A next-in-class cardiac myosin inhibitor, aficamten, led to substantial reductions in left ventricular outflow tract (LVOT) gradients compared to placebo in patients with obstructive hypertrophic cardiomyopathy (oHCM), according to phase II study results.
Most patients also experienced improvements in heart failure symptoms and clinically relevant biomarkers, the study shows.
Martin S. Maron, MD, of Lahey Hospital and Medical Center, Burlington, Massachusetts, and colleagues reported these findings in a manuscript published Monday online and in the Jan. 3/10 issue of the Journal of the American College of Cardiology.
LVOT obstruction is the most important factor in progressive heart failure symptoms for patients with oHCM. Hypercontractility of the left ventricle is a key contributor to LVOT obstruction because it promotes mitral valve-ventricular septal contact, which results in a pressure gradient between the left ventricular cavity and the systemic circulation. Current medical therapies do not provide complete symptom relief because they do not optimally reduce the LVOT gradient and can lead to off-target adverse drug effects.
Cardiac myosin inhibitors show the potential to reduce cardiac contractility and LVOT gradients, which was demonstrated with mavacamten in the phase III EXPLORER-HCM clinical trial.
The phase II REDWOOD-HCM trial, therefore, evaluated the safety and tolerability of aficamten in patients with symptomatic oHCM across a range of doses.
The study randomized 41 patients with oHCM and LVOT gradients of at least 30 mmHg at rest or at least 50 mmHg with Valsalva 2-to-1 to receive aficamten (n=28) or placebo (n=13).
The aficamten patients were divided into two cohorts. Cohort 1 was started on 5 mg of aficamten, and doses were titrated to 10 mg at week 2 and 15 mg at week 4 if echocardiographic criteria were met. Cohort 2 was started on 10 mg, and doses were titrated to 20 mg at week 2 and 30 mg at week 4 if echocardiographic criteria were met.
At weeks 2 and 4, after receiving the study drug, patients were examined with an echocardiogram; if this showed a left ventricular ejection fraction (LVEF) of at least 50% and either a resting LVOT gradient of at least 30 mmHg or a Valsalva gradient of at least 50 mmHg, patients were up-titrated to the next dosing level. Patients who did not meet these criteria remained at the same dose. The dose was reduced if LVEF dropped below 50%, and the drug was permanently discontinued if LVEF dropped below 40%.
The primary endpoint was adverse events, serious adverse events and LVEF <50%. Key secondary and exploratory endpoints included the change from baseline in resting and Valsalva LVOT gradients over 10 weeks of treatment, the proportion of patients with complete hemodynamic response (defined as resting LVOT gradient <30 mmHg and Valsalva LVOT gradient <50 mmHg), and the change from baseline in LVEF, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin and New York Heart Association (NYHA) functional class.
Aficamten reduced LVOT gradients
The mean resting LVOT gradient dropped in Cohort 1, from 54 ± 25 mmHg at baseline to 13 ± 4 mmHg at 10 weeks (least squares [LS] mean difference ± standard error [SE]: -29 ± 7.2 mmHg; 90% confidence interval [CI]: -41 mmHg to -16 mmHg; p=0.0003 vs. placebo). The drop in Cohort was from 58 ± 36 mmHg to 15 ± 22 mmHg (-28 ± 7.2 mmHg; 90% CI: -40 mmHg to -16 mmHg; p=0.0004 vs. placebo). The placebo group’s gradient also fell, but not as much, from 52 ± 27 mmHg to 44 ± 25 mmHg (-13 ± 5.2 mmHg; 90% CI: -22 mmHg to -4 mmHg).
After a 2-week washout period, at week 12, the resting LVOT gradients for aficamten patients returned to baseline levels (Cohort 1: 47 ± 32 mmHg; Cohort 2: 45 ± 35 mmHg).
The mean Valsalva LVOT gradient changes showed a similar pattern. Cohort 1’s mean Valsalva gradient fell from 74 ± 25 mmHg at baseline to 38 ± 14 mmHg (LS mean difference ± SE: -33 ± 9.2 mmHg; 90% CI: -48 mmHg to -17 mmHg; p=0.001) vs. placebo. Cohort 2’s mean Valsalva gradient dropped from 82 ± 37 mmHg to 30 ± 30 mmHg (-43 ± 9.1 mmHg; 90% CI: -59 mmHg to -28 mmHg; p<0.0001 vs. placebo). The placebo group’s mean Valsalva gradient fell from 85 ± 21 mmHg to 76 ± 23 mmHg (-8 ± 6.7 mmHg; 90% CI: -19 mmHg to 3.2 mmHg).
After the 2-week washout period, mean Valsalva gradients returned to baseline levels: 68 ± 22 mmHg for Cohort 1 and 74 ± 40 mmHg for Cohort 2).
The authors noted that after 2 weeks of aficamten therapy, 89% of the patients receiving the drug had resting LVOT gradients <30 mmHg, and 64% had Valsalva LVOT gradients <50 mmHg.
They added that a complete hemodynamic response, meeting both of those gradient benchmarks at week 10, occurred in 79% of Cohort 1 and 93% of Cohort 2, compared with just 8% of the placebo group.
LVEF levels were reduced moderately in the aficamten cohorts. Cohort 1’s mean LVEF fell from 73% ± 6% to 67% ± 9% (LS mean difference vs. placebo ± SE: -7.2 ± 2.5, p=0.0007) over the 10-week treatment period. Cohort 2’s mean LVEF dropped from 75% ± 6% to 64% ±8% (LS mean difference vs. placebo ± SE: -11.7 ± 2.5, p<0.0001). The placebo group’s mean LVEF did not change (75% ± 6% to 75% ±4%; p=0.50).
There was a dose-dependent decrease with a mean reduction in LVEF of -0.6% (SE: 0.084) per milligram of aficamten.
Symptomatic improvement of at least one NYHA functional class occurred in 31% of the placebo group, 43% of Cohort 1 and 64% of Cohort 2, which was not statistically significant.
NT-proBNP levels were decreased in both aficamten cohorts (from geometric mean of 490 pg/mL at baseline to 165 pg/mL at week 10), while the placebo group saw an increase (395 pg/mL to 460 pg/mL). Aficamten was associated with a 62% proportional reduction in NT-proBNP levels at week 10 compared to placebo.
The authors acknowledged several limitations to the study, including the short treatment duration limiting the determination of potential effects of aficamten on cardiac structure and disease modification, no prospective assessment of genetic variants within the trial, and that objective measures of functional capacity with cardiopulmonary exercise testing were not included.
The authors said that based on the REDWOOD-HCM phase II study data, the clinical safety and efficacy of aficamten will be evaluated in a phase III clinical trial, SEQUOIA-HCM.
‘Bold leap forward’
In an accompanying editorial, Ajith Nair, MD, of the Baylor College of Medicine, Houston, and colleagues called the REDWOOD-HCM phase II results “highly encouraging.” They called the LVOT gradient reduction brought about by aficamten “profound.”
While the phase III results remain to be seen, the editorialists said: “The prospect of having a second disease-modifying agent is a bold leap forward in the HCM frontier, with the potential to alter the natural course of this condition.”
The REDWOOD-HCM study was funded by Cytokinetics Inc., the drug’s manufacturer.
Maron MS, Masri A, Choudhury L, et al. Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2023;81:34–45.
Nair A, Xie L, Silva Enciso JE. Myosin Inhibitors: The Next Generation. J Am Coll Cardiol 2023;81:46-48.
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