SEQUOIA-HCM: Aficamten Boosts Exercise Capacity in Obstructive HCM

LISBON, Portugal—Patients with obstructive hypertrophic cardiomyopathy (HCM) treated with aficamten (Cytokinetics), an inhibitor of cardiac myosin, had statistically significant and clinically relevant improvements in peak oxygen uptake and other markers of health status when compared with placebo-treated patients, full results of the SEQUOIA-HCM trial show.

Investigators, who presented the results Monday during a late-breaking clinical trial session at the European Society of Cardiology’s Heart Failure 2024 Congress, showed that treatment with aficamten increased peak oxygen uptake by 1.7 mL/kg/minute over 24 weeks compared with placebo.

This increase “far exceeds the kind of change in exercise capacity we would consider to be clinically meaningful,” lead investigator Martin S. Maron, MD (Lahey Hospital and Medical Center, Burlington, MA), told TCTMD. In these patients, a 1-mL/kg/min increase in exercise capacity is typically considered clinically meaningful, and “for that reason, the outcome here in terms of the primary endpoint was really robust and strong,” he said.

The benefit was also seen across a host of secondary endpoints, including quality of life and patient symptoms. “Everything kind of moved in the right direction,” said Maron. “I’ve been at HCM a long time and it’s really unusual to see that type of consistency in HCM, let alone with treatment.”

Justin Ezekowitz, MBBCh, MSc (University of Alberta/Mazankowski Alberta Heart Institute, Edmonton, Canada), a heart failure (HF) specialist who commented on the study for TCTMD, called the improvement in peak VO₂ a “massive change.” HF patients with a peak oxygen uptake of 18 or 19 mL/kg/min at baseline, which is where patients started in SEQUOIA-HCM, are extremely limited in what they can do.

“A patient will notice 1 mL/kg/min,” he said. “It means they’ll be able to go up a flight of stairs—before they couldn’t, but now they can.”

The findings were published simultaneously online in the New England Journal of Medicine.

Increase in Peak Exercise Capacity

HCM affects approximately 1 in 500 individuals, of whom an estimated two-thirds will have the obstructive form wherein the thickened, nondilated left ventricle can interfere with the left ventricular outflow tract (LVOT), usually the result of contact between the ventricular septum and mitral valve during systole.

Mavacamten, another myosin inhibitor approved by the US Food and Drug Administration in 2022 and by European regulators in 2023, is now an option for appropriate patients, but before the advent of this new drug class, patients were managed with beta-blockers or calcium channel blockers, as well as disopyramide (Norpace), to control symptoms. When those failed, the only other options were invasive, including alcohol septal ablation or surgical myectomy.

Aficamten, like mavacamten, targets cardiac myosin to reduce left ventricular contractility, which is a mechanism that leads to LVOT obstruction, and works by reducing the number of actin-myosin crossbridges within the sarcomere.

The outcome here in terms of the primary endpoint was really robust and strong. Martin Maron

SEQUOIA-HCM was a phase III, randomized, double-blind study conducted in 282 patients with obstructive HCM between 2022 and 2023 in 14 countries. Top-line results for the trial were previously released last December. In total, 142 patients with NYHA functional class II or III HF and decreased exercise capacity were randomly assigned to receive aficamten, with 140 receiving placebo. All patients had a left ventricular ejection fraction of at least 60% and a LVOT gradient of at least 30 mm Hg at rest and at least 50 mm Hg after the Valsalva maneuver.

The mean change in peak oxygen uptake from baseline to week 24 was 1.8 mL/kg/min with aficamten compared with no change in the placebo-treated patients (placebo-corrected least-squares mean difference of 1.7 mL/kg/min; P < 0.001). This improvement was seen across a wide range of subgroups, including men and women and younger and older patients, as well as across groups defined by baseline NYHA functional class, LVEF, NT-proBNP levels, baseline peak oxygen uptake, and resting LVOT gradient.   

Aficamten also resulted in a greater improvement in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and led to more patients improving at least one NYHA class from baseline (58.6% vs 24.3% with placebo). Treatment also led to greater improvements in LVOT gradients. On aficamten, patients spent 78 fewer days eligible for septal reduction therapy during the treatment period when compared with those treated with placebo.  

“It suggests that the drug may be able to help eliminate the need for invasive treatments in some patients or at least delay it substantially,” said Maron.

Ezekowitz also emphasized this secondary endpoint, noting that surgical myectomy and alcohol septal ablation have drawbacks.

