CADTH Reimbursement Review

Mavacamten (Camzyos)

Sponsor: Bristol Myers Squibb

Therapeutic area: Obstructive hypertrophic cardiomyopathy

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

NOC = Notice of Compliance; NYHA = New York Heart Association.

Introduction

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease characterized by increased thickness of the left ventricular wall.¹ About 30% to 60% of patients with HCM have identifiable familial disease caused by mutations in cardiac sarcomere protein genes, and each offspring of an affected family member has a 50% chance of inheriting an altered gene, although not all family members who inherit an HCM mutation will develop the disease.^1-3 The distribution of HCM is equal by sex, although females have been diagnosed less frequently than males.^2,3 The age of symptom onset and the severity of symptoms varies significantly across patients with HCM.¹ Among patients with HCM who do develop symptoms, the most common symptoms include chest pain, shortness of breath with exertion, fatigue, palpitations, and light-headedness.¹ Obstructive hypertrophic cardiomyopathy (oHCM), a subclassification of HCM, is characterized by obstruction of the left ventricular outflow tract (LVOT), with the obstruction impeding blood flow from the heart to the rest of the body, defined in the 2020 clinical guidelines set by the American Heart Association (AHA) and the American College of Cardiology (ACC) as a peak LVOT gradient of 30 mm Hg or greater.³ Patients with oHCM are more likely to develop symptoms such as increased myocardial wall stress, myocardial ischemia, and, eventually, cell death and replacement scarring.¹ Associated complications include heart failure, stroke due to atrial fibrillations, arrhythmias, and sudden cardiac death.¹ The estimated prevalence of HCM in the general population is 1 in 500 adults, although most of these cases remain undiagnosed.¹ The 2020 AHA/ACC clinical guidelines suggest that oHCM is present or develops over time in most patients with HCM, with about a third of patients with HCM remaining nonobstructive.³ Estimates for the proportion of patients with HCM who have oHCM range from 22% in a study from western Sweden⁴ to 70% in a US study.⁵

Mavacamten is a first-in-class cardiac myosin inhibitor.⁶ Mavacamten modulates the number of myosin heads that can enter power-generating states, reducing force-producing systolic and residual diastolic cross-bridge formation. Mavacamten also shifts the overall myosin population toward an energy-sparing, recruitable, super-relaxed state.⁶ This is the first CADTH review for mavacamten. The Health Canada indication is for the treatment of symptomatic New York Heart Association (NYHA) class II or III oHCM in adult patients.⁶ Mavacamten is available as a 2.5 mg, 5 mg, 10 mg, or 15 mg capsule.⁶ The product monograph for mavacamten for oHCM recommends a starting dosage of 5 mg orally once daily. Patients should be assessed 4 weeks after initiation for a clinical response. If the LVOT gradient with a Valsalva maneuver is less than 20 mm Hg, the dosage should be decreased to 2.5 mg once daily. Otherwise, dosing of 5 mg once daily should be maintained.⁶ Thereafter, follow-up visits should occur at 8 and 12 weeks after treatment initiation, with dose adjustments as appropriate.⁶ The product monograph for mavacamten contains serious warnings and precautions regarding the risk of heart failure, and notes that mavacamten reduces the left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction, and that echocardiogram assessments of LVEF and LVOT gradients are required before and regularly during treatment with mavacamten. It also notes that initiation of mavacamten in patients with an LVEF of less than 55% is not recommended, and that mavacamten treatment should be interrupted if the LVEF is less than 50% at any visit or if the patient experiences symptoms of heart failure or worsening clinical status.⁶ The product monograph also states that concomitant use of mavacamten in patients on combination therapy of a calcium channel blocker (e.g., verapamil or diltiazem) and a beta-blocker should be avoided.⁶

The objective of this report is to perform a systematic review of the beneficial and harmful effects of mavacamten, 2.5 mg, 5 mg, 10 mg, and 15 mg oral capsules for the treatment of adults with symptomatic NYHA class II to III oHCM.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from a clinical expert consulted by CADTH for the purpose of this review.

Patient Input

Two patient advocacy groups, the Canadian Heart Patient Alliance (CHPA) and the HeartLife Foundation, provided input on the treatment of symptomatic oHCM in adult patients. The HeartLife Foundation gathered information from in-depth interviews with expert physicians and patients across Canada, and reviewed study material and online literature. The CHPA conducted extensive interviews with 3 clinicians (2 in the US and 1 in Italy) involved with clinical trials of mavacamten. They also gathered information by meeting with staff from the US-based Hypertrophic Cardiomyopathy Association, and reviewing recorded panel discussions, patient testimonials, and educational videos. The CHPA recruited participants by contacting US-based clinicians as well as conducting outreach using its Canadian database, with additional patient profiles and confirmatory information provided by the Hypertrophic Cardiomyopathy Association. A total of 16 patient responses were gathered, 62.5% (10 out of 16) of whom were women aged between the mid-30s and mid-70s, with 31% (5 out of 16) identifying as Canadians (1 was living in the US) and 69% (11 respondents) as Americans. All participants reported being diagnosed with oHCM, and 40% also identified as being diagnosed with NYHA functional class II and 40% with NYHA functional class III oHCM. About 25% participants mentioned being diagnosed with atrial fibrillation. Among the 16 respondents, 4 patients, all residents of the US, had been treated with mavacamten.

Both patient groups agreed that HCM has a negative impact on patient quality of life. The impact of delayed diagnosis and misdiagnosis, shortness of breath, exercise intolerance, arrythmia, palpitations, chest pain, fatigue, and fainting were some of the major issues experienced by the respondents. One patient group also noted that HCM can affect patient families and friends, both mentally and physically. While describing their experiences with currently available drugs, participants mentioned a variety of treatments, including heart surgery, implantable cardioverter-defibrillators, alcohol septal ablation, and a variety of medications (such as beta-blockers, calcium channel blockers, and antiarrhythmics). The patient groups also reported that both patients and health care providers have concerns about current treatments and patients’ symptoms, feelings of uncertainty, and unresolved anxiety associated with the available treatment options.

While evaluating improved outcomes from new treatments, patients expressed a desire to see a reduction in the risk of heart failure, including sudden death, as a current unmet need, as well as reductions in the debilitating symptoms affecting daily living activities and quality of life, including shortness of breath, irregular heartbeat, palpitations, chest pain, fatigue, stress, and anxiety. Spending time with loved ones, the ability to go to work on regular basis, pursuing outdoor activities, and the ability to travel were some of the quality-of-life indicators and experiences mentioned by patients and caregivers.

While describing the experiences with the current drug under review, 4 patients recruited by the CHPA reported “very positive” experiences, noting that they have more energy to perform daily tasks and that they were hopeful the drug will reduce their symptoms and risk of cardiac arrest. The HeartLife Foundation described findings from a clinical trial (VALOR-HCM) led by the Cleveland Clinic demonstrating a reduced need for an invasive procedure such as septal reduction therapy (SRT) in severely symptomatic patients with oHCM when mavacamten was used. However, the CHPA reiterated the need to assess their patients’ cardiac status, specifically by an echocardiogram of the LVEF, and for other illnesses (e.g., infections or chronic disease), cardiovascular symptoms (arrhythmias), and medications before the approval for mavacamten. Moreover, patients must be closely monitored by echocardiograms for the first few months, as well as on a regular basis (every 3 months), and any symptoms must be reported due to the risk of heart failure associated with mavacamten. According to the CHPA, this limits the prescription of mavacamten to patients who have access to a high-volume clinic and who are committed to regular monitoring and reporting of symptoms.

Clinician Input

Input From the Clinical Expert Consulted by CADTH

According to the clinical expert consulted for this review, standard treatment of patients with symptomatic oHCM aims to lessen the extent of LVOT obstruction and manage arrhythmias. Traditionally, beta-blockers have been the mainstay of therapy. Where beta-blockers cannot be used or are not tolerated, the nondihydropyridine calcium channel blockers diltiazem or verapamil can be prescribed. Should symptoms persist, disopyramide is recommended as add-on therapy. These drugs, taken separately or in combination, improve symptoms and quality of life. According to the clinical expert consulted by CADTH, mavacamten may address an unmet need as an add-on therapy for patients not experiencing symptom relief with beta-blockers or calcium channel blockers with or without disopyramide.

The clinical expert consulted for this review noted that mavacamten was evaluated in the EXPLORER-HCM trial as an add-on to first-line treatment with beta-blockers or calcium channel blockers in the context of improving symptoms and exercise capacity among patients with symptomatic oHCM. In terms of treatment paradigm, the clinical expert stated that mavacamten will provide another treatment option for symptomatic patients with oHCM. In the expert’s opinion, the current place in therapy for mavacamten is unclear. It may be used as an add-on to beta-blockers or calcium channel blockers or more appropriately as a third-line add-on to beta-blockers or calcium channel blockers plus disopyramide. The fact that mavacamten was not tested head-to-head with disopyramide raises uncertainty about its relative position in the treatment algorithm, according to the expert. The clinical expert stated that, while it has its own issues, disopyramide is a Class Ia antiarrhythmic drug with negative inotropic properties that have been argued to be more powerful than beta-blockers or calcium channel blockers in controlling LVOT obstruction.

According to the clinical expert, symptomatic patients with oHCM who have not responded sufficiently to current treatment and/or whose symptoms are worsening would be eligible for treatment with mavacamten. Patients would need to be sufficiently symptomatic (at least NYHA class II) to be prescribed the drug despite treatment with beta-blockers or calcium channel blockers with or without disopyramide. The metrics of response to treatment with mavacamten identified by the expert include stabilization or improvement of symptoms (e.g., fatigue, palpitations, light-headedness, and chest pain), reduction in the frequency and/or severity of symptoms, and improved ability to perform activities of daily living. In the opinion of the clinical expert, treatment should be discontinued in the event of drug side effects. If symptoms or the LVOT gradient were to progress to the point that SRT was needed, then treatment with mavacamten should be discontinued. According to the clinical expert, mavacamten should be prescribed by specialists (cardiologists) or in specialty clinics.

Clinician Group Input

Clinician group input on the review of mavacamten for the treatment of oHCM was received from 2 groups: a community-based cardiology clinic, Cardio1, and an independent cardiologist who is a member of the Hypertrophic Cardiomyopathy Clinic and the Stephenson Cardiac Imaging Centre at the Libin Cardiovascular Institute at the University of Calgary.

The clinician groups noted that beta-blockers, calcium channel blockers, and disopyramide are current treatments for oHCM. However, these treatments are used to manage symptoms; they do not modify the underlying disease. In addition, potential adverse effects associated with these drugs limit their use. Cardio1 also pointed out that SRT, such as surgical and percutaneous septal ablation, may be beneficial to those who are refractory to drugs. However, these therapies also have potential adverse effects and limitations and require proper and careful selection of patients, creating an unmet medical need for noninvasive alternatives to SRT.

Some unmet needs remain when current treatment options are deemed ineffective, are unable to reverse the course of the disease, and are used mostly for symptom relief. While both groups referred to data from studies that demonstrated the effectiveness of the drug under review in improving symptoms and reducing the need for surgery, Cardio1 focused on using available conventional therapy first and switching to the new therapy when the first line fails. The group also emphasized the proper selection of patients, as well as checking for updates regarding long-term studies on the use of this new drug. The group referred to the need for timely assessments of patients’ responses to conventional treatment and the option to switch to a new treatment to prevent unnecessary suffering.

Regarding which patients are best suited for the new medication, 1 group identified patients with oHCM and severe LVOT obstruction who are highly symptomatic, whereas Cardio1 identified patients unresponsive to currently available drug treatment as good candidates for this drug, as well as those who may not be a candidate for early SRT, those who want to delay SRT, or those who do not want SRT. While 1 group mentioned an interest in offering the new medication to patients, referring to the compelling data behind the new medication, Cardio1 pointed out the ongoing importance of monitoring the mortality, morbidity, and hospitalization outcomes of this drug.

Drug Program Input

Drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The drug plans identified implementation issues related to considerations for relevant comparators, initiation of therapy, prescribing of therapy, and systemic and economic issues. The clinical expert consulted by CADTH weighed evidence from the pivotal trials and other clinical considerations before providing responses to drug programs’ implementation questions. Table 3 provides more details.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

Two sponsor-conducted, phase III, randomized, double-blind, placebo-controlled trials, EXPLORER-HCM and VALOR-HCM — both of which met the CADTH review protocol criteria — were included in this systematic review.

The EXPLORER-HCM trial (68 sites in 13 countries; N = 251) evaluated the efficacy and safety of once-daily orally administered treatment with mavacamten (at a starting dose of 5 mg) in adult patients with symptomatic oHCM with an LVOT gradient of 50 mm Hg or greater, a documented LVEF of 55% or greater, a maximum septal wall thickness (determined by a core laboratory) of 15 mm or greater (or ≥ 13 mm with a family history of HCM), and NYHA functional class II or III symptoms. The primary outcome was composite functional response at week 30, defined as achieving an improvement of 1.5 mL/kg/min or greater in peak oxygen consumption (pVO₂) and a reduction of at least 1 NYHA functional class (or 3.0 mL/kg/min or greater in pVO₂ without NYHA class worsening). Secondary outcomes prespecified in the statistical hierarchy included changes in postexercise LVOT peak gradient, pVO₂, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) shortness of breath (SoB) domain score. Patients had a mean age of 58.5 years (standard deviation [SD] = 11.9), most patients (73%) had NYHA functional class II symptoms at baseline, and almost all patients (92%) were on background beta-blocker or calcium channel blocker therapy. Other exploratory outcomes assessed in the EXPLORER-HCM trial that were important to the CADTH review included health-related quality of life (HRQoL) as assessed by the 5-Level EQ-5D (EQ-5D-5L) questionnaire, changes in resting and Valsalva LVOT peak gradients, changes in cardiopulmonary exercise testing (CPET) parameters, cardiac structure, and biomarker-based assessments.

The VALOR-HCM trial (19 sites in the US; N = 112) evaluated the efficacy and safety of once-daily orally administered treatment with mavacamten (at a starting dose of 5 mg) in adult patients with symptomatic oHCM with an LVOT gradient of 50 mm Hg or greater, a documented LVEF of 60% or greater, a maximum septal wall thickness determined by a core laboratory of 15 mm or greater (or 13 mm or greater with family history of HCM), and NYHA functional class III or IV (or class II with exertional syncope or near syncope). Patients must have been referred within the past 12 months for SRT and be actively considering scheduling the procedure. The primary outcome was a composite of the decision to proceed with SRT before or at week 16 or be considered guideline-eligible for SRT at week 16. Guideline-eligibility criteria were based on the 2011 American College of Cardiology Foundation (ACCF)/AHA clinical and hemodynamic criteria for HCM. For the primary composite outcome, patients with a maximum LVOT gradient of 50 mm Hg or greater (from rest, Valsalva maneuver, or postexercise) and no improvement in NYHA functional class at week 16 were considered eligible for SRT. Secondary outcomes prespecified in the statistical hierarchy included changes in postexercise LVOT peak gradient, an improvement of at least 1 NYHA functional class, changes in KCCQ CSS, and changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and cardiac troponin I biomarkers.

Efficacy Results

Both pivotal trials comparing mavacamten with placebo detected a statistically significant difference in their primary outcomes, and all prespecified secondary outcomes were statistically significant in favour of mavacamten.

In the EXPLORER-HCM trial, 37% of patients on mavacamten versus 17% of patients on placebo met the primary end point at week 30 with a between-group difference of 19.4% (95% confidence interval [CI], 8.7 to 30.1; P = 0.0005). With regard to key secondary outcomes tested in the statistical hierarchy from baseline to week 30, patients in the mavacamten group compared to those in the placebo group had greater reductions in postexercise LVOT gradients, with a mean difference of −36 mm Hg (95% CI, −43.2 to −28.1; P < 0.0001); greater increases in pVO₂, with a mean difference of 1.4 mL/kg per min (95% CI, 0.6 to 2.1; P = 0.0006); more patients improving by at least 1 NYHA class (65% of patients in the mavacamten group versus 31% of patients in the placebo group), with a between-group difference of 34% (95% CI, 22.2 to 45.4; P < 0.0001); greater improvement in scores on the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ-23) CSS, with a mean difference of 9.1 (95% CI, 5.5 to 12.7; P < 0.0001); and greater reductions in severity of HCM symptoms as assessed by the HCMSQ SoB domain score, with a mean difference of −1.8, (95% CI, −2.4 to −1.2; P < 0.0001).

In the VALOR-HCM trial, for the primary composite outcome, after 16 weeks treatment, 17.9% of patients treated with mavacamten continued to meet guideline criteria for SRT or elected to undergo the procedure, compared to 76.8% of patients treated with placebo, with a treatment difference of 58.9% (95% CI, 44.0% to 73.9%; P < 0.001) favouring mavacamten. With regard to key secondary outcomes tested in the statistical hierarchy from baseline to week 16, patients in the mavacamten group compared to those in the placebo group had a greater reduction in postexercise LVOT gradient, with a mean difference of −37.2 mm Hg (95% CI, −48.1 to −26.2; P < 0.001); more patients with an improvement of at least 1 NYHA functional class, with a between-group difference of 41.1% (95% CI, 24.5% to 57.7%; P < 0.001); greater improvement in scores on the KCCQ CSS, with a mean difference of 9.4 points (95% CI, 4.9 to 14.0 points); and greater reductions in NT-proBNP and cardiac troponin I, with geometric mean ratio differences of 0.33 (95% CI, 0.26 to 0.42; P < 0.001) and 0.53 (95% CI, 0.41 to 0.70; P < 0.001), respectively.

Harms Results

In the EXPLORER-HCM trial, through to week 38, a total of 87.8% of patients in the mavacamten group and 81.3% of patients in the placebo group experienced 1 or more adverse events (AEs). The most common AEs were similar for both treatment groups. The proportion of patients who experienced 1 or more serious adverse events (SAEs) was similar between treatment groups (11.4% versus 9.4%). A total of 1.6% of patients in the mavacamten group and no patients in the placebo group discontinued treatments due to AEs. No AEs of decreased LVEF were reported. However, the incidence of a resting LVEF of less than 50% was a protocol-specified criterion for temporary treatment discontinuation in the EXPLORER-HCM trial. Throughout the 30-week treatment period, 3.6% of patients met a temporary treatment discontinuation criterion of an LVEF of less than 50%, including 5.7% of patients in the mavacamten group and 1.6% of patients in the placebo group. No patients experienced a reduction in their LVEF to 30% or less, which would have necessitated permanent treatment discontinuation. One death was reported in the placebo group due to sudden death.

In the VALOR-HCM trial, through to week 16, a total of 73.2% of patients in the mavacamten group and 61.8% of patients in the placebo group experienced at least 1 AE. The proportions of patients who had SAEs were similar for the mavacamten and placebo groups (5.4% versus 1.8%, respectively). Through to week 16 of the trial, 3.6% of patients in the mavacamten group had an LVEF of less than 50% resulting in temporary drug discontinuation; all of these patients subsequently resumed mavacamten dosing. No patients had a reduction of their LVEF to 30% or less, necessitating permanent treatment discontinuation through to week 16. No treatment discontinuations due to AEs or deaths through to week 16 were reported.

