The Phase 3 VALOR-HCM trial results were presented this morning at the American College of Cardiology annual meeting in Washington, DC by the principal investigator, Dr. Milind Desai of the Cleveland Clinic, and the results are good!
What was the VALOR-HCM study?
15 – 20 million people worldwide are estimated to have HCM, with 2/3 of this group having the obstructive form which can cause severe symptoms. Historically, these patients have been treated with medications approved for other conditions, and if those don’t relieve symptoms, they are referred on for septal reduction therapies (SRT) like alcohol septal ablation (a catheter based procedure) or septal myectomy (open heart surgery), which are invasive therapies requiring specialized care and which are not widely available.
The VALOR study was designed to compare mavacamten head to head with SRT to see if mavacamten could be a non-invasive treatment alternative for obstructive HCM.
Who were the trial participants?
The inclusion criteria for this trial were HCM patients over the age of 18 with severe symptoms and meeting criteria for New York Heart Association (NYHA) Classes III or IV heart failure, or NYHA Class II with exertional syncope or near syncope. All 112 patients who participated in the study had reached their limit of medication and had been referred for SRT in the last 12 months. All had left ventricular outflow gradients greater than or equal to 50 mmHg, and were allowed to remain on their regular medical regimens, including beta blockers, calcium channel blockers and disopyramide. Participants included an equal number of male and female patients.
What is mavacamten?
Mavacamten is an investigational drug for the treatment of HCM. It is a first generation myosin inhibitor which works by targeting the underlying cause of HCM. Mavacamten reduces the number of active intersections between actin and myosin, which are proteins in the heart muscle. Fewer intersections allow for a reduction in left ventricular outflow tract gradient and improvement in symptoms. For more about how mavacamten works click here for a description of the earlier EXPLORER-HCM trial.
What was the VALOR-HCM trial?
The VALOR trial was a double-blind trial conducted at 19 high volume HCM Centers which looked at whether patients who met eligibility criteria for septal reduction therapies (SRT) would improve enough from taking mavacamten so that they no longer met the criteria for the more invasive SRT therapies or no longer wanted to go forward with SRT.
Patients were followed once a month for 16 weeks. They were started on 5 mg. of mavacamten and then their doses were adjusted up or down at 8 and 12 weeks, depending on their ejection fraction and left ventricular outflow tract gradient as seen on serial echocardiograms.
What were the endpoints and how were the results evaluated?
The primary endpoint was whether a patient in the trial would choose to forego SRT or whether they would no longer meet the 2011 ACC/AHA guideline criteria for SRT after 16 weeks in the trial.
Secondary endpoints included:
- Change in post-exercise left ventricular outflow tract (LVOT) gradient
- Number of patients with a > 1 NYHA heart class improvement
- Change in KCCQ (Kansas City Cardiomyopathy Questionnaire) summary score (this is a subjective patient questionnaire looking at symptoms of heart failure)
- Change in biomarkers (blood indicators looks at heart wall stress) including NT-proBNP and Troponin levels
I can’t wait anymore! Tell me the results!
The trial met the primary endpoint: 82% of the patients no longer needed SRT, while 18% or 4 patients decided to continue on to surgery and/or met the guidelines for SRT eligibility. And, 95% of patients in the study have chosen to continue on with medical therapy as part of a longer term study.
The trial also met secondary endpoints:
63% of patients in the mavacamten group showed an improvement of one NYHA class, while 27% of the mavacamten patients improved two NYHA classes!
Left ventricular outflow tract (LVOT) gradient significantly improved in the mavacamten group and was stable in the placebo group.
Left ventricular ejection fraction (LVEF) was stable in both groups
KSSQ (Kansas City Cardiomyopathy Questionnaire) score significantly improved in the mavacamten group
The mavacamten group also showed significant improvements in both troponin and NT-proBNP .
How safe is mavacamten? Were there any bad side effects?
The drug was very well tolerated on the whole. 2 patients had a transient drop of their ejection fraction to below 50%, but this improved after temporarily discontinuation of mavacamten which was later resumed at a lower dose.
No one had to permanently discontinue the drug and there were no incidents of CHF, syncope or sudden cardiac death in those taking mavacamten.
Are there limitations to this study?
Long term study and follow-up on the drug is still needed to assess whether the drug will allow patients to continue to avoid SRT in long term, and whether the drug proves to be safe over a longer period of time. Also, the study was performed on predominantly white patients at high volume HCM centers, so impact in more diverse populations and in community settings is not known.
If I am a candidate for this drug once it is on the market, what should I expect?
During the question and answer session after the presentation, Dr. Desai was asked what kind of patient follow up is necessary once the drug has been approved by the FDA and is generally available to patients.
Dr. Desai suggested that he believes that clinical evaluations and frequent echocardiogram monitoring will be necessary until there is more familiarity with the drug and its effects.
Where can I find more information about mavacamten?
Where can I find more information about the VALOR trial results?
See Dr. Desai speak here: