Characterization of the patient population

The 15 patients included in our primary analysis were 53.4 ± 16.3 years old; 60% were male patients. Clinically, most patients presented with dyspnea and NYHA class III (73.3%). 40% of patients suffered from angina pectoris and 33.3% from vertigo on exertion; 26.7% had a history of syncope in the past. Mean resting LVOT gradient was 42.2 ± 23.9 mmHg; in six patients resting LVOT gradient was <30 mmHg with elevated LVOT gradients under provocation (83.2 ± 34.4 mmHg). Mean peak LVOT gradient was 100.7 ± 38.6 mmHg before treatment indicating significant LVOT obstruction in all patients. The mean HCM-Risk-Score was 3.9 ± 2.3. Genetic testing for CYP2C19 variants was performed in all patients: four patients (26.7%) were classified as intermediate metabolizers, one patient (6%) as poor metabolizer status, and the remaining patients as normal metabolizers (67.3%). Most common cardiovascular comorbidities were hypertension (20%) and hypercholesterolemia (40%). Three patients (20%) had an implantable cardioverter-defibrillator. Three patients (20%) were previously treated with TASH (mean 7.7 ± 5.6 months; median 6 [IQR 11] months prior to mavacamten initiation) and diagnosed with recurrent and significant resting (40.0 ± 30.4 mmHg) and peak LVOT gradients (96.7 ± 28.9 mmHg).

All 15 patients were taking accompanying medication before therapy initiation. 13/15 patients were on ß-blocker treatment at baseline and dosages were 51 ± 26.3% of the daily maximum dosage of the corresponding ß-blocker; dosages were not changed within the 12-week initiation period. One patient was on verapamil (see also baseline characteristics, Table 1). The baseline characteristics of the subgroup of patients (n = 7) on off-label ACE-i or ATII-b therapy are summarized in Supplement Table 1.

Table 1 Baseline characteristics of patients included in primary analysisTreatment with mavacamten improves symptoms, has an impact on echocardiographic and electrocardiographic parameters and reduces NT-proBNP levels

The majority of patients (10/15 patients; 67%) reported an improvement of at least one NYHA class after 4 and 8 weeks of treatment. Mavacamten therapy was discontinued in one patient after week 8; this patient was excluded from analysis at week 12. 86% of the remaining 14 patients reported consistent improvement of at least one NYHA class after 12 weeks of therapy. While 73.3% of all patients stated dyspnea according to a NYHA class III at baseline, 50% no longer suffered from dyspnea (NYHA class I) and 50% reported improved dyspnea (NYHA class II) at 12 weeks of treatment (Fig. 1A). The mean levels of KCCQ-12 were 57.6 ± 19.5 points at baseline and 68.3 ± 22.1 points after 8 and 70.6 ± 19 points after 12 weeks of therapy indicating an improvement of quality of life (mean change week 8: 3.9 ± 17.9 points; 95% CI [−7.2; 15.0], mean change week 12: 14.7 ± 12.1 points; 95% CI [7.8; 21.9]).

Fig. 1

NYHA classes, echocardiographic parameters and serum biomarkers during the 12-week initiation period. NYHA classes at baseline and 4, 8 and 12 weeks after initiation of mavacamten (A) Resting LVOT gradients under mavacamten therapy at baseline and after 4, 8 and 12 weeks (B) peak LVOT gradients at baseline and under mavacamten therapy after 4, 8 and 12 weeks (C) LVEF in % at baseline and week 4, 8 and 12 after initiation of mavacamten (D) and LAVI ml/m2 at baseline and after 4, 8 and 12 weeks of therapy with mavacamten (E) NT-proBNP levels at baseline and after 4, 8 and 12 weeks of treatment with mavacamten. One outlier showed distinct higher NT-proBNP levels and was taken out of this graph. NT-proBNP level of this patient: baseline (9557 pg/ml), week 4 (6164 pg/ml), week 8 (4608 pg/ml), week 12 (2612 pg/ml) (F) Complete response was met by 6/14 patients (43%) after 12 weeks of therapy (G) Data from one patient who discontinued mavacamten therapy after 8 weeks was excluded from the 12-week analyses. Data is shown as box and whiskers (min to max). ns = not significant, * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001. NYHA class = New York Heart Association Classification. LVOT = left ventricular outflow tract. LVEF = left ventricular ejection fraction. LAVI = left atrial volume index. NT-proBNP = N-terminal pro–B-type natriuretic peptide

