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Clinical Trial
. 2023 Mar 1;8(3):240-247.
doi: 10.1001/jamacardio.2022.5099.

Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial

Matthew T Wheeler  1 , Iacopo Olivotto  2   3 , Perry M Elliott  4 , Sara Saberi  5 , Anjali T Owens  6 , Mathew S Maurer  7 , Ahmad Masri  8 , Amy J Sehnert  9 , Jay M Edelberg  9 , Yu-Mao Chen  10 , Victoria Florea  9 , Rajeev Malhotra  11 , Andrew Wang  12 , Artur Oreziak  13 , Jonathan Myers  14   15
Affiliations
Clinical Trial

Effects of Mavacamten on Measures of Cardiopulmonary Exercise Testing Beyond Peak Oxygen Consumption: A Secondary Analysis of the EXPLORER-HCM Randomized Trial

Matthew T Wheeler et al. JAMA Cardiol. .

Abstract

Importance: Mavacamten, a cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the EXPLORER-HCM study. However, the full extent of mavacamten's effects on exercise performance remains unclear.

Objective: To investigate the effect of mavacamten on exercise physiology using cardiopulmonary exercise testing (CPET).

Design, setting, and participants: Exploratory analyses of the data from the EXPLORER-HCM study, a randomized, double-blind, placebo-controlled, phase 3 trial that was conducted in 68 cardiovascular centers in 13 countries. In total, 251 patients with symptomatic obstructive HCM were enrolled.

Interventions: Patients were randomly assigned in a 1:1 ratio to mavacamten or placebo.

Main outcomes and measures: The following prespecified exploratory cardiovascular and performance parameters were assessed with a standardized treadmill or bicycle ergometer test protocol at baseline and week 30: carbon dioxide output (VCO2), minute ventilation (VE), peak VE/VCO2 ratio, ventilatory efficiency (VE/VCO2 slope), peak respiratory exchange ratio (RER), peak circulatory power, ventilatory power, ventilatory threshold, peak metabolic equivalents (METs), peak exercise time, partial pressure of end-tidal carbon dioxide (PETCO2), and VO2/workload slope.

Results: Two hundred fifty-one patients were enrolled. The mean (SD) age was 58.5 (11.9) years and 59% of patients were male. There were significant improvements with mavacamten vs placebo in the following peak-exercise CPET parameters: peak VE/VCO2 ratio (least squares [LS] mean difference, -2.2; 95% CI, -3.05 to -1.26; P < .001), peak METs (LS mean difference, 0.4; 95% CI, 0.17-0.60; P < .001), peak circulatory power (LS mean difference, 372.9 mL/kg/min × mm Hg; 95% CI, 153.12-592.61; P = .001), and peak PETCO2 (LS mean difference, 2.0 mm Hg; 95% CI, 1.12-2.79; P < .001). Mavacamten also improved peak exercise time compared with placebo (LS mean difference, 0.7 minutes; 95% CI, 0.13-1.24; P = .02). There was a significant improvement in nonpeak-exercise CPET parameters, such as VE/VCO2 slope (LS mean difference, -2.6; 95% CI, -3.58 to -1.52; P < .001) and ventilatory power (LS mean difference, 0.6 mm Hg; 95% CI, 0.29-0.90; P < .001) favoring mavacamten vs placebo.

Conclusions and relevance: Mavacamten improved a range of CPET parameters beyond pVO2, indicating consistent and broad benefits on maximal exercise capacity. Although improvements in peak-exercise CPET parameters are clinically meaningful, the favorable effects of mavacamten on submaximal exertional tolerance provide further insights into the beneficial impact of mavacamten in patients with obstructive HCM.

Trial registration: ClinicalTrials.gov Identifier: NCT03470545.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wheeler received grants, in-kind medical writing support and payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Olivotto received grants from Bayer, MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Sanofi Genzyme, and Shire, now part of Takeda; personal fees from Bayer, Sanofi Genzyme, and Shire, now part of Takeda; and payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Elliott received payment as a consultant from DiNAQOR, Freeline, MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, Pfizer, Sanofi, and Sarepta; an unrestricted grant from Pfizer; and lecture fees from PeerVoice, the Radcliffe Group, and Sanofi. Dr Saberi received payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Owens reported consulting for Cytokinetics and MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Maurer received funding from the National Institutes of Health (HL139671-01, AG R21AG058348, and AG K24AG036778) and consulting income from Akcea, Alnylam, Eidos Therapeutics, Pfizer, Prothena, Novo Nordisk, and Intellia; his institution has also received funding for clinical trials for Alnylam, Eidos Therapeutics, Pfizer, and Prothena. Dr Masri received research grants from Akcea, Ionis, Pfizer, Ultromics, and the Wheeler Foundation, and fees (honoraria or consulting) from Alnylam, Attralus, Bristol Myers Squibb, Cytokinetics, Eidos Therapeutics, Ionis, Pfizer, and Tenaya. Drs Sehnert, Chen, and Florea are employees of MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, and own stock in Bristol Myers Squibb. Dr Edelberg was an employee of MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, when this work was carried out and owns stocks of Bristol Myers Squibb. Mr. Chen is an employee of Bristol Myers Squibb. Dr Malhotra received payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. Dr Wang received payments as a consultant and grants from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb, and personal fees from Cytokinetics. Dr Myers received payments as a consultant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
All randomized patients received at least 1 dose of study drug and were included in the efficacy analyses. Two patients who discontinued for other reasons (mavacamten, n = 1; placebo, n = 1) did not complete the week-30 visits within the window owing to scheduling issues. CPET indicates cardiopulmonary exercise testing; ECG, electrocardiogram. aOne patient discontinued treatment, but performed the CPET assessment at week 30.
Figure 2.
Figure 2.. Treatment Difference of the Change From Baseline to Week 30 Between Mavacamten and Placebo in Peak-Exercise Cardiopulmonary Exercise Testing (CPET) Parameters
LS indicates least squares; MET, metabolic equivalent; PETCO2, partial pressure of end-tidal carbon dioxide; VCO2, carbon dioxide output; VE, minute ventilation.
Figure 3.
Figure 3.. Treatment Difference of the Change From Baseline to Week 30 Between Mavacamten and Placebo in Submaximal Exercise Cardiopulmonary Exercise Testing (CPET) Parameters
LS indicates least squares; PETCO2, partial pressure of end-tidal carbon dioxide; VCO2, carbon dioxide output; VE, minute ventilation; VO2, oxygen uptake.
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