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
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s40262-026-01694-6.
Key Points
| Ulacamten, administered as single and multiple ascending doses, was well tolerated and no safety concerns were observed in healthy participants. |
| Ulacamten demonstrated dose linearity without a change in half-life (14–18 h) over a wide range of exposures, with steady state evident within 4 days of dosing. Ulacamten can be administered without regard for food. |
| Modest and predictable pharmacokinetic/pharmacodynamic relationships were observed with three markers of contractility, including left ventricular ejection fraction. |
Introduction
Heart failure with preserved ejection fraction (HFpEF) is a complex and increasingly prevalent syndrome defined by presence of heart failure symptoms despite left ventricular ejection fraction (LVEF) of ≥50%. The pathophysiology of HFpEF is multifaceted, involving impaired ventricular filling, increased ventricular and vascular stiffness, endothelial dysfunction, and systemic inflammation [1–3]. It is often compounded by comorbidities such as hypertension, obesity, diabetes, and atrial fibrillation [4–6]. Globally, HFpEF accounts for nearly half of all heart failure cases, and its prevalence continues to rise with the aging population and increasing rates of obesity and metabolic syndrome [7–10]. HFpEF disproportionately affects older adults and women, and is associated with frequent hospitalizations, diminished exercise capacity, and a poor quality of life [5, 10, 11].
Current therapeutic options for HFpEF are limited and have historically focused on symptomatic relief through diuretics and management of comorbidities, with only modest benefits in reducing hospitalizations or improving quality of life [12]. Many therapies effective in heart failure with reduced ejection fraction have failed in HFpEF, reflecting the syndrome’s heterogeneity and the shortcomings of a ‘one size fits all’ approach [2, 7, 8, 13]. The heterogeneity of HFpEF pathophysiology and the lack of targeted therapies underscore the need for novel treatment approaches that address the unique myocardial and systemic abnormalities in this syndrome, particularly for patients with LVEF ≥60%, who are often underrepresented in clinical trials.
Cardiac myosin inhibitors represent a promising new class of therapeutics designed to modulate cardiac contractility by directly targeting the sarcomeric myosin–actin interaction. While agents such as mavacamten and aficamten have demonstrated efficacy in hypertrophic cardiomyopathy by reducing hypercontractility and improving diastolic function, their application in HFpEF remains largely investigational, with limited data available on their use in patients with preserved or supernormal LVEF [14]. The development of novel myosin inhibitors tailored to the pathophysiological features of HFpEF, especially in those with LVEF ≥60%, holds significant potential to address the unmet therapeutic needs in this growing patient population.
Ulacamten is a small molecule allosteric inhibitor of cardiac myosin that is being developed as a chronic oral treatment for a subgroup of HFpEF patients with supranormal systolic function, such as LVEF ≥60%. The rationale for this approach is based on the hypothesis that abnormally increased cardiac contractility may contribute to disease physiology in these patients and that selective cardiac myosin inhibition may reduce sarcomere-driven contractile force. The pharmacology of ulacamten has been extensively characterized preclinically using in-vitro and in-vivo methodologies. Unlike aficamten and mavacamten, which inhibit single-headed motor domain of myosin (subfragment-1), ulacamten specifically targets the ATPase activity of two-headed heavy meromyosin and requires the presence of the myosin regulatory light chain for its effect, indicating a unique binding site and regulatory mechanism. This selectivity allows ulacamten to reduce cardiac hypercontractility without affecting calcium transients or heart rate, with minimal impact on smooth muscle myosin, ultimately resulting in favorable cardiac remodeling [15]. Because cardiac myosin inhibition is expected to reduce cardiac contractility, modest reductions in echocardiographic measures of systolic function, including LVEF, left ventricular fractional shortening (LVFS), and left ventricular ejection time (LVET), may reflect target engagement. In this report, we present the first-in-human phase I clinical study evaluating safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamics (PK/PD) of ulacamten in healthy adult participants. Additionally, the effect of food on the PK of ulacamten was also assessed to provide recommendations in the ongoing phase IIa trial (AMBER-HFpEF; NCT06793371) in participants with HFpEF. Additionally, the PK of CK-4022235, the primary, pharmacologically inactive metabolite of ulacamten, was also evaluated in this study.
Methods
This phase I study was conducted at Celerion (Tempe, AZ, USA). Both the protocol and the informed consent were approved by the study center’s institutional review board (Advarra, Inc., Columbia, MD, USA) and complied with the Declaration of Helsinki. Each participant provided written informed consent before study entry.
Study Design
This was a randomized, double-blind, placebo-controlled, single and multiple ascending dose study with an open-label food effect (FE) cohort (Fig. 1). The study was designed to identify a pharmacologically active dose range that reduced LVEF by 5–15% relative to baseline. The study was not designed to identify a maximum tolerated dose. Dose escalation was to stop when the PD range was identified or when a dose that was not tolerated was identified, whichever occurred first.
Fig. 1.
Study design schema. a SAD cohorts; b MAD cohorts; c FE cohort. FE food effect, MAD multiple ascending dose, SAD single ascending dose. Figure created using GraphPad Prism
Single Ascending Dose
Starting Dose
The prediction of human PK parameters (clearance [CL] and steady-state volume of distribution [Vss]) of ulacamten were performed using a range of methods, with the average of these methods predicting a CL of 4.5 mL/min/kg, a Vss of 5.8 L/kg, and a half-life of approximately 15 h [16, 17]. In addition, a predicted ulacamten human oral bioavailability of 50% and an absorption rate constant of 0.68 L/h were determined from oral PK studies using pentagastrin-treated beagle dogs dosed orally with 200 mg of non‑micronized ulacamten in a gelatin capsule [17]. Simulation of these predicted ulacamten human PK parameters in a one-compartment model showed that a proposed human starting dose of 10 mg of ulacamten would yield conservative safety margins of maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration–time curve from time zero to the end of the dosing interval (τ) at steady state (AUCtau,ss) ~50-fold below the observed no-adverse-effect-level observed in rat and dog 28-day toxicology studies.
