MYK-491 Demonstrated Increase in Contractility
Consistent with Data from Preclinical and Healthy Volunteer
Studies
MyoKardia, Inc. (Nasdaq: MYOK), a clinical-stage biopharmaceutical
company pioneering precision medicine for the treatment of
cardiovascular diseases, today announced topline results from the
Phase 1b single-ascending dose study of MYK-491. MYK-491 was
generally well-tolerated and increases in cardiac contractility
were observed. MYK-491 is MyoKardia’s most advanced activator
molecule designed to increase contractility of the heart (systolic
function) with minimal adverse effects on myocardial relaxation
(diastolic function). MYK-491 is being developed in
collaboration with Sanofi S.A. (Sanofi) for the treatment of
dilated cardiomyopathy (DCM) and systolic heart failure in which
the left ventricle is too distended and weak to adequately pump
blood to meet the body’s needs.
“Patients with systolic heart failure may suffer
from symptoms such as shortness of breath and fatigue that can
progress to frequent hospitalizations and death. By
increasing the heart’s contractility without detracting from the
heart’s ability to fill, we believe MYK-491 could potentially make
a meaningful difference in patients’ lives,” said Marc Semigran,
MyoKardia’s Chief Medical Officer. “Topline data from single
doses of MYK-491 are encouraging. Cardiac contractility increased
across a number of standard echocardiographic parameters, with
little discernible impact on measures of diastolic relaxation and
MYK-491 was generally well tolerated. Our Phase 2a
multiple-ascending dose trial of MYK-491 is now underway, and we
look forward to results from that study in late 2019.”
The Phase 1b clinical trial evaluated the
safety, tolerability and preliminary pharmacokinetics and
pharmacodynamics of single ascending doses of MYK-491. Eight
patients with stable heart failure were enrolled and randomized to
receive a single dose of either MYK-491 or placebo, after which
patients underwent extended observation, followed by a washout
period. This process was repeated until each patient had
received at least three doses (MYK-491 or placebo).
Administration of MYK-491 resulted in
approximately 10 percent relative increases from baseline in
cardiac contractility across multiple echocardiographic measures,
including stroke volume, left ventricular ejection fraction and
fractional shortening. In increasing the heart’s
contractility, MYK-491 did not appear to meaningfully change
duration of the contraction or the heart’s ability to relax and
fill with oxygenated blood. systolic ejection time (SET), a measure
of the time it takes to eject blood from the left ventricle, showed
a modest increase and the impact of MYK-491 on left ventricular
filling was minor across multiple measures of diastolic
relaxation. Overall, these data were consistent with results
previously reported from the single-ascending dose trial of MYK-491
in healthy volunteers and supported advancement to Phase 2.
Absolute (Relative) Change from Baseline1 of
Echocardiogram Parameters at Higher Exposure |
|
Phase 1aHealthy
volunteers(N=10) |
Phase 1bPatients
with stable heart failure(N=8) |
Contractility |
EF increase % |
3.2 (5.1%) |
3.6 (8.3%) |
FS increase % |
6.3 (20%) |
2.3 (10%) |
SV increase (mL) |
8.2 (12%) |
8.7mL (11%) |
Safety/Function |
SET prolongation (msec) |
26 |
30 |
Relaxation/Diastolic Function |
E/e’ |
-0.06 |
0.15 |
E/A |
-0.05 |
0.06 |
1 Placebo-adjusted values
MYK-491 was generally well tolerated.
There were no serious or severe adverse events (AEs)
reported. All treatment-emergent AEs were mild or moderate in
severity and occurred at most in one patient. Sporadic,
transient and mild elevations of circulating troponin proteins were
observed at baseline and during treatment in both the placebo (two
patients) and treatment arms (four patients). One patient in
the study experienced moderate cardiac discomfort, shortness of
breath and low-level troponin elevation, all of which resolved
without intervention. No other cardiac-related AEs were
observed.
The protocol for the Phase 1b clinical trial was
modified to incorporate a Phase 2a multiple-ascending dose trial in
patients with dilated cardiomyopathy and stable heart
failure. The Phase 2a study is designed to assess the safety
of MYK-491 when dosed chronically to steady state and establish
proof-of-concept. Up to 40 patients will be randomized to
receive either MYK-491 or placebo for one week, during which time
patients will be monitored to evaluate the safety, tolerability,
pharmacokinetics, and pharmacodynamics of MYK-491.
