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Long-term safety and effectiveness of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients (pts): update from PIONEER open-label extension (PIONEER-OLE) study

Session Novel therapeutic targets in hypertrophic cardiomyopathy

Speaker Andrew Wang

Event : ESC Congress 2019

  • Topic : valvular, myocardial, pericardial, pulmonary, congenital heart disease
  • Sub-topic : Myocardial Disease: Pharmacotherapy
  • Session type : Advances in Science

Authors : A Wang (Durham,US), SB Heitner (Portland,US), D Jacoby (New Haven,US), S Lester (Phoenix,US), L Fang (South San Francisco,US), G Balaratnam (South San Francisco,US), AJ Sehnert (South San Francisco,US)

A. Wang1 , S.B. Heitner2 , D. Jacoby3 , S. Lester4 , L. Fang5 , G. Balaratnam5 , A.J. Sehnert5 , 1Duke Health Center at Southpoint - Durham - United States of America , 2Oregon Health & Science University, Knight Cardiovascular Institute - Portland - United States of America , 3Yale University School of Medicine - New Haven - United States of America , 4Mayo Clinic Arizona - Phoenix - United States of America , 5MyoKardia, Inc. - South San Francisco - United States of America ,

European Heart Journal ( 2019 ) 40 ( Supplement ), 65

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.

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.

Results from PIONEER-OLE
BaselineWk 12BaselinebWk 12Change at Wk 12Wilcoxon SignedWk 24Change at Wk 24Wilcoxon Signed
Mean ± SDMean ± SDMean ± SDMean ± SDMean ± SDRankMean ± SDMean ± SDRank
(n=13)(n=13)(n=13)c(n=12)c(n=12)cP value(n=10)c(n=10)cP value
LVOT Rest gradient, mmHg69.7±53.927.8±31.367.3±42.812.0±5.4−57.9±43.20.000510.5±4.8−66.6±42.40.0020
LVOT Valsalva gradient, mmHg93.7±55.636.8±37.589.9±30.7 (n=12)23.6±20.0−66.4±35.3 (n=11)0.002021.1±11.5−67.3±33.5 (n=9)0.0039
LVEF, %73.0±5.664.6±10.572.0±4.967.6±7.2−4.4±5.50.026968.2±6.5−3.2±3.30.0195
NT-proBNP, pg/mL1601.3±2782 (n=12)684±9801836±2886181±211−1759±27890.0005170±225−2128±31040.0039
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.

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