Study Design
Seven cohorts of ten participants each (eight active, two placebo) received single ascending oral doses of ulacamten 10 mg, 30 mg, 90 mg, 135 mg, 250 mg, 350 mg, or 600 mg powder-in-capsule formulation or placebo under fasted conditions with approximately 240 mL of water. A sentinel dose strategy was used, where two participants were initially dosed (one ulacamten, one placebo) and monitored for a minimum of 24 hours before eight remaining participants (seven ulacamten, one placebo) were dosed. Safety, PK, and PD data were reviewed before dose escalation by the dose-level review committee. Appropriate echocardiographic and adverse event (AE)-based stopping criteria (Table S1, see electronic supplementary material [ESM]) were in place to ensure safe dose escalation between cohorts. Key LVEF-based stopping criteria included LVEF < 50% in ≥ 2 participants or LVEF < 45% in ≥ 1 participant, unless determined not to be related to study drug by the Investigator and dose-level review committee. Until a PD effect was observed (e.g., a reduction of ≥5% in LVEF), dose was not escalated more than ~ 3-fold that of the previous single ascending dose (SAD) cohort. Once a PD effect was observed, dose escalation for the next cohort did not exceed ~2-fold that of the previous SAD cohort.
Multiple Ascending Dose
Cohorts were evaluated in sequence with two cohorts (N = 10/cohort; eight active, two placebo) receiving 100 mg or 200 mg once daily oral powder-in-capsule formulation or placebo for 7 days under fasted conditions with approximately 240 mL of water. The 100-mg and 200-mg doses were selected for the multiple ascending dose (MAD) cohort based on their safety and tolerability in the SAD portion and projected PD activity (LVEF reduction).
Food Effect Cohort
This was an open-label, fixed, single dose, two-way crossover study in 12 healthy participants. In the fasted period, ulacamten 150 mg orally was administered as a tablet intended for phase II study after a ≥ 8-h overnight fast. The fed group received a standardized high-fat breakfast (800–1000 calories with 500–600 calories from fat) to be completed 30 min before dosing. There was a washout period of 10 days between doses.
Study Population
Eligible participants were between 18 and 55 years of age, with a body mass index (BMI) of 18.0–30.0 kg/m2, and assessed to be healthy based on their medical history, physical examination, vital signs, laboratory tests, and ECG. Participants also had to have normal cardiac structure and function, with an LVEF ≥ 60% for the first four SAD cohorts, and LVEF ≥ 65% for subsequent SAD cohorts, MAD cohorts, and a food effect (FE) cohort. Participants were not allowed to use caffeine within 48 h, over-the-counter medication (except acetaminophen) or alcohol within 7 days, any prescription medication or grapefruit-containing food within 14 days, or tobacco or nicotine within 3 months before study check-in.
Assessments
Safety
Safety was assessed by vital signs measurements, continuous 12-lead ECGs, physical exams, clinical laboratory tests, and monitoring of AEs throughout the study. All AEs were coded using the Medical Dictionary for Regulatory Activities, version 26.0, and graded using the National Cancer Institute Common Terminology Criteria for AEs (version 4.03) three-point severity scale (mild, moderate, and severe).
Twelve-lead ECGs were collected throughout the study for real-time safety review. Additionally, continuous 12-lead ECG recordings using Holter monitor recordings were obtained. Echocardiographic PD endpoints, including LVEF, were read by a board-certified cardiologist for safety assessments and reviewed by an echocardiography core laboratory for PD assessments (see Sect. 2.3.3 for additional details).
Pharmacokinetics
Intensive PK plasma sampling was conducted on Day 1 (SAD, MAD, and FE cohorts) and Day 7 (MAD cohorts only) for up to 168 hours post dose. Trough concentrations were assessed on Days 2–6 (MAD cohorts only) to assess time to steady state. For MAD cohorts, samples for urine PK analysis of ulacamten were collected at intervals of 0–12 h and 12–24 h on Day 7.
Pharmacodynamics
For PD assessments, echocardiograms were performed by certified sonographers in the SAD and MAD cohorts to evaluate LVEF, LVFS, and LVET. Echocardiograms were interpreted by the safety echocardiography reader and provided to the echocardiography core laboratory. These results were used for all data analysis and dose-level review decisions, and an immediate local interpretation of the echocardiograms was performed for safety monitoring. Cardiac chamber quantification was performed in accordance with echocardiography guidelines established by American Society of Echocardiography and the European Association of Cardiovascular Imaging [18]. Details on the PD parameter estimations (LVEF, LVFS, and LVET) are provided in a previous publication [19].
Echocardiographic measurements were collected for up to 24 h post dose on Day 1 (SAD and MAD) and Day 7 (MAD) for PD assessment of the effect of ulacamten on cardiac function. In the SAD cohorts, echocardiograms were obtained on Day –1 (check-in), predose, and at 1.5 h, 4 h, 6 h, 24 h, and 48 h post dose. In the MAD cohorts, echocardiograms were obtained on Day –1 (check-in), predose, and at 1.5 h, 24 h, and 72 h post dose on Day 1. On Day 7, echocardiograms were obtained at 1.5 h, 24 h, and 48 h post dose.
Cardiodynamics
Holter monitors were used to collect continuous 12-lead ECG data for the purpose of extracting cardiodynamic ECGs (triplicate 10-s). These analyses were performed for Day 1 (SAD and MAD combined) and Day 7 (MAD), separately. The recordings began approximately 24 h predose to capture baseline recording for storage and ended approximately 24 h post dose. The ECG parameters that were measured and calculated included heart rate (HR), respiratory rate (RR), PR, QRS, QT, and HR-corrected QT interval using Fridericia’s formula (QTcF). T-wave morphology and U-wave presence were also assessed.
Data Analyses
Pharmacokinetics
Plasma and urine PK parameters for ulacamten and its pharmacologically inactive metabolite CK-4022235 were estimated via non-compartmental analysis using Phoenix WinNonlin (version 8.3.5; Pharsight, Mountain View, CA, USA). Summary statistics were calculated by study part and day for each PK parameter. Standard PK parameters were calculated on Days 1 (SAD and MAD) and 7 (MAD), including maximum plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve from 0 h to the 24-h measurable plasma concentration (AUC0–24), AUC extrapolated to infinity (AUC0–∞), AUC from 0 h to the last measurable plasma concentration (AUC0–t), AUC over a dosing interval (AUC0–tau for Day 7), apparent oral clearance (CL/F for Day 7 [MAD]), and apparent volume of distribution (Vz/F; Day 1 only).
