Multiple-Dose Up-Titration Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Omecamtiv Mecarbil in Healthy Chinese Subjects - Abstract and Study Design

Sep 28, 2026

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Phase I multiple-dose up-titration study evaluates omecamtiv mecarbil given as 25 mg twice daily, followed by titration to 37.5 or 50 mg twice daily in healthy Chinese participants. Fifty participants were randomized into three groups: two active-dose pathways with period 2 titration and a placebo group receiving placebo across both periods. Pharmacokinetics were characterized by half-life, exposure accumulation, and concentration ratios; no serious adverse events occurred, and reported events included creatine kinase increases, glucose elevations, and bradycardia.

LanguageEnglish

CategoryHealthcare

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Pages10

Reading Time25 min

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Abstract

Background and Objectives

Methods

Results

Conclusions

Drugs in R&D (2025) 25:377–386 [https://doi.org/10.1007/s40268-025-00532-7](https://doi.org/10.1007/s40268-025-00532-7) Multiple‑Dose Up‑Titration Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Omecamtiv Mecarbil in Healthy Chinese Subjects Xuening Li1 · Hui Li1 · Hongrong Xu1 · Fei Yuan1 · Hanjing Chen1 · Chao Liu1 · Mengjie Yang1 · Jing Li1 · Lei Sheng1 Received: 7 July 2025 / Accepted: 13 November 2025 / Published online: 8 December 2025 © The Author(s) 2025 Abstract Background and Objectives This phase I study was designed to evaluate the safety, tolerability, and pharmacokinetics of omecamtiv mecarbil with multiple oral doses at 25 mg twice daily, followed by titration to either 37.5 or 50 mg twice daily in healthy Chinese participants. Methods Fifty healthy participants were enrolled and randomly assigned into three groups: Group A (20 subjects) received omecamtiv mecarbil 25 mg in period 1 and either 37.5 mg or 25 mg in period 2; Group B (20 subjects) received omecamtiv mecarbil 25 mg in period 1 and either 50 mg or 25 mg in period 2; and Group C (10 subjects) received a placebo in both periods. Results The pharmacokinetics of omecamtiv mecarbil were well characterized in healthy Chinese participants. Across all subgroups, the mean terminal elimination half-life ranged from 18.3 to 21.3 h. Mean accumulation ratios of area under the curve from time 0 to 12 h ranged from 4.54 to 5.01 in period 1 and 2. The mean maximum observed concentration/plasma concentration before dosing ratios varied between 1.23 and 1.31 on days 8 and 34 across subgroups. No subjects experienced serious adverse events. The most frequently reported adverse events were an increased blood creatine kinase levels (12.5% of subjects in the omecamtiv mecarbil group, 10% in the placebo group), increased blood glucose levels (7.5%, 0), and bradycardia (10%, 0) . Conclusions Omecamtiv mecarbil was well tolerated at the dose levels of 25–50 mg in healthy Chinese participants according to a pharmacokinetic-based titration scheme. Exposure of omecamtiv mecarbil was dose proportional, and no dose-related trends were observed in treatment-emergent adverse events. * Lei Sheng [shenglei@fudan.edu.cn](shenglei@fudan.edu.cn) 1 Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai 200032, China 1 Introduction Omecamtiv mecarbil is a novel, selective, cardiac myosin activator that has shown promise in treating heart failure with reduced ejection fraction (HFrEF) by stabilizing the actin-bound myosin conformation, leading to an increase in the number of myosin heads that are in the “forcegenerating” state [1] . In several clinical trials, omecamtivmecarbil has shown promise in reducing heart failure (HF) events and improving cardiovascular outcomes in patients with HF according to a predefined pharmacokinetic (PK) -based titration scheme [2–5] . The phase II COSMIC-HF trial demonstrated significant improvements in cardiac function and biomarkers under the PK-based titration scheme, including changes in systolic ejection time, stroke volume, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, and N-terminal pro B-type natriuretic peptide levels [4] . The phase III GALACTIC-HF trial showed that omecamtiv mecarbil under a PK-based dose titration scheme significantly reduced the risk of cardiovascular death or HF events in patients with HFrEF when added to standard therapy [5] . Despite the promising efficacy observed in the GALACTIC-HF, omecamtiv mecarbil was not approved by the US Food and Drug Administration in 2023. The advisory committee had concerns about the modest treatment effect and questions regarding the overall benefit-risk profile [6] . The pharmacokinetics and pharmacodynamics of omecamtiv mecarbil have been investigated in both healthy participants and patients with HFrEF [7–10] . Omecamtiv mecarbil is well tolerated when administered orally or intra

FAQs

What was the primary purpose of this phase I study?

To evaluate the safety, tolerability, and pharmacokinetics of omecamtiv mecarbil using a multiple oral-dose regimen with PK-based titration in healthy Chinese participants.

How were participants assigned to treatment groups?

Fifty healthy participants were randomized into three groups: Group A (25 mg in period 1 with 37.5 or 25 mg in period 2), Group B (25 mg in period 1 with 50 or 25 mg in period 2), and Group C (placebo in both periods).

What were the main pharmacokinetic and safety findings?

Omecamtiv mecarbil pharmacokinetics were well characterized, with terminal elimination half-life around 18.3–21.3 h and no serious adverse events. The most frequent adverse events included increased blood creatine kinase, increased blood glucose, and bradycardia.

Sep 28, 2026

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