“When you tell a patient with hypertrophic cardiomyopathy that you might need alcohol septal ablation, they understand it's invasive,” he said. “That's a risk—it’s not a benign procedure—and open surgery is a risk. Any reduction [in the need for invasive procedures] is important.”  

In an editorial, Steve Ommen, MD (Mayo Clinic, Rochester, MN), said longer-term trials are still needed to know if cardiac myosin inhibitors have the same long-term benefits as invasive therapies targeting septal reduction.

“Surgical myectomy and septal ablation, when performed by experienced surgeons, have success rates of 90 to 95% and 75 to 80%, respectively,” he writes, noting that this is superior to the myosin inhibitors. Surgery and septal ablation have also led to a regression in LV wall thickness “remote from the surgical site,” and both have been “associated with normalization of long-term survival relative to matched populations.” Additionally, these invasive procedures may eliminate the need for ongoing drug therapy, writes Ommen.

Despite those caveats, Ommen views the availability of cardiac myosin inhibitors as a benefit for symptomatic patients with HCM.

Effect on LVEF: No Worrisome Signs

Serious adverse events occurred in eight patients treated with aficamten versus 13 patients treated with placebo. At week 24, the LVEF in aficamten-treated patients was “modestly lower” than in the placebo group (mean difference 4.8%), but no differences were seen after the 4-week washout period.

To TCTMD, Maron explained that the pharmacodynamic properties of aficamten differ from mavacamten, with the still investigational drug having a shorter half-life and wider therapeutic window than mavacamten. “With the wider therapeutic window, what that means is that the dose-response curve is a little different,” he said. “There are smaller decreases in ejection fraction as the dose of aficamten increases.”

That’s important because one of the worries with cardiac myosin inhibitors is the effect on LVEF. Mavacamten is only available through the FDA’s risk evaluation and mitigation strategy (REMS) safety program because of concerns about the risk of HF with systolic dysfunction. The US label for mavacamten warns prescribers about this risk, noting that 6% of treated patients in the phase III EXPLORER-HCM trial developed  transient systolic dysfunction. 

It means they’ll be able to go up a flight of stairs—before they couldn’t, but now they can. Justin Ezekowitz

“What we saw in SEQUOIA is that the incidence of low EF was very low, lower than the phase III study with mavacamten,” said Maron. “It wasn’t zero, but it was very low, and in those patients who had low EF events in SEQUOIA, there was no dose interruption at all. We didn’t have to stop the drug.”

The shorter half-life is also an advantage, said Maron, as study investigators were able to uptitrate the dose quickly. This allowed patients to get symptomatic relief as early as 2 weeks. By 6 to 8 weeks, the vast majority of patients were on their steady-state dose, he said.

Ezekowitz said the possible change in LVEF, if aficamten is approved, will be a known effect of treatment, something physicians will keep an eye on. “There’s always going to be a handful of patients where you have to dial back the drug, either with a lower dose or to stop the drug,” he said.

Costs of New Drugs

On the whole, Ezekowitz said he’s excited by the possibility of two myosin inhibitors, adding that further cost-effectiveness and cost-utility analyses will be warranted given that these are lifelong therapies for those with obstructive HCM. It’s hoped that with another competing agent, costs will come down.

The price of mavacamten varies depending on treatment plans and insurance coverage, but widely quoted estimates place the drug north of $75,000 USD per year. From a “patient-facing perspective,” Ezekowitz likened mavacamten and aficamten to cancer therapies, noting that HCM is an autosomal dominant condition, with affected patients having a 50% chance of passing it to their children.

“If you treat this like a cancer, it’s very different,” he said. “Our suppression therapies for cancer are quite expensive as well.”

The American Heart Association (AHA) and the American College of Cardiology (ACC), along with several other professional societies, recently updated their guidelines for the management of HCM patients. Beta-blockers are first recommended (class 1) if there is symptomatic LVOT obstruction, and if these fail or are not tolerated, a nondihydropyridine calcium channel blocker should be substituted (class 1 recommendation). Cardiac myosin inhibitors are also a class 1 recommendation for those who are not responding to or tolerating first-line therapies.

Ommen, who chaired the AHA/ACC guideline-writing committee, says it’s “prudent” to start with beta-blockers and calcium channel blockers, but “all options should be discussed, including treatment with disopyramide or cardiac myosin inhibitors and invasive septal reduction therapy” should first-line therapy not work.