A Phase 2 Open-label Pilot Study Evaluating MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction (PIONEER-HCM)

A Phase 2 Open-label Pilot Study to Evaluate Efficacy, Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of MYK-461 in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction

The purpose of this phase 2 open-label pilot study is to evaluate the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of MYK-461 in subjects with symptomatic HCM and LVOT obstruction aged 18-70 years.

Study Overview

• Status: Completed
• Conditions: Cardiomyopathy, Hypertrophic Obstructive; Left Ventricular Outflow Tract Obstruction
• Intervention / Treatment: Drug: MYK-461

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States
      • Mayo Clinic Arizona
  • Connecticut
    • New Haven, Connecticut, United States
      • Yale New Haven Hospital
  • Massachusetts
    • Boston, Massachusetts, United States
      • Tufts Medical Center
  • Missouri
    • Saint Louis, Missouri, United States
      • Washington University St. Louis
  • North Carolina
    • Durham, North Carolina, United States
      • Duke Health Center at Southpoint
  • Oregon
    • Portland, Oregon, United States
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Hospital of the University of Pennsylvania (Penn Heart and Vascular Center)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Diagnosed with HCM (hypertrophied and non-dilated left ventricle in absence of systemic or other known cause), with LV wall thickness ≥ 15 mm at time of initial diagnosis or ≥ 13 mm with a positive family history of HCM.
• Age 18-70
• BMI 18-37kg/m2
• Documented LVEF ≥ 55% at the Screening visit as determined by the investigator and the investigational site's echocardiography laboratory.
• Resting LVOT gradient ≥ 30 mg Hg and post-exercise peak LVOT gradient ≥ 50 mm Hg
• NYHA functional class II or higher

Key Exclusion Criteria:

• History of sustained ventricular tachyarrhythmia.
• History of syncope with exercise within past 6 months.
• Active infection.
• Persistent atrial fibrillation or atrial fibrillation at Screening or history of paroxysmal atrial fibrillation with resting rate document > 100bpm within 1 year of screening.
• Has QTc Fridericia (QTcF) > 500 ms, or any other ECG abnormality considered by the investigator to pose a risk to subject safety (e.g. second degree atrioventricular block type II).
• Aortic stenosis or fixed subaortic obstruction.
• History of LV systolic dysfunction (LVEF < 45%) at any time during their clinical course.
• History of obstructive coronary artery disease.
• History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator or MyoKardia physician, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.
• Part A: Ongoing therapy with beta blockers, calcium channel blockers, or disopyramide. Subjects on any of these medications who, in the opinion of the investigator, can safely be withdrawn are eligible as long as medication is discontinued at least 14 days prior to the Screening visit.
• Part B: Ongoing therapy with calcium channel blockers or disopyramide. Subjects on any of these medications who, in the opinion of the investigator, can safely be withdrawn are eligible as long as medication is discontinued at least 14 days prior to the Screening visit.
• Prior treatment with cardiotoxic agents such as doxorubicin or similar, or current treatment with antiarrhythmic drugs that have negative inotropic activity, e.g. flecainide or propafenone.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open Label; MYK-461	Drug: MYK-461

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Post-exercise Peak LVOT Gradient From Baseline to Week 12	Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Achieving a Post-exercise Peak LVOT Gradient Response of < 30 mmHg. Gradient < 30 mmHg	LVOT gradients are assessed after a treadmill stress test by echocardiography.	Baseline and Week 12
Change in Dyspnea Symptom Score From Baseline to Week 12	The scale name is Dyspnea Numeric Rating Scale (NRS). It is intended to measure how much shortness of breath you have had in the past week. 0 = no shortness of breath and 10 = shortness of breath as the worst possible.	Baseline and Week 12
Change in Peak VO2 From Baseline to Week 12	Peak VO2 is assessed using a cardiopulmonary exercise test.	Baseline and Week 12
Change in VE/VCO2 From Baseline to Week 12	VE/VCO2 is assessed from cardiopulmonary exercise testing results.	Baseline and Week 12
Change in Resting LVEF From Baseline to Week 12	LVEF is assessed by echocardiography.	Baseline and Week 12
Change in LV Fractional Shortening (LVFS) From Baseline to Week 12	LVFS is assessed using echocardiography measures.	Baseline and Week 12
Change in Global Longitudinal Strain (GLS) From Baseline to Week 12	GLS is assessed using echocardiography measures.	Baseline and Week 12
Change in Post-exercise Peak LVOT Gradient From Week 12 to Week 16	Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography.	Weeks 12 and 16

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NYHA Functional Class From Baseline to Week 12		Baseline and Week 12
Change in KCCQ OSS From Baseline to Week 12		Baseline and Week 12
Change in NT-proBNP From Baseline to Week 12		12 weeks
Number of Subjects Achieving an LVOT Gradient Response of Post-exercise Peak Gradient < 10 mmHg at Week 12	Post-exercise peak LVOT gradients are assessed after a treadmill stress test by echocardiography.	Baseline and Week 12

Collaborators and Investigators

• Sponsor: MyoKardia, Inc.
• Investigators: Study Chair: Amy Sehnert, MD, MyoKardia, Inc.

Publications and helpful links

General Publications

• Heitner SB, Jacoby D, Lester SJ, Owens A, Wang A, Zhang D, Lambing J, Lee J, Semigran M, Sehnert AJ. Mavacamten Treatment for Obstructive Hypertrophic Cardiomyopathy: A Clinical Trial. Ann Intern Med. 2019 Jun 4;170(11):741-748. doi: 10.7326/M18-3016. Epub 2019 Apr 30.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: July 20, 2016
• First Submitted That Met QC Criteria: July 20, 2016
• First Posted (Estimate): July 22, 2016

Study Record Updates

• Last Update Posted (Actual): June 8, 2021
• Last Update Submitted That Met QC Criteria: June 3, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Hypertrophy; Cardiomyopathies; Cardiomyopathy, Hypertrophic
• Other Study ID Numbers: MYK-461-004