Aficamten Emerges as a Potential First-Line Therapy in Hypertrophic Cardiomyopathy

In a recent discussion, Michael Fifer, MD, highlighted the groundbreaking results of the MAPLE-HCM trial, the first head-to-head comparison of the cardiac myosin inhibitor aficamten and the beta-blocker metoprolol in patients with obstructive hypertrophic cardiomyopathy (HCM). Fifer explained that the findings not only reinforced the SEQUOIA trial’s demonstration of aficamten’s superiority over placebo but also revealed the limited effectiveness of metoprolol—long regarded as a first-line therapy for six decades. He noted that these surprising results could have a profound impact on treatment guidelines, potentially moving cardiac myosin inhibitors such as aficamten into a first-line position once approved.

Pharmacy Times: MAPLE-HCM is the first head-to-head comparison of a cardiac myosin inhibitor with a standard-of-care beta-blocker. What do you see as the most important takeaways from aficamten’s superiority over metoprolol?

Michael Fifer, MD: So, MAPLE-HCM, which was a head-to-head comparison of the cardiac myosin inhibitor aficamten and the beta-blocker metoprolol, was the first direct comparison of those two types of drugs in obstructive hypertrophic cardiomyopathy. MAPLE reinforced the results of SEQUOIA, which showed that aficamten was superior to placebo in patients receiving conventional treatment for obstructive HCM.

The superiority of aficamten over metoprolol reinforces the findings of SEQUOIA. More surprisingly, MAPLE-HCM showed that metoprolol by itself was not very effective at all for obstructive hypertrophic cardiomyopathy—having no effect on the left ventricular outflow tract gradient, only minimal effect on symptoms, and no effect on NT-proBNP, a marker of heart disease and heart failure. In fact, NT-proBNP levels went up with metoprolol and down with aficamten.

Pharmacy Times: Given that beta-blockers have been first-line therapy for more than 60 years, how do you think these results may influence treatment guidelines and clinical decision-making for obstructive HCM?

Fifer: So, I think these surprising results of MAPLE with regard to the effects of metoprolol may have a profound impact on what has been our conventional therapy for, as you say, six decades. I myself have treated hundreds of patients with obstructive HCM using metoprolol. If the findings of the study are followed to their logical extreme, they may change the guidelines. Currently, the guidelines on both sides of the Atlantic list beta-blockers as first-line therapy and cardiac myosin inhibitors such as mavacamten, and now aficamten if it’s approved, as second-line therapy. One might expect that the guideline writers will be influenced by this study and may move cardiac myosin inhibitors—aficamten in particular, when it’s approved, if it’s approved—to first-line therapy.

Pharmacy Times: MAPLE-HCM included patients with less severe disease compared to SEQUOIA-HCM. What do the consistent benefits in this broader group suggest about aficamten’s potential role earlier in the treatment pathway?

Fifer: These results suggest that if a patient with obstructive HCM has symptoms related to the disease and, by definition, a left ventricular outflow tract gradient, then perhaps no matter what the severity of the symptoms or the magnitude of the gradient, the patient may respond favorably to aficamten. This could push the use of aficamten earlier.

There is another group of patients that has not been well studied—those who don’t have gradients at rest or with the Valsalva maneuver, but who do develop gradients with exercise. That’s another group that may one day benefit from the use of aficamten.

Pharmacy Times: What role do you see pharmacists playing in optimizing care for patients on aficamten, particularly around patient education, monitoring, and medication adherence?

Fifer: We always value the participation of pharmacists in the care of our patients with regard to education, monitoring, and adherence. If anything, I think the lives of providers and the lives of pharmacists may be easier if aficamten is approved, compared to mavacamten, which is the currently approved cardiac myosin inhibitor. Mavacamten has many drug-drug interactions, and that’s where pharmacists have been invaluable in my experience managing patients on the drug. Aficamten does not have those drug–drug interactions, so I think it’s going to be simpler for all of us.

Pharmacy Times: Beyond obstructive HCM, aficamten is being studied in non-obstructive and pediatric populations. Which future research directions do you find most critical to fully understanding its role in HCM management?

Fifer: Well, we certainly want to extend the benefits of aficamten to children if we can show that it’s effective, and that’s where the CEDAR-HCM trial will come in. There is also a very large group of patients with non-obstructive HCM where there is a need for therapies. We were disappointed in the results of the ODYSSEY trial of mavacamten in non-obstructive HCM, which was presented just a week ago, as that was a negative trial. Still, we are somewhat hopeful that the ACACIA trial of aficamten in non-obstructive HCM may have a different result, and we should find that out early next year.

One of the ultimate goals in managing HCM is modifying the progression of the disease, particularly with regard to progressive hypertrophy of the heart muscle and progressive fibrosis of the heart muscle. There is some thought, based on experimental data, that cardiac myosin inhibitors may have a beneficial effect in slowing the progression of the disease—and that’s something we hope to learn from longer-term studies.