Dose proportionality of primary PK parameters (AUC and Cmax) of ulacamten and CK-4022235 was assessed on Day 1 (SAD) or Day 7 (MAD) over the tested dose range using a linear regression model. A comparison of PK parameters of ulacamten and CK-4022235 after single (Day 1) and multiple (Day 7) dose administration of ulacamten (MAD) was conducted to assess attainment of steady state (trough concentration [Ctrough]) and extent of drug accumulation (AUC and Cmax). Metabolite-to-parent ratios were calculated for AUC and Cmax and corrected for differences in molecular weight. Urine PK parameters for ulacamten and CK-4022235 included amount excreted in urine from 0 to 24 h post dose, fraction of dose excreted in urine from 0 to 24 h post dose, and renal clearance (CLr).
The effect of concomitant food intake on ulacamten PK was assessed by statistical comparison of primary PK parameters (AUC and Cmax) under fed and fasted conditions. To evaluate the effect of food on ulacamten PK, a mixed-effects linear model was used, with treatment as a fixed effect and participant as a random effect. 90% confidence intervals (CIs) were constructed for the ratio of geometric means of AUC and Cmax of ulacamten dosed under fed versus fasted conditions.
Pharmacodynamics
In SAD and MAD cohorts, changes in echocardiography parameters following ulacamten administration were analyzed using a linear mixed model for repeated measures (MMRM analysis of covariance [ANCOVA]). Change from baseline (last predose measurement) in each PD parameter was compared between active treatment and pooled placebo at each post-dose time point. The model included treatment, time point, time point by treatment interaction, and baseline as a covariate, with repeated measures accounted for by an unstructured covariance structure. Analyses were conducted separately for each cohort and parameter. For each comparison, least squares means, treatment–placebo differences, and associated 95% CIs were presented.
Pharmacokinetics/Pharmacodynamics
LVEF, LVFS, and LVET are considered to be relevant measures of systolic function in a healthy participant population and were chosen for PK/PD analyses. The PK/PD relationships between coincidental ulacamten plasma concentration and change from baseline in LVEF, LVFS, and LVET were evaluated via linear mixed-effects modeling. Inter-subject variability was applied to baseline PD and not the PK/PD slope estimate. Participant demographics (e.g., age, sex, and baseline PD value) were evaluated as model covariates and deemed not significant. Potential non-linear (e.g., Emax) models were considered, but the linear models better fit the data.
Cardiodynamics
Descriptive statistics, including change from baseline, were provided for QTcF, QT, PR, and RR intervals, QRS duration, and HR by treatment and scheduled time point. Baseline and placebo-adjusted change in QTcF were also summarized by treatment and scheduled time point. The ECG analysis was based on defining the central tendency of all ECG interval parameter changes (HR, QTcF, PR, and QRS) as a change from baseline. The baseline ECG data were compared with the post-dose ECGs. Categorical analysis was performed on QTcF, PR, QRS, and HR.
Statistical Analysis
Sample size was based on feasibility and not using formal power calculations. All participants who received at least one dose of the study drug (ulacamten or placebo) were included in safety analyses. All participants who received at least one dose of the study drug and had at least one evaluable PK plasma profile were included in the PK analysis set. All participants in the safety analysis set who had at least one resting echocardiographic PD parameter were included in the PD analysis set. All participants who received the study drugs (ulacamten or placebo) and had at least one predose and one post-dose echocardiographic PD measurement were used in the PK/PD analysis set.
Bioanalysis
Blood and urine samples were collected to determine the plasma and urine PK profiles of ulacamten and metabolite CK-4022235. Analyte concentrations were determined in plasma and urine using fully validated high-performance liquid chromatography tandem mass spectrometry assays by Celerion (Lincoln, NE, USA). All samples were analyzed within the time frame supported by frozen established stability durations supported by the validation data for each analyte. The analytical range (lower and upper limits of quantitation) was 0.500–1000 ng/mL for both ulacamten and CK-4022235 in human plasma and urine. The intra-day and inter-day accuracy and precision from plasma and urine validations are listed in Table S2 in the ESM.
Results
Disposition and Demographics
A total of 102 participants were enrolled and all completed the study. There were 70 participants across seven SAD cohorts (56 received ulacamten and 14 received placebo), 20 participants across two MAD cohorts (16 received ulacamten 100 mg or 200 mg once daily and four received placebo), and 12 participants in the FE cohort. Detailed demographics and baseline characteristics are provided in Table S3 in the ESM.
In the SAD cohorts, the majority of participants were male (74%; n = 52), White (84%; n = 59), and Hispanic (71%; n = 50), with a mean age of 39.7 years (range 19–55 years) and mean BMI of 26.2 kg/m2 (range 20.3–29.9 kg/m2). In the MAD cohorts, the majority of participants were male (95%; n = 19), White (80%; n = 16), and Hispanic (65%; n = 13), with a mean age of 40.1 years (range 29–55 years) and mean BMI of 27.1 kg/m2 (range 22.8–29.9). In the FE cohort, all participants were male, the majority were White (92%; n = 11), and Hispanic (83%; n = 10), with a mean age of 37.4 years (range 23–50 years) and mean BMI of 28.4 kg/m2 (range 26.4–29.9).
Safety and Tolerability
Single and multiple doses of ulacamten were generally well tolerated when administered in the fasted or fed state. There were no deaths, serious AEs (SAEs), or discontinuations during the study. The most frequently reported AEs (≥ 10% of participants) during the study are presented in Table 1. All AEs were considered grade 1 (mild) or grade 2 (moderate) in severity. The most common treatment-related AE in the SAD cohort was headache (9%; n = 5 participants), in the MAD cohort was constipation (25%; n = 4 participants), and in the FE cohort were headache (17%; n = 2 participants) and pruritus (17%; n = 2 participants). All AEs resolved without sequelae.
Table 1.
