Paediatric Gradient Holds at 56 Weeks but Payer and Functional Proof Still Missing

BMS Reports Sustained Camzyos Benefit in Pediatric oHCM at 56 Weeks

Bristol Myers Squibb (BMS) announced longer-term 56-week data from its Phase III SCOUT-HCM trial evaluating Camzyos (mavacamten) in paediatric patients aged 12 to less than 18 years with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). The data showed that patients on continuous mavacamten achieved a mean baseline reduction of 48.1mmHg in Valsalva left ventricular outflow tract (LVOT) gradient after 56 weeks. Patients initially on placebo who switched to Camzyos after 28 weeks also experienced similar reductions. Importantly, no participant in the trial experienced a left ventricular ejection fraction below 50% throughout the 56-week period, indicating a favorable safety profile. These results build upon the 28-week data that supported the US FDA's approval of Camzyos for eligible paediatric patients in September 2026.

• The SCOUT-HCM trial demonstrated sustained efficacy of Camzyos in paediatric oHCM patients over 56 weeks. Patients receiving continuous mavacamten achieved a significant mean baseline reduction of 48.1mmHg in Valsalva left ventricular outflow tract (LVOT) gradient. This reduction was consistent with that observed in patients who initially received placebo for 28 weeks and then switched to active treatment, reinforcing the drug's therapeutic benefit in reducing LVOT obstruction, a key pathological feature of oHCM.
• The safety profile of Camzyos remained favorable throughout the 56-week study period. A critical safety finding was that no participant experienced a left ventricular ejection fraction (LVEF) below 50%, which is an important measure of cardiac function. The trial reported five treatment-related adverse events and two serious events in the continuous arm over 56 weeks, and one event with no serious events in the placebo-mavacamten arm over 28 weeks, suggesting a manageable safety profile for this patient population.
• The longer-term 56-week data provide additional confidence following the US FDA's approval of Camzyos in September 2026 for paediatric patients weighing at least 30kg, which was based on the initial 28-week SCOUT-HCM results. Camzyos, an allosteric cardiac myosin inhibitor, has also received regulatory approvals in over 60 countries and regions globally, supported by other Phase III studies like EXPLORER-CN (China) and HORIZON-HCM (Japan), highlighting its widespread recognition and utility for oHCM.

SCOUT-HCM: Sustained Efficacy and Safety for Pediatric oHCM

Recent studies in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) have evaluated the cardiac myosin inhibitors mavacamten and aficamten against placebo, standard therapy, and in long-term extension. These trials assessed left ventricular outflow tract gradients, functional class, biomarkers, septal reduction therapy eligibility, and left ventricular ejection fraction safety signals.

• VALOR-HCM (mavacamten, 5 mg daily, titrated up to 15 mg based on LVOT gradient and LV ejection fraction): After 16 weeks, 43 of 56 placebo patients (76.8%) and 10 of 56 mavacamten patients (17.9%) met guideline criteria or underwent SRT, difference (58.9%; 95% CI: 44.0%-73.9%; P < 0.001). Secondary differences favoring mavacamten included mean differences in post-exercise peak LVOT gradient -37.2 mm Hg; ≥1 NYHA functional class improvement 41.1%; improvement in patient-reported outcome 9.4 points; and NT-proBNP and cardiac troponin I between-groups geometric mean ratio 0.33 and 0.53.

• SEQUOIA-HCM (aficamten 5-20 mg daily vs placebo for 24 weeks): Patients treated with aficamten vs placebo showed limiting symptoms (71% vs 42%), complete hemodynamic response (68% vs 7%), enhanced exercise capacity (47% vs 24%), and decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%, with no treatment interruptions or heart failure worsening for LVEF <50% and no major adverse cardiovascular events associated with aficamten.

• FOREST-HCM long-term open-label extension (aficamten, cumulative exposure 352 patient-years; median follow-up 51.6 weeks): At Weeks 12 and 96, aficamten reduced Valsalva left ventricular outflow tract gradient by 56 ± 43 and 62 ± 33 mmHg from baseline (both P < 0.0001), with 69% and 93% of participants having at least one NYHA class improvement. Treatment-emergent serious adverse events (TESAEs) occurred in 36 (12.2%) patients; no deaths, heart failure, or events considered related to aficamten were reported, with LVEF<50% in 10 (3.4%) patients and new-onset atrial fibrillation in seven (2.4%) patients.

• MAPLE-HCM monotherapy comparison (aficamten 5 to 20 mg vs metoprolol 50 to 200 mg over 24 weeks): Compared with metoprolol, aficamten decreased resting LVOT-G (-30 mm Hg [95% CI: -37 to -23 mm Hg]; P < 0.001) and Valsalva LVOT-G (-35 mm Hg [95% CI: -44 to -26 mm Hg]; P < 0.001), reduced left atrial volume index (-7.0 mL/m [95% CI: -9.1 to -4.8 mL/m]; P < 0.001), and improved lateral E/e' -2.8 [95% CI: -4.0 to -1.6] and septal E/e' -3.1 [95% CI: -4.5 to -1.7], with LVEF -4% [95% CI: -5% to -3%] and no significant change in resting cardiac output between groups.

