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MYK-491, a novel cardiac myosin activator, increases cardiac contractility in healthy volunteers

Session Poster Session 3

Speaker Jean-Francois Tamby

Event : Heart Failure 2019

  • Topic : heart failure
  • Sub-topic : Chronic Heart Failure: Pharmacotherapy
  • Session type : Poster Session

Authors : J-F Tamby (South San Francisco,US), L Fang (South San Francisco,US), J Lickliter (Melbourne,AU), S Hegde (Boston,US), H Surks (Bridgewater,US), S Reele (South San Francisco,US), S Teichman (South San Francisco,US), C Yang (South San Francisco,US), S Fernandes (South San Francisco,US), J Lambing (South San Francisco,US), M Semigran (South San Francisco,US), J Lee (South San Francisco,US), S Solomon (Boston,US)

Authors:
J-F Tamby1 , L Fang1 , J Lickliter2 , S Hegde3 , H Surks4 , S Reele1 , S Teichman1 , C Yang1 , S Fernandes1 , J Lambing1 , M Semigran1 , J Lee1 , S Solomon3 , 1MyoKardia - South San Francisco - United States of America , 2Nucleus Network - Melbourne - Australia , 3Brigham and Womens Hospital, Cardiovascular Division - Boston - United States of America , 4Sanofi - Bridgewater - United States of America ,

Citation:

Background: MYK-491 is a novel small-molecule selective cardiac myosin activator, in clinical development for the treatment of heart failure with reduced ejection fraction. In non-clinical studies, MYK-491 increased myocardial contraction, with minimal impact on relaxation and without perturbing calcium homeostasis. We report results of the first-in-human study.

Methods: The effects of oral MYK-491 were evaluated in a single ascending dose study conducted in healthy volunteers across 8 sequential dose cohorts (6 active and 2 placebo subjects per cohort). Assessments included evaluation of clinical safety and tolerability, serial plasma drug concentrations, cardiac echo-doppler, ECG and clinical laboratory values.

Results: 64 healthy volunteers were studied (40 male, 24 female, median age 27 years).

MYK-491 was safe and well tolerated. One subject experienced a serious adverse event (brief asymptomatic episodes of heart block lasting 4-8 sec during sleep that resolved spontaneously and led to prolongation of monitoring). Dose-proportional increases in drug exposure (Cmax, AUC) were observed up to dose cohort 7.  Echocardiography parameters by MYK-491 Plasma Concentration Groups (6h post dose) are shown in Table (placebo-corrected LS mean changes from baseline) are shown

Conclusions: MYK-491 administration in healthy volunteers was safe and led to an increase in echocardiographic measures of cardiac contractility which were associated with a modest increase in SET and no discernable effect on diastolic function.

Baseline (n=48)

MYK-491 Concentration Group
Lower (n=29) Medium (n=9) Higher (n=10)
Ejection Fraction (%) 63 0.3 2.2 3.2*
Fractional Shortening (%) 32 -0.6 3.5* 6.3*
Global Longitudinal Strain (%) -20.4 -0.5 -1.3 -1.8*
Stroke Volume (mL) 70 2.6 2.5 8.2*
End Systolic Diameter (cm) 3.2 0.03 -0.16* -0.31*
End Systolic Volume (mL) 34 -1.2 -4.1* -6.0*
End Diastolic Diameter (cm) 4.7 -0.01 -0.04 -0.12*
End Diastolic Volume (mL) 93 -2.2 -6.1 -9.7*
Systolic Ejection Time (SET, msec) 328 11 23* 26*
E/e' Ratio 6.1 -0.24 0.14 -0.06
E/A Ratio 1.9 0.15 0.18 -0.05
* p < 0.05 (change from baseline, MYK-491 concentration group versus placebo)

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