Long-term follow-up data from two phase III studies of Camzyos demonstrate consistent and durable response in patients with symptomatic obstructive hypertrophic cardiomyopathy .- BMS

Results from the 56-week analysis of the VALOR-HCM long-term extension (LTE) study were presented as a late-breaking oral presentation, with simultaneous publication in JAMA Cardiology, and results from the cumulative 120-week analysis of the EXPLORER cohort of the MAVA-LTE study were presented as an oral presentation at the European Society of Cardiology (ESC) Congress 2023.

Key findings from the 56-week analysis of VALOR-HCM LTE include: Treatment with Camzyos demonstrated sustained improvements across key study endpoints in both the original Camzyos group over 56 weeks and those transitioned to the placebo cross-over group over 40 weeks. i. At Week 56, 5 of 56 patients (8.9%) in the original Camzyos group and 10 of 52 patients (19.2%) in the placebo cross-over group at Week 40 decided to proceed with septal reduction therapy (SRT) or were SRT-eligible. ii. Camzyos demonstrated sustained reduction in peak resting LVOT gradient (-34.0 mmHg for the original Camzyos group [95% CI -43.5 to -24.5] and -33.2 mmHg for the placebo cross-over group [95% CI -41.9 to -24.5]). iii. Proportion with NYHA class improvement of at least 1 class was observed in 93% of patients in the original Camzyos group at Week 56 and 73% of patients from the placebo cross-over group at Week 40. iv. On the patient-reported 23-item Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-23 CSS), average scores of symptom frequency, symptom burden and physical limitation continued to improve with a 14.1 point increase for the original Camzyos group (95% CI 9.9 to 18.3) and 11.7 point increase for the placebo crossover group (95% CI 6.9 to 16.4).v. Camzyos was also associated with sustained reduction across biomarkers of cardiac wall stress and myocardial injury including reduction in N-terminal pro brain natriuretic peptide (NT-proBNP), with -376 ng/L for the original Camzyos group (95% CI -723 to -225) and -423 ng/L for the placebo cross-over group (95% CI -624 to -252) and reduction in cardiac troponin I with -7.0 ng/L for the original Camzyos group (95% CI -10 to -2.3) and -6.2 ng/L for the placebo cross-over group (95% CI -11.5 to -3.3). vi. No new safety signals were observed, and safety and efficacy were consistent across both patient groups.

"The 56-week late-breaking analysis of VALOR-HCM LTE builds upon previous findings and demonstrates the consistent impact of this oral treatment for severely symptomatic obstructive HCM patients by showing that nearly 9 out of 10 patients treated with this drug have continued in this long-term extension trial without SRT at either 40 or 56 weeks of treatment,” said Milind Desai, M.D., MBA, director, center for hypertrophic cardiomyopathy and vice chair of education in the Heart, Vascular & Thoracic Institute at Cleveland Clinic. “These findings are important for our continued understanding of this treatment and encouraging for patients hoping for non-surgical options.”

Key findings from the cumulative 120-week analysis of EXPLORER-LTE : include: i. No new safety signals were observed. ii. Overall, 75.9% of patients improved by at least 1 NYHA class from baseline at the start of the LTE study to Week 120. Of the 14 patients who were in NYHA class I, 12 remained in NYHA class I at the latest available assessment. iii. Treatment with Camzyos was associated with sustained improvements from baseline at the start of the LTE study in echocardiographic parameters, including E/e average and NT-proBNP. iv. Mean LVEF remained within the normal range at all study visits. Since the previous interim analysis in August 2021, one new patient experienced a transient reduction in LVEF <50% resulting in temporary treatment interruption.></50%>

"The presentation of data - the largest and longest analysis of patients on CAMZYOS to-date - illustrates the promise of this game-changing treatment for patients with symptomatic obstructive HCM,” said Pablo García-Pavia, M.D., Ph.D., head of the Inherited Cardiac Diseases and Heart Failure Unit at the Department of Cardiology of Hospital Universitario Puerta de Hierro and professor at the Spanish Cardiovascular Research Institute (CNIC) in Madrid, Spain. “Studies like EXPLORER-LTE are important for understanding longer-term results that assess key cardiac measures and support the use of Camzyos in patients living with this chronic condition..

