Another Myosin Inhibitor Raises Hopes for Obstructive HCM in Early Study

September 13, 2021

DENVER — Patients with obstructive hypertrophic cardiomyopathy (HCM) treated with an agent that targets the disorder's underlying disease process showed important gains in hemodynamics and other benefits, with few adverse effects, in a small phase 2 trial.

The drug, aficamten (previously CK-274, CytoKinetics), a myosin inhibitor and the second in its class to reach the clinical trial stage in obstructive HCM, is given to reduce left ventricular outflow tract (LVOT) pressure gradients, an echocardiographic hallmark of the genetic disorder.

Such pressure gradients were all but abolished in most of the trial's patients, who received aficamten in escalating doses, with 90% of participants reaching the highest dosage level.

The hemodynamic boost that patients experienced manifested as significant declines in natriuretic peptide levels, although the degree of accompanying symptom relief fell short of significance in the trial, called REDWOOD-HCM.

Aficamten comes on the scene after mavacamten (MyoKardia), the first myosin inhibitor to reach the phase 3 trial stage with last year's publication of EXPLORER-HCM. Mavacamten seemed to work as planned. Patients taking the drug in the placebo-controlled trial showed across-the-board improvements in symptoms, exercise performance, echo parameters, and quality of life over 30 weeks without important adverse effects or tolerance issues.

In REDWOOD-HCM, the 41 patients were required to be on stable doses of a beta blocker or calcium channel blocker, standard therapies in obstructive HCM, but could not have been on disopyramide or antiarrhythmics with negative inotropy in the previous month.

"So far, the evidence supports aficamten as an additional medical option for symptomatic obstructive HCM," Martin S. Maron, MD, Tufts Medical Center, Boston, told | Medscape Cardiology.

"You could imagine it potentially being an option that patients with obstructive HCM would be offered if they didn't feel better after a trial of beta blocker or calcium channel blocker therapy, instead of moving forward at that point to, for example, an invasive septal reduction therapy like surgery or alcohol ablation. I think that's where, at the moment, it seems to be fitting in."

Maron, who directs his center's Hypertrophic Cardiomyopathy Center and Research Institute, presented REDWOOD-HCM during the Heart Failure Society of America Annual Scientific Meeting, conducted virtually and also live in Denver.

He described aficamten as a second-generation cardiac myosin inhibitor with some pharmacokinetic advantages over mavacamten, starting with its plasma half-life of 3.4 days, in contrast to the mavacamten half-life of about 7.0 days. And aficamten achieves steady-state concentrations in 2 weeks, rather than the 4 to 6 weeks with the other drug. As a result, Maron said, dosages can be uptitrated more rapidly with the newer agent or withdrawn quickly, as necessary, in response to adverse effects.

"If it does have a shorter half-life with that rapid reversibility, it seems attractive," Dipti Itchhaporia, MD, Hoag Heart and Vascular Institute, Newport Beach, California, told | Medscape Cardiology. It would be useful to directly compare aficamten and mavacamten for pharmacokinetics to see if a shorter half-life really does give aficamten such advantages, said Itchhaporia, who comoderated the meeting session that featured Maron's REDWOOD-HCM presentation.

There is indeed room for better medical therapy in patients with obstructive HCM, she noted. "Some of these patients are prone to sudden death and some will go on to develop significant functional impairment from heart failure, so we have not had very good therapies for some of them."

The results of REDWOOD-HCM as presented were "fantastic," Itchhaporia said. "I would love to see a drug like that for my symptomatic patients. If this holds true, so that you can achieve this kind of decrease in the left ventricular outflow tract gradient and symptomatic relief, I think it would benefit these patients."

Still, she added, whether those gains will translate into better clinical outcomes, such as fewer hospitalizations or reduced mortality, remains unknown. "So, we're going to need longer-term data."

REDWOOD-HCM entered adults with symptomatic obstructive HCM who were stable on conventional therapy. Their left ventricular ejection fraction (LVEF) had to be at least 60%, giving them a reserve in the event of the drop in LVEF that can occur on myosin inhibitors.

