Carolyn Y Ho1, Iacopo Olivotto2, Daniel Jacoby3, Steven J Lester4, Matthew Roe5, Andrew Wang6, Cynthia Burstein Waldman7, David Zhang8, Amy J Sehnert8, Stephen B Heitner9. 1. Brigham and Women's Hospital, Boston, MA (C.Y.H.). 2. Careggi University Hospital, Florence, Italy (I.O.). 3. Yale University, New Haven, CT (D.J.). 4. Mayo Clinic, Phoenix, AZ (S.J.L.). 5. Duke Clinical Research Institute, Durham, NC (M.R.). 6. Duke University School of Medicine, Durham, NC (A.W.). 7. HCMBeat.com, Los Angeles, CA (C.B.W.). 8. MyoKardia, Inc, Brisbane, CA (D.Z., A.J.S.). 9. Knight Cardiovascular Institute, Oregon Health and Sciences University, Portland (S.B.H.).
Abstract
BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. METHODS:EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. CONCLUSIONS:EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.
RCT Entities:
BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. METHODS: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. CONCLUSIONS: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03470545.
Authors: Monika Halas; Paulina Langa; Chad M Warren; Paul H Goldspink; Beata M Wolska; R John Solaro Journal: Mol Pharmacol Date: 2022-03-02 Impact factor: 4.054
Authors: Rudolf A de Boer; Stephane Heymans; Johannes Backs; Lucie Carrier; Andrew J S Coats; Stefanie Dimmeler; Thomas Eschenhagen; Gerasimos Filippatos; Lior Gepstein; Jean-Sebastien Hulot; Ralph Knöll; Christian Kupatt; Wolfgang A Linke; Christine E Seidman; C Gabriele Tocchetti; Jolanda van der Velden; Roddy Walsh; Petar M Seferovic; Thomas Thum Journal: Eur J Heart Fail Date: 2022-01-14 Impact factor: 17.349
Authors: Matthew Reaney; Veleka Allen; Amy J Sehnert; Liang Fang; Albert A Hagège; Srihari S Naidu; Iacopo Olivotto Journal: Pharmacoecon Open Date: 2022-06-02
Authors: Matthew Reaney; Prithvi Addepalli; Veleka Allen; John A Spertus; Chantal Dolan; Amy J Sehnert; Jennifer T Fine Journal: Pharmacoecon Open Date: 2022-06-20
Authors: Razvan Capota; Sebastian Militaru; Alin Alexandru Ionescu; Monica Rosca; Cristian Baicus; Bogdan Alexandru Popescu; Ruxandra Jurcut Journal: Health Qual Life Outcomes Date: 2020-10-30 Impact factor: 3.186