Summary of number of participants reporting treatment-emergent adverse events after receiving ulacamten
| SAD | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Adverse event | 10 mg (n = 8) |
30 mg (n = 8) |
90 mg (n = 8) |
135 mg (n = 8) |
250 mg (n = 8) |
350 mg (n = 8) |
600 mg (n = 8) |
Pooled PBO (n = 14) |
Ulacamten overall (N = 56) |
| Abdominal discomfort | 1 (13%) | 1 (2%) | |||||||
| Abdominal pain | 1 (13%) | 1 (2%) | |||||||
| Back pain | 1 (13%) | 1 (2%) | |||||||
| Blood thyroid stimulating hormone increased | 1 (13%) | 1 (2%) | |||||||
| Chest discomfort | 1 (13%) | 1 (2%) | |||||||
| Discomfort | 1 (13%) | 1 (2%) | |||||||
| Dizziness | 1 (13%) | 1 (2%) | |||||||
| Dizziness postural | 1 (13%) | 1 (2%) | |||||||
| Dry skin | 1 (13%) | 1 (2%) | |||||||
| Ejection fraction decreased | 1 (13%) | 1 (2%) | |||||||
| Eye irritation | 1 (13%) | 1 (2%) | |||||||
| Fatigue | 1 (13%) | 1 (2%) | |||||||
| Feeling hot | 1 (13%) | 1 (2%) | |||||||
| Flatulence | 1 (13%) | 1 (2%) | |||||||
| Headache | 1 (13%) | 2 (25%) | 1 (13%) | 1 (13%) | 5 (9%) | ||||
| Muscle spasms | 1 (13%) | 1 (2%) | |||||||
| Musculoskeletal chest pain | 1 (13%) | 1 (2%) | |||||||
| Nervousness | 1 (13%) | 1 (2%) | |||||||
| Palpitations | 1 (13%) | 1 (2%) | |||||||
| Photosensitivity reaction | 1 (13%) | 1 (2%) | |||||||
| Skin discoloration | 1 (13%) | 1 (2%) | |||||||
| Somnolence | 1 (13%) | 1 (7%) | 1 (2%) | ||||||
| Supraventricular tachycardia | 1 (13%) | 1 (2%) | |||||||
| Thirst | 1 (13%) | 1 (2%) | |||||||
| MAD | ||||
|---|---|---|---|---|
| Adverse event | 100 mg (n = 8) |
200 mg (n = 8) |
Pooled PBO (n = 4) |
Ulacamten overall (N = 16) |
| Abdominal pain | 1 (13%) | 1 (6%) | ||
| Back pain | 1 (13%) | 1 (25%) | 1 (6%) | |
| Constipation | 3 (38%) | 1 (13%) | 4 (25%) | |
| Decreased appetite | 1 (13%) | 1 (6%) | ||
| Diarrhea | 1 (13%) | 1 (6%) | ||
| Fatigue | 1 (13%) | 1 (6%) | ||
| GERD | 1 (13%) | 1 (6%) | ||
| Headache | 1 (13%) | 1 (6%) | ||
| Muscle twitching | 1 (13%) | 1 (6%) | ||
| Musculoskeletal discomfort | 1 (13%) | 1 (6%) | ||
| Neck pain | 1 (13%) | 1 (6%) | ||
| Paresthesia | 1 (13%) | 1 (6%) | ||
| Peripheral coldness | 1 (13%) | 1 (6%) | ||
| Throat irritation | 1 (13%) | 1 (6%) | ||
| Toothache | 1 (13%) | 1 (6%) | ||
| Food effect | |||
|---|---|---|---|
| Adverse event | 150 mg fasted (n = 12) |
150 mg fed (n = 12) |
Ulacamten overall (N = 12) |
| Headache | 2 (17%) | 2 (17%) | |
| Pruritus | 2 (17%) | 2 (17%) | |
GERD gastroesophageal reflux, MAD multiple ascending dose, PBO placebo, SAD single ascending dose
In the SAD cohort, one participant experienced ECG-related mild AE of supraventricular tachycardia (exacerbation) following ulacamten 600 mg upon Holter data review. The event resolved and there were no abnormalities in the 12-lead ECG. The participant had a history of supraventricular tachycardia. There were two participants who experienced an asymptomatic decrease in ejection fraction during the study: one participant in the SAD cohort following ulacamten 250 mg (baseline LVEF 63%, LVEF 55.8% at the time of the event) and one participant in the FE cohort following ulacamten 150 mg (baseline LVEF 62%, LVEF 49% at the time of the event). These AEs were considered mild, of short duration, and resolved without sequelae by 3 hours post dose.
Overall, there were no notable or clinically significant changes in hemodynamic, ECG measurements, or laboratory parameters in participants in the SAD, MAD, or FE cohorts. In addition, stopping criteria, as defined in the protocol, were not met in any parts of the study.
Pharmacokinetics
Single Ascending Dose
The mean plasma concentration–time profiles are shown in Fig. 2, and the primary PK parameters are presented in Table 2. Following ulacamten single-dose oral administration, ulacamten was steadily absorbed, with a median tmax ranging from 1.5 to 5.0 h. Ulacamten plasma concentrations declined in an apparent simple exponential manner after reaching peak levels. The median terminal elimination half-life (t½) was consistent across the single-dose cohorts, ranging from approximately 14–17 h, consistent with preclinical human prediction half-life (15 h). Ulacamten exposure (Cmax and AUC0–∞) was generally dose proportional across the evaluated dose range of 10–600 mg. Ulacamten concentrations were consistently measurable (above lower limit of quantification of 0.1 ng/mL) through ≥ 48 h post dose in all participants.
Fig. 2.
Mean (SD) plasma concentration–time profiles following single oral doses of ulacamten 10–600 mg. a Ulacamten and b CK-4022235 profiles are plotted on a semi-logarithmic scale. SD standard deviation.
Figure created using GraphPad Prism
Table 2.
