Mavacamten in HCM: Reasons for Optimism and Caution

The novel first-in-class drug mavacamten looks like an advance for patients with symptomatic hypertrophic cardiomyopathy. But there are reasons for caution.

At the American College of Cardiology (ACC) 2022 Scientific Session, Milind Desai, MD, from the Cleveland Clinic, presented results of the VALOR-HCM trial. We have known for 6 weeks, from a company press release, that the placebo-controlled trial found a positive result for mavacamten.

We learned today that the results were very positive.

The trial enrolled 112 patients with hypertrophic cardiomyopathy who had severe symptoms and left ventricular outflow tract (LVOT) obstruction. All enrolled patients met criteria for septal reduction therapy (SRT) with myectomy or alcohol ablation of a septal coronary artery.

The primary endpoint was the avoidance of SRT at 16 weeks, by either patient-clinician decision or no longer meeting eligibility criteria. As secondary endpoints, the authors also reported specific clinical and echocardiography parameters.

Patients in this trial had severe disease. More than 90% had New York Heart Association (NYHA) class III symptoms and a mean postexercise gradient of more than 80 mm Hg. Most were receiving background therapy with β-blockers, calcium channel blockers, or a combination.

Desai noted that these patients had been referred for SRT. In fact, the trial duration was only 16 weeks because it would have been unethical to randomly assign symptomatic patients to placebo for longer. He said the drug takes approximately 4 to 8 weeks to exert its effects. Patients could elect to proceed with SRT at any time.

VALOR-HCM Results

The VALOR-HCM results strongly favored mavacamten. Only 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. The driver of the composite was no longer meeting SRT eligibility.

Mavacamten also performed well in clinical and echocardiography parameters. Improvement in one or more NYHA functional class, resting LVOT gradient, Valsalva LVOT gradient, N-terminal pro–brain natriuretic peptide (NT-pro-BNP) level, and troponin I level all favored mavacamten over placebo.

Adverse effects did not raise much concern. Two patients in the mavacamten arm developed a left ventricular ejection fraction less than 50%. Desai said that both patients underwent dose titration and remained in the study.

Desai had a nice slide on limitations. He noted that the primary endpoint was driven by reduction in guideline eligibility rather than choosing to avoid SRT. The trial was short in duration, and so we don't whether the drug will allow patients to escape SRT over the long term. He also said that VALOR cannot evaluate safety, such as the effects on arrhythmias and sudden death.

More Safety Data Needed

One of the ways mavacamten works is by inhibiting sarcomere force output and reducing contractility. Neither VALOR nor EXPLORER can assess safety over the long term. Once approved, which is expected to occur later this month, these drugs will be widely used.

In a more perfect world, we'd expect and demand that the makers of mavacamten, Bristol Myers Squibb, would fund a longer-term trial.

My gut feeling is that because biomarkers, such as NT-pro-BNP and troponin, trend in favor of mavacamten, safety is unlikely to be an issue. But it would be nice to have data rather than hunches.

Blinding

The primary endpoint was driven by patients no longer meeting criteria for SRT. This could have been due to symptom reduction or improvement in echocardiography parameters. If it were mostly due to symptom reduction, it would be crucial that patients remained blinded.

Here is why: patients in VALOR-HCM had serial echocardiography exams that led to frequent dose adjustments. Presumably, patients in the placebo arm had few if any adjustments. Could patients tell they were receiving the study drug and thus be more apt to report fewer symptoms? I would have liked to see a table listing the reasons patients no longer met SRT eligibility criteria.

Translation to Practice

Trials are often a best-case scenario for an intervention because they select ideal patients and then closely follow them.

This is especially so for VALOR-HCM. Patients were enrolled at centers of excellence and then had intense monitoring and dose titrations. I won't even hedge here: this cannot be simulated in real-world practice.

Another translation issue pertains to the diagnosis of obstructive hypertrophic cardiomyopathy. Experts enrolled patients in these trials. The presence of a new drug and its marketing will bring "disease awareness," and I worry that mavacamten will be offered to people with lesser degrees of disease. That may eventually turn out to be wise, but there ought to be evidence supporting broader use.

What's more, the exclusion criteria of VALOR-HCM were strict. Patients with atrial fibrillation and those who were to have an implantable cardioverter-defibrillator were excluded. And patients had to be able to perform an exercise test to be enrolled. These three criteria exclude a lot of patients with hypertrophic cardiomyopathy.

Massive Effect Sizes

An absolute risk difference of 58 percentage points is as big an effect size as I can recall.

An empirical evaluation of studies with very large treatment effects found that these results often emerge from small studies, and when additional trials are performed, the effect sizes typically become much smaller.

Maybe mavacamten is this good, but we are about to unleash a drug on the basis of trial data in fewer than 400 patients. That gives me pause.

Transparency

There will be a paper coming soon. The details in a full manuscript and supplement will exceed that of a few slides.

Bristol Myers Squibb sponsored, funded, and conducted the statistical analysis of the study. This is not unusual. But I look forward to the Food and Drug Administration review—because they will have access to the raw data. If confirmatory, such an independent analysis of the data will enhance confidence in this novel agent.

Conclusion

Patients with advanced hypertrophic cardiomyopathy face tough choices. Avoiding the morbidity of septal reduction therapy is an excellent outcome. The early data on the myosin inhibition agent mavacamten looks promising. I am cautiously optimistic, but there is more to learn about the details of the trial and long-term effects of this new drug.

Also exciting is that myosin inhibition may be a class effect. Another myosin inhibitor is showing promise for disease modification in hypertrophic cardiomyopathy.

It feels good to be optimistic about a potential breakthrough for a tough disease.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.

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