228Long-term safety and effectiveness of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients (pts): update from PIONEER open-label extension (PIONEER-OLE) study
Authors: Wang A , Heitner S B , Jacoby D , Lester S , Fang L , Balaratnam G , Sehnert A J 
Published: October 2019

Abstract

Background
In a phase 2 PIONEER-HCM study, pts with symptomatic, obstructive hypertrophic cardiomyopathy (oHCM) showed improvement in left ventricular outflow tract (LVOT) obstruction, exercise capacity, and symptoms after 12 wk of treatment with the novel myosin modulator, mavacamten (Mava).

Purpose
To examine the long-term safety and effectiveness of Mava in PIONEER-OLE study

Methods
PIONEER-OLE (NCT03496168) is an ongoing 2-y multicenter study for adults with symptomatic oHCM who completed PIONEER-HCM (NCT02842242). The starting dose of Mava is 5 mg/d with titration at wk 6 to an individualized therapeutic dose (5, 10, or 15 mg). Evaluations are at wk 4, 6, 8, 12 and every 12 wk thereafter to monitor LV ejection fraction (LVEF), LVOT gradient, New York Heart Association (NYHA) class, NT-proBNP, drug concentration, and safety.

Results
13 pts (mean age, 57.8 y; 9 male; 12 on beta-blockers) were enrolled. Mean baseline LVOT obstruction and LVEF, and wk 12 changes from baseline, were similar to those in PIONEER-HCM (Table). Mava significantly reduced resting and provoked LVOT gradients and NT-proBNP at wk 12 and 24 compared with baseline (P<0.004). Of 10 pts who reached wk 24, 8 reported improvement in NYHA class (1 improved Class III to II; 7 improved Class II to I), and 2 pts remained Class II. Mava has been well tolerated up to 40 wk; 31 adverse events (AEs; 22 mild, 5 moderate) were reported in 8 pts; 1 pt had 3 severe and 1 serious AE (cholangiocarcinoma); all AEs were unrelated to study drug.
Results from PIONEER-OLE Parameter PIONEER-HCMa PIONEER-OLE Baseline Wk 12 Baselineb Wk 12 Change at Wk 12 Wilcoxon Signed Wk 24 Change at Wk 24 Wilcoxon Signed Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Rank Mean ± SD Mean ± SD Rank (n=13) (n=13) (n=13)c (n=12)c (n=12)c P value (n=10)c (n=10)c P value LVOT Rest gradient, mmHg 69.7±53.9 27.8±31.3 67.3±42.8 12.0±5.4 −57.9±43.2 0.0005 10.5±4.8 −66.6±42.4 0.0020 LVOT Valsalva gradient, mmHg 93.7±55.6 36.8±37.5 89.9±30.7 (n=12) 23.6±20.0 −66.4±35.3 (n=11) 0.0020 21.1±11.5 −67.3±33.5 (n=9) 0.0039 LVEF, % 73.0±5.6 64.6±10.5 72.0±4.9 67.6±7.2 −4.4±5.5 0.0269 68.2±6.5 −3.2±3.3 0.0195 NT-proBNP, pg/mL 1601.3±2782 (n=12) 684±980 1836±2886 181±211 −1759±2789 0.0005 170±225 −2128±3104 0.0039 Data extraction date January 24, 2019. aCombined results shown for pts from PIONEER-HCM originally in cohort A (n=5) and cohort B (n=8). bBaseline in PIONEER-OLE occurred 6–18 months after completion of PIONEER-HCM. cNumber of pts with data available for analysis, unless otherwise specified.

Conclusion
Despite management with current therapies, pts enrolled in PIONEER-OLE with similar levels of obstruction and hypercontractility as in PIONEER-HCM. In this longest observation period, Mava significantly reduced obstruction (LVOT gradient) in pts with oHCM beyond standard HCM therapy, while maintaining normal LVEF and improving symptoms.

Acknowledgement/Funding
MyoKardia