Plasma PK parameters after single ascending doses
| PK parameters | 10 mg (n = 8) |
30 mg (n = 8) |
90 mg (n = 8) |
135 mg (n = 8) |
250 mg (n = 8) |
350 mg (n = 8) |
600 mg (n = 8) |
|---|---|---|---|---|---|---|---|
| Ulacamten | |||||||
| t½ (h) |
16.8 (15.1, 18.4) |
17.3 (15.8, 20.7) |
15.6 (13.1, 17.0) |
15.1 (13.8, 17.4) |
14.0 (13.0, 15.5) |
13.8 (11.2, 17.6) |
15.0 (13.9, 16.1) |
| tmax (h) |
1.47 (1.00, 2.24) |
2.51 (1.47, 4.50) |
2.02 (1.47, 2.51) |
3.02 (2.24, 4.00) |
4.00 (2.24, 4.50) |
4.99 (3.01, 5.52) |
3.50 (2.51, 5.00) |
| Cmax (ng/mL) | 29.4 (31.4) | 76.5 (45.7) | 192 (30.3) | 303 (44.4) | 493 (52.9) | 598 (27.5) | 765 (40.0) |
| AUC0–24 (h*ng/mL) | 253 (15.4) | 786 (35.5) | 2050 (38.0) | 3250 (39.8) | 6110 (44.5) | 8460 (38.1) | 11,500 (41.8) |
| AUC0–t (h*ng/mL) | 377 (22.1) | 1300 (43.6) | 3140 (44.1) | 5480 (59.9) | 9510 (52.1) | 13,300 (50.5) | 20,200 (52.0) |
| AUC0–∞ (h*ng/mL) | 398 (21.6) | 1320 (42.8) | 3160 (43.7) | 5540 (61.1) | 9530 (51.9) | 13,400 (50.7) | 20,200 (52.0) |
| CL/F (L/h) | 26.3 (25.0) | 27.4 (48.9) | 37.2 (68.4) | 32.0 (52.2) | 32.3 (46.5) | 32.1 (46.3) | 36.9 (46.5) |
| Vz/F (L) | 631 (15.0) | 672 (37.5) | 732 (44.1) | 703 (39.4) | 647 (38.0) | 632 (38.9) | 816 (45.8) |
| CK-4022235 | |||||||
| t½ (h) |
17.6 (16.8, 18.4) |
16.2 (14.4, 22.7) |
17.1 (13.2, 18.2) |
15.7 (12.9, 18.3) |
14.9 (13.6, 17.3) |
14.2 (13.1, 18.0) |
16.4 (14.3, 16.9) |
| tmax (h) |
4.53 (3.50, 5.00) |
4.51 (4.00, 5.00) |
4.00 (4.00, 4.11) |
3.51 (3.01, 4.00) |
4.00 (4.00, 5.00) |
4.50 (4.00, 5.01) |
4.50 (4.00, 5.00) |
| Cmax (ng/mL) | 3.8 (18.3) | 11.4 (27.7) | 38.6 (13.7) | 62.6 (24.5) | 101 (35.1) | 139 (16.8) | 156 (23.2) |
| AUC0–24 (h*ng/mL) | 54.5 (18.7) | 156 (24.5) | 496 (19.5) | 764 (23.6) | 1300 (28.7) | 1940 (20.1) | 2490 (24.7) |
| AUC0–t (h*ng/mL) | 74.6 (23.5) | 249 (25.2) | 760 (29.8) | 1270 (38.4) | 2100 (32.3) | 3230 (40.1) | 4600 (42.8) |
| AUC0–∞ (h*ng/mL) | 90.8 (21.3) | 270 (23.3) | 780 (29.7) | 1300 (38.3) | 2120 (31.9) | 3260 (40.1) | 4620 (42.7) |
tmax and t½ values are presented as median (Q1, Q3). All other parameters are presented as arithmetic mean (%CV)
%CV percent coefficient of variation, AUC0–24 area under the plasma concentration–time curve from 0 h to the 24-h measurable plasma concentration, AUC0–∞ area under the concentration–time curve extrapolated to infinity, AUC0–t area under the plasma concentration–time curve from 0 h to the last measurable plasma concentration, Cmax maximum plasma concentration, CL/F apparent oral clearance, PK pharmacokinetic, Q quartile, t½ terminal elimination half-life, tmax time to maximum plasma concentration, Vz/F(Day 1 only) apparent volume of distribution during the terminal phase after oral administration
In the dose-proportionality assessment for ulacamten following single doses (Fig. 3), the slope estimates for Cmax and AUC0–∞ were 0.81 (95% CI 0.74–0.90) and 0.94 (95% CI 0.85–1.04), respectively. The estimate of the slope of AUC0–∞ as a function of dose was close to 1, indicating dose proportionality. Ulacamten Cmax increased with increasing dose in a linear but slightly less than proportional manner across the dose range evaluated. Ulacamten Cmax may start to plateau at higher doses (>250 mg).
Fig. 3.
Dose linearity of ulacamten AUC0–∞ and Cmax after single ascending doses of ulacamten (10–600 mg). AUC0–∞ area under the plasma concentration-time curve from time zero to infinity, Cmax maximum plasma concentration. Figure created using GraphPad Prism
CK-4022235 is the primary, pharmacologically inactive metabolite of ulacamten. It appeared rapidly in plasma, with a Cmax occurring between 3.51 and 4.53 h post dose (median tmax). The median t½ of CK-4022235 ranged from 14 to 18 h. Across the ulacamten doses evaluated, CK-4022235 plasma exposures (AUC0–∞ and Cmax) increased with dose in a generally dose-proportional manner. In the dose-proportionality assessment for CK-4022235, following single doses, the slope estimates for Cmax and AUC0-∞ were 0.95 (95% CI 0.90–1.01), and 0.97 (95% CI 0.91–1.03), respectively. CK-4022235 Cmax increased with increasing dose in both a linear and proportional manner across the dose range evaluated. CK-4022235 circulated in plasma with mean exposures (AUC0–∞) of 24–29% of those of the parent drug following single doses of ulacamten (metabolite ratio AUC0–∞ = 0.24–0.29).
Multiple Ascending Dose
The mean plasma concentration–time profiles are shown in Fig. 4, and the PK parameters are presented in Table 3. Day 7 ulacamten PK parameters were as expected from observed PK after Day 1 administration. Ulacamten was rapidly absorbed across the dose levels tested, with plasma concentrations declining in an apparent simple exponential manner. Median tmax was attained between 2 and 4 h and t½ was reached by 15–18 h. Ulacamten peak-to-trough ratio within a 24-h dosing interval was 3.1–3.2. Ulacamten AUC0–24 (4220–6520 h*ng/mL) and Cmax (312–457 ng/mL) increased <2-fold with doubling of ulacamten dose (100–200 mg). Based on evaluation of a succession of ulacamten plasma Ctrough values, steady-state conditions were approximated by the fourth dose (p > 0.05) (Table 4). Consistent with t½ estimates, Day 7 ulacamten AUC0–24 and Cmax accumulation ratios (ARs) demonstrated that ulacamten accumulated 37–69% (geometric mean ratio [GMR]: 137–169%) at steady state.
Fig. 4.
