REDWOOD-HCM OLE: Aficamten Improves Patient-Measured Health Status

The cardiac myosin inhibitor aficamten (Cytokinetics) is associated with improvements in self-reported health status in patients with obstructive hypertrophic cardiomyopathy (OHCM), according to new data from the REDWOOD-HCM Open Label Extension (OLE) study.

In data presented earlier this year at the European Society of Cardiology Heart Failure 2022 congress, the investigators had shown that over 24 weeks, patients on the drug had significant reductions in left ventricular outflow tract (LVOT) gradients and 78% improved by at least one NYHA class.

But hemodynamics and markers of heart muscle strain “don't necessarily give you a real picture of what the person with HCM is actually experiencing in their day-to-day life,” Sara Saberi, MD (University of Michigan, Ann Arbor), told TCTMD.

Presenting the health status data at a late-breaking presentation at the Heart Failure Society of America (HFSA) 2022 meeting last Sunday, Saberi showed that patients in the trial experienced parallel improvements in symptom burden, social functioning, physical functioning, and quality-of-life (QoL) outcomes as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

“It’s rewarding for us as investigators to be able to see that there is a profound impact on how patients feel,” she added.

Aficamten is the second cardiac myosin inhibitor to show promise in OHCM. In the randomized EXPLORER-HCM trial, mavacamten (Camzyos; Bristol Myers Squibb) showed the potential to increase peak exercise capacity and improve postexercise LVOT gradient, peak VO2, and NYHA class.  As TCTMD previously reported, the health status analysis from that trial showed a mean change in KCCQ overall summary score at 30 weeks that was 9.1 points greater in the mavacamten group than in the placebo group.

The US Food and Drug Administration approved mavacamten earlier this year for the treatment of symptomatic OHCM on the basis of the EXPLORER-HCM findings. In the VALOR-HCM trial, mavacamten showed potential for reducing the need for surgical or interventional septal reduction when added to maximally tolerated medical therapy.

Both aficamten and mavacamten ease the hypercontractility of OHCM and improve diastolic function.

Improvements Seen in All Domains

REDWOOD-HCM OLE is the 5-year extension study of the phase II multicenter, randomized REDWOOD-HCM trial, which thus far has 24-week data on 42 patients with OHCM (mean age 59 years; 60% female). Doses of aficamten were titrated based on echocardiographic guidance and ranged from 5 to 20 mg.

The 23-item KCCQ was administered at baseline and at weeks 12 and 24. Statistically significant improvement compared with baseline was reported across all domains at 12 weeks and that improvement was sustained out to 24 weeks, Saberi said in her presentation. Looking at categorical changes, approximately 70% of patients had at least a 5-point improvement in their scores through week 24, with more than half reporting improvements of 20 points or more in the QoL domain.

Concurrent with health status improvements, there were hemodynamic improvements as well. According to Saberi, aficamten “obliterated resting obstruction by 4 weeks of treatment,” with LVOT gradients falling well below 30 mm Hg from a mean of 46.7 mm Hg at baseline and declining further to below 20 mm Hg by 24 weeks (P < 0.0001 for both time comparisons). There also were improvements in dynamic obstruction by 6 weeks of treatment, while left ventricular ejection fraction remained steady.

At baseline, 48% of patients had NYHA class III symptoms. By week 12 and 24, only 8% and 7%, respectively, were still in class III. Twenty-nine patients (45%) had improved to NYHA class I at week 24 (P < 0.0001 for ≥ 1 NYHA class improvement). Specifically, 14% of patients improved by two classes, 62% improved by one class, and 24% had no change. Saberi said no patients had a worsening of NYHA class from baseline.

N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, which were a mean of 642.6 pg/mL at baseline, fell 70% by week 12 and continued to decrease at week 24 (P < 0.0001 for both time comparisons). Similarly, cardiac troponin I fell from a baseline mean of 15.2 ng/L to below 10 ng/L by week 12, a drop of approximately 30% that was sustained at week 24 (P < 0.005 for both time comparisons).

Aficamten was well tolerated overall in the study, with two patients requiring a temporary dose reduction/interruption (for alcohol-triggered atrial fibrillation and suspected QTc prolongation). Both later resumed aficamten and currently are in NYHA class I, Saberi said.

SEQUOIA and Hypercontractility Questions

Following Saberi’s presentation, session co-moderator Gerasimos Filippatos, MD (National & Kapodistrian University of Athens Medical Center, Greece), asked whether the investigators could discern any differences between patients who had the most improvement in KCCQ scores and those with less improvement or the 24% with no improvement, saying: “I don’t agree with those who say let’s find a clinically meaningful improvement in the [QoL] scoring.”

Saberi said a responder analysis has not been conducted, nor a correlation analysis to look for predictors or correlates of change in KCCQ. While it may be possible, she said, that a more-robust response on the KCCQ is indicative of greater LVOT gradient reduction, that remains unknown.

To TCTMD, she said part of the reason why those type of analyses have not been done is the small number of patients available for analysis.

“This is a cohort of 42 people. If we start splitting them up into quartiles and breaking small data down even further it’s not going to yield meaningful clinical information,” she added. What likely will provide much more needed data on aficamten, is the ongoing phase III SEQUOIA-HCM trial, which will be the largest OHCM trial to date with a planned enrollment of 270 patients. The trial will follow participants for 24 weeks, after which all will be rolled over into REDWOOD-HCM OLE, including placebo patients who—presuming benefit is confirmed—will be offered aficamten.

In the session, John Cleland, MD (University of Glasgow, Scotland), commented that it is an “exciting time” for HCM research, “with at least two members of this class showing very similar results.” One question still needing answers, he said, is whether having LVOT obstruction is key to the success of cardiac myosin inhibitors, or whether their action on slowing hypercontractility might be beneficial in HF patients with supranormal left ventricular ejection fraction (LVEF >70%), many of whom “presumably” have OHCM.

Saberi said more answers on that front are expected to come from cohort 4 of REDWOOD-HCM, which includes patients with nonobstructive HCM. Cohort 4 began enrolling in March 2022, with an expected enrollment of 30 to 40 patients.