What the Camzyos approval means for adolescents with obstructive HCM

The FDA approval of mavacamten (Camzyos; Bristol Myers Squibb) for adolescents aged 12 years to younger than 18 years with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) introduces the first cardiac myosin inhibitor for this patient population. The approval provides pediatric cardiologists with a disease-targeted treatment designed to address the underlying cardiac hypercontractility that contributes to left ventricular outflow tract (LVOT) obstruction in oHCM.

The decision was supported by results from the phase 3 SCOUT-HCM trial, which enrolled 44 adolescents with symptomatic oHCM. At 28 weeks, patients treated with mavacamten had a least-squares mean reduction of 48.5 mm Hg in Valsalva-provoked LVOT gradient from baseline, compared with a 0.5-mm Hg reduction with placebo. The safety profile in adolescents was generally consistent with previous experience in adults, and no patient experienced a reduction in left ventricular ejection fraction below 50%.

In this Q&A with Contemporary Pediatrics, Joseph Rossano, MD, chief of the Division of Cardiology at Children’s Hospital of Philadelphia, discusses what the approval means for adolescents with symptomatic oHCM and the clinicians who care for them. Rossano addresses how mavacamten may fit into the existing treatment pathway, which patients may be appropriate candidates, considerations for monitoring and safety, and the questions that remain as clinicians gain experience using a cardiac myosin inhibitor in younger patients.

Contemporary Pediatrics: What does the FDA approval of mavacamten for adolescents aged 12 to younger than 18 years with symptomatic obstructive hypertrophic cardiomyopathy mean for the treatment landscape, particularly given the limited disease-specific options previously available for these patients?

Joseph Rossano, MD: This approval represents an important change in the treatment landscape because it gives pediatric cardiologists, for the first time, a therapy that directly targets the underlying hypercontractility responsible for obstruction in hypertrophic cardiomyopathy. Historically, treatment in this age group has relied largely on medications such as beta-blockers or calcium-channel blockers, with much of that practice extrapolated from adult experience. Although those medications can help control symptoms, they do not specifically address the molecular mechanism of the disease. Adolescents who remained symptomatic despite medical therapy could ultimately require an invasive septal-reduction procedure. Mavacamten adds a disease-targeted, evidence-based option for these symptomatic patients. It will not be appropriate for every adolescent with HCM—it was studied in patients with symptomatic obstructive disease—but for eligible patients it gives clinicians and families a meaningful new choice.

Contemporary Pediatrics: In SCOUT-HCM, mavacamten produced a significant reduction in Valsalva-provoked left ventricular outflow tract gradient compared with placebo. How might this reduction translate into meaningful changes in symptoms, exercise capacity, and everyday functioning for adolescents with oHCM?

Rossano: The left ventricular outflow tract gradient is not merely an imaging measurement; it reflects the resistance the heart must overcome to pump blood forward, particularly during exertion. In SCOUT-HCM, the least-squares mean Valsalva gradient fell by 48.5 mm Hg with mavacamten, compared with 0.5 mm Hg with placebo. Reducing that obstruction can improve forward blood flow and lower intracardiac pressures and often translates into fewer symptoms, including less shortness of breath, chest discomfort, fatigue, and exercise intolerance. The study also reported supportive improvements in resting and post-exercise gradients, peak oxygen consumption, functional class, and symptom measures. These findings make the physiological improvement clinically encouraging.

Contemporary Pediatrics: The safety profile in SCOUT-HCM was generally consistent with the experience in adults, and no patients had a reduction in left ventricular ejection fraction below 50%. What should pediatric cardiologists know about monitoring adolescents receiving mavacamten in clinical practice?

Rossano: The absence of an ejection fraction reduction below 50% in SCOUT-HCM was reassuring. However, mavacamten does reduce cardiac contractility, so patients do need to be followed closely for reductions in ejection fraction. Pediatric cardiologists should follow the FDA label closely, obtaining a baseline echocardiogram and serial assessments of left ventricular ejection fraction, outflow tract gradient, clinical response, and dosing eligibility. New or worsening dyspnea, fatigue, chest pain, palpitations, edema, syncope, arrhythmia, or a significant intercurrent illness should prompt reassessment. Treatment should be interrupted if the ejection fraction falls below the threshold specified in the label or if clinical status deteriorates.

Contemporary Pediatrics: Because hypertrophic cardiomyopathy can affect adolescents during a period of increasing independence, sports participation, and social activity, how could having a disease-targeted therapy change conversations with patients and families about managing the condition?

Rossano: A disease-targeted therapy can shift the conversation from one focused mainly on restrictions and symptom accommodation toward one that also includes the possibility of improving the obstruction that contributes to those limitations. This will hopefully give these patients a greater sense of agency and make discussions about goals, including appropriate exercise, travel, friendships, and growing independence, more concrete and hopeful. Ideally, therapy becomes part of enabling a fuller life rather than allowing HCM to define the adolescent’s identity.

However, treatment should not be presented as removing the diagnosis or all of its risks. A lower outflow gradient does not necessarily eliminate the risk of arrhythmia or sudden cardiac death, nor does it automatically clear a patient for unrestricted competitive sports.
Decisions about activity should be part of shared decision-making with the patient and family and remain individualized, taking into account the patient's individual risk.

Contemporary Pediatrics: Now that mavacamten is approved for this younger population, what unanswered questions remain regarding its long-term use in adolescents, including durability of response, safety, and its potential role relative to other medical or invasive treatment strategies?

Rossano: The most immediate question is whether the benefits observed over 28 weeks remain durable over years. Longer follow-up is needed to determine whether improvements in obstruction, symptoms, exercise capacity, wall thickness, diastolic measures, and cardiac biomarkers persist and whether treatment changes the underlying natural history of pediatric HCM rather than controlling physiology while the medication is being taken. Long-term safety is equally important. We need more information about sustained effects on systolic function, arrhythmias, growth and development, reproductive health, medication adherence, and clinically important drug interactions. Several other important questions remain. Should mavacamten be used as a first-line agent or as an add-on to current conventional therapies? Can it reduce or defer the need for surgical myectomy? Questions also remain about treatment discontinuation, use in children younger than 12, and use in nonobstructive or syndromic forms of HCM.