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Randomized Controlled Trial
. 2023 Oct 1;8(10):968-977.
doi: 10.1001/jamacardio.2023.3342.

Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 56 Results From the VALOR-HCM Randomized Clinical Trial

Milind Y Desai  1   2   3 , Anjali Owens  4 , Kathy Wolski  2   3 , Jeffrey B Geske  5 , Sara Saberi  6 , Andrew Wang  7 , Mark Sherrid  8 , Paul C Cremer  2   3 , Neal K Lakdawala  9 , Albree Tower-Rader  10 , David Fermin  11 , Srihari S Naidu  12 , Nicholas G Smedira  1   13 , Hartzell Schaff  14 , Ellen McErlean  2   3 , Christina Sewell  2   3 , Lana Mudarris  15 , Zhiqun Gong  15 , Kathy Lampl  15 , Amy J Sehnert  15 , Steven E Nissen  2   3
Affiliations
Randomized Controlled Trial

Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 56 Results From the VALOR-HCM Randomized Clinical Trial

Milind Y Desai et al. JAMA Cardiol. .

Abstract

Importance: There is an unmet need for novel medical therapies before recommending invasive therapies for patients with severely symptomatic obstructive hypertrophic cardiomyopathy (HCM). Mavacamten has been shown to improve left ventricular outflow tract (LVOT) gradient and symptoms and may thus reduce the short-term need for septal reduction therapy (SRT).

Objective: To examine the cumulative longer-term effect of mavacamten on the need for SRT through week 56.

Design, setting, and participants: This was a double-blind, placebo-controlled, multicenter, randomized clinical trial with placebo crossover at 16 weeks, conducted from July 2020 to November 2022. Participants were recruited from 19 US HCM centers. Included in the trial were patients with obstructive HCM (New York Heart Association class III/IV) referred for SRT. Study data were analyzed April to August 2023.

Interventions: Patients initially assigned to mavacamten at baseline continued the drug for 56 weeks, and patients taking placebo crossed over to mavacamten from week 16 to week 56 (40-week exposure). Dose titrations were performed using echocardiographic LVOT gradient and LV ejection fraction (LVEF) measurements.

Main outcome and measure: Proportion of patients undergoing SRT, remaining guideline eligible or unevaluable SRT status at week 56.

Results: Of 112 patients with highly symptomatic obstructive HCM, 108 (mean [SD] age, 60.3 [12.5] years; 54 male [50.0%]) qualified for the week 56 evaluation. At week 56, 5 of 56 patients (8.9%) in the original mavacamten group (3 underwent SRT, 1 was SRT eligible, and 1 was not SRT evaluable) and 10 of 52 patients (19.2%) in the placebo crossover group (3 underwent SRT, 4 were SRT eligible, and 3 were not SRT evaluable) met the composite end point. A total of 96 of 108 patients (89%) continued mavacamten long term. Between the mavacamten and placebo-to-mavacamten groups, respectively, after 56 weeks, there was a sustained reduction in resting (mean difference, -34.0 mm Hg; 95% CI, -43.5 to -24.5 mm Hg and -33.2 mm Hg; 95% CI, -41.9 to -24.5 mm Hg) and Valsalva (mean difference, -45.6 mm Hg; 95% CI, -56.5 to -34.6 mm Hg and -54.6 mm Hg; 95% CI, -66.0 to -43.3 mm Hg) LVOT gradients. Similarly, there was an improvement in NYHA class of 1 or higher in 51 of 55 patients (93%) in the original mavacamten group and in 37 of 51 patients (73%) in the placebo crossover group. Overall, 12 of 108 patients (11.1%; 95% CI, 5.87%-18.60%), which represents 7 of 56 patients (12.5%) in the original mavacamten group and 5 of 52 patients (9.6%) in the placebo crossover group, had an LVEF less than 50% (2 with LVEF ≤30%, one of whom died), and 9 of 12 patients (75%) continued treatment.

Conclusions and relevance: Results of this randomized clinical trial showed that in patients with symptomatic obstructive HCM, mavacamten reduced the need for SRT at week 56, with sustained improvements in LVOT gradients and symptoms. Although this represents a useful therapeutic option, given the potential risk of LV systolic dysfunction, there is a continued need for close monitoring.

Trial registration: ClinicalTrials.gov Identifier: NCT04349072.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Desai reported receiving consultant fees from Bristol Myers Squibb, Cytokinetics, Tenaya, and Medtronic during the conduct of the study. Dr Owens reported receiving consulting fees from Bristol Myers Squibb, Cytokinetics, Tenaya, Lexicon, Biomarin, Pfizer, Renovacor, and Stealth during the conduct of the study. Dr Geske reported being a principal site investigator for Bristol Myers Squibb and Cytokinetics during the conduct of the study and receiving advisory fees from Cytokinetics outside the submitted work. Dr Saberi reported receiving grants from Bristol Myers Squibb and personal fees from Cytokinetics outside the submitted work. Dr Wang reported receiving grants and personal fees from Bristol Myers Squibb and grants from Cytokinetics outside the submitted work. Dr Sherrid reported receiving consultant fees from Pfizer outside the submitted work. Dr Lakdawala reported receiving personal fees from Bristol Myers Squibb, Cytokinetics, Pfizer, Tenaya, and Akros and grants from Pfizer outside the submitted work. Dr Tower-Rader reported receiving grants from Bristol Myers Squibb and Cytokinetics outside the submitted work. Dr Fermin reported receiving personal fees from Bristol Myers Squibb, BridgeBio, and Alnylam, and grants from Pfizer outside the submitted work. Dr Naidu reported receiving consultant and research fees from Bristol Myers Squibb and Cytokinetics outside the submitted work. Dr McErlean reported receiving grants from Bristol Myers Squibb outside the submitted work. Dr Sewell reported receiving research fees from Bristol Myers Squibb during the conduct of the study. Dr Mudarris reported being employed by and receiving a salary and stock options from Bristol Myers Squibb outside the submitted work. Dr Gong reported receiving personal fees from Bristol Myers Squibb outside the submitted work. Dr Lampl reported being an employee of Bristol Myers Squibb outside the submitted work. Dr Sehnert reported being an employee of and receiving a salary and stock options from Bristol Myers Squibb during the conduct of the study and having a patent pending for Methods of Treatment With Myosin Modulator and for Methods of Administering Myosin Inhibitors. Dr Nissen reported receiving grants from Bristol Myers Squibb during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Consolidated Standards of Reporting Trials Diagram Detailing the Recruitment, Randomization, and Patient Flow in the 56-Week Long-Term Extension Trial A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy (VALOR-HCM)
aAlso met permanent study drug discontinuation criteria.
Figure 2.
Figure 2.. Efficacy and Safety Parameters From Baseline to Week 56 for the Original Mavacamten and the Placebo Crossover Groups
A, Septal reduction therapy (SRT) composite at baseline, weeks 16, 32, and 56. B, Improvement in New York Heart Association class. C, Peak left ventricular outflow tract gradient at rest. D, Peak left ventricular outflow tract gradient after Valsalva maneuver. Plotted values in panels B to D represent means and SEs.
See this image and copyright information in PMC

Comment in

References

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