Understanding Aficamten and the SEQUOIA-HCM Design, with Martin Maron, MD

Martin Maron, MD

The approval of mavacamten (Camzyos), cardiac myosin inhibitor from Bristol Myers Squibb, from the US FDA for treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM) in April 2022 was met with applause from the cardiology community.

Based on the results of the EXPLORER-HCM trial, the FDA approved mavacamten for of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (obstructive HCM) to improve functional capacity and symptoms. To date, it is the only FDA-approved allosteric and reversible inhibitor selective cardiac myosin inhibitor targeting the underlying pathophysiology of obstructive HCM, but that could be changing in the near future.

Now, the next-generation cardiac myosin inhibitor, aficamten, is riding that same aforementioned wave of excitement as the community awaits the results of the phase 3 SEQUIOA-HCM trial, with additional excitement brought forth by the results of the phase 2 REDWOOD-HCM. At the Heart Failure Society of America (HFSA) 2022 annual scientific meeting, a pair of presentations focused on data related to quality of life and symptom burden from the REDWOOD-HCM OLE trial as well as data related to the design of the SEQUOIA-HCM trial.

With an interest in learning more about aficamten and the landscape of HCM management, Practical Cardiology sat down with Martin Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Health Medical Center, at HFSA 2022. A transcript of that conversation can be found below.

Practical Cardiology: As a next-generation cardiac myosin inhibitor, what do we know about the differences between aficamten and the previous generation cardiac myosin inhibitor, mavacamten?

Maron: Aficamten is the next generation myosin inhibitor to follow from the first generation mavacamten. Aficamten is in currently phase 3 study for treatment of symptomatic obstructive HCM. I think, as a next generation myosin inhibitor, aficamten works in a similar way as mavacamten. It decreases the number of myosin head and actin filament interactions, which decreases the force of contractility, and, through that mechanism, can lower outflow tract gradients. By doing that, we can improve how patients feel.

One of the differences between aficamten and mavacamten relates to the pharmacodynamic profile or the pharmacologic profile of the drug. There are some distinctions related to its shorter half-life and a difference in the dose response curves of the drug. So, those are the distinguishing features right now. There's a different pharmacodynamic profile compared to mavacamten and one of the questions that's being investigated is whether that difference in the pharmacology of aficamten will translate into differences in efficacy and potentially decreases in issues related to safety of the drug. We don't know the answer to that yet. Of course, that's going to be part of what will be looked at and that is the SEQUIOA-HCM study.

Coming back to the phase 2 REDWOOD-HCM study, REDWOOD demonstrated that aficamten, over several weeks of treatment, can substantially lower both resting and provokable outflow tract gradients in patients that have symptomatic obstructive HCM and can improve significantly the symptom burden in those patients as well. The study showed aficamten was also very well tolerated in terms of safety.

Now, of course, we are going to get a much better idea about how efficacious aficamten with a larger, broader, more expansive clinical trial with the SEQUIOA initiative. So, I think there's a lot more we're going to be learning about this drug soon and, as that experience with aficamten expands, I think we'll be more able to make some sense of how aficamten may compare to mavacamten, but I think it's just way too early to try to do that at this point. We just don't have the information to really kind of provide any kind of reliable comparisons between the two at this point. We are just too early in the experience.

Practical Cardiology: How did what we learned from the EXPLORER-HCM in mavacamten and phase 2 REDWOOD-HCM trial with aficamten influence the design of SEQUIOA-HCM?

Maron: Well, I think the overall study design of SEQUIOA-HCM is pretty similar, not identical, but similar to EXPLORER-HCM. I think what we, perhaps, learned from the mavacamten and EXPLORER experience is avenues for how we will ultimately address the important issue of dosage adjustments: As patients get started on the drug, what they will require in terms of longitudinal echo studies to assess systolic function, which, again, is one of the most important potential safety issues with these drugs. I think it was approximately 7% of patients in the EXPLORER-HCM trial had systolic dysfunction that was very relevant and led the US FDA warning of systolic dysfunction and heart failure for these drugs.

So, I think what we're hoping to learn more in SEQUIOA with aficamten, which, again, has a different pharmacodynamic profile than mavacamten, is whether or not the issue of systolic dysfunction is as present. We are also hoping to learn how we can best address that issue in terms of longitudinal echo follow ups for patients that go aficamten, will they need that less than what we know from the EXPLORER-HCM trial, will it be fewer and far between? I think a lot of the interest is for safety; part of the focus in the SEQUIOA trial is really to try to understand that aspect of this drug better than we know currently from the phase 2 effort.

Practical Cardiology: Where is the most pressing gap in knowledge related to hypertrophic cardiomyopathy?

Maron: I would say that the biggest or most relevant treatment gap or unmet need in the disease right now is in the treatment of symptomatic nonobstructive HCM—1-in-3 patients with this disease have nonobstructive HCM. Among these patients, a small, but important, subgroup develop end-stage heart failure. Right now, we have no therapy currently to help mitigate or prevent that progression to heart failure and we have very few treatment options when patients develop end-stage heart failure with nonobstructive HCM other than heart transplant.

So, there is no question that I think that it would be very fair to say that, as we go forward here, I hope the focus shifts in a way to exploring new therapies for the nonobstructive group of patients. Since those, again, are the patients that perhaps have the most to gain from new therapies at this point the greatest unmet need for the disease.

Editor’s Note: This transcript has been edited for length and clarity.