Critical Appraisal

Internal Validity

Both the EXPLORER-HCM and VALOR-HCM trials appeared to have acceptable methods for blinding, allocation concealment, and randomization with stratification. The clinical expert consulted for this review stated that the differences in the proportion of patients taking neither beta-blockers nor calcium channel blockers at baseline in the EXPLORER-HCM trial (3.3% mavacamten versus 12.5% placebo) may have introduced bias in favour of mavacamten, as a greater proportion of patients in the placebo group were not receiving any background therapy. The baseline and demographic characteristics in the VALOR-HCM trial appeared to be generally balanced between the treatment groups. Treatment discontinuation and study discontinuation among patients were low in both pivotal trials. The clinical expert consulted for this review indicated that the primary efficacy outcomes of the EXPLORER-HCM trial (pVO₂ and NYHA functional class) are appropriate measures of functional capacity and symptom severity, respectively, in the indicated population. In both pivotal trials, HRQoL was measured using the KCCQ-23 CSS as a key secondary outcome. The clinical expert indicated that such tools are not typically used in clinical practice but have been used in multiple studies. Disease-related symptoms were assessed using the newly developed HCMSQ instrument, with the SoB domain assessed as a key secondary outcome in the EXPLORER-HCM trial. Because KCCQ-23 CSS or HCMSQ SoB data for more than 30% of patients were not collected at baseline or the week-30 visit in the EXPLORER-HCM trial, there is a risk of bias as those who completed the questionnaires may be fundamentally different than those who did not (i.e., differences in treatment response). However, for all imputation scenarios, ad hoc sensitivity analyses were generally supportive of the findings of the primary analyses.

The VALOR-HCM trial is evaluating the use of mavacamten to reduce the need for SRT in patients who are guideline-eligible and willing to participate in invasive therapies. As such, no direct evidence of mavacamten compared to SRT is available for this review. Direct evidence comparing mavacamten to disopyramide is also limited. Patients taking disopyramide were excluded from the EXPLORER-HCM trial and less than 20% of enrolled patients (n = 22) used disopyramide at baseline as monotherapy or in combination with beta-blockers and/or calcium channel blockers in the VALOR-HCM trial. Subgroup analyses based on disopyramide use at baseline was not available for the VALOR-HCM trial, |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||| ||||||||||||| |||||||||| ||||||||| The comparative effectiveness of disopyramide versus mavacamten in this patient population is therefore unknown. In terms of subgroups of interest, both pivotal trials included subgroup analyses by baseline background therapy (beta-blocker or calcium channel blocker use) and the EXPLORER-HCM trial also examined NYHA class (II versus III) as a prespecified subgroup. For the primary end point in the EXPLORER-HCM trial, results were not statistically significantly different for the subgroup of patients taking beta-blockers. However, all key secondary end points in the EXPLORER-HCM trial showed a benefit from mavacamten compared with placebo across the evaluated subgroups, irrespective of beta-blocker use. The subgroup analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. All subgroup analyses are therefore exploratory in nature. No clinical study reports or statistical analysis plans were available for the VALOR-HCM trial at the time of this review, preventing CADTH from fully appraising the potential for bias within the trial.

Compared to the population in Canada, racial diversity in the pivotal trials was limited as most patients were white. In addition, no patients were recruited from Canada in either pivotal trial. However, the clinical expert consulted for this review noted that the lack of representation of patients in Canada does not reduce the generalizability of the results to Canadian clinical practice. While mavacamten has been approved by Health Canada for use in adult patients with symptomatic NYHA functional class II or III oHCM, the VALOR-HCM trial included an unknown number of patients with NYHA functional class IV oHCM. The VALOR-HCM trial is an ongoing randomized controlled trial (RCT) evaluating the use of mavacamten to reduce the need for SRT in patients who are guideline-eligible for invasive therapies, with descriptive data available through to week 32. As such, it is uncertain if mavacamten can reduce the need for SRT among patients with symptomatic oHCM in the long term.

Indirect Comparisons

No indirect evidence was available.

Other Relevant Evidence

Additional descriptive efficacy and safety data for the VALOR-HCM trial through to week 32 and data from 1 open-label extension study (MAVA-LTE) are summarized in this report.

Description of Studies

An additional study report for the VALOR-HCM trial examined data up to week 32 among patients initially randomized to mavacamten (32 weeks of drug exposure) and patients initially randomized to placebo who crossed over to mavacamten at week 16 (16 weeks of drug exposure).⁷ A total of 4 patients in the placebo group who elected to undergo SRT treatment or withdrew from the study during the first 16 weeks were not included in this analysis.

MAVA-LTE is an ongoing, dose-blinded, 5-year, long-term extension (LTE) study to assess the long-term efficacy and safety of mavacamten in patients who completed the EXPLORER-HCM trial through to week 38 (the EXPLORER-LTE cohort) and MAVERICK-HCM (a phase II trial involving patients with nonobstructive HCM that is not assessed in this report). A total of 224 patients who enrolled in the EXPLORER-LTE cohort started mavacamten treatment at 5 mg once daily, regardless of their treatment group in the EXPLORER-HCM pivotal trial. Dose adjustments at weeks 4, 8, and 12 were based on site-read echocardiograms of Valsalva LVOT gradient and LVEF. At LTE baseline, a total of 5.8% of patients in the EXPLORER-LTE cohort were NYHA functional class I, 65.2% were NYHA functional class II, 29.0% were NYHA functional class III, and none were NYHA functional class IV.

Efficacy Results

In the VALOR-HCM trial, at week 32, an improvement of at least 1 NYHA class was observed in 48 of 53 patients (90.6%) in the original mavacamten group and 35 of 50 patients (70%) in the crossover group. In the original mavacamten group, the mean change from baseline to week 32 in the KCCQ-23 CSS was 13.1 points (95% CI, 9.2 to 17.1), while in the placebo crossover group, the mean change in the KCCQ-23 CSS from week 16 to week 32 was 8.0 points (95% CI, 3.2 to 12.8). At week 32, 6 patients (10.7%) in the original mavacamten group and 7 patients (13.5%) in the placebo crossover group continued to meet guideline criteria for SRT or elected to undergo the procedure. In the original mavacamten group, there was a reduction in resting, Valsalva, and postexercise LVOT gradients from baseline to week 32. A similar reduction in LVOT gradients in the crossover group was seen after 16 weeks of mavacamten exposure.

Among patients in the EXPLORER-LTE cohort, from LTE baseline to week 48 of the extension study, 35 patients (71.4%) had an improvement of at least 1 NYHA class versus |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| ||||||||||||||| |||||||||||||||||||| |||| |||||| |||||||||||||||| Reductions from the LTE study baseline were observed in both resting and Valsalva LVOT gradients from mavacamten treatment as assessed by both site and central readings in the extension study. However, the number of patients was relatively small during the end time points, making it difficult to draw any conclusions about the effects of mavacamten on LVOT gradients. ||||||||||||| |||||||||| ||||||||| || ||||||||||||||| |||||||||||| ||||||||||||||| || |||||||||||| |||||||||||||||||| ||||||||||||| ||||| |||||| ||||| |||||||||| ||||||| ||||| but a reduction in left atrial volume index (LAVI) was observed. In line with the EXPLORER-HCM pivotal trial, NT-proBNP concentrations decreased at LTE week 4, and the decreases were sustained over time to LTE |||||||

Harms Results

In the VALOR-HCM trial, through to week 32, the rate of SAEs was similar between the original mavacamten group and the placebo crossover group. No deaths, myocardial infarctions, or strokes were reported in either group. Through to week 32, a total of 9 patients, comprising 7 members (12.5%) of the original mavacamten group and 2 (3.8%) of the placebo crossover group, required a temporary drug discontinuation due to an LVEF of less than 50%. One patient in the placebo crossover group had a reduced LVEF of less than 30% at week 31 associated with paroxysmal atrial fibrillation and heart failure. Following permanent mavacamten discontinuation, the patient’s LVEF recovered and normalized.

Among patients in the EXPLORER-LTE cohort, 62.9% experienced at least 1 AE. The most common AEs |||||||||||| |||||||||| ||||| ||||||||||||| ||||||||||| ||||| |||||||| |||||| |||||||||| |||| |||||||||||||||| |||||||||||||||| One death, which was due to bacterial endocarditis, occurred in the EXPLORER-LTE cohort but was deemed by the investigator to be unrelated to mavacamten. |||||||||||||||| ||||||||||||||||||||| ||||||||||||||| |||||||| ||||| |||||||||||||| ||||||||||||| ||||||| A total of 2 patients (0.9%) permanently discontinued treatment due to AEs, with 1 patient discontinuing due to worsening of systemic lupus erythematosus and the other due to cardiac failure. No patients met the permanent discontinuation criteria of an LVEF of 30% or less. A total of 11 (4.9%) patients demonstrated a total of |||||||||||||||||| meeting the criteria for a temporary treatment discontinuation, 4 (1.8%) of whom experienced an LVEF of less than 50%.

Critical Appraisal

Results at week 32 of the VALOR-HCM trial provided additional data on the safety and efficacy of mavacamten. As all patients on placebo crossed over to mavacamten treatment week at 16, there was no active comparator, and all outcomes were descriptive in nature, making it difficult to make causal conclusions of the findings. Once placebo patients crossed over to active treatment at week 16, investigators and patients were aware that all patients were receiving active treatment, and their expectations of treatment could have affected reporting of subjective outcomes, such as NYHA class, HRQoL, and AEs.

Among patients in the EXPLORER-LTE cohort, the baseline and demographic characteristics were similar to those seen in the pivotal trial. Treatment discontinuation and study discontinuation rates among patients were low in the extension study, as observed in both pivotal trials. Peak oxygen consumption from the pivotal trial was not assessed in the extension study, ||||||||| |||||||| |||| |||||||||||||||| |||||||||| ||||||| ||||| |||||||||| ||||||| |||||| ||||||| ||||||||||| ||||| |||||||| |||||||||| ||||||||||||||| The absence of these parameters in the interim analysis makes it difficult to interpret the efficacy results of mavacamten for the extension study. |||||||| |||||||||||||||| ||||||| |||||||| ||||||||||||| |||||||||| ||||||| ||||||||| |||||||||| the number of patients at later time points in all efficacy analyses were relatively few at the time of the data cut, and these results should be interpreted with caution. The generalizability of the efficacy and harms outcomes and the lack of racial diversity mentioned in the main studies are applicable to the extension study.

Conclusions

In the EXPLORER-HCM trial, among patients with symptomatic NYHA class II or III oHCM, mavacamten was statistically significantly more efficacious than placebo in improving NYHA class and exercise capacity (pVO₂), as measured by the primary composite outcome. In the VALOR-HCM trial, among patients with symptomatic NYHA class III or IV oHCM (or class II oHCM with exertional syncope or near syncope), significantly fewer patients were eligible for SRT at week 16 in the mavacamten group than in the placebo group. The results of both pivotal trials were statistically significantly in favour of mavacamten for key secondary outcomes of an improvement of at least 1 NYHA class, postexercise LVOT peak gradient, and HRQoL as assessed by the KCCQ-23 CSS, all of which were found to be clinically meaningful by the clinical expert consulted by CADTH for this review. The EXPLORER-HCM trial assessed disease-related symptoms, and a statistically significantly greater improvement in the HCMSQ SoB domain score was observed in the mavacamten group compared with the placebo group. The VALOR-HCM trial found statistically significantly greater reductions in assessed biomarkers among patients in the mavacamten group compared with those in the placebo group. While descriptive results for the VALOR-HCM trial are available through to week 32, it is uncertain if mavacamten can reduce the need for SRT among patients with symptomatic oHCM in the long-term. Furthermore, no direct evidence comparing mavacamten with SRT was available for this review. Only the VALOR-HCM trial enrolled patients who were receiving disopyramide; however, as no subgroup analyses based on disopyramide use at baseline were available, the comparative effectiveness of disopyramide versus mavacamten in patients with symptomatic oHCM is unknown. Because the EXPLORER-HCM trial evaluated mavacamten as an add-on to first-line treatment with beta-blockers or calcium channel blockers, the clinical efficacy of mavacamten as a first-line therapy or third-line therapy after disopyramide is unknown. The effectiveness of mavacamten in combination with disopyramide and beta-blockers or calcium channel blockers is also unknown. In both pivotal trials, overall rates of AEs and SAEs were comparable for patients in both the mavacamten and placebo groups. In the EXPLORER-HCM trial, 1 patient in the placebo group experienced sudden death, and no deaths were reported through to week 32 in the VALOR-HCM trial. The safety results showed that mavacamten was well tolerated and generally comparable to placebo, with no new safety signals identified in the MAVA-LTE study among patients in the EXPLORER-LTE cohort.

Introduction

Disease Background

HCM is a common genetic heart disease characterized by increased thickness of the left ventricular wall.¹ About 30% to 60% of patients with HCM have identifiable familial disease caused by mutations in cardiac sarcomere protein genes, and each offspring of an affected family member has a 50% chance of inheriting the altered gene, although not all family members who inherit an HCM mutation will develop the disease.^1-3 The distribution of HCM is equal by sex, although women have been diagnosed less frequently than men.^2,3 The age of symptom onset and the severity of symptoms varies significantly across patients with HCM.¹ Among patients with HCM who do develop symptoms, the most common symptoms include chest pain, shortness of breath with exertion, fatigue, palpitations, and light-headedness.¹ oHCM, a subclassification of HCM, is characterized by LVOT obstruction, with the obstruction impeding blood flow from the heart to the rest of the body, defined in the 2020 AHA/ACC clinical guidelines as a peak LVOT gradient of 30 mm Hg or greater.³ Patients with oHCM are much more likely to develop symptoms due to increased left ventricular pressures and mitral regurgitation that result from restriction of blood flow out of the heart, which leads to increased wall stress, myocardial ischemia, and, eventually, cell death and replacement scarring.¹ Associated complications include heart failure, stroke due to atrial fibrillations, arrhythmias, and sudden cardiac death.¹ In a retrospective study, the estimated incidence rate of sudden cardiac death caused by HCM in patients aged 10 to 65 in Ontario was 0.05% per year.⁸

The estimated prevalence of HCM in the general population is 1 in 500 adults, although most of these cases remain undiagnosed.¹ Among diagnosed patients, about 50% are symptomatic.⁹ AHA/ACC clinical guidelines suggest that oHCM is present or develops over time in most patients with HCM, with about a third remaining nonobstructive.³ Estimates of the proportion of patients with HCM who have oHCM range from 22% in a study from western Sweden⁴ to 70% in a US study.⁵

According to the clinical expert consulted for this review, treatment of oHCM can be completed by a cardiologist.

Standards of Therapy

According to AHA/ACC clinical guidelines, first-line therapy for patients with oHCM who are experiencing symptoms attributable to LVOT obstruction includes nonvasodilating beta-blockers titrated to maximal tolerated doses.³ In patients for whom beta-blockers are ineffective or not tolerated, use of nondihydropyridine calcium channel blockers (e.g., verapamil or diltiazem) is recommended. Patients with oHCM with persistent severe symptoms despite these therapies are candidates for more advanced therapies, including disopyramide in combination with 1 of the aforementioned treatments or SRT, either surgical myectomy or alcohol septal ablation.³

According to the clinical expert, for patients with symptomatic oHCM, standard treatment aims to lessen the extent of LVOT and manage arrhythmias. Traditionally, beta-blockers have been the mainstay of therapy. Given their negative inotropic and chronotropic effects, the drugs are most effective for exercise-induced (contraction-related) obstruction, but less so for resting obstruction. By relieving obstruction, beta-blockers can result in less shortness of breath and/or chest discomfort and help prevent the development of diastolic dysfunction, pulmonary hypertension, and heart failure with preserved ejection fraction. Where beta-blockers cannot be used or are not tolerated, nondihydropyridine calcium channel blockers can be prescribed. Should symptoms persist, disopyramide is recommended as add-on therapy. Taken separately or in combination, these drugs improve symptoms and quality of life. They do not address the underlying pathophysiology of HCM, obstructive or otherwise.

Drug

Mavacamten is a first-in-class cardiac myosin inhibitor.⁶ In HCM, excessive myosin-actin cross-bridge formation can result in hypercontractility, impaired relaxation, excess energy consumption, and myocardial wall stress. Mavacamten modulates the number of myosin heads that can enter power-generating states, reducing force-producing systolic and residual diastolic cross-bridge formation. Mavacamten also shifts the overall myosin population toward an energy-sparing, recruitable, super-relaxed state.⁶ This is the first CADTH review for mavacamten. The Health Canada indication is for the treatment of symptomatic NYHA class II to III oHCM in adult patients, with a Notice of Compliance granted on November 8, 2022.⁶ The sponsor has requested reimbursement according to the indication. Mavacamten is available as a 2.5 mg, 5 mg, 10 mg, or 15 mg capsule.⁶ The product monograph recommends a starting dosage of mavacamten for oHCM of 5 mg orally once daily. Patients should be assessed 4 weeks after initiation for a clinical response. If an LVOT gradient with a Valsalva maneuver is less than 20 mm Hg, the dosage should be decreased to 2.5 mg once daily. Otherwise, dosing at 5 mg once daily should be maintained.⁶ Thereafter, follow-up visits should occur at 8 and 12 weeks after treatment initiation, with dose adjustments as appropriate.⁶ The product monograph for mavacamten contains serious warnings and precautions regarding the risk of heart failure and notes that mavacamten reduces the LVEF and can cause heart failure due to systolic dysfunction, and that echocardiogram assessments of the LVEF and LVOT gradient are required before and regularly during treatment with mavacamten. It also notes that initiation of mavacamten in patients with an LVEF of less than 55% is not recommended, and that mavacamten treatment should be interrupted if the LVEF is less than 50% at any visit or if the patient experiences symptoms of heart failure or worsening clinical status.⁶ The product monograph also states that concomitant use of mavacamten in patients on a combination therapy of a calcium channel blocker (e.g., verapamil or diltiazem) and a beta-blocker should be avoided.⁶

Mavacamten has received FDA approval for the treatment of adult patients with symptomatic class II or III oHCM. Key characteristics of commonly used medical treatments for oHCM are presented in Table 2.

Table 2: Key Characteristics of Mavacamten, Beta-Blockers, Nondihydropyridine Calcium Channel Blockers, and Disopyramide

LVOT = left ventricular outflow tract; NA = not applicable; NYHA = New York Heart Association; oHCM = obstructive hypertrophic cardiomyopathy.

^aHealth Canada–approved indication.

Sources: Product monographs for Camzyos,⁶ bisoprolol,¹⁰ verapamil,¹¹ and Rythmodan.¹²

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient inputs received by CADTH have been included in the stakeholder section at the end of this report.

