Comprehensive in vitro pro‐arrhythmic assays demonstrate that omecamtiv mecarbil has low pro‐arrhythmic risk

Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration IC₅₀] = 125.5 µM) and Nav1.5 and Cav1.2 assays (IC₅₀ > 300 µM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 µM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF assay, OM shortened AP duration (APD)₆₀ and APD₉₀ significantly from 3 to 30 µM. In perfused IRH, ventricular repolarization (corrected QT and corrected JT intervals) was decreased significantly at greater than or equal to 1 µM OM. In summary, the comprehensive proarrhythmic assessment in human and non‐rodent cardiac models provided data indicative that OM did not delay ventricular repolarization at therapeutic relevant concentrations, consistent with clinical findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

A new therapeutic agent, omecamtiv mecarbil (OM), increases cardiac contractility by prolonging systolic ejection time, however, there is no published data assessing its pro‐arrhythmic risks.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Pro‐arrhythmic risk assessment of OM in in vitro and ex vivo safety pharmacology models compliant with International Conference on Harmonization S7B guideline and Comprehensive In Vitro Proarrhythmia Assay initiative.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Comprehensive in vitro pro‐arrhythmic risk assays demonstrate that OM has low pro‐arrhythmic risk and translate into clinical safety observations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Low pro‐arrhythmic risks consistently identified in preclinical in vitro models translate well into clinical observations (i.e., negative preclinical pro‐arrhythmic findings can predict negative clinical outcomes).