May 13 2022 This Week in Cardiology

COMMENTARY

May 13, 2022 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

May 13, 2022

2

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast on Apple Podcasts, Spotify, or your preferred podcast provider. This podcast is intended for healthcare professionals only.

In This Week’s Podcast

For the week ending May 13, 2022, John Mandrola, MD comments on the following news and features stories.

Mavacamten

Big news came from the US Food and Drug Administration (FDA) this month with their approval of the novel drug mavacamten, which I covered in the April 8 podcast. To briefly review, mavacamten is totally novel and first in its class. It is a reversible inhibitor of cardiac myosin. That is important in hypertrophic cardiomyopathy (HCM), as excess myosin-actin cross-bridge formation and dysregulation cause HCM. Mavacamten shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In short, it is a negative inotrope.

The FDA approval was based on the EXPLORER HCM trial, published first in the Lancet in August 2020. EXPLORER was a placebo-controlled randomized control trial (RCT) conducted in 13 countries. Enrolled patients had a left ventricular outflow tract (LVOT) gradient of just over 50 mmHg and class 2 or 3 New York Heart Association heart failure (HF). The trial included 251 patients.

Patients in the mavacamten arm had dose adjustments to optimize response — decrease in LVOT gradient on Valsalva and maintenance of LV ejection fraction (EF) > 50%. The primary endpoint for EXPLORER-HCM was a composite functional endpoint, assessed at 30 weeks, and was defined by objective measures of function and subjective reduction in NYHA class.

  • A greater proportion of patients met the primary endpoint at week 30 in the mavacamten group compared with the placebo group (37% vs 17%).

  • Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (−36 mm Hg, 95% confidence interval [CI] −43·2 to −28·1; p<0·0001), and improved symptom scores (Kansas City Cardiomyopathy Clinical Summary score, +9.1, CI 5.5 to 12.7; HCM Symptom Questionnaire-Shortness-of-Breath score, −1·8, CI −2.4 to −1.2;p<0·0001).

That was in 2020. At the American College of Cardiology meeting in April, EXPLORER-HCM authors reported the long-term follow-up study called MAVA-LTE, which is a dose-blinded extension study in patients who completed EXPLORER HCM.

This paper is not yet published, but we were told that:

  • Improvements in gradients, NT-BNP, and NYHA class were sustained at a median follow-up of 62 weeks.

  • There were some safety signals:

    • 11% of patients had temporary treatment interruptions for things like QTc prolongation,

    • Mavacamten concentration > 1000

    • 5% of patients had LVEF < 40%

  • Overall, 77% patients remained on the treatment over the long-term. (Recall that this is in a super-careful RCT.)

Neither the FDA nor the Bristol Myers Squibb press release mentioned the VALOR HCM, another study presented at ACC, which also showed positive results for the novel cardiac myosin inhibitor.

VALOR HCM enrolled patients with HCM who were referred to big centers for septal reduction therapy with either surgical myectomy or septal alcohol ablation. These patients had quite severe HCM. The primary endpoint was avoidance of septal reduction therapy.

  • The results strongly favored mavacamten.

    • 18% of the mavacamten arm met the primary endpoint vs 77% of patients in the placebo arm.

    • The absolute risk difference was 59 percentage points.

  • Mavacamten also performed well in clinical and echocardiography parameters.

  • Improvement in one or more NYHA functional class, resting LVOT gradient, Valsalva LVOT gradient, NT-pro-BNP level, and troponin I level all favored mavacamten over placebo.

Comments: As with most new drugs, there will be a learning curve. Mavacamten looks especially challenging.

  • You need lots of echocardiograms, before and during, and there are dose escalations.

  • You should not start the drug if the LVEF is below 55% and should stop it if the EF < 50%.

  • There is a black box warning for the possibility of HF.

  • The drug-drug interactions are huge:

    • Use of mavacamten with cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to high mavacamten levels.

    • Thus, the use of mavacamten is contraindicated with moderate to strong CYP2C19 inhibitors or moderate to strong CYP3A4 inhibitors

That is a lot of drugs that will either preclude use of mavacamten or require extra caution in the use of this drug. Fortunately, mavacamten will only be available through a restricted program called the Mavacamten REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the program include:

  • Prescribers must be certified by enrolling in the REMS Program.

  • Patients must enroll in the REMS Program and comply with ongoing monitoring requirements.

  • Pharmacies must be certified by enrolling in the program and must only dispense to patients who are authorized to receive mavacamten.

  • Wholesalers and distributors must only distribute to certified pharmacies.

Maya E. Guglin, MD, professor of clinical medicine and an advanced heart failure physician at Indiana University (IU), Indianapolis said that mavacamten represents "an almost revolutionary change" for treating obstructive HCM. I think the drug holds promise but after reading that 25% of participants could not continue it in a seriously rigorous clinical trial, and the details of the prescribing information, and the lack of clinical outcomes data, I would emphasize the “almost” modifier for revolutionary change.

But it is potential progress and that is a good thing for these patients. We must keep alert for safety signals.

  • 2

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....

Medscape

Log in or register for free to unlock more Medscape content

Unlimited access to our entire network of sites and services