Two patient advocacy groups, the CHPA and the HeartLife Foundation, provided input for the treatment of symptomatic oHCM in adult patients. The HeartLife Foundation gathered information from in-depth interviews with expert physicians and patients across Canada, and reviewed study material and online literature. The CHPA conducted extensive interviews with 3 clinicians (2 in the US and 1 in Italy) involved with clinical trials for mavacamten. They also gathered information by meeting with staff from the US-based Hypertrophic Cardiomyopathy Association and reviewing recorded panel discussions, patient testimonials, and educational videos. The CHPA recruited participants by contacting US-based clinicians and conducted outreach using the database for the CHPA in Canada, with additional patient profiles and confirmatory information provided by the Hypertrophic Cardiomyopathy Association. A total of 16 patients responded, 62.5% (10 out of 16) of whom were female, aged between 35 to 75 years, with 31% (5 out of 16) identifying as Canadians (1 living in the US) and 69% (11 respondents) as Americans. All participants reported being diagnosed with oHCM, and 40% also identified as being diagnosed with NYHA functional class II and 40% with NYHA functional class III oHCM. About 25% of participants reported being diagnosed with atrial fibrillation. Among the 16 respondents, 4 patients had been treated with mavacamten, all of whom were residents of the US.

Both patient groups agreed that HCM has a negative impact on patients’ quality of life. Delayed diagnosis, misdiagnosis, shortness of breath, exercise intolerance, arrythmia, palpitations, chest pain, fatigue, and fainting were some of the major issues experienced by the respondents. One group also noted that HCM can affect patients’ families and friends, both mentally and physically. While describing their experiences with currently available drugs, participants mentioned several treatments, including heart surgery, implantable cardioverter-defibrillators, alcohol septal ablation, and a variety of medications (such as beta-blockers, calcium channel blockers, and antiarrhythmics). However, both the groups reported concerns from both patients and health care providers regarding current treatments, patients’ symptoms, feelings of uncertainty, and unresolved anxiety with the available treatment options.

While evaluating improved outcomes from new treatments, patients expressed a desire to see a reduction in the risk of heart failure, including sudden death, as a current unmet need, as well as reductions in the debilitating symptoms affecting daily living activities and quality of life, including shortness of breath, irregular heartbeat, palpitations, chest pain, fatigue, stress, and anxiety. Spending time with loved ones, the ability to go to work on regular basis, pursuing outdoor activities, and the ability to travel were some of the quality-of-life indicators and experiences patients and caregivers mentioned.

While describing their experiences with the current drug under review, 4 patients recruited by the CHPA reported “very positive” experiences, noting that they had more energy to perform daily tasks and were hopeful that the drug would reduce their symptoms and risk of cardiac arrest. The HeartLife Foundation described findings from a clinical trial (VALOR-HCM) led by the Cleveland Clinic demonstrating a reduced need for an invasive procedure such as SRT in severely symptomatic patients with oHCM when mavacamten was used. However, the CHPA reiterated the need to assess patients, specifically by echocardiogram of the LVEF, for their cardiac status and as well as other illnesses (e.g., infections or chronic disease), cardiovascular symptoms (arrhythmias), and medications, before the approval of mavacamten. Moreover, patients must be closely monitored with echocardiograms for the first few months, as well as on a regular basis (every 3 months), and any symptoms must be reported due to the risk of heart failure associated with mavacamten. The CHPA noted that this limits the prescription of mavacamten to patients who have access to a high-volume clinic and who are committed to regular monitoring and reporting of symptoms.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by a clinical specialist with expertise in the diagnosis and management of cardiovascular diseases.

Unmet Needs

According to the clinical expert consulted for this review, mavacamten may address an unmet need as an add-on therapy for patients not experiencing symptom relief with beta-blockers or calcium channel blockers with or without disopyramide.

Place in Therapy

The clinical expert consulted for this review noted that mavacamten was evaluated in the EXPLORER-HCM trial as an add-on to first-line treatment with beta-blockers or calcium channel blockers in the context of improving symptoms and exercise capacity among patients with symptomatic oHCM. In terms of the treatment paradigm, the clinical expert stated that mavacamten will provide another treatment option for symptomatic patients with oHCM. In the expert’s opinion, the current place in therapy for mavacamten is unclear. It may be used as an add-on to beta-blockers or calcium channel blockers, or more appropriately as a third-line add-on to beta-blockers or calcium channel blockers plus disopyramide. According to the expert, the fact that mavacamten was not tested head-to-head with disopyramide raises uncertainty about its relative position in the treatment algorithm. The clinical expert stated that, while it has its own issues, disopyramide is a class 1a antiarrhythmic with negative inotropic properties and may be more powerful than beta-blockers or calcium channel blockers in controlling LVOT obstruction.

Patient Population

According to the clinical expert, symptomatic patients with oHCM who have not responded sufficiently to current treatment and/or whose symptoms are worsening despite such treatment would be eligible for treatment with mavacamten. Patients prescribed the drug would need to be sufficiently symptomatic (have received a diagnosis of at least NYHA class II oHCM) despite treatment with beta-blockers or calcium channel blockers with or without disopyramide. According to the expert, response to mavacamten cannot be predicted with sufficient accuracy to warrant advocating its use before beta-blockers or calcium channel blockers.

Assessing Response to Treatment

According to the expert, the metrics of response to treatment with mavacamten include stabilization or improvement of symptoms (e.g., fatigue, palpitations, light-headedness, and chest pain), reduction in the frequency and severity of symptoms, and improved ability to perform activities of daily living.

Discontinuing Treatment

In the opinion of the clinical expert, treatment should be discontinued if drug side effects occur. If symptoms or the LVOT gradient proceed to the point that SRT is needed, treatment with mavacamten should no longer be required.

Prescribing Conditions

According to the clinical expert, mavacamten should be prescribed by specialists (cardiologists) or in specialty clinics.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full and original clinician group inputs received by CADTH have been included in the stakeholder section at the end of this report.

Clinician group input on the review of mavacamten for the treatment of oHCM was received from 2 clinician groups: a community-based cardiology clinic, Cardio1, and an independent cardiologist who is a member of the hypertrophic Cardiomyopathy Clinic at the and the Stephenson Cardiac Imaging Centre at the Libin Cardiovascular Institute at the University of Calgary.

The clinician groups mentioned that beta-blockers, calcium channel blockers, and disopyramide are current treatments for oHCM. However, these treatments manage symptoms, and they do not modify the underlying disease. Potential adverse effects are also associated with these drugs limiting their use. Cardio1 pointed out that SRT such as surgical and percutaneous septal ablation may be beneficial to those who are refractory to drugs but can have potential adverse effects and limitations, and requires proper and careful selection of patients, indicating an unmet medical need for a noninvasive alternative to SRT.

Some unmet needs remain when current treatment options are deemed ineffective, are unable to reverse the course of the disease, and are used mostly for symptom relief. While both groups referred to data from studies demonstrating the effectiveness of the drug under review in improving symptoms and reducing the need for surgery, Cardio1 focused on using available conventional therapy first and switching to the new therapy when the former fails. The group also emphasized the importance of proper selection of patients and checking for updates on long-term studies on this new drug. The group noted the need for timely assessment of patients’ responses to conventional treatment, and switching to new treatment to prevent unnecessary suffering.

Regarding which patients are best suited for the new medication, 1 group identified patients with oHCM with severe LVOT obstruction who are highly symptomatic, whereas Cardio1 indicated that patients unresponsive to currently available treatments would be good candidates for this drug, as well as those who may not be candidates for early SRT, those who want to delay SRT, or those who do not want an SRT procedure. While 1 group expressed a strong interest in offering the new medication to patients, referring to the compelling data behind the new medication, Cardio1 pointed out the need to monitor the mortality, morbidity, and hospitalization outcomes of this drug.

Drug Program Input

Drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CADTH are summarized in Table 3.

Table 3: Summary of Drug Plan Input and Clinical Expert Responses

BIA = budget impact analysis; CDEC = CADTH Canadian Drug Expert Committee; HCM = hypertrophic cardiomyopathy; LV = left ventricle; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NYHA = New York Heart Association; oHCM = obstructive hypertrophic cardiomyopathy; pCPA = pan-Canadian Pharmaceutical Alliance; SRT = septal reduction therapy.

Clinical Evidence

The clinical evidence included in the review of mavacamten is presented in 2 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes sponsor-submitted LTE studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of mavacamten in the form of 2.5 mg, 5 mg, 10 mg, and 15 mg oral capsules for the treatment of symptomatic NYHA class II or III oHCM in adult patients.

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 4. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The systematic review protocol was established before the granting of a Notice of Compliance from Health Canada.

Table 4: Inclusion Criteria for the Systematic Review

AE = adverse event; CPET = cardiopulmonary exercise testing; HCMSQ = Hypertrophic Cardiomyopathy Symptom Questionnaire; HRQoL = health-related quality of life; ICD = implantable cardioverter-defibrillator; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LAVI = left atrial volume index; LV = left ventricular ejection fraction; LVMI = left ventricular mass index; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; oHCM = obstructive hypertrophic cardiomyopathy; pVO₂ = peak oxygen consumption; SAE = serious adverse event; VE = volume expired; VCO₂ = carbon dioxide production vs. = versus; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed using Ovid deduplication for multifile searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Camzyos (mavacamten). Clinical trials registries searched included the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Appendix 1 provides the detailed search strategies.

The initial search was completed on October 21, 2022. Regular alerts updated the search until the meeting of the CADTH Canadian Drug Expert Committee on February 22, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.¹⁴ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Appendix 1 provides more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A literature review identified 119 studies for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 5. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 5: Details of Included Studies

ACCF = American College of Cardiology Foundation; AHA = American Heart Association; CPET = cardiopulmonary exercise testing; CSS = clinical summary score; EQ-5D-5L = 5-Level EQ-5D; ESC = European Society of Cardiology; HCM = hypertrophic cardiomyopathy; HCMSQ = Hypertrophic Cardiomyopathy Symptom Questionnaire; ICD = implantable cardioverter-defibrillator; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LV = left ventricle; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; oHCM = obstructive hypertrophic cardiomyopathy; pVO₂ = peak oxygen consumption; QTcF = QT interval corrected using Fridericia’s formula; RCT = randomized controlled trial; RER = respiratory exchange ratio; SoB = shortness of breath; SRT = septal reduction therapy; TTE = transthoracic echocardiogram.

Sources: Clinical Study Reports for EXPLORER-HCM trial,¹⁸ Desai et al. (2021),¹⁶ Desai et al. (2022),¹⁷ and Olivotto et al. (2020).¹⁵

Description of Studies

Two double-blind, placebo-controlled RCTs (EXPLORER-HCM and VALOR-HCM) met the inclusion criteria for the systematic review (Table 5). In both trials, patients started treatment with mavacamten 5 mg or matching placebo once daily. Subsequent dose adjustments of active treatment were implemented in a blinded, stepwise manner according to protocol-defined dose-titration criteria to 1 of 4 dose strengths (2.5 mg, 5 mg, 10 mg, or 15 mg). All dose strengths of mavacamten and placebo capsules were identical in appearance.

The objective of the EXPLORER-HCM study was to determine the efficacy, safety, and tolerability of mavacamten compared with placebo in patients with symptomatic oHCM. The trial took place in 68 sites across 13 countries, with 31 sites in the European Union, 29 sites in the United States, 6 sites in Israel, and 2 sites in the UK, with no Canadian sites. The study included a 35-day screening period, 30 weeks of double-blind treatment, and an 8-week follow-up period (Figure 2). A total of 251 patients with an LVOT gradient of 50 mm Hg or greater and an NYHA functional class of II or III were randomized 1:1 to receive mavacamten (n = 123) or placebo (n = 128) once daily for 30 weeks, followed by 8 weeks of post-treatment follow-up. Randomization was stratified by NYHA class (II or III), current treatment with beta-blockers (yes or no), planned type of ergometer used during the study (treadmill or exercise bicycle), and consent for a cardiac MRI (CMR) substudy (yes or no). The primary outcome was a composite functional end point at week 30, defined as achieving 1 of the following: an improvement of 1.5 mL/kg/min or greater in pVO₂ as determined by CPET and a reduction of at least 1 NYHA class, or an improvement of 3.0 mL/kg/min or greater in pVO₂ with no worsening in NYHA class. The EXPLORER-HCM trial also included a substudy at selected sites aimed to assess the effect of mavacamten on cardiac mass and structure as evaluated by CMR among eligible patients who did not have either an implantable cardioverter-defibrillator or pacemaker and did not have atrial fibrillation at screening (17 patients in the mavacamten group and 18 patients in the placebo group).

The objective of the ongoing VALOR-HCM study (19 sites across the US) was to determine if the addition of mavacamten to maximally tolerated medical therapy would allow patients with severely symptomatic oHCM to improve sufficiently that they no longer met guideline criteria for SRT or chose not to undergo SRT. The study included a 2-week screening period, followed by 16 weeks of placebo-controlled treatment, 16 weeks of active blinded treatment, a 96-week LTE, and an 8-week post-treatment follow-up visit (Figure 3). A total of 112 patients with a LVOT gradient of 50 mm Hg or greater and NYHA functional class III or IV (or class II with exertional syncope or near syncope) were randomized 1:1 to receive mavacamten (n = 56) or placebo (n = 56). Randomization was stratified by the type of SRT recommended (surgical myectomy or alcohol ablation) and NYHA functional class. The primary outcome was a composite of the decision to proceed with SRT before or at week 16 or be considered guideline-eligible for SRT at week 16. Guideline eligibility criteria were based on 2011 ACCF/AHA clinical and hemodynamic criteria for HCM. Patients with a maximum LVOT gradient of 50 mm Hg or greater (from rest, Valsalva, or postexercise) and no improvement in NYHA functional class at week 16 were considered eligible for SRT.

As the VALOR-HCM trial was ongoing at the time this report was drafted, a Clinical Study Report was not yet available. Sponsor-submitted publications^16,17 provided data up to week 16 (the placebo-controlled period) of the VALOR-HCM trial. Additional descriptive data published for up to week 32 of the VALOR-HCM trial⁷ (including the active blinded period) are presented in the Other Relevant Evidence section of this report.

Figure 2: Study Schematic for EXPLORER-HCM Trial

Figure was redacted due to confidential information.

Figure 3: Study Schematic for VALOR-HCM Trial

EOT = end of treatment; NYHA = New York Heart Association; QD = once daily; SRT = septal reduction therapy; TTE = transthoracic echocardiogram.

Source: Sponsor submission.¹⁹

Populations

Inclusion and Exclusion Criteria

As shown in Table 5, both pivotal trials enrolled adult patients aged 18 years or older and diagnosed with oHCM such that patients had unexplained LV hypertrophy with a maximal LV wall thickness of 15 mm or greater (13 mm or greater in cases of familial hypertrophic cardiomyopathy) and an LVOT peak gradient of 50 mm Hg or greater at rest, after a Valsalva maneuver or postexercise, and patients had to have an oxygen saturation at rest of 90% or greater at screening.

Patients in the EXPLORER-HCM trial had to have NYHA functional class of II or III oHCM, an LVEF of 55% or greater at screening, and be able to safely perform CPET with a respiratory exchange ratio of 1.0 or greater at screening. Patients were excluded if they had a history of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months before screening; atrial fibrillation present at screening; or previous treatment or planned treatment with disopyramide, ranolazine, or a combination of beta-blockers and calcium channel blockers.

Patients in the VALOR-HCM trial were included if they had NYHA functional class of III or IV or class II oHCM with exertional symptoms of syncope or near syncope; an LVEF of 60% or greater at screening; targeted anterior septal thickness sufficient to perform SRT safely in the judgment of the individual operator; and had been in the past 12 months considered for and willing to participate in SRT. Patients were excluded if they had atrial fibrillation at screening, a planned invasive procedure, defibrillator placement, or pulse generator change during the first 32 weeks of the study; had any intracardiac procedure planned; or had been previously treated with invasive septal reduction.

Baseline Characteristics

Baseline characteristics are shown in Table 6 and Table 7 for the EXPLORER-HCM and VALOR-HCM trials, respectively. The age of patients was similar across both pivotal trials, with an overall mean age of 58.5 years (SD = 11.9) in the EXPLORER-HCM trial and 60 years (SD = 12.0) in the VALOR-HCM trial. In both trials, most patients were white (91.2% and 89.3%, respectively) and used beta-blocker monotherapy at baseline (75.3% and 45.5%, respectively). In both trials, disease duration was similar and balanced between treatment groups. In the EXPLORER-HCM trial, the mean duration of oHCM was 7 years (SD = 7.2) for the mavacamten group and 7 years (SD = 6.6) for the placebo group. Similarly, in the VALOR-HCM trial, the mean duration of oHCM was 7.5 years (SD = 9.4) for the mavacamten group and 6.7 years (SD = 7.4) for the placebo group.

In the EXPLORER-HCM trial, at baseline, the mavacamten group compared to the placebo group had more females (46.3% versus 35.2%), fewer patients with a history of atrial fibrillation (9.8% versus 18.0%), a higher percentage of patients taking calcium channel blockers (20.3% versus 13.3%), and fewer patients taking neither beta-blockers nor calcium channel blockers (3.3% versus 12.5%). More than half of patients were from a region outside the US (i.e., the European Union, the UK, or Israel) (56.9% mavacamten versus 57.0% placebo) and most patients had NYHA functioning class II symptoms (71.5% mavacamten versus 74.2% placebo). A total of 11 patients (8.9%) in the mavacamten group and 8 patients (6.3%) in the placebo group had prior SRT.

In the VALOR-HCM trial, patients were enrolled from 19 sites in the US and most patients had symptoms of NYHA functioning class III or greater oHCM (92.9% mavacamten versus 92.9% placebo). Most patients were recommended to undergo a myectomy in both the mavacamten and placebo groups at baseline (85.7% versus 87.5%). Slightly more patients in the mavacamten group than in the placebo group were taking both beta-blockers and disopyramide at baseline (19.6% versus 5.4%) and fewer patients in the mavacamten group than the placebo group were taking both beta-blockers and calcium channel blockers at baseline (10.7% versus 17.9%).

Table 6: Summary of Baseline Characteristics in the EXPLORER-HCM Trial

%CV = percent coefficient of variation; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter-defibrillator; LAVI = left atrial volume index; LV = left ventricular; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NSVT = nonsustained ventricular tachycardia; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; oHCM = obstructive hypertrophic cardiomyopathy; pVO₂ = peak oxygen consumption; SD = standard deviation; SRT = septal reduction therapy; VT = ventricular tachycardia.

||||||||| |||||||||||||||||||| ||||||| ||||||| |||||||| |||||||||| ||| ||||||||||||||

Source: Clinical Study Report for EXPLORER-HCM trial.¹⁸

Table 7: Summary of Baseline Characteristics in the VALOR-HCM Trial

CSS = clinical summary score; HCM = hypertrophic cardiomyopathy; IQR = interquartile range; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LAVI = left atrial volume index; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; oHCM = obstructive hypertrophic cardiomyopathy; SD = standard deviation.

^aRace was self-reported.

^bThe KCCQ-23 CSS ranges from 0 to 100 points, where higher scores reflect better health status.