The trial assigned 41 such patients to two cohorts, each of which compared escalating dosages of aficamten with placebo over 10 weeks. In one cohort, the aficamten group received the drug on a lower-dose uptitration regimen; in the other, actively treated patients received it on a higher-dose regimen. The 10-week regimens were followed by a 2-week washout period.

The lower-dose aficamten group started the drug at 5 mg daily, which was uptitrated under echocardiographic guidance to 10 mg and later to 15 mg for the duration of the 10-week period. The higher-dose group started at 10 mg daily with uptitrations to 20 mg and 30 mg.

LVOT gradients both at rest and at a Valsalva maneuver dropped significantly soon after the start of both aficamten regimens and remained lower at weeks 4, 6, 8, and 10, compared with gradients in the control group.

Left Ventricular Outflow Tract Gradient at Rest and With Valsalva, by Aficamten Dosage vs Placebo
LVOT Gradient Conditions Pooled Placebo, mm Hg (n = 13) Lower-dose Aficamten, mm Hg (n = 14) Higher-dose Aficamten, mm Hg (n = 14) P vs Placebo (Lower-dose, Higher-dose)
Baseline 52.1 53.8 58.2  
Week 4 47.1 27.3 16.1 .025, .0006
Week 10 44.0 13.4 15.1 .0003, .0004
Baseline 84.6 74.4 82.2  
Week 4 71.3 51.3 32.3 .038, .0005
Week 10 76.0 38.1 29.8 .001, <.0001

Only 8% of patients who received placebo met the trial's definition for a complete treatment response, a resting LVOT gradient less than 30 mm Hg and a provoked LVOT gradient less than 50 mm Hg by 10 weeks. But 79% of patients in the lower-dose escalation group and 93% of those in the higher-dose escalation group had responses meeting that standard.

Almost a third of those in the placebo group, 31%, improved at least one step in NYHA functional class by week 10. That compares with 43% in the lower-dose aficamten cohort, which wasn't significantly different, and 64% in the higher-dose active-therapy cohort (P = .08), an improving trend short of significance.

As it happens, aficamten was not associated with serious adverse effects, and such events of any kind were no more common with the active drug than with placebo, Maron reported. There were no therapy interruptions in the aficamten group, he said. In particular, no patients met the trial's prespecified criteria for treatment withdrawal due to a drop in LVEF to less than 40%.

Still, mean LVEF in both actively treated groups fell further than in control group (P < .05) and remained significantly lower until week 10. But group averages never went below 60%. In contrast, LVEFs in two higher-dosage patients were measured at less than 50% on one of the follow-up days.

The drop in LVEF that can be part of myosin inhibitor therapy might seem like an adverse effect, but "we don't really know whether or not that's true here," Maron said in an interview.

A decline of maybe 5 or 10 points from baseline on the drugs "may have no long-term consequences at all" in obstructive HCM, he said. "I think the interplay between gradients and LVEF and their consequences are things that we just don't fully know the answer to yet."

And that applies to other issues regarding both myosin inhibitors, Itchhaporia observed. Not everyone in REDWOOD-HCM or the mavacamten trials was on both a beta blocker and a calcium channel blocker, so it's unknown whether the newer drugs should be given with one or both of those classes. They didn't follow patients long enough to see whether there was a treatment effect on risk for sudden death. Nor did those trials include NYHA class 4 patients, or many women or African Americans, she said.

"I think we need longer-term data, we need to see a variety of different patient populations, and we need to monitor for arrhythmias. So, I think there's still too many unanswered questions."

Maron has disclosed consulting for and serving on a trial steering committee for Cytokinetics.

Heart Failure Society of America (HFSA) Annual Scientific Meeting 2021: Late Breaking Clinical Trials I. REDWOOD-HCM: A Randomized, Double-blind, Placebo-Controlled, Dose-Finding Trial of the Cardiac Myosin Inhibitor Aficamten, in Obstructive Hypertrophic Cardiomyopathy. Presented September 9, 2021.

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