About the VALOR-HCM and LTE Trial : VALOR-HCM (NCT04349072) was a randomized, double-blind, placebo-controlled, multicenter Phase III study of patients with symptomatic, obstructive HCM (NYHA class II-IV) who met guideline criteria for septal reduction therapy (SRT; LVOT gradient of greater than 50 mmHg and NYHA class III-IV, or class II with exertional syncope or near syncope) and had been referred or under active consideration (within the past 12 months) for an invasive procedure. Patients were required to have LVOT peak gradient greater than 50 mmHg at rest or with provocation, and LVEF greater than 60%. The study enrolled 112 patients (mean age of 60 years; 51% men; 93% greater than NYHA class III) randomized on a 1:1 basis to receive mavacamten or placebo. At baseline, 95% of patients were on background therapies of a beta blocker, calcium channel blocker, disopyramide or a combination. The primary endpoint was a composite of the proportion of patients who decided to proceed with SRT prior to or at Week 16 or who remained SRT-guideline eligible (LVOT gradient of greater than 50 mmHg and NYHA class III-IV, or class II with exertion induced syncope or near syncope) at Week 16. Key secondary endpoints included the change from baseline on post-exercise LVOT gradient, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score and cardiac biomarkers (NT-proBNP and Cardiac Troponin I) at Week 16.

The group initially randomized to Camzyos continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded Camzyos from Week 16 to Week 32. From the 112 randomized patients with obstructive HCM, 108 (mean age, 60.3 years; 50% men; 94% in NYHA class III/IV) qualified for Week 32 evaluation (56 in the original Camzyos group and 52 in the placebo cross-over group) and continued once-daily Camzyos until Week 128. During this LTE period, Camzyos dose remained blinded.

About the EXPLORER-HCM and the MAVA-LTE Trials : The EXPLORER-HCM Phase III trial (NCT03470545) was a double-blind, randomized, placebo-controlled, parallel group trial that enrolled a total of 251 adult patients with symptomatic (NYHA class II or III) obstructive hypertrophic cardiomyopathy. All participants had measurable left ventricular ejection fraction (LVEF) greater than 55% and at least one peak LVOT gradient greater than 50 mmHg (at rest or with provocation at diagnosis); in addition, Valsalva LVOT gradient greater than 30 mmHg at baseline was required at screening. Ninety-two percent of patients were on background therapies of a beta blocker or calcium channel blocker. The primary endpoint was a composite functional endpoint, assessed at 30 weeks, and was defined as the proportion of patients who achieved either improvement of mixed venous oxygen tension (pVO2) by greater than 1.5 mL/kg/min plus improvement in NYHA class by at least 1 or improvement of pVO2 by greater than 3.0 mL/kg/min plus no worsening in NYHA class. Key secondary endpoints include impact on exercise gradient LVOT, pVO2, NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) and Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ) at Week 30.

EXPLORER-LTE is a cohort of the MAVA-LTE study (NCT03723655), an ongoing, dose-blinded, 5-year study of Camzyos in patients with symptomatic obstructive HCM who completed the EXPLORER-HCM trial. All participants in the EXPLORER-LTE cohort started on 5 mg of Camzyos daily and dose adjustments were made at Weeks 4, 8 and 12 based on site-read echocardiography measures of Valsalva LVOT gradient and LVEF only. Dose adjustment was also possible at Week 24 following site-read echocardiography assessment of post-exercise LVOT gradient. Subsequent to Week 24, dose adjustment was possible if site-read Valsalva LVOT gradient was greater 30 mmHg and LVEF greater than 50%.

See- "Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction": Week 56 Results From the VALOR-HCM Randomized Clinical Trial"; Milind Y. Desai, MD, MBA; Anjali Owens, MD; Kathy Wolski, MPH; et al..JAMA Cardiol. Published online August 28, 2023. doi:10.1001/jamacardio.2023.3342.