Source: Desai et al. (2022).¹⁷

Interventions

In both pivotal trials, patients were randomly assigned to receive once-daily orally administered treatment with mavacamten (starting dose 5 mg) or matching placebo. Detailed dose-titration regimens are shown in Table 8. In the EXPLORER-HCM trial, doses of mavacamten could be blindly down-titrated by 1 step (e.g., 5 mg to 2.5 mg) at any time during the 30 weeks of treatment if a patient had a mavacamten plasma trough concentration of greater than 700 ng/mL and less than 1,000 ng/mL. Doses could be blindly up-titrated by 1 step at week 8 or 14 if a patient’s mavacamten plasma trough concentration was less than 350 ng/mL and their Valsalva LVOT gradient was 30 mm Hg or greater at their previous assessment at weeks 6 and 12, respectively. Patients in the placebo group received the same titration assessments to maintain study blinding. Treatment was temporarily discontinued if the LVEF was less than 50% or the mavacamten plasma trough concentration was 1,000 ng/mL or greater, or due to prolongation of the QT interval corrected using Fridericia’s formula. Treatment was permanently discontinued if the LVEF was 30% or less. Patients who met the temporary discontinuation criteria could restart treatment 2 to 4 weeks after a follow-up visit at a single-step reduced dose if the temporary discontinuation parameters returned to an acceptable range. To maintain blinding, randomly selected patients from the placebo group underwent unscheduled follow-up visits.

The VALOR-HCM trial had 3 dosing periods. In the first placebo-controlled period, from day 1 to week 16, patients received treatment with mavacamten 5 mg or matching placebo once daily. Patients were evaluated for possible down-titration at week 4 (if their Valsalva LVOT gradient was less than 30 mm Hg) and up-titration at weeks 8 and 12 (if their Valsalva LVOT gradient was 30 mm Hg or greater). In the second active-controlled period, from week 16 to week 32, all patients received mavacamten once daily. Patients who received mavacamten during the first period continued the same dose they received at week 16, while patients who received placebo in the first period began mavacamten 5 mg/day at week 16 and were evaluated for down-titrations at week 20 and up-titrations at weeks 24 and 28. In the third LTE dosing period, from weeks 32 to 128, all patients received mavacamten once daily and their dose could be up-titrated to a maximum of 15 mg/day. If the LVEF was 50% or less at any time during treatment, mavacamten was temporarily discontinued for 2 to 4 weeks. Treatment was permanently discontinued if the LVEF was 30% or less. Patients who met the temporary discontinuation criteria could restart treatment 2 to 4 weeks after a reassessment visit at a single-step reduced dose if the LVEF was 50% or greater at reassessment. |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| |||| |||||||||| ||||||| |||||||||||||| ||||| |||||| |||||||||||| ||||||||| Sponsor-submitted publications provided data up to week 16 for the VALOR-HCM trial, with additional descriptive data available through to week 32 described in the Other Relevant Evidence section of this report.

Table 8: Dose Titrations in the EXPLORER-HCM and VALOR-HCM Trials

LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; QTcF = QT interval with Fridericia correction.

Sources: Clinical Study Reports for EXPLORER-HCM trial¹⁸ and Desai et al. (2022).¹⁷

Concomitant Medications

In the EXPLORER-HCM trial, background therapy (monotherapy with beta-blockers or calcium channel blockers) was permitted during the trial and was to be maintained at a stable dose throughout the study unless safety or tolerability concerns arose. Patients were prohibited from using disopyramide beginning 14 days before screening to the end of the study.

In the VALOR-HCM trial, patients were permitted to use standard-of-care HCM medications, including beta-blockers, calcium channel blockers, and disopyramide administered as monotherapy or in combination.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are further summarized in the following section. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 4.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

CPET = cardiopulmonary exercise testing; HCMSQ = Hypertrophic Cardiomyopathy Symptom Questionnaire; ICD = implantable cardioverter-defibrillator; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LAVI = left atrial volume index; LV = left ventricular; LVMI = left ventricular mass index; LVOT = left ventricular outflow tract; NR = not reported; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; pVO₂ = peak oxygen consumption; VCO₂ = carbon dioxide production; VE = volume expired.

Sources: Clinical Study Reports for EXPLORER-HCM trial,¹⁸ Desai et al. (2021),¹⁶ and Desai et al. (2022).¹⁷

Change NYHA Functional Class and Change in pVO₂

The EXPLORER-HCM trial used both objective assessments of exercise capacity (pVO₂ measured by CPET) and subjective assessments of symptom burden (NYHA functional class) as the primary composite outcome to evaluate clinically meaningful treatment benefits for oHCM. |||||| ||||||| ||||||||||||| ||||||||||| |||||| |||||| ||||||| ||||| ||||||| |||||||| CPET by standardized treadmill or bicycle ergometer was performed ||||||||||| |||||||| ||| ||||||||| |||||| |||||||| ||||||||| The primary composite outcome was defined as achieving 1 of the following at week 30:

• an improvement of 1.5 mL/kg/min or greater in peak oxygen consumption (pVO₂) as determined by CPET and a reduction of at least 1 NYHA class

• an improvement of 3.0 mL/kg/min or greater in pVO₂ with no worsening in NYHA class.

The VALOR-HCM trial did not examine change in pVO₂ as an outcome. The proportion of patients who achieved an improvement of at least 1 NYHA class was examined as a key secondary outcome in both pivotal trials, through to week 30 in the EXPLORER-HCM trial and through to week 16 in the VALOR-HCM trial.

Health-Related Quality of Life

Kansas City Cardiomyopathy Questionnaire

The KCCQ-23 is a self-administered, 23-item, disease-specific, HRQoL questionnaire originally developed in 2000 to measure a patient’s perception of their health status within a 2-week recall period.^20-22 The items of the KCCQ can be categorized into the following domains: physical limitation, symptoms (frequency, severity, and recent change over time), social limitation, self-efficacy, and HRQoL. All items are measured using a Likert scale with 5 to 7 response options. Responses are scored using ordinal values, beginning with 1 for the response that implies the lowest level of functioning. Domain scores are transformed to a 0-to-100 scale by subtracting the lowest possible scale score, dividing by the range of the scale, and multiplying by 100. Various combinations of the KCCQ domains create 3 summary scores, including a total symptom score (TSS), a CSS, and an overall summary score (OSS). The TSS combines the symptom burden and symptom frequency domains and evaluates patient-reported swelling in the feet, ankles, or legs; fatigue; shortness of breath; and disturbed sleep.²³ The CSS includes the physical limitation and total symptom domains, and the OSS combines the physical limitation, total symptom, social limitation, and HRQoL domains into a single score. Summary scores are then transformed to a 0-to-100 scale, with larger scores representing a better outcome: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent.^20,22

The KCCQ questionnaire is a generally valid, reliable, and responsive instrument for cardiovascular diseases.^20,23-29 Convergent validity has been demonstrated through moderate-to-strong correlations of the KCCQ OSS and domain scores with a variety of external indicators of clinical status.^24-26,28 Internal consistency reliability was demonstrated in a number of studies, in which the KCCQ summary and domain scores had Cronbach alpha values of greater than 0.7.^20,24,25 Test-retest reliability has been demonstrated (intraclass correlation coefficient [ICC] > 0.7) for the KCCQ symptom, social, and limitation domains.^20,25 High responsiveness of the KCCQ domains, the CSS, and the OSS has been found when the external indicators of clinical status were NYHA class, the Short Form (36) Health Survey, and the 6-minute walk distance (6MWD).²⁰ The estimated minimal important differences (MIDs) were evaluated with 2 anchor-based methods in patients with heart failure, and were approximately 5 points for the KCCQ OSS and TSS, and 6 points for the CSS.³⁰

5-Level EQ-5D Questionnaire

The 5-Level EQ-5D (EQ-5D-5L) questionnaire is a generic self-reported HRQoL outcome measure that can be applied to a variety of health conditions and treatments. The EQ-5D-5L was developed by the EuroQol Group as an improvement to the 3-Level EQ-5D questionnaire to measure small and medium health changes and reduce ceiling effects.^31,32 The instrument comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on 5 levels: level 1 indicates “no problems,” level 2 “slight problems,” level 3 “moderate problems,” level 4 “severe problems,” and level 5 “extreme problems” or “unable to perform.”^31,32 A total of 3,125 unique health states are possible, with 55555 representing the worst health state and 11111 representing the best state. The corresponding scoring of EQ-5D-5L health states is based on a scoring algorithm derived from preference data obtained from interviews using choice-based techniques (e.g., time trade-off) and discrete choice experiment tasks.^31,32 The lowest and highest scores vary depending on the scoring algorithm used. Scores of less than 0 represent health states that are valued by society as being worse than dead, while scores of 0 and 1.00 are assigned to the health states “dead” and “perfect health,” respectively. As an example, a Canadian scoring algorithm results in a score of −0.148 for health state 55555 (worst health state) and a score of 0.949 for health state 11111 (best health state).^31,32 In the EXPLORER-HCM trial, the EQ-5D-5L index score was calculated according to a US-based value set and ranged from 0 to 1, with lower scores indicating worse health states. The instrument was not used in the VALOR-HCM trial.

Disease-Related Symptoms

Hypertrophic Cardiomyopathy Symptom Questionnaire

The HCMSQ is a newly developed, self-administered, 11-item instrument specifically designed to evaluate symptomatic burden in patients with HCM.³³ It measures the main symptoms of HCM, including shortness of breath, fatigue and tiredness, dizziness and light-headedness, heart palpitations, chest pain, and syncope. The scores on the instrument range from 0 to 12.5, with lower scores indicating fewer and less-severe symptoms. The change from baseline to week 30 in patient-reported severity of HCM symptoms was assessed by the HCMSQ SoB domain score in the EXPLORER-HCM trial, in which a decrease from baseline of 2.5 or more points in the HCMSQ SoB domain score was used as the threshold for a clinically meaningful response. The HCMSQ was not used in the VALOR-HCM trial.³³ A clinically meaningful responder-definition range of 1 to 2 points was selected for the HCMSQ SoB and TSS, and approximately 1 point was used for the tiredness and cardiovascular symptom scores.³³

Change in Postexercise, Resting, and Valsalva LVOT Peak Gradient

According to the 2020 AHA/ACC clinical guidelines, the presence of a peak LVOT gradient of 30 mm Hg or greater is indicative of obstruction, with resting or provoked gradients of 50 mm Hg or greater generally considered the threshold for SRT in patients with drug-refractory symptoms.³ Change from baseline in postexercise LVOT peak gradient to week 30 in the EXPLORER-HCM trial and to week 16 in the VALOR-HCM trial were the first of 5 sequentially tested, alpha-controlled secondary end points in both pivotal trials. Change from baseline in resting and Valsalva LVOT peak gradients were explored as exploratory outcomes in both trials. The proportion of patients with postexercise LVOT peak gradients of less than 30 mm Hg or less than 50 mm Hg were exploratory outcomes in the EXPLORER-HCM trial.

Change in Septal Reduction Therapy Status

The primary end point in the VALOR-HCM trial was the composite of the patient’s decision to proceed with SRT before or at week 16 or be considered guideline-eligible for SRT at week 16. Guideline-eligibility criteria for SRT were based on the 2011 ACCF/AHA HCM clinical and hemodynamic criteria.³⁴ Eligibility criteria for SRT required an NYHA functional class III or IV status or an NYHA functional class II status with exertion-induced syncope or near syncope, and a dynamic LVOT gradient at rest or with provocation (i.e., Valsalva maneuver or exercise) of 50 mm Hg or greater.

The EXPLORER-HCM trial did not examine change in SRT status as an outcome.

Change in CPET Parameters

In the EXPLORER-HCM trial, CPET was conducted using a standardized treadmill or bicycle ergometer |||||||||| ||| |||||||| |||| |||||||| ||||||||||| Concomitant medications (i.e., beta-blockers or calcium channel blockers) may have been administered before all exercise testing. The same modality (treadmill or upright bicycle) had to be used for all CPETs conducted for a given participant. Cardiovascular and multiple other performance parameters were assessed at rest and at peak exercise.

Change in Cardiac Structure

Both pivotal trials assessed echocardiographic indices of atrial and ventricular chamber size and volumes. |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| ||||||| |||| |||||||| |||||||||| |||||||

Biomarker-Based Assessment

Both pivotal trials assessed patients for reduction in cardiac biomarkers NT-proBNP (an indicator of cardiac wall stress) and cardiac troponin I (an indicator of cardiac injury).¹⁸

Harms Outcomes

||||||| ||||||||||||| |||||||| ||||||||||||| ||||||||||| ||||| || |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||| ||||||||||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| ||||||||||||||||| |||||| ||||||| |||||||||||||| ||||||||||| |||||||||| ||| ||||||||| |||||||||||| ||||||||| ||||||||||||| ||| ||||||||| ||||||||| |||||||||||||||| |||||||||||||||||| |||||

Statistical Analysis

Sample-Size Determination and Power Calculation

In the EXPLORER-HCM trial, calculations resulted in a target sample size of N = 220 patients to achieve a 96% power to detect a 25% treatment difference for the primary outcome (2-sided test, significance level of 0.05) assuming the composite function end point would be achieved by 50% of patients in the mavacamten group and 25% in the placebo group.

In the VALOR-HCM trial, a sample size of 100 patients was prespecified to provide a 95% power to detect a 50% relative difference between groups for the primary end point (2-sided test, significance level of 0.05). There was 1 planned interim analysis for the primary outcome, which was conducted after 50 patients had completed the week-16 visit or terminated the study early (2-sided test, significance level of 0.001).

Statistical Test or Model

In the pivotal trials, categorical outcomes including the primary efficacy outcomes and the key secondary outcome of proportion of patients with an improvement of at least 1 NYHA class were analyzed with the Cochran-Mantel-Haenszel test for stratified categorical data.

In the EXPLORER-HCM trial, continuous outcomes of change in LVOT gradient and pVO₂ were analyzed using analysis of covariance (ANCOVA) with the treatment group (mavacamten versus placebo), baseline value of the corresponding outcome of interest, and the 3 stratification factors (beta-blocker use, NYHA class, and ergometer type) treated as fixed effects. A mixed model for repeated measures (MMRM) was used for the key secondary outcomes of the KCCQ-23 CSS and HCMSQ SoB, which included the patient as a random effect and time point (as a categorical variable) and the interaction between treatment and time point as fixed effects in addition to the fixed effects described previously. Changes from baseline to week 30 in CMR parameters were summarized by treatment group for the CMR substudy population using descriptive statistics. |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| |||||||| Between-group differences in the magnitude and direction of those changes were evaluated using Wilcoxon-Mann–Whitney tests.

In the VALOR-HCM trial, continuous variables were analyzed using ANCOVA or an MMRM for comparisons between the 2 groups. Baseline values were included in the ANCOVA model and the stratification factors (type of procedure and NYHA functional class) were treated as fixed effects. The MMRM included the treatment group, stratification factors, baseline value, time point, and the interaction between treatment group and time point as fixed effects. Biomarker data were log-transformed for model fits.

Data Imputation Methods

In the EXPLORER-HCM trial, missing NYHA classes at week 30 were imputed using the value for week 26, if available, in the case of the primary end point and NYHA response. Patients with a nonevaluable primary end point and NYHA secondary end point were considered nonresponders, whereas the LVOT gradient and pVO2 were analyzed with all available data without imputation, and patient-reported outcomes were analyzed with all available data using an MMRM, which implicitly handles the missing data in the patients who have baseline and 1 or more postbaseline values in the analysis.

In the VALOR-HCM trial, for the primary efficacy outcome, patients who discontinued the study or whose response status could not be assessed after the 16-week dosing period were classified as drug treatment failures (SRT-eligible). Missing data for secondary and exploratory efficacy analyses were not imputed.

Subgroup Analyses

Of the subgroups of interest to this review, both pivotal trials conducted preplanned analyses for select efficacy outcomes based on drug class of background therapy, including current treatment with beta-blockers (yes versus no) and current treatment with calcium channel blockers (yes versus no). The EXPLORER-HCM trial also conducted preplanned subgroup analyses based on NYHA functional class (II versus III). The results from the subgroup analyses may not have enough power to detect a treatment effect as no formal sample-size calculation was performed for individual subgroups and no adjustments were made for multiplicity. As such, the subgroup analyses are exploratory in nature.

Sensitivity Analyses

In the EXPLORER-HCM trial, an unstratified analysis using a chi-square test was performed as a sensitivity analysis for the primary efficacy outcome and for the key secondary outcome of proportion of patients who experienced an improvement of at least 1 NYHA class from baseline at week 30 (Table 10). An ad hoc sensitivity analysis assessed the impact of the missing data on 2 patient-reported outcomes (KCCQ-23 CSS and HCMSQ SoB), imputing missing data with unfavourable outcomes for the mavacamten group and favourable outcomes for the placebo group.

In the VALOR-HCM trial, a sensitivity analysis was performed to evaluate the number of patients with both improvement of NYHA functional class and reduction of all resting and provokable LVOT gradients of less than 50 mm Hg. Additional sensitivity analyses included using an alternative definition of SRT eligibility defined as either no improvement in NYHA functional class or maximum LVOT gradient of 50 mm Hg or greater as well as the need for SRT as determined by the investigator on the case report form.

Multiplicity Testing

In the EXPLORER-HCM trial, a sequential testing procedure was used to adjust for multiplicity. Upon achieving statistical significance in the primary end point, each of the secondary efficacy end points were tested sequentially at a 2-sided alpha level of 0.05, in the following order, as change from baseline to week 30:

• postexercise LVOT peak gradient

• pVO₂ as determined by CPET

• the proportion of patients with an improvement of at least 1 NYHA functional class

• patient-reported health status as assessed by the KCCQ-23 CSS

• patient-reported severity of HCM symptoms as assessed by the HCMSQ SoB domain score.

In the VALOR-HCM trial, a sequential testing procedure was used to adjust for multiplicity. Upon achieving statistical significance in the primary end point, each of the secondary efficacy end points were tested sequentially at a 2-sided alpha level of 0.05, in the following order, as change from baseline to week 16:

• postexercise LVOT peak gradient

• the proportion of patients with an improvement of at least 1 NYHA functional class

• patient-reported health status as assessed by the KCCQ-23 CSS

• NT-proBNP

• cardiac troponin I.

In both pivotal trials, if any of the secondary end points did not differ statistically significantly between the mavacamten and placebo groups, the tests for all subsequent end points were not considered statistically significant, despite nominal P values. The analyses of other efficacy outcomes, including the individual components of these composite outcomes, were not subject to any multiplicity adjustment.

Table 10: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; CPET = cardiopulmonary exercise testing; CSS = clinical summary score; HCMSQ = Hypertrophic Cardiomyopathy Symptom Questionnaire; HRQoL = health-related quality of life; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LVOT = left ventricular outflow tract; MMRM = mixed model for repeated measures; NR = not reported; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; PVO₂ = peak oxygen consumption; SoB = shortness of breath (domain score); SRT = septal reduction therapy.

^aThe VALOR-HCM publications did not specify which statistical test was used for continuous outcomes.

Sources: Clinical Study Report for EXPLORER-HCM trial,¹⁸ Desai et al. (2021),¹⁶ and Desai et al. (2022).¹⁷

Analysis Populations

In both pivotal trials, efficacy outcomes were analyzed in the intention-to-treat population, which included all the patients included all randomized patients, regardless of whether they received study drug. The safety population in both trials included all randomized patients who received at least 1 dose of the study drug, with analyse s conducted according to the actual study drug received.