Addressing Unmet Needs in Pediatric Obstructive HCM

Recent literature on obstructive hypertrophic cardiomyopathy (oHCM) focuses on refining septal reduction for refractory patients and expanding targeted pharmacotherapy with cardiac myosin inhibitors. Surgical septal myectomy remains the definitive treatment for symptomatic patients with sustained relief of left ventricular outflow tract (LVOT) obstruction, while mavacamten and aficamten have been evaluated to improve gradients, symptoms and exercise capacity.

• Medically refractory patients needing septal reduction therapy: Alcohol septal ablation (ASA) is a well-established procedure for septal reduction therapy in patients with obstructive hypertrophic cardiomyopathy, significant at rest or provocable outflow tract gradients, and medically refractory symptoms, with current guidelines published in 2020 supporting ASA as a class 1 indication, similar to surgical myectomy, when no concomitant significant coronary or valve surgical indication exists. Mavacamten can delay or even obviate the need for septal reduction therapy, with PIONEER-HCM, EXPLORER-HCM and VALOR-HCM demonstrating improvements in peak LVOT gradient both at rest and post-exercise, cardiac biomarkers, New York Heart Association (NYHA) functional class and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores.

• High surgical risk versus complex anatomy: Alcohol septal ablation should be preferred in individuals who are at high surgical risk, while surgical myectomy may be preferred in the presence of intrinsic mitral valve disease, papillary muscle abnormalities, markedly thickened septum, multiple levels of obstruction, long length of mid-cavity obstruction, and absence of a suitable septal artery. Surgical myectomy has a lower incidence of heart block and a lower residual gradient, and often exceeds outcomes seen with alcohol septal ablation, particularly in patients with marked hypertrophy or complex anatomy, with operative mortality rates - less than 0.5% at experienced centers and symptomatic improvement in over 90% of patients.

• Very-high gradients and mid-ventricular obstruction: A sub-analysis of SEQUOIA-HCM evaluated aficamten in oHCM and very-high Valsalva left ventricular outflow tract gradients (LVOT-G) ≥100 mmHg (N = 73), where aficamten significantly reduced Valsalva LVOT-G by 66% from 123 ± 28 mmHg to 41 ± 30 mmHg (p = 0.001), including to <30 mmHg in 42% of aficamten patients. Two HCM patients having mid-ventricular obstruction effectively treated with mavacamten 5 mg daily showed reduction of peak gradient to 11 mmHg in mid-ventricular tract and to 10 mmHg, with NT-proBNP levels decreasing from 1287 to 178 ng/L and from 3910 to 718 ng/L at 16-week follow-up.

• Patients unsuitable for myectomy or ASA and optimization of background therapy: Radiofrequency ablation improved NYHA functional class and LVOT gradient at rest and with stimulation and reduced septal thickness, suggesting RA is effective in patients refractory to pharmacological therapy and unsuitable for alcohol septal ablation or myectomy. Discontinuation of afterload-reducing drugs including angiotensin-converting enzyme inhibitors, angiotensin-1 receptor blocker and dihydropyridine-calcium channel blocker significantly decreased median LVOT gradient from 86.5 [60.5-109.3] mmHg to 61.5 [28.3-97.50] mmHg (p = 0.0004), while combination therapy with aficamten and disopyramide (mean disopyramide dose 331 ± 146 mg/d) was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone.

• Diverse and comparator-defined populations: The EXPLORER-CN phase 3, randomized, double-blind, placebo-controlled trial at 12 hospitals in China enrolled patients with oHCM and LVOT gradient of 50 mm Hg or more and NYHA class II or III symptoms, showing least-squares mean difference of -70.3 mm Hg (95% CI, -89.6 to -50.9 mm Hg) in Valsalva LVOT peak gradient with mavacamten (starting at 2.5 mg once daily) versus placebo. The MAPLE-HCM trial randomly assigned patients with oHCM and LVOT-G ≥30 mm Hg at rest and/or ≥50 mm Hg with Valsalva to aficamten (n = 88) or metoprolol (n = 87), with aficamten monotherapy superior to metoprolol monotherapy in improving peak oxygen uptake with least-squares mean between-group difference of 2.3 ml per kilogram per minute (95% CI, 1.5 to 3.1; P<0.001).

Beyond oHCM: Mavacamten's Expanding Therapeutic Reach

Mavacamten is being trialled beyond obstructive HCM in symptomatic non-obstructive HCM (nHCM) and in heart failure with preserved ejection fraction (HFpEF) with left ventricular ejection fraction of 60% or greater. In nHCM its role remains investigational with biomarker effects but no definitive patient-centered benefit, while in HFpEF preliminary data suggest favorable effects on diastolic parameters and cardiac biomarkers.