for patients. FDA acceptance of the filing for this expanded indication has the potential to strengthen the profile of Camzyos, while further reinforcing our commitment to delivering transformative cardiovascular therapies to patients.”

Mavacamten is a first-in-class, oral, allosteric modulator of cardiac myosin designed to decrease contractile function and improve VO2 in patients with oHCM, which often results in dynamic left ventricular outflow tract (LVOT) obstruction. oHCM thickens the heart walls and makes it more difficult for the heart to expand normally and fill with blood. Mavacamten aims to target the underlying pathophysiology of the condition.

Mavacamten has previously been found to reduce cardiac muscle contractility by inhibiting excessive myosin-actin cross-bridge formation that results in hypercontractility, left ventricular hypertrophy, and reduced compliance.

The sNDA submission was based on the results of VALOR-HCM, a phase 3 placebo-controlled study that evaluated mavacamten in patients with symptomatic, oHCM who met the 2011 ACC/AHA guideline criteria for SRT and who have not been referred for an invasive procedure.

VALOR-HCM randomized 112 patients 1:1 to receive mavacamten or placebo. The study includes 3 treatment periods over 128 weeks: a 16-week placebo-controlled period, a 16-week active treatment period in which all patients received mavacamten, and a 96-week long-term extension period in which all patients received mavacamten.

VALOR-HCM met its primary and all secondary endpoints with a high degree of statistical significance, with no new safety signals observed.

This safety finding is similar to what has been found in prior clinical studies of the drug. In the EXPLORER-CM clinical trial of mavacamten, adverse effects (AEs) were mild to moderate. Mavacamten was found to be generally well tolerated, with 97% of patients completing the trial with a total of 5 withdrawals.

Three patients withdrew from the trial due to AEs. Two patients administered mavacamten experienced atrial fibrillation and syncope, and 1 placebo patient suffered sudden death.

Eight percent of patients who finished mavacamten treatment experienced at least 1 serious AE, including atrial fibrillation, syncope, stress cardiomyopathy, diverticulitis, infection, contusion, or forearm fracture; 9% of patients in the placebo group also reported at least 1 serious AE.

REFERENCE

U.S. Food and Drug Administration (FDA) Accepts Supplemental New Drug Application for CAMZYOS® (mavacamten) in Symptomatic Obstructive Hypertrophic Cardiomyopathy to Reduce the Need for Septal Reduction Therapy. Bristol Myers Squibb. October 21, 2022. Accessed October 21, 2022. https://news.bms.com/news/corporate-financial/2022/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-CAMZYOS-mavacamten-in-Symptomatic-Obstructive-Hypertrophic-Cardiomyopathy-to-Reduce-the-Need-for-Septal-Reduction-Therapy/default.aspx