August 30, 2026Clinical Pharmacokinetics
A First-in-Human Study of Ulacamten, a Novel Cardiac Myosin Inhibitor for HFpEF
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Key result
Ulacamten is well tolerated and predictably reduces LVEF in healthy adults.
- n=102
Why the study?
Ulacamten is a novel cardiac myosin inhibitor in development for HFpEF, requiring evaluation of its safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect in a first-in-human study.
Is ulacamten safe, tolerable, and what are its pharmacokinetic and pharmacodynamic profiles in healthy adult participants?
Key Points
- To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of the novel cardiac myosin allosteric inhibitor ulacamten in healthy adults.
- Phase I, double-blind, randomized, placebo-controlled, single and multiple ascending dose (SAD, MAD) and open-label food effect trial (NCT05877053) conducted in healthy adults with left ventricular ejection fraction (LVEF) ≥ 60% or ≥ 65% at screening.
- Seven SAD cohorts received oral doses of 10−600 mg (n = 10 per cohort; eight active, two placebo), two MAD cohorts received 100 and 200 mg once daily for 7 days, and one food effect cohort received a single 150-mg dose.
- Intensive plasma pharmacokinetics were evaluated through 168 hours post dose, safety was monitored continuously, and serial echocardiograms were performed over 24 hours post dose to assess pharmacodynamic changes in systolic function.
- Ulacamten exhibited steady absorption with a median plasma half-life of 14−18 h, a median tmax of 1.5−5 h, and linear, dose-proportional pharmacokinetics that reached steady state by Day 4 with 37−69% mean accumulation.
- Ulacamten plasma concentrations produced a modest and predictable pharmacokinetic/pharmacodynamic relationship with reductions from baseline in systolic function, including LVEF.
- All adverse events were mild or moderate in severity, no study stopping criteria were met, and dosing was well tolerated without food effects.
Study Design
Type
RCT (n=102)
Blinding
Double-blind
Randomization
Randomized
Multicenter
No
Structured PICO
Is ulacamten safe, tolerable, and what are its pharmacokinetic and pharmacodynamic profiles in healthy adult participants?
P
Population
102 healthy adult participants aged 18-55 years with normal cardiac function (LVEF ≥ 60%) evaluated in a Phase I single and multiple ascending dose study.
I
Intervention
Ulacamten (oral). Single ascending doses (SAD) of 10-600 mg; multiple ascending doses (MAD) of 100 or 200 mg once daily for 7 days; or a single 150-mg dose for food effect (FE) evaluation.
C
Comparator
Matching placebo (for SAD and MAD cohorts).
O
Outcome
Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effect (FE) of ulacamtensafety
In this first-in-human study, the novel cardiac myosin inhibitor ulacamten was well tolerated and demonstrated predictable pharmacokinetics and pharmacodynamics, supporting its continued development for HFpEF.
Limitations
- Small sample size
- Conducted in healthy participants rather than the target HFpEF patient population
- Short duration of dosing (up to 7 days)
Ask about this paper
Answers are grounded in this paper and cite their sources.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The results from this Phase 1 study replicate pre-clinical findings that show CK-586 directly reduces cardiac contractility at the level of the sarcomere. Importantly, CK-586 was observed to have a shallow and predictable PK/PD relationship and half-life that enables a once-daily fixed dosing regimen in patients with HFpEF.”
Implication
Supports advancement to patient trials with defined dosing; extends Phase I data for predictable cardiac myosin inhibition.
Abstract
Background and Objectives Ulacamten (CK-4021586) is a small molecule allosteric inhibitor of cardiac myosin in development for treating heart failure with preserved ejection fraction. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and food effect (FE) of ulacamten in healthy adult participants. Methods This was a phase I, double-blind, randomized, placebo-controlled, single and multiple ascending dose escalation (SAD, MAD) and FE study. Seven SAD cohorts (n = 10; eight active, two placebo) received oral doses of 10−600 mg, two MAD cohorts received 100 and 200 mg once daily for 7 days, and one FE cohort received a single 150-mg dose. Participants were required to have left ventricular ejection fraction (LVEF) ≥ 60% or ≥ 65% at screening. Intensive PK plasma sampling was conducted (Days 1, 7 [MAD only] for 168 h post dose). Safety was monitored throughout the study. Multiple echocardiographic measurements were collected (for 24 h post dose) for PD assessment. Results Ulacamten was steadily absorbed, with median plasma half-life of 14−18 h, median tmax of 1.5−5 h, and generally dose-proportional exposure. Following multiple-dose administration, PK was linear with time, steady state was achieved by Day 4, and mean accumulation of exposure at steady state was 37−69%, consistent with the half-life. Ulacamten plasma concentrations demonstrated a modest and predictable PK/PD relationship with change from baseline in systolic function measures. All adverse events were mild or moderate in severity. Stopping criteria were not met in this study. Conclusions Ulacamten demonstrated dose-proportional exposure, a predictable PK/PD relationship with respect to LVEF, and good tolerability, supporting its further clinical development. Clinical Trial Registration ClinicalTrials.gov identifier: NCT05877053, registered May 23, 2023
Discussion
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Cite This Study
Lutz et al. (2026) conducted an RCT in Healthy participants (n=102). Ulacamten vs. Placebo was evaluated on Safety, tolerability, pharmacokinetics, and pharmacodynamics (LVEF). Ulacamten was well tolerated and demonstrated dose-proportional exposure with a predictable pharmacokinetic/pharmacodynamic relationship reducing left ventricular ejection fraction in healthy adults.
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