The mean resting and peak LVOT gradients decreased from 42.2 ± 23.9 to 100.7 ± 38.6 mmHg at baseline to 14.5 ± 13.9 and 33.4 ± 33.4 at 8 weeks and 12.2 ± 10.6 mmHg and 36.4 ± 30.8 mmHg at 12 weeks, respectively. Mean changes in resting and peak LVOT gradients were 27.7 ± 28.4 mmHg (95% CI [13.4; 42.1], p < 0.0001) and 69.6 ± 50.4 mmHg (95% CI [43.2; 96.0], p < 0.0001) at 8 weeks and 28.2 ± 28.9 mmHg (95% CI [12.4; 43.9], p < 0.0001) and 63.4 ± 59.4 mmHg (95% CI [31.1; 95.7], p = 0.0002) at 12 weeks, respectively (Fig. 1B, C). LVEF did not deteriorate over time (Fig. 1D), and we noticed a non-significant reduction of the left atrial volume index (LAVI) (Fig. 1E). In addition, the mean serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) level significantly decreased from 1406.3 ± 2322.7 pg/ml (median: 722.0 pg/ml [IQR: 791.0]) at baseline to 672.8 ± 1197.9 pg/ml (median: 210.0 pg/ml [IQR: 383.0]) at 8 weeks and 358.5 ± 666.7 pg/ml (median 167.0 pg/ml [IQR: 223.0]) at 12 weeks. Mean changes in NT-proBNP were 733.4 ± 1362.6 pg/ml (95% CI [44.0; 1422.9], p = 0.019) at 8 weeks and 1104.9 ± 1751.1 pg/ml (95% CI [187.7; 2022.2], p = 0.0013) at 12 weeks (Fig. 1F). Complete response was met by 4/15 (27%) patients after 8 weeks and by 6/14 (43%) patients after 12 weeks (Fig. 1G). The subgroup of seven patients with off-label usage of ACE-i or ATII-b before and after mavacamten initiation depicted comparable responses to treatment (Supplement Fig. 1).

Evaluation of resting ECGs revealed nine patients (60%) with inverted T-waves before therapy initiation. In seven out of nine patients, T-wave inversions were persisting to a lesser extent, while in two patients T-wave inversions were no longer detectable after 8 or 12 weeks of therapy. Figure 2 shows changes of T-wave inversions, reduction of LVOT velocity and serum NT-proBNP levels of one representative patient with complete therapy response during the 12-week initiation period.

Fig. 2

Exemplary presentation of T-wave inversion, LVOT velocity and NTproBNP levels in one representative patient with complete response during the 12-week titration period. Changes in T-wave inversions, LVOT velocity and NT-proBNP values at baseline, 4, 8 and 12 weeks under therapy with mavacamten. Peak LVOT gradients at baseline: 155 mmHg, at week 4: 12 mmHg, at week 8: 11 mmHg, at week 12: 12 mmHg. ECG calibration: paper speed 50 mm/s, calibration spike 10 mm/mV (indicated in baseline). LVOT velocity in m/s at baseline and cm/s at week 4, 8 and 12. ECG = electrocardiogram. LVOT = left ventricular outflow tract. NT-proBNP = N-terminal pro–B-type natriuretic peptide

Reasons for dosage adaptation, pausing or discontinuation of mavacamten therapy during the 12-week initiation period

While therapy with mavacamten was generally well-tolerated in most patients, four patients (27%) paused treatment due to deteriorating LVEF (<50%, n = 1, week 8), gastrointestinal (n = 2 at week 4 and 8, respectively) and ophthalmological (n = 1, at week 8) complaints. Therapy was reinitiated at lower dosage in three of these four cases without any further side effects. The patient with persistent LVEF reduction was already on the lowest available mavacamten dose, thus therapy was discontinued after week 8. In two additional cases, the mavacamten dosage was reduced due to peak LVOT gradient reduction < 20 mmHg. In the subgroup of patients with continued off-label ACE-i or ATII-b therapy, treatment with mavacamten was paused in one additional case due to transient LVEF deterioration below 50% at week 4; therapy was recontinued at week 8 (Fig. 3).

Fig. 3

Reasons for changes in mavacamten dose and management over 12 weeks of therapy. § Indicating one patient with continued Angiotensin-Converting-Enzyme-Inhibition therapy