Anjali Owens, MD: And speaking of options which we all like to have, Andrew, can you tell us about the next in class cardiac myosin inhibitor aficamten, which is currently still in clinical trials, not yet FDA approved, but walk us through the data we have for that agent?

Andrew Wang, MD: Aficamten is a cardiac myosin inhibitor that works at a different site on the myosin head, but also reduces the actin-myosin interaction by inhibiting myosin ATPase. So it has a very similar effect to mavacamten at the chemical or biochemical level in that it reduces the power stroke and the hyper-contractility in patients with hypertrophic cardiomyopathy [HCM] and reduces the ejection fraction a few percentage points, just like mavacamten does. It has been studied and in a published phase 2 trial called the REDWOOD-HCM trial in which there were 41 patients, it was a randomization 2 to 1 aficamten to placebo and among the patients treated with aficamten, often there was a lower dose arm and then a subsequent higher dose arm. The study showed that there was a dose-dependent reduction in left ventricular outflow tract gradient [LVOT] to greater than 50% of baseline. So the higher doses were more effective, and this was associated with really the same benefits that we saw in the PIONEER=HCM trial as well as the EXPLORER--trial. That that degree of reduction in left ventricular outflow tract gradient was associated with that just as a grade of 50% greater reduction in. NT-BNP [N-terminal natriuretic peptide] level, improvement of their New York Heart Association [NYHA] class and their quality of life. So really, I think this confirms that cardiac myosin inhibitors are very effective for treating outflow tract obstruction, and by doing that, improving all of the hemodynamic abnormalities that we see in in patients with obstructive hypertrophic cardiomyopathy. Aficamten has completed its phase 3 clinical trial enrollment and we are waiting for the readout of that study, which will probably be later this year or early 2024. So in that study, it was a 1 to 1 randomization in patients with obstructive symptomatic hypertrophic cardiomyopathy randomized to aficamten versus placebo and the primary endpoint was a little bit different. It did not include a composite with NYHA class. It was just peak VO2 [peak oxygen consumption] but NYHA class, LVOT gradient, BNP, quality of life—all of those are included as secondary endpoints. So I think we're all very excited to see those results. It does have a much shorter half-life which allows it to be titrated more rapidly in in 2-week intervals to see the effect on the outflow track gradient. The washout as a result is much quicker if a patient does have side effects from it, discontinuation of it will lead to a quicker washout.

Anjali Owens, MD: Right. I think we've sort of touched us on this on the edges, but you know it, we really need to address up front that these agents modulate contractility. The safety concern is that if you get too much of the drug that you can have a drop in ejection fraction. Many of the patients in the trials and now we've seen in real life are asymptomatic with that drop in ejection fraction and because of that, you really need to monitor them with serial echocardiograms. If the objection fraction drops below 50, then, as we've said several times in the panel, you either reduce the dose if you're dealing with the drug like aficamten that has a relatively short or half-life, or you temporarily discontinue the drug, in the situation of mavacamten that has a long half-life. Then you repeat the echocardiogram, await the ejection fraction to return above 50, which again these agents are reversible and cardiac specific. So once you do that, repeat the echocardiogram, the ejection fraction is above 50, then you can restart at a lower dose.

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