Mean (SD) plasma concentration–time profiles following multiple oral doses of ulacamten 100 mg and 200 mg q.d. for 7 days. a Ulacamten and b CK-4022235 profiles are plotted on a semi-logarithmic scale. q.d. once daily, SD standard deviation. Figure created using GraphPad Prism
Table 3.
Plasma PK parameters after multiple ascending doses
| PK parameters | 100 mg (n = 8) |
200 mg (n = 8) |
|---|---|---|
| Ulacamten | ||
| t½ (h) | 18.0 (12.8, 20.2) | 14.7 (13.5, 18.0) |
| tmax (h) | 2.02 (1.48, 3.00) | 4.00 (2.52, 5.50) |
| Cmax (ng/mL) | 312 (40.3) | 457 (33.2) |
| Peak-to-trough ratio | 3.21 (33.7) | 3.07 (25.1) |
| AUC0–24 (h*ng/mL) | 4220 (50.2) | 6520 (42.7) |
| AUCtau (h*ng/mL) | 4220 (50.2) | 6520 (42.7) |
| Cmin (ng/mL) | 109 (66.5) | 155 (53.3) |
| AUC0–24 accumulation ratio | 1.72 (21.0) | 1.52 (20.6) |
| Cmax accumulation ratio | 1.58 (37.8) | 1.44 (29.0) |
| Fe0–24 (%) | 1.09 (± 0.971) | 0.878 (± 0.668) |
| CLR (L/h) | 0.245 (± 0.115) | 0.271 (± 0.218) |
| CK-4022235 | ||
| t½ (h) | 19.4 (14.6, 22.7) | 16.8 (14.5, 20.2) |
| tmax (h) | 3.07 (3.01, 4.00) | 3.50 (3.00, 4.00) |
| Cmax (ng/mL) | 65.5 (33.6) | 114 (16.8) |
| Peak-to-trough ratio | 2.59 (28.8) | 3.03 (26.5) |
| AUC0–24 (h*ng/mL) | 948 (31.6) | 1530 (21.9) |
| AUC0–24 accumulation ratio | 1.93 (20.2) | 1.63 (21.2) |
| Cmax accumulation ratio | 1.81 (27.7) | 1.61 (27.5) |
| AUC0–24 metabolite-to-parent ratio | 0.271 (28.5) | 0.280 (29.4) |
| Fe0–24 (%) | 0.704 (± 0.360) | 0.550 (± 0.169) |
| CLR (L/h) | 0.671 (± 0.273) | 0.681 (± 0.193) |
tmax and t½ values are presented as median (Q1, Q3). All other parameters are presented as arithmetic mean (%CV)
%CV percent coefficient of variation, AUC0–24 area under the plasma concentration–time curve from 0 h to the 24-h measurable plasma concentration, AUCtau area under the concentration–time curve from 0 h to the end of the dosing interval, CLR renal clearance, Cmax maximum plasma concentration, Cmin minimum concentration, Fe fraction (in percentage) of dose excreted in urine per sampling interval, PK pharmacokinetic, t½ terminal elimination half-life, tmax time to maximum plasma concentration
Table 4.
Summary of steady-state assessment of ulacamten Ctrough values following multiple oral doses of ulacamten for 7 days
| Dose level (mg) | Ctrough day | Geometric LSM | p value |
|---|---|---|---|
| 100 mg | Ctrough, Day 1 | 57.8 | 0.0003 |
| Ctrough, Day 2 | 81.3 | 0.0007 | |
| Ctrough, Day 3 | 88.0 | 0.0536 | |
| Ctrough, Day 4 | 95.9 | 0.5223 | |
| Ctrough, Day 5 | 92.3 | 0.4008 | |
| Ctrough, Day 6 | 94.9 | – | |
| 200 mg | Ctrough, Day 1 | 97.0 | 0.0001 |
| Ctrough, Day 2 | 134 | 0.1697 | |
| Ctrough, Day 3 | 143 | 0.5905 | |
| Ctrough, Day 4 | 152 | 0.3050 | |
| Ctrough, Day 5 | 146 | 0.6885 | |
| Ctrough, Day 6 | 144 | – |
Ctrough, Day 1 = predose Day 2; Ctrough, Day 2 = predose Day 3; Ctrough, Day 3 = predose Day 4; Ctrough, Day 4 = predose Day 5; Ctrough, Day 5 = predose Day 6; Ctrough, Day 6 = predose Day 7. Concentrations were natural log transformed before analysis. Geometric LSMs were obtained by taking exponentials of the LSMs from ANOVA. p value corresponds to the Helmert contrast, i.e., the comparison of that day versus the average of the remaining days
ANOVA analysis of variance, Ctrough trough concentration, LSM least squares mean
Following multiple oral dosing of ulacamten, metabolite CK-4022235 appeared rapidly in the plasma, with a Cmax occurring between 3.07 and 3.50 h post dose (median tmax). The t½ of CK-4022235 was similar to that of the parent drug, ranging from about 17–19 h. CK-4022235 AUC0–24 and Cmax ARs (Day 7 relative to Day 1) were 56–89% (GMR: 156–189%). Calculation of the metabolite-to-parent AUC0–∞ ratio (MR AUC0–∞) of CK-4022235 relative to ulacamten suggests that the CK-4022235 metabolite circulates at 27–28% of parent (MR AUC0–∞ = 0.27–0.28).
Urine PK
Urine concentrations of ulacamten were determined from 0 to 24 h post dose for each participant receiving multiple oral doses (Day 7) of 100 mg and 200 mg under fasted conditions. The mean CLr of ulacamten ranged from 0.2 to 0.27 L/h and the mean cumulative excretion as a percentage of dose (%Fe) of ulacamten in the urine over 24 hours was 1.1% and 0.88% of the dose following 100-mg and 200-mg multiple doses, respectively. The mean percent dose excreted in urine as CK-4022235 was 0.70% and 0.55% following 100-mg and 200-mg multiple doses, respectively.
Food Effect
Concentration–time profiles of ulacamten in the fasting and fed state are presented in Fig. 5. One participant in the FE cohort (ulacamten 150 mg fed) was excluded from the PK-evaluable population (fed PK) due to a protocol deviation (antibiotics administered for skin infection).
Fig. 5.