Results

Patient Disposition

A summary of the patient disposition in the pivotal trials is available in Table 11. In the EXPLORER-HCM trial, 183 (42.7%) of 429 screened patients failed at least 1 screening criterion. Five of these 183 patients were randomized into the study before learning that they had failed a screening criterion, for a total of 251 randomized patients (58.5%). |||||||| |||||||| ||||||||||||||| |||||||||||||| |||| |||||||||||||||| ||| ||||| ||||||||| |||||||||| ||||||||||||| |||| |||||||||||||||| |||||| |||||||| |||||||||||| ||||||||||||| ||||||| |||||||||||||| |||||||||| ||||||||| |||||||||| ||| |||||| |||||||||||||||||||||| |||| |||||||||||||||| ||||||| ||||||||||||||||| ||||||||||||| |||||||||||||||||||| ||||| |||||||||||||| ||||||||||||||||||||| ||||||||||||||||||| ||||||| ||||||||||| |||||||||| |||||||||||||||||||| ||||||||| |||| ||||||||||| |||||||||||| ||||||||||||||||||| |||||||||||||||||| |||||| ||||||||||||||| |||||||| ||||||| ||||||| ||||||||| A total of 96.7% of patients in the mavacamten group and 98.4% in the placebo group completed the study when these patients were included. A total of 7 patients (2.8%) discontinued treatment, 4 (3.3%) in the mavacamten group and 3 (2.3%) in the placebo group.

In the VALOR-HCM trial, of the 152 patents screened, 73.7% were randomized, with 56 patients assigned to each of the mavacamten and placebo groups, respectively. A total of 2 patients (3.6%) in the placebo group discontinued the study through to week 16, and 2 patients (3.6%) in each treatment group discontinued treatment and elected to undergo SRT before or at week 16.

Table 11: Patient Disposition

NA = not applicable.

^aIn the context of COVID-19, 67 patients in the EXPLORER-HCM trial who completed telephone visits at week 38 rather than onsite visits were categorized as “other” but did complete the study, for a total of 178 + 67 = 245 patients who completed the study (97.6%).

^bPatient found ineligible after enrolment.

Sources: Clinical Study Reports for EXPLORER-HCM trial,¹⁸ Desai et al. (2021),¹⁶ and Desai et al. (2022).¹⁷

Exposure to Study Treatments

In the EXPLORER-HCM trial, ||||||||||||||| ||| ||||||| |||||||||||||| ||||||||||||||| |||||||||||||| |||||||||||||||| ||||||||||||| ||||||| ||||||| ||||| ||||| ||| (Table 12). The average daily dose in the mavacamten group was 6.7 mg (SD = 2.2) and approximately 50% of patients remained on mavacamten 5 mg/day throughout the treatment period. A total of 40 patients (32.5%) in the mavacamten group received a dose increase from 5 to 10 mg/day at weeks 8 or 14 and remained on 10 mg/day for the remainder of the treatment period; 13 patients (10.6%) received a dose increase from 5 to 10 mg at week 8 and a further dose increase from 10 to 15 mg/day and week 14 and remained on 15 mg/day for the remainder of the treatment period. Overall, 97.6% of patients in the mavacamten group had a compliance rate of 80% or greater.

Information related to duration of exposure was not reported in the VALOR-HCM trial publications. In terms of dose titrations, 23.2% of patients in the mavacamten group were receiving 5 mg/day and 33.9% were receiving 10 mg/day as their last measured dose during the double-blinded treatment period.

Table 12: Duration of Exposure (Safety Population)

NA = not applicable; NR = not reported; SD = standard deviation.

^aDuration of exposure in weeks is the interval between first dose date and last dose date and calculated as (last dose date – first dose date + 1)/7.

^bAdjusted duration of exposure is the duration of exposure with adjustment for the period of protocol-specified dose interruptions (i.e., triggered by an interactive response system or due to a treatment-emergent adverse event).

||||||||| ||||||||||| |||| |||||||||||||||| ||| |||||||| |||||||||| ||||||||| ||||||||||||

Sources: Clinical Study Reports for EXPLORER-HCM trial,¹⁸ Desai et al. (2021),¹⁶ and Desai et al. (2022).¹⁷

Protocol Deviations

Important protocol deviations in the EXPLORER-HCM trial are summarized in Table 13. |||||||||||||| ||||||||||||||| |||||||||||| |||| |||||||||||| |||||||| |||||||| |||||||||||||||||| ||||||||||||| |||||||| ||||||||| |||||| ||||||||| |||||||||||||||| ||||||| |||||||| |||||||||||||||| |||||||| |||||||||| |||||||||| ||| ||||||||||||| ||||||| ||||||||||| ||||||| |||||||||||| ||||||||| ||||| ||||||||||||||| |||||||||||||| || ||||||||||||||||||| |||||||||||||| |||||||||||||| ||||||||||||| |||||||||||||||||| |||||||| |||||||||| |||||||| ||||||||||||| |||||||||| |||||||||||||| |||||||||||||||| |||||||| |||| ||||| ||||||||||| ||||||| |||||||| |||||| |||||||||||||| ||||| |||||||||||| |||||||||||||||| |||||||||||| |||||||||||| ||||||||||||||||||||| ||| ||||||||||| |||| |||||||||||||||| ||||||||| ||||| |||||||||| |||||||||||||||||||

Table 13: Redacted

||||||||||||||| |||||| |||||||||| ||||||||| |||||||| |||||||||||||| |||||| |||||||| ||||||| |||||||||| |||| ||||||||||||| |||||||||||| |||||||||||^||||||||||||||||||||| |||||| ||||||| ||||||||||||| ||||||||||||||| |||||||||||| |||||||||||||| ||||||||| |||||||||||||||| |||||||||||||||||| |||||||||||||||||| |||||| |||||||| |||| |||||||||||||||| ||||| ||||| ||||||||| ||||||

This table was redacted due to confidential information.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported here. Appendix 3 provides detailed efficacy data.

Change in NYHA Functional Class

The proportion of patients with improvement of at least 1 NYHA class from baseline to end of treatment in the EXPLORER-HCM and VALOR-HCM trials are reported in Table 14 and Table 17, respectively. In the EXPLORER-HCM trial, a total of 80 patients (65%) in the mavacamten group and 40 patients (31.3%) in the placebo group experienced an improvement of at least 1 NYHA class from baseline to week 30, with a between–treatment group difference of 33.8% (95% CI, 22.2 to 45.4; P < 0.0001). As shown in Appendix 3, in the mavacamten group, 52 patients (42.3%) improved from class II to class I, 19 (15.4%) improved from class III to class II, and 9 (7.3%) improved from class III to class I. One patient (0.8%) in the mavacamten group worsened from NYHA class II at baseline to class III at week 30. In the placebo group, 24 patients (18.8%) improved from class II to class I, 13 patients (10.2%) improved from class III to class II, and 3 patients (2.3%) improved from class III to class I. Nine patients (7.0%) in the placebo group worsened from NYHA class II at baseline to class III at week 30. No patients worsened to NYHA class IV.

In the VALOR-HCM trial, a total of 35 patients (62.5%) in the mavacamten group and 12 patients (21.4%) in the placebo group experienced an improvement of at least 1 NYHA class from baseline to week 16 with a between–treatment group difference of 41.1% (95% CI, 24.5 to 57.7; P < 0.001).

In the EXPLORER-HCM trial, the sensitivity analysis for change in NYHA class was consistent with the results of the primary efficacy analysis.

Subgroup Analysis

In the EXPLORER-HCM trial, the subgroup analyses were generally consistent with the overall results (Appendix 3). The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Change in NYHA Class and pVO₂

Key results of the primary composite outcome in the EXPLORER-HCM trial are summarized in Table 16. A higher proportion of patients in the mavacamten group than in the placebo group (36.6% versus 17.2%) achieved the composite outcome at week 30 with a difference between treatment groups of 19.4% (95% CI, 8.7 to 30.1; P = 0.0005). A higher proportion of patients achieved both an increase of 3 mL/kg/min or greater in pVO₂ and an improvement of at least 1 NYHA class in the mavacamten group compared with the placebo group (20.3% versus 7.8%), with a between–treatment group difference of 12.5% (95% CI, 4.0 to 21.0).

In the EXPLORER-HCM trial, the results of a sensitivity analysis of the primary composite outcome were consistent with those of the primary efficacy analysis. The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Change in pVO₂ and change in NYHA class combined was not examined in the VALOR-HCM trial.

Subgroup Analysis

In the EXPLORER-HCM trial, analyses of the primary efficacy end points of use of calcium channel blockers at baseline (yes versus no) and stratification factors of NYHA functional class at baseline (II versus III) showed a consistent effect in favour of mavacamten. Among patients using beta-blockers at baseline, there was no statistically significant difference between treatment groups with a between-group difference of 8.7% (95% CI, −3.6 to 21.1) compared to a treatment-group difference of 52.6% (95% CI, 32.9 to 72.2) among patients not using beta-blockers at baseline. The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Health-Related Quality of Life

Kansas City Cardiomyopathy Questionnaire

Key summary results for KCCQ-23 CSS are reported in Table 14 and Table 17 for the EXPLORER-HCM and VALOR-HCM trials, respectively.

In the EXPLORER-HCM trial, the mean change from baseline to week 30 in the KCCQ-23 CSS was 13.6 (SD = 14.4) in the mavacamten group and 4.2 (SD = 13.7) in the placebo group, with a least squares mean difference of 9.1 (95% CI, 5.5 to 12.7; P < 0.0001). At week 30, 53.9% of patients in the mavacamten group achieved an increase of 10 points or greater (i.e., improvement) in the KCCQ-23 CSS from baseline compared with 33.8% of patients in the placebo group.

In the VALOR-HCM trial, the mean change from baseline to week 16 in the KCCQ-23 CSS was 10.4 (SD = 16.1) in the mavacamten group and 1.9 (SD = 12.0) in the placebo group, with a least squares mean difference of 9.4 (95% CI, 4.9 to 14.0; P < 0.001).

In the EXPLORER-HCM trial, greater mean improvements were found in the mavacamten group compared to the placebo group in the KCCQ-23 OSS and TSS from baseline to week 30 (Table 15). The mean change from baseline to week 30 in the KCCQ-23 OSS was 14.9 (SD = 15.8) in the mavacamten group and 5.4 (SD = 13.7) in the placebo group, with a least squares mean difference of 9.1 (95% CI, 5.5 to 12.8). The mean change from baseline to week 30 in the KCCQ-23 TSS was 12.4 (SD = 15.0) in the mavacamten group and 4.8 (SD = 15.9) in the placebo group, with a least squares mean difference of 7.7 (95% CI, 3.7 to 11.5).

Sensitivity Analyses

In the EXPLORER-HCM trial, ad hoc sensitivity analyses were conducted to assess if the between-group difference in the KCCQ-23 CSS key secondary end point remained robust when missing data were imputed with unfavourable outcomes for mavacamten group and favourable outcomes for the placebo group. For all imputation scenarios, results were supportive of the results of the primary analysis, although the treatment effect size decreased.

Subgroup Analysis

In the EXPLORER-HCM trial, the subgroup analyses were generally consistent with the overall results. The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

5-Level EQ-5D

In the EXPLORER-HCM trial, the mean EQ-5D-5L index scores remained close to baseline values for both treatment groups at week 30, with mean changes from baseline of 0.08 (SD = 0.16) for the mavacamten group and 0.009 (SD = 0.16) for the placebo group (Table 15).

The EQ-5D-5L instrument was not used in the VALOR-HCM trial.

Disease-Related Symptoms

Hypertrophic Cardiomyopathy Symptom Questionnaire

As shown in Table 14, in the EXPLORER-HCM trial, mavacamten-treated patients demonstrated a statistically significant decrease (i.e., an improvement) in HCMSQ SoB domain scores compared with placebo patients. Mean HCMSQ SoB domain scores decreased by 2.8 |||||||| points from baseline to week 30 in the mavacamten group compared to a decrease of 0.9 |||||||| points in the placebo group (between-group difference −1.8; 95% CI, ||||||||||||; P < 0.0001). A greater proportion of patients taking mavacamten compared to placebo achieved an improvement of 2.5 or more points between baseline and week 30 in the HCMSQ SoB domain score (50.0% versus 21.3%).

|||||||| ||||||||| |||||||||||||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||||||||| |||||||| |||||||||||||||||| |||||||| |||||||||| ||||||||| ||||||||||||||| ||||||||| |||||||||| ||||||||||||||||||||| ||||||||||

The HCMSQ instrument was not examined in the VALOR-HCM trial.

Sensitivity Analysis

In the EXPLORER-HCM trial, exploratory sensitivity analyses were conducted to assess if the between-group difference in the HCMSQ SoB domain remained robust when missing data were imputed with unfavourable outcomes for the mavacamten group and favourable outcomes for the placebo group. For both imputation scenarios, results were supportive of the results of the primary analysis, although the treatment effect size decreased.

Subgroup Analysis

In the EXPLORER-HCM trial, subgroup analyses were generally consistent with the overall results. The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Table 14: Summary of Key Response Variables at Week 30 in the EXPLORER-HCM Trial (ITT Population)

ANCOVA = analysis of covariance; CI = confidence interval; CPET = cardiopulmonary exercise testing; CSS = clinical summary score; HCMSQ = Hypertrophic Cardiomyopathy Symptom Questionnaire; ITT = intention-to-treat; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LVOT = left ventricular outflow gradient; NYHA = New York Heart Association; pVO₂ = peak oxygen consumption; SD = standard deviation; SoB = shortness of breath.

^aThe mean difference estimate, its 95% CI, and P values are from the ANCOVA which controls for treatment group (mavacamten vs. placebo), baseline value of the corresponding end point of interest, and the 3 stratification factors (beta-blocker use, NYHA class, ergometer type based on an interactive response system).

^bThe missing NYHA class at week 30 is imputed using available NYHA at week 26. After imputation, patients whose response status at week 30 is still missing will be classified as nonresponders.

|||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| |||||||

^dThe analysis was stratified on NYHA class, beta-blocker use, and exercise type (based on an interactive response system). Odds ratio was estimated using Cochran-Mantel-Haenszel method. An odds ratio greater than 1 indicates better outcome when comparing to placebo. P values and 95% CIs were derived using the exact method.

^eBased on mixed model for repeated measures, with data up to week 30, which includes baseline value, treatment group, visit, interaction between treatment group and visit, and the 3 stratification factors (beta-blocker use, NYHA class, exercise type based on an interactive response system) as fixed effects and the patient as a random effect.

^fTotal N is the number of patients with a baseline score of up to 100 minus 10 (i.e., the clinically meaningful threshold). Patients with missing data at the postbaseline visit were considered nonresponders for that visit.

^gTotal N is the number of patients with a baseline score of 2.5 or greater (i.e., the clinically meaningful threshold).

Source: Clinical Study Report for EXPLORER-HCM.¹⁸

Table 15: Exploratory Patient-Reported Outcomes at Week 30 in the EXPLORER-HCM Trial (ITT Population)

CI = confidence interval; EQ-5D-5L = 5-Level EQ-5D; HCMSQ = Hypertrophic Cardiopathy Symptom Questionnaire; ITT = intention-to-treat; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; NYHA = New York Heart Association; OR = odds ratio; OSS = overall summary score; SD = standard deviation; TSS = total symptom score.

^aBased on a mixed model for repeated measures with data up to week 30, which includes baseline value, treatment group, visit, interaction between treatment group and visit, and the 3 stratification factors (beta-blocker use, NYHA class, exercise type based on an interactive response system), as fixed effects and the patient as a random effect.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report for EXPLORER-HCM.¹⁸

Change in pVO₂

As shown in Table 14, in the EXPLORER-HCM trial, the mean changes from baseline to week 30 in pVO₂ were 1.4 mL/kg/min (SD = 3.1) in the mavacamten group and −0.05 mL/kg/min (SD = 3.0) in the placebo group, with a difference between treatment groups of 1.4 mL/kg/min (95% CI, 0.6 to 2.1; P = 0.0006) in favour of mavacamten.

Change in pVO₂ was not examined in the VALOR-HCM trial.

Subgroup Analysis

In the EXPLORER-HCM trial, subgroup analyses based on use of calcium channel blockers at baseline (yes versus no) and NYHA functional class at baseline (II versus III) support the results seen in the main analysis of the trial. Regarding the subgroup analysis based on use of beta-blockers at baseline (yes versus no), the between-group difference in change from baseline to week 30 in pVO₂ was lower among patients who used beta-blockers at baseline (1.0 mL/kg/min, 95% CI, 0.1 to 2.0) than among those who did not use beta-blockers at baseline (2.7 mL/kg/min, 95% CI, 1.3 to 4.1). However, the subgroup analyses may not have been powered to detect a treatment effect as no formal sample size calculation was performed for individual subgroups. As such, the subgroup analyses are exploratory in nature.

Change in Postexercise, Resting, and Valsalva LVOT Peak Gradient

The mean change from baseline to end of treatment in postexercise, resting, and Valsalva LVOT peak gradient are reported in Table 14 and Table 17 for the EXPLORER-HCM and VALOR-HCM trials, respectively.

In the EXPLORER-HCM trial the mean postexercise LVOT gradient change from baseline to week 30 was −47.2 mm Hg (SD = 40.3) in the mavacamten group versus −10.4 mm Hg (SD = 29.6) in the placebo group with a treatment-group difference of −35.6 mm Hg (95% CI, −43.2 to −28.1; P < 0.0001). Similarly, in the VALOR-HCM trial, the mean postexercise LVOT gradient change from baseline to week 16 was −39.1 mm Hg (SD = 36.5) in the mavacamten group versus −1.8 mm Hg (SD = 28.8) in the placebo group with a treatment-group difference of −37.2 mm Hg (95% CI, −48.1 to −26.2; P < 0.001).

Table 16: Summary of Primary Composite Functional End Point at Week 30 in the EXPLORER-HCM Trial (ITT Population)

CI = confidence interval; HCM = hypertrophic cardiomyopathy; ITT = intention-to-treat; NYHA = New York Heart Association; pVO₂ = peak oxygen uptake.

^aThe composite functional end point was defined as either type 1 (an improvement of at least 1.5 mL/kg/min in pVO₂ and improvement of 1 or more NYHA classes) or type 2 (an improvement of at least 3.0 mL/kg/min in pVO₂ with no worsening in NYHA class, unless otherwise denoted). Missing NYHA class at week 30 was imputed using available NYHA class at week 26. After the imputation, the patients whose response status at week 30 was still missing were classified as nonresponders.

^bThe 95% CIs of the response differences between mavacamten and placebo groups are based on normal approximation.

^cThe analysis was stratified on NYHA class, beta-blocker use, and exercise type (based on an interactive response system). The odds ratio was estimated using the Cochran-Mantel-Haenszel method. An odds ratio greater than 1 indicates a superior outcome when comparing to placebo. The P value and 95% CI were derived using the exact method.

^dThese are the most stringent pVO₂ and NYHA class components of the composite functional end point.