Enrollment of patients in the Phase 2a clinical trial is
ongoing, with data anticipated in the fourth quarter of
2019.
About MYK-491MYK-491 is an
oral, small molecule, allosteric activator of myosin. 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, in which the
left ventricle of the heart is too distended and weak to adequately
pump blood to meet the body’s needs, MYK-491 is intended to
increase myosin-actin engagement, thereby targeting the
biomechanical defects underlying disease and improving cardiac
contractility. Based on data from preclinical research across
multiple animal models and Phase 1 studies, MYK-491 may hold
potential for controlled increases in the heart’s contractility
with minimal impact on relaxation. MYK-491 is currently being
studied in a Phase 2a multiple-ascending dose trial patients with
stable heart failure. MYK-491 is being developed in an ongoing
collaboration between MyoKardia and Sanofi.
About MyoKardia
MyoKardia is a clinical-stage biopharmaceutical
company pioneering a precision medicine approach to discover,
develop and commercialize targeted therapies for the treatment of
serious and rare cardiovascular diseases. MyoKardia’s initial
focus is on the development of small molecule therapeutics aimed at
the cardiac muscle proteins that modulate cardiac muscle
contraction and underlie diseases of systolic and diastolic
dysfunction. Based on an in-depth understanding of disease
biology, MyoKardia applies a precision medicine approach to develop
its therapeutic candidates for patient populations with shared
characteristics, such as causal genetic mutations or disease
subtypes. MyoKardia’s most advanced product candidate is mavacamten
(formerly MYK-461), a novel, oral, allosteric modulator of cardiac
myosin intended to reduce hypercontractility. Mavacamten has
advanced into a pivotal Phase 3 clinical trial, known as
EXPLORER-HCM in patients with symptomatic, obstructive hypertrophic
cardiomyopathy (HCM). MyoKardia is also developing mavacamten
in a second indication, non-obstructive HCM, in the Phase 2
MAVERICK-HCM clinical trial. MYK-491, MyoKardia’s second
product candidate, is designed to increase cardiac output among
patients with systolic heart dysfunction by increasing the overall
extent of the heart’s cardiac contractility. MyoKardia is currently
evaluating MYK-491 in a Phase 1b/2a study in stable heart failure
patients. MyoKardia has formed a collaboration with Sanofi to
support the commercialization of mavacamten outside the U.S. and
for MYK-491’s worldwide late-stage development and
commercialization. MyoKardia’s mission is to change the world
for patients with serious cardiovascular disease through bold and
innovative science.
Forward-Looking StatementsStatements we make in
this press release may include statements which are not historical
facts and are considered forward-looking within the meaning of
Section 27A of the Securities Act of 1933, as amended, and Section
21E of the Securities Exchange Act of 1934, as amended, which are
usually identified by the use of words such as "anticipates,"
"believes," "estimates," "expects," "intends," "may," "plans,"
"projects," "seeks," "should," "will," and variations of such words
or similar expressions. We intend these forward-looking statements
to be covered by the safe harbor provisions for forward-looking
statements contained in Section 27A of the Securities Act and
Section 21E of the Securities Exchange Act and are making this
statement for purposes of complying with those safe harbor
provisions. These forward-looking statements, including statements
regarding the clinical and therapeutic potential of MYK-491 and the
availability of data from the MYK-491 Phase 2a multiple ascending
dose trial, reflect our current views about our plans, intentions,
expectations, strategies and prospects, which are based on the
information currently available to us and on assumptions we have
made. Although we believe that our plans, intentions, expectations,
strategies and prospects as reflected in or suggested by those
forward-looking statements are reasonable, we can give no assurance
that the plans, intentions, expectations or strategies will be
attained or achieved. Furthermore, actual results may differ
materially from those described in the forward-looking statements
and will be affected by a variety of risks and factors that are
beyond our control including, without limitation, risks associated
with the development and regulation of our product candidates, as
well as those set forth in our Quarterly Report on Form 10-Q for
the quarter ended September 30, 2018, and our other filings with
the SEC. Except as required by law, we assume no obligation to
update publicly any forward-looking statements, whether as a result
of new information, future events or otherwise.
Contacts
Michelle Corral
Senior Director, Corporate Communications and Investor Relations
MyoKardia, Inc.
650-351-4690
ir@myokardia.com
Hannah Deresiewicz (investors)
Stern Investor Relations, Inc.
212-362-1200
hannahd@sternir.com
Steven Cooper (media)
Edelman
415-486-3264
steven.cooper@edelman.com
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