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April 5, 2022

ACC 22: mavacamten improves health status in symptomatic hypertrophic cardiomyopathy

Mavacamten is a selective cardiac myosin inhibitor currently in pre-registration for hypertrophic cardiomyopathy (HCM) in the US.

By GlobalData Healthcare

At the 71st annual American College of Cardiology (ACC) meeting, results were presented from MAVA-LTE, the ongoing five-year study of mavacamten in obstructive hypertrophic cardiomyopathy (oHCM). Of the 244 patients who completed the Phase III EXPLORER-HCM trial, 231 enrolled in MAVA-LTE and the updated interim results on the long-term safety and efficacy with mavacamten from the EXPLORER-LTE cohort of the MAVA-LTE study at ACC-22.

Mavacamten is a selective cardiac myosin inhibitor that decreases contractility of the myocardium by inhibiting excessive myosin-actin cross-bridge formation. The EXPLORER-HCH Phase III study previously demonstrated that mavacamten reduced the left ventricular outflow tract (LVOT) gradient and improved symptoms and functional capacity after 30 weeks when compared to placebo in patients with symptomatic oHCM, with a similar safety profile between treatment and placebo arms.

Mavacamten’s ability to continually demonstrate a significant improvement in quality of life will undoubtedly strengthen its impending market launch, as it is currently in pre-registration for HCM in the US. With the benefits that mavacamten treatment provides, GlobalData predicts that this therapy is likely to achieve a dominant share of the oHCM market, capturing significant market share from currently marketed therapies that have poor long-term outcomes.

HCM is a primary myocardial disorder that results from unexplained left ventricular (LV) hypertrophy, which is often caused by pathogenic variants in sarcomeric genes. There are two major types of HCM, oHCM and non-oHCM, with the key difference being that in oHCM blood flow is blocked or severely restricted due to stiffening of the left ventricular wall as a result of HCM. The current treatment regimen for both types of HCM has a primary goal of improving symptoms and cardiac function using beta-blockers and other cardiovascular drugs such as verapamil, an anti-hypertensive, and disopyramide, an anti-arrhythmic. Mavacamten has a significant advantage in entering the oHCM portion of the cardiovascular disease market as it is a first-in-class cardiac myosin inhibitor, whereas the current pharmacological options are not disease-specific and are inadequate or poorly tolerated.

All patients in MAVA-LTE received an initial 5mg dose of mavacamten following a wash-out period, with this dose titrated at the fourth, eighth and 12th weeks on the basis of site-reach echocardiography (ECG) measure of Valsalva LVOT gradient and left ventricular ejection fraction (LVEF). In addition, the dose could be adjusted at week 24 based on ECG measures of post-exercise LVOT gradient, with possible doses being 2.5g, 5g, 10g or 15mg. It was determined that an LVEF <50% would be a prespecified criterion for temporarily discontinuing treatment with mavacamten, and there was a median follow-up of 62 weeks in this current analysis.

There were several significant efficacy outcomes observed for this trial, including that both resting and Valsalva LVOT improved rapidly within four weeks following the onset of treatment with mavacamten. This improvement was sustained until 84 weeks (resting LVOT gradient: mean change from baseline at week 48: -35.6 [DS 32.6] mmHg and at week 84: -32.8 [35.9] mmHg; Valsalva LVOT gradient: mean change from baseline at week 48: -45.3 [SD 35.9] mmHg and at week 84: -46.4 [SD 35.8] mmHg) and a reduction in LVEF was also observed. The reduction in LVEF was an expected and known outcome of mavacamten, consistent with its mechanism of action, with the mean change (SD) in LVEF from baseline of -7.0% (8.3%) at week 48 and -9.0% (8.1%) at week 84. There was significant decline in serum NT-proBNP observed at the fourth week and this reduction was sustained through week 84 (median change from baseline to week 48: -480 ng/L, IQR -1104 to -179 ng/L; median change from baseline to week 84: -488 ng/L, IQR -1098 to -166 ng/L). At week 48, 67.5% of patients improved by at least one New York Heart Association (NYHA) functional class and 7.3% improved by 2 NYHA functional classes.

Finally, the safety outcomes observed were also fairly positive, with a total of 34 patients (14.7%) experiencing a serious adverse event (both related and unrelated to mavacamten) and mavacamten-related serious adverse events occurring in five patients (2.2%). A total of 26 patients (11%) had to temporarily stop treatment and of those, 20 patients were able to restart therapy with mavacamten while ten (4.3%) had to permanently discontinue treatment. There were three deaths reported in total, none of which were deemed to be related to mavacamten.

These interim results of the long-term extension study of EXPLORE-HCM demonstrate that mavacamten resulted in improvements in LVOT gradients, NYHA class and NT proBNP levels at and beyond 48 weeks in patients with symptomatic oHCM. Mavacamten was observed to be well-tolerated and no significant safety issues were observed that required a longer-term follow-up. Mavacamten will likely dominate the oHCM market as the first-in-class cardiac myosin inhibitor and rapidly steal market share from the non-specific therapies that are part of the current treatment regimen. As the new data underscores what was previously recognized from EXPLORE-HCM, mavacamten is on course to address this gap in the oHCM market.

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