074: A First-in-Human, Single & Multiple Ascending Dose Study of CK-4021586, A Novel Cardiac Myosin Inhibitor

Statement of Purpose, Innovation or Hypothesis: A small molecule allosteric inhibitor of cardiac myosin, CK-4021586 (CK-586), is in development as a potential long-term oral treatment for patients with heart failure with preserved ejection fraction (HFpEF). A first-in-human study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of CK-586 in healthy adult participants.

Description of Methods & Materials: This Phase 1 study was double-blinded, randomized, placebo-controlled, and conducted in two parts: seven single ascending dose cohorts (10, 30 mg, 90 mg, 135 mg, 250 mg, 350 mg, 600 mg), and two multiple ascending dose cohorts (100 and 200 mg once daily for 7 days). Healthy participants (N=10/cohort) were administered CK-586 (N=8/cohort) or placebo (N=2/cohort) orally under fasted conditions. Participants were required to have left ventricular ejection fraction (LVEF) ≥60% at screening. Intensive PK plasma sampling was conducted (up to 168 hours post-dose) for bioanalysis, followed by PK analysis, of CK-586 and the primary pharmacologically inactive metabolite (CK-4022235). PK parameters were estimated. Multiple echocardiographic measurements were collected (up to 24 hrs post-dose) for PD assessment of CK-586 effect on cardiac function, including LVEF and left ventricular fractional shortening. The PKPD relationship between CK-586 concentration and change from baseline in LVEF was evaluated. Safety and tolerability were assessed throughout. Appropriate echocardiographic- and adverse event-based stopping criteria were in place to ensure safe dose escalation between cohorts.

Data & Results: Single dose administration demonstrated a mean plasma half-life of 14–17 hours, mean T_max of 1.5-5 hours, and generally dose-proportional exposure (Table 1). Multiple dose administration was as expected from single doses: PK was linear with time, steady-state was achieved by 7 days, and the mean accumulation of exposure at steady-state was 49-69%, consistent with the half-life. CK-4022235 circulated in plasma, with mean exposures 20–25% of the parent and a half-life approximating that of the parent. CK-586 plasma concentration demonstrated a modest and predictable PKPD relationship with change from baseline in LVEF. An approximate 148 ng/ml increase in CK-586 plasma concentration decreased LVEF by 1% (Figure 1). CK-586 was generally safe and well tolerated across all cohorts. One participant experienced an asymptomatic decrease in LVEF < 50% (specifically 48%) after single dose administration of 250 mg with a return to baseline within 3 hours. Stopping criteria were not met in this study.

Interpretation, Conclusion or Significance: CK-586 demonstrated ideal clinical pharmacologic properties for once daily administration: a half-life of 14–17 hours, dose- and time-linearity over a wide range of exposures, and modest and predictable PKPD relationship with LVEF. CK-586 was well tolerated across all doses studied. These results provide key insights for future Phase 2 evaluations of CK-586 in patients with HFpEF.

Disclosures: Cytokinetics Inc sponsored this study; authors are employed by and/or hold stock in Cytokinetics.

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