Source: Clinical Study Report for EXPLORER-HCM.¹⁸

In both pivotal trials, the mean change in resting and Valsalva LVOT peak gradients from baseline to end of treatment were higher in the mavacamten group than in the placebo group. |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||||||| In the VALOR-HCM trial the mean change from baseline to week 16 in resting LVOT peak gradient was −36.0 mm Hg (SD = 28.8) for the mavacamten group and −1.5 mm Hg (SD = 26.5) for the placebo group, and the mean change from baseline to week 30 in Valsalva peak gradient was −45.2 mm Hg (SD = 28.5) for the mavacamten group and 0.4 mm Hg (SD = 29.7) for the placebo group.

Subgroup Analysis

In the EXPLORER-HCM trial, the effect of mavacamten on the change in postexercise LVOT peak gradient (mm Hg) was generally consistent across prespecified subgroups . The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Change in Septal Reduction Therapy Status

As shown in Table 17, in the VALOR-HCM trial, a lower proportion of patients in the mavacamten group (17.9%) than in the placebo group (76.8%) met the primary composite outcome of a decision to proceed with SRT by week 16 or were guideline-eligible at week 16, with a difference between treatment groups of 58.9% (95% CI, 44.0% to 73.9%; P < 0.001). A total of 3.6% patients in each of the mavacamten and placebo groups made the decision to proceed with SRT by week 16, and 14.3% of patients in the mavacamten group versus 69.6% of patients in the placebo group were defined as SRT-eligible based on guideline criteria.

Table 17: Summary of Primary and Secondary Response Variables at Week 16 in the VALOR-HCM Trial (ITT Population)

ACCF = American College of Cardiology Foundation; AHA = American Heart Association; CI = confidence interval; CSS = clinical summary score; HCM = hypertrophic cardiomyopathy; ITT = intention-to-treat; KCCQ-23 = 23-item Kansas City Cardiomyopathy Questionnaire; LV = left ventricular; LVOT = left ventricular outflow tract; NR = not reported; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; SD = standard deviation; SRT = septal reduction therapy.

^aTreatment difference and 95% CI were generated in an analysis of covariance model, including baseline variable as a covariate and baseline stratification factors for type of SRT recommended (alcohol septal ablation or myectomy) and NYHA functional class (II or III-IV).

^bCochran-Mantel-Haenszel method stratified by baseline NYHA criteria (II vs. higher) and type of SRT recommended (myectomy vs. alcohol septal ablation). Difference in proportions estimated as placebo rate minus mavacamten rate, where a positive value indicates a beneficial treatment effect.

^cThe guideline criteria are based of the 2011 ACCF/AHA clinical and hemodynamic criteria for HCM. Patients with a maximum LVOT gradient of 50 mm Hg or greater gradient (from rest, Valsalva, or postexercise) and no improvement in NYHA functional class at week 16 are considered eligible for SRT.

^dAssuming that both patients in the placebo group did not meet the primary end point, the result shows a treatment difference of similar magnitude to the primary analysis with same level of significance. The treatment difference was 55.36 (95% CI, 40.02 to 70.69; P < 0.0001).

^eGeometric mean ratios of less than 1.0 represent an x-fold decrease for mavacamten compared with placebo.

Source: Desai et al. (2022). Copyright 2022 The Authors. Reprinted in accordance with Creative Licence Attribution Licence CC BY-NC-ND 4.0.¹⁷

Exploratory sensitivity analyses were conducted using alternative definitions of SRT eligibility, as shown in Appendix 3. The sensitivity analyses were generally supportive of the primary analysis, but the magnitude of effect for mavacamten was not as strong in the analysis that used the alternative definition of SRT eligibility of no improvement in NYHA functional class or a maximum LVOT gradient of 50 mm Hg or greater.

Change in SRT status was not examined in the EXPLORER-HCM trial.

Subgroup Analysis

As shown in Appendix 3, in the VALOR-HCM trial, analyses of the primary efficacy end points were generally in line with the primary efficacy analysis and in favour of mavacamten. Potential differences were noted depending on use of calcium channel blockers (yes versus no) (P value for interaction < 0.05). The analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Change in CPET Parameters

Changes in CPET parameters from baseline to week 30 in the EXPLORER-HCM trial are shown in Table 18. Mean changes were greater for patients in the mavacamten group compared with the placebo group, with greater increases in peak circulatory power and a least squares mean difference of 372.9 (95% CI, 153.1 to 592.6), peak metabolic equivalents of task with a least squares mean difference of 0.4 (95% CI, 0.2 to 0.6), percent predicted pVO₂ with a least squares mean difference of 8.4 (95% CI, 5.3 to 11.5), ventilatory power with an least squares mean difference 0.6 (95% CI, 0.3 to 0.9), and a greater decrease in ratio of volume expired to carbon-dioxide production slope, with a least squares mean difference of −2.6 (95% CI, −3.6 to −1.5).

Change in CPET parameters were not examined in the VALOR-HCM trial.

Table 18: Change in CPET Parameters at Week 30 in the EXPLORER-HCM Trial (ITT Population)

CI = confidence interval; ITT = intention-to-treat; VE/VCO₂ = volume expired/carbon-dioxide production; SD = standard deviation; VO₂ = oxygen consumption.

^aThe least squares means (95% CI) and the P values are from a mixed model for repeated measures with data up to week 30, which includes baseline value, treatment group, visit, interaction between treatment group and visit, and the 3 stratification factors (beta-blocker use, NYHA class, and exercise type based on an interactive response system) as fixed effects and the patient as a random effect.

^bP value has not been adjusted for multiple testing (i.e., the type I error rate has not been controlled).

Source: Clinical Study Report for EXPLORER-HCM.¹⁸

Change in Cardiac Structure

Table 19 shows mean changes in measures of cardiac structure by echocardiography from baseline to week 30 in the EXPLORER-HCM trial. The mean change from baseline in LAVI was −7.5 mL/m² ||||||| in the mavacamten group compared to −0.1 mL/m² ||||||| in the placebo group. There was a reduction from baseline to week 30 in mean left ventricular mass index (LVMI) in the mavacamten group of −7.4 g/m² |||||||| versus an increase in the placebo group of 8.9 g/m² ||||||||. There was little change from baseline in echocardiographic measures of interventricular septal or posterior wall thicknesses following 30 weeks of treatment for either group. As shown in Appendix 3, in the CMR substudy of the EXPLORER-HCM trial, changes from baseline to week 30 in measures of cardiac structure including LAVI, LVMI, and LV maximal wall thickness were greater for patients in the mavacamten group than in the placebo group. As the CMR substudy outcomes were not controlled for multiplicity and, due to the small sample sizes in the substudy, results should be interpreted as supportive evidence for mavacamten.

In the VALOR-HCM trial, as shown in Table 17, changes in LAVI and LVMI from baseline to week 16 were greater among patients in the mavacamten group than in the placebo group with a treatment-group difference of −4.4 (95% CI, −7.1 to −1.7) and −6.5 (95% CI, −13.2 to 0.1), respectively.

Table 19: Change in Measures of Cardiac Structure at Week 30 in the EXPLORER-HCM Trial (ITT Population)

ITT = intention-to-treat; LAVI = left atrial volume index; LVMI = left ventricular mass index; SD = standard deviation.

Source: Clinical Study Report for EXPLORER-HCM trial.¹⁸

Biomarker-Based Assessment

In the EXPLORER-HCM trial, as shown in Table 20, exploratory analyses found that the reduction from baseline to week 30 in NT-proBNP (in ng/L) was 80% greater for those in the mavacamten group than for those in placebo group (the proportion of geometric mean ratio between groups was 0.2 [95% CI, 0.2 to 0.2]) and the reduction from baseline to week 30 in cardiac troponin I (in ng/L) was more than 40% greater for those in the mavacamten group than for those in the placebo group (the proportion of geometric mean ratio between groups was 0.6 [95% CI, 0.5 to 0.7]).

In the VALOR-HCM trial, as shown in Table 17, analyses of key secondary outcomes found that the reduction from baseline to week 16 in NT-proBNP (in ng/L) was 67% greater for those in the mavacamten group than for those in placebo group. The proportion of the geometric mean ratio between groups was 0.3 (95% CI, 0.3 to 0.4; P value < 0.001) and the reduction from baseline to week 16 in cardiac troponin I (in ng/L) was 47% greater for those in the mavacamten group than for those in the placebo group (the proportion of the geometric mean ratio between groups was 0.5 [95% CI, 0.4 to 0.7; P value < 0.001]).

Table 20: Change in Biomarker Measures at Week 30 in the EXPLORER-HCM Trial (ITT Population)

%CV = percent coefficient of variation; CI = confidence interval; ITT = intention-to-treat; NT-proBNP = N-terminal pro–B-type natriuretic peptide.

^aThe proportion of the geometric mean ratio from week 30 to baseline between the mavacamten and placebo groups, the corresponding 95% CI, and P values are estimated from a mixed model for repeated measures, with data up to week 30 fitted with log-transformed baseline NT-proBNP values, treatment group, time, interaction between treatment group and time, and the 3 stratification factors (beta-blocker use, NYHA class, and exercise type based on an interactive response system) as fixed effects and the patient as a random effect.

Source: Clinical Study Report for EXPLORER-HCM trial.¹⁸

Prevention of Atrial Fibrillation or Flutter

This efficacy outcome was not reported in the pivotal trials. AEs of atrial fibrillation or flutter are reported in Table 21 and Table 22 for the EXPLORER-HCM and VALOR-HCM trials, respectively.

Prevention of Stroke

This efficacy outcome was not reported in the pivotal trials. AEs of stroke are reported in Table 21 and Table 22 for the EXPLORER-HCM and VALOR-HCM trials, respectively.

Prevention of Sudden Cardiac Death

This efficacy outcome was not reported in the pivotal trials. AEs of sudden cardiac death are reported in Table 21 and Table 22 for the EXPLORER-HCM and VALOR-HCM trials, respectively.

Need for Implantation of Cardioverter-Defibrillator

This efficacy outcome was not reported in the pivotal trials.

Harms

Only those harms identified in the review protocol are reported here. Table 21 and Table 22 provide detailed harms data.

Adverse Events

In the EXPLORER-HCM trial, through to week 38, a total of 87.8% of patients in the mavacamten group and 81.3% of patients in the placebo group experienced at least 1 AE. The most common AEs were generally similar for both treatment groups. Dizziness was the most frequently reported AE for both the mavacamten and placebo groups, with a higher proportion of patients experiencing dizziness in the mavacamten group compared with the placebo group (21.1% versus 13.3%).

In the VALOR-HCM trial, through to week 16, a total of 73.2%% of patients in the mavacamten group and 61.8% of patients in the placebo group experienced at least 1 AE. Noted AEs of interest were similar for both treatment groups. A slightly higher proportion of patients in the mavacamten group experienced fatigue (8.9%) compared with those in the placebo group (3.6%). Fewer patients in the mavacamten group compared with the placebo group experienced headache (3.6% versus 9.1%, respectively) and nonsustained ventricular tachycardia (0% versus 9.1%, respectively).

Serious Adverse Events

In the EXPLORER-HCM trial, through to week 38, the proportions of patients with SAEs were similar for the mavacamten and placebo groups (11.4% versus 9.4%, respectively). The most common SAEs included atrial fibrillation (2.4%), syncope (2.4%), and stress cardiomyopathy (1.6%) among patients in the mavacamten group and atrial fibrillation (3.9%) among patients in the placebo group.

In the VALOR-HCM trial, through to week 16, the proportion of patients who had SAEs was slightly higher for the mavacamten group versus the placebo group (5.4% versus 1.8%, respectively). The SAEs included atrial fibrillation (3.6%) and COVID-19 (1.8%) among patients in the mavacamten group and alcohol poisoning (1.8%) among patients in the placebo group.

Withdrawals due to Adverse Events

In the EXPLORER-HCM trial, a total of 1.6% of patients in the mavacamten group discontinued treatment due to AEs of atrial fibrillation and syncope, respectively. No patients in the placebo group discontinued treatment due to AEs.

No treatment discontinuations due to AEs were reported in the VALOR-HCM trial through to week 16.

Mortality

In the EXPLORER-HCM trial, through to week 38, a single death (representing 0.8% of the placebo group) due to sudden death was reported. No deaths were reported in the VALOR-HCM trial through to week 16.

Notable Harms

Cardiac Failure

As shown Table 21, in the EXPLORER-HCM trial, through to week 38, the proportion of patients with AEs of cardiac failure (including acute and congestive cardiac failure and cardiogenic shock) was 2.4% in the mavacamten group and 3.9% in the placebo group.

No events of cardiac failure were reported through to week 16 in the VALOR-HCM trial.

Sudden Cardiac Death

In the EXPLORER-HCM trial, through to week 38, 1 patient (0.8%) died due to sudden death in the placebo group. No events of sudden death were reported through to week 16 in the VALOR-HCM trial.

LVEF Less Than 50% or Less Than 30%

In the EXPLORER-HCM trial, no AEs of decreased LVEF were reported. However, the incidence of a resting LVEF of less than 50% was a protocol-specified criterion for temporary treatment discontinuation. In the EXPLORER-HCM trial, during the 30-week treatment period, 9 patients (3.6%) met the temporary treatment discontinuation criterion of an LVEF of less than 50%, including 7 patients (5.7%) in the mavacamten group and 2 patients (1.6%) in the placebo group. Five of these patients (3 in the mavacamten group and 2 in the placebo group) underwent temporary treatment discontinuation and subsequently resumed dosing and completed the study. The remaining 4 patients had no further dose adjustments as their LVEFs of less than 50% occurred at the week-30 visit.

In the VALOR-HCM trial, through to week 16, 2 patients (3.6%) had an LVEF of less than 50% resulting in temporary drug discontinuation, and subsequently resumed mavacamten dosing.

In both pivotal trials, no patients had a reduction in their LVEF of 30% or less necessitating permanent treatment discontinuation.

|||||||||||||||||||||| ||||||||||||||||| |||||||||||||||||| |||||| |||||||||||| |||||||||||| |||||||||| ||||||| |||||||||||| ||||||||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| ||||| |||||| ||||||||||||||| |||||| ||||||||||| ||||||||||||||||| ||||||||||||||||||||| |||||||||||| ||||||| ||| ||||||||||| ||||||||||||||| ||||||||||||| ||||||||||||| ||||||| |||||||||||| ||||||||||||||||| |||||||||||| |||||||| |||||| ||||||| |||||||| |||||||||| |||||||| ||||| |||||| |||||||||||| |||||||||||||||

Data related to cardiovascular hospitalizations were not available for the VALOR-HCM trial.

Table 21: Summary of Harms in the EXPLORER-HCM Trial Through Week 38^a (Safety Population)

LVEF = left ventricular ejection fraction; SAE = serious adverse event.

|||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| ||||||||

^bFrequency greater than 5%.

^cReported in at least 1 patient.

||||||||||| ||||||| ||||||||| |||||||||| |||||| |||| |||||||||||| |||||||||||| |||| ||||||||||||||

Source: Clinical Study Report for EXPLORER-HCM trial.¹⁸

Critical Appraisal

Internal Validity

Both the EXPLORER-HCM and the VALOR-HCM trials appeared to have acceptable methods for blinding, allocation concealment, and randomization with stratification. Small differences between treatment groups in demographic and baseline patient characteristics in the EXPLORER-HCM trial were noted (the mavacamten group had more females, fewer patients with a history of atrial fibrillation, more patients taking calcium channel blockers at baseline, and fewer patients taking neither beta-blockers nor calcium channel blockers at baseline). The clinical expert consulted for this review stated that the difference in the proportions of patients taking neither beta-blockers nor calcium channel blockers at baseline (3.3% of the mavacamten group versus 12.5% of the placebo group) may have introduced bias in favour of mavacamten as a greater proportion of patients in the placebo group were not receiving any background therapy. In the VALOR-HCM trial, more patients in the mavacamten group than in the placebo group were taking both beta-blockers and disopyramide at baseline (19.6% versus 5.4%, respectively) and fewer patients in the mavacamten group than in the placebo group were taking both beta-blockers and calcium channel blockers at baseline (10.7% versus 17.9%, respectively). The clinical expert consulted stated that neither of these differences would likely bias the results. Treatment discontinuation and study discontinuation rates among patients were low in both pivotal trials.

Table 22: Summary of Harms in the VALOR-HCM Trial Through Week 16 (Safety Population)

LVEF = left ventricular ejection fraction.

^aSerious adverse events in 4 patients also involved hospitalization.

Source: Desai et al. (2022).¹⁷

The clinical expert consulted for this review indicated that the primary efficacy outcomes of EXPLORER-HCM, consisting of pVO₂ as measured by CPET and NYHA functional class are appropriate measures of objective functional capacity and subjective symptom severity, respectively, in the indicated population. In both pivotal trials, HRQoL was measured using the KCCQ-23 CSS as a key secondary outcome, and the EQ-5D-5L was used in the EXPLORER-HCM trial as an exploratory outcome. The KCCQ-23 is a generally valid, reliable, and responsive questionnaire for cardiovascular diseases, including oHCM. The clinically meaningful threshold of 10 or more points used in the EXPLORER-HCM trial for the KCCQ-23 CSS was greater than the reported MID range of 4.5 to 6 points for patients with heart failure. A literature search completed by CADTH did not find any evidence dealing with the validity, reliability, responsiveness, and MID of the EQ-5D-5L instrument in patients with oHCM. The clinical expert consulted by CADTH indicated that these tools are not typically used in clinical practice but have been used in multiple studies. Disease-related symptoms were assessed using the newly developed HCMSQ instrument, with the SoB domain assessed as a key secondary outcome in the EXPLORER-HCM trial. Available evidence on the HCMSQ SoB domain suggests it is valid, reliable, and responsive to change. Because data on the KCCQ-23 CSS or HCMSQ SoB for more than 30% of patients were not collected at baseline or at the week-30 visit in the EXPLORER-HCM trial, and those who completed the questionnaires may be fundamentally different than those who did not (i.e., differences in treatment response), there is a risk of bias. However, for all imputation scenarios, ad hoc sensitivity analyses were generally supportive of the findings of the primary analyses.

The VALOR-HCM trial is evaluating the use of mavacamten to reduce the need for SRT in patients who are guideline-eligible and willing to participate in invasive therapies. As such, no direct evidence comparing mavacamten to SRT is available for this review. There is also limited direct evidence comparing mavacamten to disopyramide. Patients taking disopyramide were excluded from the EXPLORER-HCM trial and less than 20% of enrolled patients (n = 22) in the VALOR-HCM trial used disopyramide at baseline as monotherapy or in combination with beta-blockers or calcium channel blockers.

In terms of subgroups of interest, both pivotal trials included subgroup analyses by baseline background therapy (beta-blocker or calcium channel blocker use) and the EXPLORER-HCM trial also examined NYHA class (II versus III) as a prespecified subgroup. For the primary end point in the EXPLORER-HCM trial, results were not statistically significantly different for patients taking beta-blockers. All key secondary end points showed a benefit from mavacamten treatment compared with placebo across the evaluated subgroups, irrespective of beta-blocker use. The subgroup analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

No Clinical Study Report or statistical analysis plan was available for the VALOR-HCM trial at the time of this review, preventing CADTH from fully appraising the potential for bias within the trial.