Mean (SD) concentration–time profiles following administration of single oral doses of ulacamten 150 mg under fed and fasting conditions. a Ulacamten b CK-4022235 profiles are plotted on a semi-logarithmic scale. SD standard deviation. Figure created using GraphPad Prism
Administration of ulacamten under fed conditions compared with fasted conditions resulted in prolonged absorption of ulacamten (median tmax increased from 1.75 to 4.01 h), numerical decrease in Cmax (from 387 to 358 ng/mL), and a slight numerical increase in AUC0–∞ (from 7020 to 8140 h*ng/mL). Statistical comparisons of these PK parameters are summarized in Table 5. For ulacamten, AUC0–∞ increased slightly in the fed state, with a GMR (90% CI) of 110% (101–118), whereas Cmax was modestly reduced under fed conditions, with a GMR (90% CI) of 91% (75–110). Although the lower bound of the 90% CI for Cmax fell just below the standard bioequivalence limit of 80%, the upper bound was within the acceptable 80–125% range. As expected from the corresponding observed ulacamten PK profiles, the PK profiles for CK-4022235 after fasted and fed administration of ulacamten tablet formulation were similar. Administration of ulacamten under fed conditions compared with fasted conditions resulted in delayed plasma presentation of CK-4022235 (median tmax increased from 3.51 to 5.00 h), similar Cmax (54.4 and 55.1 ng/mL), and a slight numerical increase in AUC0–∞ (from 1390 to 1520 h*ng/mL). Fed administration demonstrated no significant change (GMR [90% CI]) in CK-4022235 AUC0–∞ (109% [98.7–120]) and Cmax (99.3% [84.3–117]) compared with fasted.
Table 5.
Ulacamten PK following single-dose administration of ulacamten 150 mg in fasted and fed conditions
| PK parameters | Test Ulacamten 150 mg fed (n = 11) |
Reference Ulacamten 150 mg fasted (n = 12) |
% Geometric mean ratio (90% CI) |
Intra-participant %CV |
|---|---|---|---|---|
| Ulacamten | ||||
| AUC0–t (h*ng/mL) | 7110 | 6500 | 109 (101–118) | 9.89 |
| AUC0–∞ (h*ng/mL) | 7180 | 6550 | 110 (101–118) | 10.1 |
| Cmax (ng/mL) | 327 | 360 | 90.8 (74.6–110) | 26.1 |
| CK-4022235 | ||||
| AUC0–t (h*ng/mL) | 1450 | 1330 | 109 (98.6–120) | 13.1 |
| AUC0–∞ (h*ng/mL) | 1470 | 1350 | 109 (98.7–120) | 13.0 |
| Cmax (ng/mL) | 53.2 | 53.6 | 99.3 (84.3–117) | 21.9 |
Geometric LSMs are calculated by exponentiating the LSMs derived from the ANOVAs. Geometric mean ratio = 100 × (test/reference). Intra-participant %CV = 100 × (square root (exp[MSE]1)), where MSE = residual variance from ANOVA. One participant was excluded from statistical analysis following administration of ulacamten 150 mg under fed conditions due to AE and subsequent medication administration
%CV percent coefficient of variation, AE adverse event, ANOVA analysis of variance, AUC0–∞ area under the concentration–time curve extrapolated to infinity, AUC0–t area under the plasma concentration–time curve 0 h to the last measurable plasma concentration, CI confidence interval, Cmax maximum plasma concentration, LSM least squares mean, MSE residual variance from ANOVA, PK pharmacokinetic(s)
Pharmacodynamics
The effect of ulacamten on cardiac function was assessed using comprehensive echocardiography. Summary statistics for measures of cardiac contractility, including LVEF, LVFS, and LVET, are presented in Table S4 (see ESM).
Following single ascending doses, the mean values for all echocardiographic PD parameters across dose levels were generally comparable with pooled placebo and remained within the normal range for healthy participants. A modest, transient trend of decrease in LVEF and LVFS was observed at the higher dose levels. Specifically, participants receiving 250 mg and 600 mg of ulacamten exhibited numerically larger mean decreases from baseline in LVEF at 1.5 h post dose (–6.38% and –4.44%, respectively) compared with placebo (–0.85%). These differences were attenuated by 4 hours post dose and returned to baseline levels by 24 h. A similar pattern was observed for LVFS, with the largest mean decreases from baseline occurring at the 350-mg and 600-mg dose levels (–3.49% and –5.27% at 1.5 and 4 hours post dose, respectively) compared with placebo. Statistically significant increases in HR and decreases in LVET were also observed at the 250-, 350-, and 600-mg doses. These effects were attenuated by 4 hours post dose and returned to baseline levels by 24 h.
Statistical analysis (MMRM ANCOVA) found no statistically significant trend across the dose range for the primary measures of cardiac contractility (LVEF, LVFS, and LVET). Statistically significant effects compared with placebo were largely confined to the highest dose (600 mg), which showed significant decreases in these parameters.
The vast majority of individual LVEF values and mean LVEF remained ≥ 50% throughout the study. Four participants (three on ulacamten, one on placebo) had a single post-dose LVEF value fall below 50% (lowest value was 46.2%); all were asymptomatic and LVEF values recovered rapidly. No participant had an LVEF value ≤ 45% at any time. Two mild, transient, and asymptomatic treatment-emergent AEs of decreased ejection fraction were reported; both resolved without intervention.
Following MAD, the mean values for LVEF and LVFS for the 100-mg and 200-mg doses were comparable with pooled placebo at all time points. A slightly greater mean reduction from baseline in LVEF and LVFS was observed for the 200-mg dose compared with the 100-mg dose and placebo, but these changes were small and not clinically significant. A similar pattern of a slightly greater effect for the 200-mg dose was observed for LVET and HR.
PK/PD Correlation
PK/PD model parameters were reliably estimated, with nearly all demonstrating a percent residual standard error (RSE) <30% (Fig. 6). Participant demographics were deemed not significant as model covariates. The 90% CIs of the slope estimates all lay below zero, indicating a statistically significant relationship between the absolute or change from baseline in the PD measure and ulacamten plasma concentrations and confirming material target engagement at the evaluated ulacamten doses. Similar relationships are observed when treating the PD measure as absolute or change from baseline. In the model-based PK/PD analysis, ulacamten plasma concentrations demonstrated modest but consistent relationships with all evaluated echocardiographic PD measures: (a) approximately a 1% decrease from baseline in LVEF for every 267-ng/mL increase in ulacamten; (b) an approximately 1% decrease from baseline in LVFS for every 187-ng/mL increase in ulacamten; and (c) an approximately 1-ms decrease from baseline in LVET for every 59-ng/mL increase in ulacamten.
