We are using our understanding of heart muscle biology to discover new medicines targeted at disruptions in heart muscle contraction.

Preclinical

Phase 1

Phase 2

Phase 3

hypertrophic cardiomyopathy

• Mavacamten

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Obstructive HCM

Non-obstructive HCM

Targeted HFpEF

Mavacamten

for Obstructive & Non-obstructive Hypertrophic Cardiomyopathy

Mavacamten for Obstructive Hypertrophic Cardiomyopathy

Mavacamten is the first therapeutic candidate in a new class of direct myosin inhibitors that targets the excessive contractility and impaired relaxation, myocardial energetics and compliance, with the intent of correcting the abnormal function of the hypertrophic cardiomyopathy (HCM) heart. MyoKardia has advanced mavacamten into multiple late-stage clinical studies looking at its potential to treat the obstructive and non-obstructive forms HCM.

Mavacamten has received breakthrough therapy and orphan drug designations for the potential treatment of symptomatic, obstructive HCM. In a randomized, controlled, pivotal Phase 3 clinical trial, known as EXPLORER-HCM, patients with symptomatic, obstructive HCM who were treated with mavacamten experienced statistically significant and clinically meaningful improvements in symptoms, functional status and key aspects of quality of life. Mavacamten treatment was also shown to bring levels of key biomarkers of cardiac wall stress and injury, closer to the normal range. Mavacamten was well tolerated, and safety results for mavcamten treatment were similar to placebo. MyoKardia plans to submit a New Drug Application (NDA) for U.S. regulatory approval in this indication in the first quarter of 2021.

MyoKardia to expand on the existing body of evidence supporting mavacamten’s use as a potential backbone therapy for HCM. The VALOR-HCM Phase 3 clinical trial designed to provide direct clinical evidence of mavacamten’s ability to mitigate the need for invasive septal reduction therapy (SRT) procedures is the first of several planned studies. VALOR is currently enrolling individuals with obstructive hypertrophic cardiomyopathy (HCM) who have been referred for SRT and are refractory to current therapeutic options, including those who have severe symptoms (NYHA Class IV).

We are conducting two long-term extension studies to evaluate safety and activity with chronic dosing of mavacamten. The PIONEER open-label extension (PIONEER-OLE) enrolled patients who participated in MyoKardia’s Phase 2 PIONEER-HCM clinical trial. The MAVA long-term extension (MAVA-LTE) study is enrolling participants from the MAVERICK-HCM and EXPLORER-HCM clinical trials.

Mavacamten for Non-Obstructive Hypertrophic Cardiomyopathy

Impaired diastolic filling is a primary driver of disease in non-obstructive HCM and certain populations of patients with HFpEF. Clinical and non-clinical studies of mavacamten have shown that mavacamten reduces cardiac muscle contractility and improves left ventricular compliance, allowing the heart to fill during diastole. In the Phase 2 MAVERICK-HCM clinical trial of symptomatic, non-obstructive HCM, mavacamten treatment over 16 weeks showed meaningful reductions in biomarkers of cardiac stress were observed and clear signals of clinical benefit were noted in a subgroup with elevated cardiac filling pressures and in a pre-specified group of patients at higher risk for morbidity and mortality..

MyoKardia plans to advance mavacamten into additional studies in defined groups of patients with non-obstructive HCM and heart failure with preserved ejection fraction (HFpEF)

• MYK-224

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HCM

MYK-224

MYK-224 is our second therapeutic candidate that specifically targets cardiac myosin to reduce the excess myosin-actin cross-bridge formation underlying HCM. MYK-224 is designed to preserve the unique advantages of mavacamten’s mechanism, including the ability to reduce excess contractility and potentially address impaired relaxation while reducing pharmacokinetic variability. With a shorter half life, MYK-224 may reduce the time required to achieve steady state and thereby provide dosing flexibility. We initiated a Phase 1 clinical study of MYK-224 in healthy volunteers in August 2019 with initial data anticpated in mid-2020.

diastolic heart failure

• LUS-1

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Precision Diastolic Disease Indications

LUS-1

Our LUS-1 discovery-stage program is identifying novel therapeutics that target diastolic relaxation without reducing the force of contraction. In preclinical studies of LUS-1 molecules, we have observed improved compliance without a loss of stroke volume.

systolic heart failure

• Danicamtiv

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Genetic Dilated Cardiomyopathy (DCM)

Systolic Dysfunction and Atrial Fibrilation

Danicamtiv

for Precision Systolic Disease

Our portfolio of precision cardiovascular therapeutics includes multiple cardiac muscle activator programs aimed at increasing contraction of the heart muscle to improve blood flow. We are initially targeting precision indications in systolic heart failure and specifically, dilated cardiomyopathies (DCM).

Danicamtiv (formerly MYK-491) is an oral small molecule, selective cardiac myosin activator. In the heart, myosin is the motor protein that binds to actin to generate the force and movement of contraction. In patients with dilated cardiomyopathy and systolic heart failure, contraction is inadequate as the left ventricle of the heart is too distended and weak to adequately pump blood to meet the body’s needs. The goal of danicamtiv is to increase the ensemble force of contraction and improve cardiac output during systole without detracting from the ability of the heart to relax and fill with blood during diastole. Danicamtiv has been shown to increase the probability for myosin-actin engagement while preserving the detachment of myosin from actin at the end of contraction, thereby improving cardiac contractility while preserving diastolic function and allowing for normal filling.

MyoKardia intends to advance danicamtiv into two Phase 2 clinical trials in distinct patient subgroups: dilated cardiomyopathy patients with certain genetic mutations, and patients with reduced systolic function and atrial fibrillation.

In early clinical testing, danicamtiv has demonstrated an ability to improve in stroke volume without impairing the heart’s ability to relax and fill. In our Phase 2a placebo-controlled multiple-ascending dose study in patients with stable heart failure with reduced ejection fraction, danicamtiv treatment was associated with clinically meaningful improvements in left ventricular (LV) contractility, including statistically significant increases in LV stroke volume, without impairing the heart’s ability to relax and fill. Danicamtiv treatment also improved left atrial (LA) volume and function, a new and potentially important finding given left atrial size is a well-established prognostic factor for atrial fibrillation. Nonclinical studies indicated danicamtiv directly activates the left ventricle and left atrium, providing compelling mechanistic rationale for the robust changes observed clinically.

Danicamtiv has been generally well tolerated in early-stage clinical studies intended to assess safety and tolerability and no maximum tolerated dose or dose-limiting toxicities have been identified. Adverse events observed in our phase 1 and Phase 2 studies were benign and transient.

• ACT-1

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Precision Systolic Disease Indications

ACT-1

ACT-1 is our preclinical activator program targeting DCM due to sarcomeric mutations and impaired calcium regulation. In preclinical models, our ACT-1 prototype molecules successfully increase contractility, without prolonging systolic ejection time and with minimal impact on relaxation. We currently anticipate advancing our first ACT-1 program compound into clinical development in late 2020 or early 2021.

our scientific approach

researchers

patients

Coming together as a community.

For me, the SHaRe registry demonstrates what we can do when we come together as a community with a shared goal and a spirit of collaboration. The collective data from leading centers is producing a greater understanding of the burden of HCM on patients’ lives. And in turn, SHaRe has grown into a resource for patients to learn about the latest research and to gather for education and support.

Wendy Borsari ⁠— HCM patient, SHaRe Patient Education & Outreach Coordinator