External Validity

In general, the clinical expert consulted by CADTH for this review confirmed that the populations of both the EXPLORER-HCM and VALOR-HCM trials were similar to patients seen in Canadian clinics, and the study results would be generalizable, with some limitations, to patients with oHCM in Canada. Compared to the population in Canada, the racial diversity in the pivotal trials was limited, as most patients were white. Although no patients were recruited from Canada in either pivotal trial, the clinical expert noted that the lack of representation of patients in Canada does not reduce the generalizability of the results to Canadian clinical practice. The EXPLORER-HCM trial reported that more than 40% of patients screened were excluded from the study for failing to meet 1 or more eligibility criteria, possibly limiting the generalizability of the findings. |||||||| ||||||| |||||||| ||||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||||| ||||||| ||||||||||| ||||| ||||||| ||||||

While mavacamten has been approved by Health Canada for use in adult patients with symptomatic NYHA functional class II to III oHCM, the VALOR-HCM trial included an unknown number of patients with NYHA functional class IV oHCM. The VALOR-HCM trial is an ongoing RCT evaluating the use of mavacamten to reduce the need for SRT in patients who are guideline-eligible for invasive therapies, with descriptive data available through to week 32. It is therefore uncertain if mavacamten can reduce the need for SRT among patients with symptomatic oHCM in the long term.

Indirect Evidence

A focused literature search for indirect treatment comparisons dealing with HCM was run in MEDLINE All (1946–) on October 21, 2022. No limits were applied to the search. No relevant studies were identified.

Other Relevant Evidence

Additional descriptive efficacy and safety data were provided for the VALOR-HCM trial through to week 32. The ongoing open-label extension study, MAVA-LTE, provides long-term safety and efficacy data that supplement the evidence from the EXPLORER-HCM pivotal trial in the systematic review.

VALOR-HCM Trial Through to Week 32

Methods

An additional study report for the VALOR-HCM trial examined data up to week 32 among patients initially randomized to mavacamten (32 weeks of drug exposure) and those initially randomized to placebo who crossed over to mavacamten at week 16 (16 weeks of drug exposure).⁷ The 4 patients in the placebo group who elected to receive SRT treatment or withdrew from the study during the first 16 weeks were not included in this analysis.

Safety outcomes included the incidence of an LVEF of less than 50%, hospitalization for cardiac failure, and atrial fibrillation or ventricular tachyarrhythmia.

Interventions

In the VALOR-HCM trial, after 16 weeks, patients originally randomized to placebo were crossed over to mavacamten 5 mg daily and a dose-blinded titration was performed in the same manner used for patients originally randomized to mavacamten. Patients initially randomized to mavacamten continued with the same dose they were receiving at week 16 and continued study assessments every 4 weeks. If the LVEF fell below 50% at any time during treatment, mavacamten was temporarily discontinued, with a follow-up 4 to 6 weeks later, and, if at that time the LVEF was 50% or greater, the dose was decreased from the last treatment dose by 1 level. If the LVEF decreased to 30% or less, mavacamten was permanently discontinued. All patients and study staff remained blinded to the original treatment assignment, mavacamten dose, and echocardiographic findings until week 32.

Outcomes

The principal end point at week 32 was the composite of a patient decision to proceed with SRT or eligibility for SRT according to the 2011 ACCF/AHA guidelines. Patients who discontinued the study or whose response status could not be assessed after 32 weeks were classified as SRT-eligible (treatment failure). Additional end points included the changes from baseline in postexercise LVOT gradient, NYHA functional class, KCCQ-23 CCS, NT-proBNP, and cardiac troponin I. Additional echocardiographic end points studied included changes from baseline in LV mass index, LV systolic and diastolic volume index, LAVI, and the ratio of the peak early mitral inflow velocity over the early diastolic mitral annular velocity (E/e′).

Statistical Analysis

The analysis included all patients originally randomized to mavacamten and initial placebo patients who crossed over to mavacamten at 16 weeks in the VALOR-HCM trial. Categorical variables were reported as number and percent. The principal outcome was the proportion of patients meeting SRT eligibility or deciding to proceed with SRT, summarized as number and percentage. For placebo patients who crossed over to mavacamten, the week-16 pretreatment value was used as the baseline for NYHA class assessment, laboratory, and echocardiographic measurements. Changes from baseline for continuous variables were summarized using the mean and 95% CIs. Continuous variables were presented as mean (SD) and compared via a t-test while biomarkers were presented as median (interquartile range) and compared using a nonparametric Wilcoxon rank sum test.

Patient Disposition

Of the 112 patients with symptomatic oHCM enrolled in the VALOR-HCM trial, 108 qualified for the 32-week evaluation. All patients originally randomized to mavacamten (n = 56), and those who crossed over from placebo to mavacamten after 16 weeks (n = 52) were included. The 4 patients excluded from the original placebo group included 2 patients who underwent SRT during the first 16 weeks and 2 who discontinued the study early. Of the remaining patients, the mean age was 60.3 years and 50% were male. All patients were symptomatic (94% NYHA functional class III or IV) on maximally tolerated HCM therapy. The mean LVEF and peak resting, Valsalva, and postexercise LVOT gradients were 68% (SD = 3.5), 49 mm Hg (SD = 30), 77 mm Hg (SD = 30), and 83 mm Hg (SD = 35), respectively.

Efficacy

In the original mavacamten group, an additional 15 patients experienced an improvement of 1 NYHA class between weeks 16 to 32 and 48 patients (91%) had an improvement of 1 or more NYHA class at 32 weeks. Furthermore, in the original mavacamten group, 7 patients had an improvement of 2 NYHA classes between weeks 16 to 32, and 16 patients (30.2%) experienced an improvement of 2 or more classes by week 32. In the placebo crossover group, 35 patients (70%) improved by 1 or more NYHA classes and 12 patients (24%) improved by 2 or more NYHA classes at week 32 after 16 weeks of mavacamten exposure. In the original mavacamten group, there was a reduction in resting, Valsalva, and postexercise LVOT gradients between weeks 16 and 32. A similar reduction in LVOT gradient in the crossover group was seen after 16 weeks of mavacamten exposure.⁷

In the original mavacamten group, the mean change from baseline to week 32 in the KCCQ-23 CSS was 13.1 points (95% CI, 9.2 to 17.1), while in the placebo crossover group, the mean change from week 16 to week 32 in KCCQ-23 CSS was 8.0 points (95% CI, 3.2 to 12.8).⁷

In the VALOR-HCM trial, at week 32, a total of 6 patients (10.7%) in the original mavacamten group and 7 patients (13.5%) in the placebo crossover group continued to meet guideline criteria for SRT or elected to undergo the procedure. In the original mavacamten group, at week 32, a total of 3 patients (5.4%) chose to undergo SRT (1 additional patient decided to proceed with SRT between weeks 16 and 32) and 2 patients (3.6%) were guideline-eligible for SRT. (Of the 8 patients who were guideline-eligible at week 16, a single patient remained guideline-eligible at week 32 and another became guideline-eligible between weeks 16 and 32.) In the original mavacamten group, the SRT status of 1 patient who withdrew consent at week 28 was not evaluable at week 32 and was imputed as meeting the criteria for the outcome. A total of 2 patients (3.8%) in the placebo crossover group chose to undergo SRT at week 32, 3 patients (5.8%) were eligible for SRT based on guideline criteria, and 2 patients (3.8%) were imputed as meeting criteria for the outcome as their SRT status was not evaluable (1 patient had an LVEF of less than 30% at week 31 and the other was withdrawn by the study investigator due to noncompliance at week 20).⁷

In the original mavacamten group, improvements from baseline were seen through to week 32 in NT-proBNP, with a median change of −417 ng/L (95% CI, −706 to −186); cardiac troponin I, with a median change of −7.4 ng/L (95% CI, −11.1 to −4.8); LVMI, with a mean change of −13.0 g/m² (95% CI, −18.5 to −7.5); and LAVI, with a mean change of −6.8 mL/m² (95% CI, −9.4 to −4.3). In the placebo crossover group between weeks 16 and 32, there were improvements in NT-proBNP, with a median change of −451 ng/L (95% CI, −581 to −298); cardiac troponin I, with a median change of −6.8 ng/L (95% CI, −8.5 to −4.3); LVMI, with a mean change of −10.8 g/m² (95% CI, −16.1 to −5.5); and LAVI, with a mean change of −5.5 mL/m² (95% CI, −8.3 to −2.7).⁷

Harms

In the VALOR-HCM trial, through to week 32, the rate of SAEs was similar between the original mavacamten group and the placebo crossover group. A total of 4 patients (7.1%) in the original mavacamten group experienced an SAE, the most common of which was atrial fibrillation (3 patients, 5.4%). A total of 4 patients (7.7%) in the placebo crossover group experienced an SAE from week 16 to week 32, consisting of 1 (1.9%) each of congestive heart failure, a fall, nephrolithiasis, and peripheral venous disease. No deaths, myocardial infarctions, or strokes were reported in either group.⁷

Through to week 32, a total of 7 patients (12.5%) in the original mavacamten group and 2 patients (3.8%) in the placebo crossover group met temporary drug discontinuation criteria of an LVEF of less than 50% (median = 45%, range = 38 to 49%). All patients were asymptomatic. A single patient (1.9%) in the placebo crossover group had an LVEF reduction of less than 30% at week 31 associated with paroxysmal atrial fibrillation and heart failure. Following permanent mavacamten discontinuation, the patient’s LVEF recovered and normalized. No patients in the original mavacamten group met the criteria for permanent discontinuation.⁷

Critical Appraisal

Results at week 32 of the VALOR-HCM trial provided additional data on the safety and efficacy of mavacamten. As all placebo patients crossed over to mavacamten treatment at week 16, there was no active comparator, and all outcomes were descriptive in nature, making it difficult to draw causal conclusions from the findings. Once placebo patients crossed over to active treatment at week 16, investigators and patients were aware that all patients were receiving active treatment, and their expectations of treatment may have affected the reporting of subjective outcomes such as HRQoL, NYHA functional class, and adverse effects.

Long-Term Extension Study

The primary objective of this extension study, MAVA-LTE, was to assess the long-term safety and tolerability of mavacamten in patients with oHCM previously enrolled in the EXPLORER-HCM trial (the EXPLORER-LTE cohort). Secondary and exploratory objectives included assessing the long-term effects of mavacamten on symptoms and echocardiographic measures of cardiac function and LVOT obstruction, and the long-term effects of mavacamten on disease biomarkers.

Description of Study

The MAVA-LTE trial is an ongoing, dose-blinded, 5-year extension study to assess the long-term efficacy and safety of mavacamten following patients who completed the EXPLORER-HCM trial through to week 38 (EXPLORER-LTE cohort) and patients who completed the MAVERICK-HCM trial (a phase II study of nonobstructive HCM that is not assessed in this report). Patients included in the EXPLORER-LTE cohort received mavacamten treatment at a starting dosage of 5 mg once daily ||||||||| |||||||||||||||| |||||| ||||||||||||||| |||||||||||| ||||||||||||| ||||||||||||||| |||||||||||| ||||||||||||||||||| |||||||||||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||||||||||| Dose adjustments occurred at weeks 4, 8, and 12, guided by echocardiogram assessments of Valsalva LVOT gradient and LVEF. Site-read stress echocardiography was also conducted at week 24 to evaluate the postexercise LVOT gradient and to determine whether further dose adjustments were needed. |||||||||| |||||||||||||| |||||||| ||||||| ||||||| |||||||| |||| |||||||||||||||| ||| ||||||||||||| |||| |||||||||||||||| ||| |||||||| ||||||||| ||||||||||||| |||||||||||||| ||||||||||||||||| ||||||||||| ||||||||||||| ||||| |||||||||||||| |||||||||| ||||||| ||||||||| |||||||||| |||||||| |||||||| ||||||||||||| |||||| || ||||||||||| |||||||||||||||||| |||| ||||||| ||||||||| ||||||| ||||||||||||| |||||||||||||| ||||||||||||||| ||||||||||||||| ||||||||| ||||| |||||||||| At the time of the data cut-off for this interim analysis, no patient from either study cohort had completed the week-104 visit.

Figure 4: Study Schematic for EXPLORER-LTE Cohort

NT-proBNP = N-terminal pro–B-type natriuretic peptide; PK = pharmacokinetics; QD = once daily; TTE = transthoracic echocardiogram; wks = weeks.

Source: Clinical Study Report for Extension Study MYK-461 to 007.³⁵

Populations

Inclusion and Exclusion Criteria

Patients meeting the following inclusion criteria were included in this study:

• completion of the parent study through to the EOS visit within 90 days of signing consent

• body weight exceeding 45 kg

• LVEF of 50% or greater by an echocardiography core laboratory read of screening transthoracic echocardiograms at rest

• adequate acoustic windows to enable accurate echocardiograms

• |||||||| |||| |||||||||||||||| ||| |||||||||||||||||||

• safety laboratory parameters within normal limits, ||||||||||||||||||| ||||||||| |||||||||||| ||||||||||||||||

• |||| |||||||||||||||| |||||||||| ||||||| ||||||||| |||| |||||||||||||||| ||| ||||||||||||||| ||||||||| ||||||||||||| |||||||||| |||||||||||| |||||||| |||||||||| |||||||||||||||| ||||||||||||||| ||||||||||||| ||||||||||||||| |||| |||||||||||||||| |||| |||||||||| |||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||

• not pregnant or lactating.

Temporary Discontinuation of Treatment

Temporary treatment discontinuation was considered in cases of an AE or SAE or for another reason. Patients were considered to be temporarily discontinued from study drug dosing for any of the following qualifying events:

• a resting LVEF of less than 50%

• a mavacamten plasma trough concentration of 1,000 ng/mL or greater

• a QT interval corrected using Fridericia’s formula of more than 15% above the baseline value.

|||||||||||||||| |||| |||||||||||||||| ||||||||||| |||||||||||||||||||||| ||||||| ||||||||||||||| |||||| ||||||||||| ||||||||||| ||||||||||||||| |||| |||||||||||||||| |||| ||||||||||||||| ||||||||||||||||||| |||||||||||||||||||| |||| |||||||||||||||| |||||||||||||

Baseline Characteristics

Table 23 summarizes the baseline characteristics for EXPLORER-LTE cohort. The characteristics are similar to those of the parent pivotal trials.

Table 23: Summary of Baseline Characteristics in EXPLORER-LTE Trial

HCM = hypertrophic cardiomyopathy; LVEF = left ventricular ejection fraction; LVOT = left ventricular outflow tract; NT-proBNP = N-terminal pro–B-type natriuretic peptide; NYHA = New York Heart Association; SD = standard deviation.

^aIncludes verapamil, verapamil hydrochloride, diltiazem, and diltiazem hydrochloride.

Source: Clinical Study Report for Extension Study MYK-461 to 007.³⁵

Patient Disposition

Figure 5 and Table 24 summarize the patient disposition for the EXPLORER-LTE cohort. ||||||| |||||||||||| ||||| ||||||||| ||||||||||| |||||||||||||||| ||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| ||||||||||||||||| |||||||| ||||||||| |||||||| ||||||||||| |||||||||||||||||||| ||||||||||| ||||| ||||| |||||||||||||||| |||||||||| |||||||||||||||| |||||||||||||||| |||||||||||||| ||||| |||||||||||||| |||||||||| |||||||||||| |||||||||| |||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||||| ||||||||||||| ||||||||| ||||||||||||||||| |||||||| |||||||| ||||||| ||||||| ||||||||||||| ||||||||| |||||||| |||||||| ||||||||||||||| |||||| |||||| ||||||||||||| |||||

Figure 5: Redacted

Figure 5 was redacted due to confidential information.

Table 24: Patient Disposition

|||||||||| |||| |||||||||||||||| ||| |||||||| ||||||||||||| |||||||||| |||||||||| |||| ||||||||||| ||||| |||||||||| |||||||| ||||| |||||||||||| ||||||||| |||||||||||||||| |||||||||| ||||||||||||||||||||| |||||||||||||||| |||||||||||||||||| ||||||||||||||||||||| |||||||| ||||||| ||||| |||||||||||| ||||| ||||||||| ||||| |||||||| |||||||||||||| || |||||||| ||||||||||||| |||| ||||||| |||||||||| |||||||||| ||||||||||

This table has been redacted for confidential information.

Efficacy

Change in NYHA Class

Table 25 summarizes the shifts in NYHA functional classification from baseline for the EXPLORER-LTE cohort. ||||||| ||||||||||| ||||||||||||| ||||||||||||||||| |||||||||||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||||||||| ||||||||| ||||||||||||| |||||||||||||||| ||||||||||||||||||| ||||||||||||| |||||||||||| |||||||||||| ||||||| |||||||||||||| |||||||||||| |||||||| |||||| ||||||||| ||||||||| |||||||||||||||||| ||||||| |||||||||||| |||||||||| |||| ||||||||||||| ||||||||||| ||||||||| |||| |||||||||||||||||| |||||||||| ||||||||| |||||||||| || |||||| |||| ||||||||| ||||| ||||| |||||| |||||||||| |||| ||||| ||||| ||||||||||||| |||||||||||||| ||||||||||||||| ||||||||||||||| ||||| |||||| ||||| |||| |||||||||||||||| ||| |||||||||||| ||||||||| |||||||||| |||||| |||||||| |||||| |||||| ||||||||||| ||||||||||| ||| |||||||| ||||||||| |||||||| |||||||||||||||||| ||||||||||||| ||||||||| |||||||||||| |||||||||||| |||||| |||||||||||||||| |||||||| ||||||||||||| |||||||||||||| ||||||||||||||

Table 25: Shift in NYHA Function Classification by Study Visit for the EXPLORER-LTE Cohort (ITT Population)

ITT = intention-to-treat; NYHA = New York Heart Association.

|||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||| |||||||||||| ||||||||| ||||||||| |||||||||| ||||||||| ||||||||||| ||||||||||||||| ||||||||||| ||||||||| ||||||||| |||||||| ||||||| ||||||||||| ||||||| |||||||||||| ||||||||| |||||||||||| |||||||| |||| |||||||||||||||||| ||||||||||||||| |||||||||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| ||||||||||

Source: Clinical Study Report for Extension Study MYK-461 to 007.³⁵

Resting LVOT Gradients and Valsalva LVOT Peak Gradients and Postexercise LVOT Peak Gradients

Table 26 summarizes the baseline values for site and central reads of resting and Valsalva LVOT gradients by study visit and change from baseline values. Reductions from baseline were observed in both resting and Valsalva LVOT gradients with mavacamten treatment as assessed by both site and central readings in the extension study, indicating beneficial effects of mavacamten on LVOT gradients. The number of patients was relatively small during the end time points, making it difficult to draw any conclusion about the effects of mavacamten on LVOT gradients.