Fig. 6.
Change from baseline in three markers of contractility as a function of ulacamten plasma concentrations following single and multiple doses of ulacamten. a LVEF; b LVET; c LVFS. Blue line (gray shaded area) indicates model estimated relationship (90% prediction interval). Dashed black line indicates locally smoothed estimate of central tendency. LVEF left ventricular ejection fraction, LVET left ventricular ejection time, LVFS left ventricular fractional shortening. Figure created using GraphPad Prism
Cardiodynamic ECGs
ECG data were collected on Day 1 (SAD and MAD) and Day 7 (MAD). Detailed cardiodynamic categorical summary data by treatment on Day 1 and Day 7 are presented in Tables S5–6 (see ESM). All cardiodynamic parameters fell within normal categorical ranges, except for two participants in the SAD cohort who exhibited slightly higher-than-normal PR interval values (> 200 ms and ≤ 220 ms). There were no significant observations in the categorical or waveform analyses.
Discussion
Ulacamten is a small molecule cardiac myosin inhibitor in development for potential treatment of patients with HFpEF. It directly reduces cardiac contractility at the level of the cardiac sarcomere [15]. The objective of this phase I study was to characterize safety, tolerability, PK, and PD of ulacamten in healthy participants to inform further clinical development in patients with HFpEF.
Ulacamten had a favorable safety and tolerability profile over the dose range and duration evaluated in this healthy participant study, including single doses that ranged from 10 to 600 mg and multiple doses of 100–200 mg once daily for 7 days. AEs were mild or moderate in severity and resolved by the end of the study. Across the study, there were no SAEs, deaths, or any notable changes in laboratory values, vital signs, or ECG results following ulacamten administration, suggesting no major safety signals over the evaluated doses and duration.
Ulacamten demonstrated PK properties supporting once-daily administration. Following single and multiple oral doses across the dose range evaluated (10–600 mg), ulacamten was rapidly absorbed, with Cmax achieved between 1.5 and 5 h post dose (median tmax) and a median steady-state half-life ranging between 14 and 18 h. Consistent with half-life and once-daily dosing, only 37–69% accumulation of ulacamten was observed at steady state (7 days of dosing). Ulacamten single- and multiple-dose exposure increased in a generally linear and dose-proportional manner over a wide range of doses.
CK-4022235, the primary, pharmacologically inactive metabolite of ulacamten, circulated in plasma with mean exposure (AUC0–∞) of 28% of the parent drug. The plasma PK for CK-4022235 mirrored trends observed for ulacamten with respect to linearity, accumulation, and effect of food. The t½ of CK-4022235 was similar to the parent drug, ranging from about 17 to 19 h. CK-4022235 AUC∞ and Cmax increased with increasing dose in both a linear and proportional manner across the dose range evaluated. Evaluation of total amount of unchanged ulacamten excreted in urine over a dosing interval (0–24 h) at steady state (Day 7) indicated that renal elimination of ulacamten was minimal in the urine as parent (%Fe of 0.88–1.09%) or metabolite (Fe of 0.55–0.70%).
The effect of food on the PK of ulacamten was evaluated following the administration of a single 150-mg tablet under fed or fasted conditions. Presence of food (high-fat meal) resulted in prolonged absorption and a small but significant increase in exposure of ulacamten (AUC0–∞ increased by 10%, with no change in Cmax). There was no significant change in CK-4022235 exposures. Although the presence of food modestly increased the exposure of ulacamten, it is not anticipated to impact clinical safety. Therefore, ulacamten can be taken with or without food.
ECG parameters were within the normal range throughout the study and comparable for ulacamten treatments and pooled placebo. Modest, transient decreases in echocardiographic PD measures LVEF, LVFS, and LVET were observed, most notably at the highest doses, without a linear dose-response. Critically, these on-target effects were not associated with clinical concern in healthy participants; individual LVEF values were predominantly ≥ 50%, and all instances below this threshold were transient and asymptomatic.
The model-based PK/PD analyses demonstrated that increased ulacamten plasma concentrations provide for a direct but consistent decrease in key echocardiographic measures of systolic function (LVEF, LVFS, and LVET). This analysis used individual concentration and PD data across dose levels and time points, providing a concentration–response assessment distinct from the cohort-level PD analyses. Decreases in these PD measures are evidence of target engagement of the cardiac myosin by ulacamten. Furthermore, the observed PK/PD relationships are modest but consistent, suggesting minimal decrease in systolic function will occur over a large range of ulacamten exposures.
The sample size and treatment duration is considered appropriate for a phase I healthy participant study, which allows for focus on safety and PK. Considering the PD assessments (LVEF, LVFS, and LVET) were obtained in healthy participants with normal cardiac structure and function, PK/PD and short-term tolerability findings should be extrapolated with caution in patients with HFpEF. The study population had limited demographic diversity, which may limit generalizability of certain study findings to the broader HFpEF population.
Taken together, the favorable safety profile, predictable PK, and evidence of target engagement support further clinical evaluation of ulacamten in patients with HFpEF. These data provide early clinical experience with ulacamten in the context of HFpEF, diverging from other agents in this class that have historically targeted hypertrophic cardiomyopathy. These first-in-human data therefore establish a foundation for determining whether the selective modulation of cardiac contractility can offer a needed therapeutic strategy for this condition with limited treatment options.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the volunteers and staff who participated in the study. The authors would like to thank Sunila Reddy, PharmD, for her support with the manuscript writing.
Author contributions
J.D.L., T.S., G.L., C.D., R.S., S.B.H., S.K., and P.G. designed the study; J.D.L., N.M., and P.G. wrote the manuscript; J.D.L., N.M., T.S., G.L., C.D, K.C. performed the study; J.D.L., N.M., T.S., A.G., G.L., S.B.H., S.K., and P.G. analyzed the data.
Funding
This study was funded by Cytokinetics, Inc.
Declarations
Conflict of interest
All authors are employees of and shareholders in Cytokinetics, Inc.
Availability of data and material
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials and can also be obtained from the corresponding author upon reasonable request. This study was conducted in compliance with the ethical principles set forth in the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice (ICH GCP) and was registered at ClinicalTrials.gov.
Consent to participate
All participants provided written informed consent.
Consent for publication
Not applicable.
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