Table 27 summarizes the postexercise gradients for patients who underwent postexercise assessments at week 24 for the EXPLORER-LTE cohort. |||||||||||| |||||||||||||| |||||||||||| |||||||||| ||| |||||| ||||||||| ||||||||| |||||||||||| |||| |||||||||| |||| || |||||||||||| ||||||||||||||||| |||||||| |||||||||||||| ||||||||||| |||||| |||||||||| |||| ||||| |||||||||| |||||||||| |||||||| |||||| |||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||

Table 26: Baseline and Change From Baseline in LVOT Gradient (at Rest and During Valsalva) by Study Visit for the EXPLORER-LTE Cohort (ITT Population)

||||||||||| |||||||| ||||||| |||||||||||||| |||||||| ||||| ||||||| |||| |||||| ||| ||||||||| ||||||||||| ||||||||||||| ||||||||| ||||||| ||||||||||||||| ||||||||||||||| |||||||||||||| ||||||||| |||||||| |||||||||||||||||| |||||| |||||||| ||||||||||| ||||||||||| ||||||||||||||||| |||||||||||||||||| |||||||||||||||||| |||||||||

Source: Clinical Study Report for Extension Study MYK-461 to 007.³⁵

Table 27: Redacted

||||||||||||||||||| |||||||||||| ||||||

This table has been redacted for confidential information.

Change in Cardiac Structure

|||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||||||||||| ||| |||||||| |||||||||||||| |||||||| ||||| |||||||||| |||| |||||||||||||||| |||| |||||||||| |||||||||| ||||| |||||| ||||||||| |||||||||| ||||||||||||||| |||||||||||| |||||||||| ||||||||||| ||||||| ||||| ||||||||||| |||||||||| |||| ||||||| |||||||||||||||||| |||||| |||||||||||||||| |||||||||| ||||||||||||||| |||||| |||||||| ||||||||||||| ||||||||||| |||| ||| ||||||||| ||||||||||||||||||

Table 28: Redacted

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This table has been redacted for confidential information.

Table 29: Redacted

|||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||| |||| |||||||||||||||| ||| ||||||||| ||||||||| |||||||||||||||||| ||||||||||||||||| |||||| ||||||||||||||| |||||||||| |||| ||||||||||| |||||||||||||||| |||||||||||||||||| ||||||| ||||||||| ||||||||||| |||||||||||| || ||||| |||||||||| |||||||||||| |||||||||||||||||||| ||||||||| ||||||||| |||| ||||||| | ||||| |||||||||||| |||||||||||| |||||||||||| ||||||||| ||||||||||||||||||| |||||||||||||||| ||||||||||| |||||||| ||||| |||||||

This table has been redacted for confidential information.

Biomarker-Based Assessment

Table 30 and Figure 6 summarize NT-proBNP change from baseline for the intention-to-treat population of the EXPLORER-LTE cohort. The beneficial effects of mavacamten could be observed through a decreasing trend of NT-proBNP concentrations. While the change was rapid during the initial phases of the trial, |||||||||||||| |||| |||||| ||||||||| |||||| ||||| ||||||| |||||||||| ||||||||||||| |||||||||||| |||||||||||||||| The trend can be seen in Figure 6. However, the number of patients at these later time points was relatively small at the time of the data cut-off.

Table 30: Redacted

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This table has been redacted for confidential information.

Figure 6: Redacted

Figure 6 was redacted due to confidential information.

Harms

Adverse Events

Table 31 summarizes the harms outcomes for the EXPLORER-LTE cohort. In all, 62.9% of patients experienced at least 1 AE. |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||| The most common AEs were |||||||| |||| |||||||||||||||| ||| ||||||||||| ||||||| ||||||||||||| |||||||| |||||| ||||||| |||||||| |||||||||||||| |||||| |||||| One death, due to bacterial endocarditis, occurred in the EXPLORER-LTE cohort, but the investigator considered it unrelated to mavacamten.

Serious Adverse Events

In EXPLORER-LTE cohort, the most common SAEs among patients were ||||||| |||||||| |||||||||| |||||||||||| |||||||||||| ||||||||||||||||

Withdrawals due to Adverse Events

In the EXPLORER-LTE cohort, 2 patients (0.9%) discontinued treatment due to AEs, with 1 patient discontinuing due to worsening of systemic lupus erythematosus and 1 patient due to cardiac failure.

Notable Harms

In the EXPLORER-LTE cohort, |||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||

Temporary Treatment Discontinuation

A total of 11 (4.9%) patients demonstrated a total of ||||||||| ||||||||| that met the criteria for temporary treatment discontinuation:

• |||||||||| |||||| |||||||||||||| |||||||||||||| ||||||||||||| ||||| |||||||| |||||||||||||| |||||||||| ||||||||||

• ||||||||||||| |||||||||||| |||||||| ||||||||||| |||| |||||||||| |||||||||||| |||||||||||||||| ||||||||||||| |||||

• |||||||| |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||

• |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||||||||

• |||||||| |||| |||||||||||||||| ||| |||||||||||||| |||| |||||||||||||||| ||| |||| |||||||||||||||| ||||||||||||

Table 31: Summary of Harms in EXPLORER-LTE Cohort (Safety Population)

LVEF = left ventricular ejection fraction.

^aFrequency equal to or greater than 1 patient.

Source: Clinical Study Report for Extension Study MYK-461 to 00735.

Critical Appraisal

Internal Validity

The ongoing EXPLORER-LTE cohort was designed as a dose-blinded study and was run in parallel to the parent study evaluating the long-term safety and tolerability of mavacamten in patients with oHCM. While study-site investigators remained blinded to study drug dose, they were unblinded to the site-read echocardiography results. There was potential selection bias, as patients who respond to mavacamten and are able to tolerate treatment are more likely to continue therapy than patients with less-favourable outcomes. In addition to potential selection bias, the interpretation of the longer-term results in the LTE study is limited by the lack of a control group and the fact that investigators and patients were aware that patients were receiving active treatment. Their expectations of treatment therefore may have affected reporting of subjective outcomes, such as NYHA functional class.

The baseline and demographic characteristics were similar to the characteristics seen in the pivotal trials. Treatment discontinuation and study discontinuation rates among patients were low in the extension study, as observed in both pivotal trials. While the primary efficacy outcome of pVO₂ from the pivotal trial was not assessed in the extension study, ||||||||| ||||||||||| ||||||||||| |||||||||||| |||||||||||||| ||||||||||||| ||||||||| |||||||||||||||||||| ||||||| ||||||||||||||||||| |||||| The absence of these parameters in the interim analysis makes it difficult to interpret the efficacy and safety results of mavacamten for the LTE.

|||| ||||||||| ||||||||| ||||||||| |||||||| |||| |||||||||||||||| ||| |||||||| ||||||||||||| |||||||||| ||||||||| the number of patients at later time points in all efficacy analyses were relatively few at the time of the data cut-off, and the results should be interpreted with caution.

External Validity

The generalizability of the efficacy and harms outcomes and the lack of racial diversity mentioned in the main report are applicable to the extension study.

Discussion

Summary of Available Evidence

Two sponsor-conducted phase III, randomized, double-blind, placebo-controlled trials, EXPLORER-HCM and VALOR-HCM, both of which met the CADTH review protocol criteria, were included in this systematic review. The EXPLORER-HCM trial (68 sites in 13 countries, N = 251) evaluated the efficacy and safety of once-daily oral administration of mavacamten (with a starting dose of 5 mg) in adult patients with symptomatic oHCM and an LVOT gradient of 50 mm Hg or greater, a documented LVEF of 55% or greater, a maximum septal wall thickness determined by a core laboratory of 15 mm or greater (or 13 mm or greater with a family history of HCM), and NYHA functional class II or III symptoms. The primary outcome was the composite functional response at week 30, defined as achieving an improvement (increase) of 1.5 mL/kg/min or greater in pVO₂ and a reduction of at least 1 NYHA functional class (or a 3.0 mL/kg/min or greater increase in pVO₂ without worsening of NYHA class). Harms and notable harms (identified in the CADTH systematic review protocol) were assessed.

The VALOR-HCM trial (19 sites in the US, N = 112) is an ongoing, 32-week trial evaluating the efficacy and safety of once-daily orally administered treatment with mavacamten (with a starting dose of 5 mg) in adult patients with symptomatic oHCM and an LVOT gradient of 50 mm Hg or greater, a documented LVEF of 60% or greater, and a maximum septal wall thickness determined by a core laboratory of 15 mm or greater (or 13 mm or greater with a family history of HCM) and a NYHA functional class III or IV (or class II with exertional syncope or near syncope). Patients must have been referred within the past 12 months for SRT and been actively considering scheduling the procedure. The primary outcome was a composite of the decision to proceed with SRT before or at week 16 or be considered guideline-eligible for SRT at week 16. Guideline-eligibility criteria were based on the 2011 ACCF/AHA clinical and hemodynamic criteria for HCM. Patients with a maximum LVOT gradient of 50 mm Hg or greater (from rest, Valsalva, or postexercise) and no improvement in NYHA functional class at week 16 were considered eligible for SRT. Harms and notable harms (identified in the CADTH systematic review protocol) were assessed. Additional descriptive efficacy and safety data were provided for the VALOR-HCM trial through to week 32.

The MAVA-LTE trial is an ongoing, dose-blinded, 5-year LTE study of the long-term efficacy and safety of mavacamten following EXPLORER-HCM and MAVERICK-HCM (a phase II trial of patients with nonobstructive HCM). The trial included 224 patients who completed treatment in the phase III EXPLORER-HCM trial (the EXPLORER-LTE cohort). All patients in EXPLORER-LTE cohort started mavacamten treatment at 5 mg once daily, with dose adjustments at weeks 4, 8, and 12 based on site-read echocardiography measures of LVOT Valsalva gradient and LVEF.

Interpretation of Results

Efficacy

The clinical expert consulted for this review indicated that pVO₂ and NYHA functional class are appropriate measures of functional capacity and symptom severity, respectively, for the indicated population. The EXPLORER-HCM trial reported a statistically significant difference in the proportion of patients meeting the primary composite efficacy outcome in favour of mavacamten. Subgroup analyses examining beta-blocker use at baseline (yes versus no) in the EXPLORER-HCM trial found that, for the primary composite outcome and for the key secondary outcome of change in pVO₂ from baseline to week 30, there was no statistically significant difference between treatment groups among patients receiving beta-blockers. However, all key secondary end points in the EXPLORER-HCM trial showed a benefit from mavacamten treatment compared with placebo across the evaluated subgroups, irrespective of beta-blocker use. The subgroup analyses may not have been powered to detect a treatment difference and no adjustments were made for multiplicity. As such, all subgroup analyses are exploratory in nature.

Both pivotal trials found statistically significant results in key secondary outcomes of an improvement of at least 1 NYHA functional class and change from baseline to end of treatment in postexercise LVOT peak gradient in favour of mavacamten, and the clinical expert consulted for this review found these results to be clinically meaningful. An additional 48 weeks of data were available from the ongoing, uncontrolled, open-label extension study (MAVA-LTE), which suggested that improvements from baseline in oHCM symptoms assessed by NYHA class for the EXPLORER-LTE cohort were consistent with those observed in the EXPLORER-HCM pivotal trial. In addition to potential selection bias, interpretation of the longer-term results in the LTE study is limited by the lack of a control group and the fact that investigators and patients were aware that patients were receiving active treatment. Their expectations of treatment therefore may have affected reporting of subjective outcomes such as NYHA functional class.

Input from patient groups and the clinical expert emphasized that improvements in HRQoL and reductions in symptoms (i.e., shortness of breath) are important treatment goals for patients. Both pivotal trials assessed HRQoL using the KCCQ-23, which has been reported to be a generally valid, reliable, and responsive tool. In both pivotal trials, there was a significant difference between treatment groups in change in KCCQ-23 CSS from baseline to end of treatment in favour of mavacamten. In the EXPLORER-HCM trial, 20.1% more patients in the mavacamten group achieved a 10-point change in the KCCQ-23 CSS score from baseline to week 30, a threshold that is higher than the estimated MID for the KCCQ-23 CSS for patients with heart failure (between 4.5 and 6 points) (Appendix 4). Results of the EXPLORER-HCM trial found improvements in the KCCQ-23 OSS and TSS, from baseline to week 30, in favour of mavacamten; however, these results should be interpreted as supportive evidence for mavacamten, as no adjustment was made for multiplicity. In terms of disease symptoms, the EXPLORER-HCM trial found a statistically significant decrease (i.e., improvement) in the HCMSQ SoB domain scores among patients in the mavacamten group compared to those in the placebo group. In the EXPLORER-HCM trial, KCCQ-23 CSS or HCMSQ SoB data for more than 30% of patients were not collected at baseline or at the week-30 visit. There is therefore a risk of bias as those who completed the questionnaires may be fundamentally different than those who did not (i.e., differences in treatment response are possible). However, for all imputation scenarios, ad hoc sensitivity analyses were generally supportive of the findings of the primary analyses.

In the VALOR-HCM trial, the primary end point was achieved, as demonstrated by a statistically significantly reduced eligibility for invasive SRT procedures at 16 weeks in the mavacamten group compared with the placebo group. The results were primarily driven by SRT eligibility based on guideline criteria, with 14.3% and 69.6% of patients eligible for SRT at week 16 in the mavacamten and placebo groups, respectively. Additional descriptive data for the VALOR-HCM trial through to week 32 found that mavacamten treatment sustained a reduction in the proportion of patients proceeding to SRT or remaining guideline-eligible, with similar effects observed in patients who crossed over from placebo after 16 weeks of treatment with mavacamten. However, these additional results at week 32 were descriptive in nature and should be interpreted as supportive evidence of mavacamten.

In the VALOR-HCM trial, mavacamten demonstrated statistically significant improvements at week 16 in NT-proBNP and cardiac troponin I levels, which are biomarkers of long-term outcomes in HCM for cardiac wall stress and cardiac injury, respectively. The clinical expert found these results to be clinically meaningful and stated that it is reasonable to assess these biomarkers in the clinical setting. The reduction in NT-proBNP and cardiac troponin I may be a consequence of reduced LVOT obstruction. In the EXPLORER-HCM trial, patients in the mavacamten group experienced greater reductions in NT-proBNP and cardiac troponin I levels at week 30. Among patients in the EXPLORER-LTE cohort, NT-proBNP concentrations decreased at LTE week 4 and decreases were sustained through to LTE week 72.

Changes from baseline in cardiac structure as measured by echocardiography in both pivotal trials and as measured in the CMR substudy in the EXPLORER-HCM trial were generally directionally favourable for patients treated with mavacamten. The clinical expert consulted for this review noted that uncertainty remains regarding the impact mavacamten will have on cardiac structure in the long-term. In the LTE study, among those in the EXPLORER-LTE cohort, there was little change from baseline to week 48 in echocardiographic measures of interventricular septal or posterior wall thicknesses or the LVMI, but a reduction in LAVI was observed. These results were exploratory, with outcomes not controlled for multiplicity, and should be interpreted with caution because of the potential for inflated type I error rate that accompanies the small sample sizes in the CMR substudy.

The VALOR-HCM trial is an ongoing RCT evaluating the use of mavacamten to reduce the need for SRT in patients who are guideline-eligible for invasive therapies, with descriptive data available through to week 32. It is therefore uncertain if mavacamten can reduce the need for SRT among symptomatic patients with oHCM in the long-term. Furthermore, no direct evidence comparing mavacamten with SRT was available for this review. There is also limited direct evidence comparing mavacamten to disopyramide. Patients taking disopyramide were excluded from the EXPLORER-HCM trial and less than 20% of enrolled patients (n = 22) in the VALOR-HCM trial used disopyramide at baseline as monotherapy or in combination with beta-blockers or calcium channel blockers. ||| ||||||| |||||||||||| ||||||||||||||| |||||||||||||||| |||||||| |||||||||| |||||||||||| ||||||||| |||||||||| |||||||||||||||| ||||||||| ||||||||||||| ||||||||||| |||||||||||| |||||||||||| ||||||||||| |||||||| The comparative effectiveness of disopyramide versus mavacamten in this patient population is therefore unknown.

With regards to external validity, the product monograph states that the drug is indicated for adult patients with symptomatic NYHA functional class II to III oHCM. However, the VALOR-HCM trial included an unknown number of patients with NYHA functional class IV oHCM.

Harms

In both pivotal trials, overall rates of AEs and SAEs, including atrial fibrillation and ventricular tachycardia, were comparable for patients in both the mavacamten and placebo groups. In the EXPLORER-HCM trial, 1 patient in the placebo group died due to sudden death and no deaths were reported through to week 32 in the VALOR-HCM trial. In both trials, a higher proportion of patients in the mavacamten group than in the placebo group met the temporary discontinuation criteria of an LVEF of less than 50%. The product monograph for mavacamten includes a serious warning stating that mavacamten reduces the LVEF and can cause heart failure due to systolic dysfunction. Patient input submitted for this review suggested that this limits the prescription of mavacamten to patients who have access to a high-volume clinic and are committed to regular monitoring and reporting of symptoms. No new safety signals were identified based on interim data in the MAVA-LTE trial for the EXPLORER-LTE cohort, with 1 death occurring due to bacterial endocarditis, which the investigator considered to be unrelated to mavacamten.

Conclusions

In the EXPLORER-HCM trial, among patients with symptomatic NYHA class II or III oHCM, mavacamten was statistically significantly more efficacious than placebo in improving NYHA class and exercise capacity (pVO₂), as measured by the primary composite outcome. In the VALOR-HCM trial, among patients with symptomatic NYHA class III or IV oHCM (or class II oHCM with exertional syncope or near syncope), significantly fewer patients were eligible for SRT at week 16 in the mavacamten group than in the placebo group. The results of both pivotal trials were statistically significantly in favour of mavacamten for key secondary outcomes of an improvement of at least 1 NYHA class, postexercise LVOT peak gradient, and HRQoL as assessed by the KCCQ-23 CSS, all of which were found to be clinically meaningful by the clinical expert consulted by CADTH for this review. The EXPLORER-HCM trial assessed disease-related symptoms, and a statistically significantly greater improvement in the HCMSQ SoB domain score was observed in the mavacamten group compared with the placebo group. The VALOR-HCM trial found statistically significantly greater reductions in assessed biomarkers among patients in the mavacamten group compared with those in the placebo group. While descriptive results for the VALOR-HCM trial are available through to week 32, it is uncertain if mavacamten can reduce the need for SRT among patients with symptomatic oHCM in the long-term. Furthermore, no direct evidence comparing mavacamten with SRT was available for this review. Only the VALOR-HCM trial enrolled patients who were receiving disopyramide; however, as no subgroup analyses based on disopyramide use at baseline were available, the comparative effectiveness of disopyramide versus mavacamten in patients with symptomatic oHCM is unknown. Because the EXPLORER-HCM trial evaluated mavacamten as an add-on to first-line treatment with beta-blockers or calcium channel blockers, the clinical efficacy of mavacamten as a first-line therapy or third-line therapy after disopyramide is unknown. The effectiveness of mavacamten in combination with disopyramide and beta-blockers or calcium channel blockers is also unknown. In both pivotal trials, overall rates of AEs and SAEs were comparable for patients in both the mavacamten and placebo groups. In the EXPLORER-HCM trial, 1 patient in the placebo group experienced sudden death, and no deaths were reported through to week 32 in the VALOR-HCM trial. The safety results showed that mavacamten was well tolerated and generally comparable to placebo, with no new safety signals identified in the MAVA-LTE study among patients in the EXPLORER-LTE cohort.

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