Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants
ABSTRACT Aficamten is a next‐in‐class, small‐molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2‐part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (n = 10) was an open‐label study to find the appropriate...
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Wiley
2025-04-01
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| Series: | Clinical and Translational Science |
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| Online Access: | https://doi.org/10.1111/cts.70218 |
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| author | Neha Maharao Donghong Xu Tyrell J. Simkins Owen Bowles Genzhou Liu Youcef Benattia Adrienne Griffith Stephen B. Heitner Stuart Kupfer Polina German |
| author_facet | Neha Maharao Donghong Xu Tyrell J. Simkins Owen Bowles Genzhou Liu Youcef Benattia Adrienne Griffith Stephen B. Heitner Stuart Kupfer Polina German |
| author_sort | Neha Maharao |
| collection | DOAJ |
| description | ABSTRACT Aficamten is a next‐in‐class, small‐molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2‐part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (n = 10) was an open‐label study to find the appropriate dose for thorough QT (TQT) evaluation in Part B. Part B (n = 34) was a double‐blind, 3‐way crossover TQT study conducted as per ICH E14 guidance using negative (placebo) and positive (moxifloxacin) controls. A single 50 mg aficamten dose achieved exposures (Cmax range: 124–1660 ng/mL) comparable to the highest clinical dose (20 mg QD) in obstructive HCM patients (NCT05186818; [Cmax range: 131–1230 ng/mL]) and was chosen for TQT evaluation. Using concentration‐QT (C‐QT) modeling, the placebo‐ and baseline‐corrected QT interval using Fridericia's correction (ΔΔQTcF) was −1.82 msec (90% CI: −3.43, −0.214) at peak aficamten concentrations (298.3 ng/mL) following the 50 mg dose. The 90% CI upper bound of ΔΔQTcF for aficamten was < 10 msec at all post‐dose time points. Assay sensitivity was established by the 90% CI lower bound for moxifloxacin (ΔΔQTcF) exceeding 5 msec. Aficamten did not cause QTc prolongation (using C‐QT and by time point analyses) within observed plasma concentrations up to 1660 ng/mL (aficamten), 213 ng/mL (metabolite CK‐3834282), and 343 ng/mL (metabolite CK‐3834283). No clinically meaningful effect on electrocardiogram parameters, including absolute QTcF (≤ 450 msec) and change from baseline in QTcF (≤ 30 msec) was noted in aficamten‐treated participants. Aficamten was generally well tolerated. In conclusion, there was no evidence of aficamten‐mediated QTc prolongation across the therapeutic concentration range in a formal TQT study. |
| format | Article |
| id | doaj-art-c997a24c000943ecb71643ee83cdb7fd |
| institution | OA Journals |
| issn | 1752-8054 1752-8062 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| series | Clinical and Translational Science |
| spelling | doaj-art-c997a24c000943ecb71643ee83cdb7fd2025-08-20T02:18:43ZengWileyClinical and Translational Science1752-80541752-80622025-04-01184n/an/a10.1111/cts.70218Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy ParticipantsNeha Maharao0Donghong Xu1Tyrell J. Simkins2Owen Bowles3Genzhou Liu4Youcef Benattia5Adrienne Griffith6Stephen B. Heitner7Stuart Kupfer8Polina German9Department of Clinical Pharmacology Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Pharmacology Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Research Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Operations Cytokinetics, Incorporated South San Francisco California USADepartment of Biostatistics Cytokinetics, Incorporated South San Francisco California USADepartment of Drug Safety and Pharmacovigilance Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Pharmacology Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Research Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Research Cytokinetics, Incorporated South San Francisco California USADepartment of Clinical Pharmacology Cytokinetics, Incorporated South San Francisco California USAABSTRACT Aficamten is a next‐in‐class, small‐molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2‐part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (n = 10) was an open‐label study to find the appropriate dose for thorough QT (TQT) evaluation in Part B. Part B (n = 34) was a double‐blind, 3‐way crossover TQT study conducted as per ICH E14 guidance using negative (placebo) and positive (moxifloxacin) controls. A single 50 mg aficamten dose achieved exposures (Cmax range: 124–1660 ng/mL) comparable to the highest clinical dose (20 mg QD) in obstructive HCM patients (NCT05186818; [Cmax range: 131–1230 ng/mL]) and was chosen for TQT evaluation. Using concentration‐QT (C‐QT) modeling, the placebo‐ and baseline‐corrected QT interval using Fridericia's correction (ΔΔQTcF) was −1.82 msec (90% CI: −3.43, −0.214) at peak aficamten concentrations (298.3 ng/mL) following the 50 mg dose. The 90% CI upper bound of ΔΔQTcF for aficamten was < 10 msec at all post‐dose time points. Assay sensitivity was established by the 90% CI lower bound for moxifloxacin (ΔΔQTcF) exceeding 5 msec. Aficamten did not cause QTc prolongation (using C‐QT and by time point analyses) within observed plasma concentrations up to 1660 ng/mL (aficamten), 213 ng/mL (metabolite CK‐3834282), and 343 ng/mL (metabolite CK‐3834283). No clinically meaningful effect on electrocardiogram parameters, including absolute QTcF (≤ 450 msec) and change from baseline in QTcF (≤ 30 msec) was noted in aficamten‐treated participants. Aficamten was generally well tolerated. In conclusion, there was no evidence of aficamten‐mediated QTc prolongation across the therapeutic concentration range in a formal TQT study.https://doi.org/10.1111/cts.70218cardiovascular diseasephase 1QTQTc intervalsafety |
| spellingShingle | Neha Maharao Donghong Xu Tyrell J. Simkins Owen Bowles Genzhou Liu Youcef Benattia Adrienne Griffith Stephen B. Heitner Stuart Kupfer Polina German Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants Clinical and Translational Science cardiovascular disease phase 1 QT QTc interval safety |
| title | Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants |
| title_full | Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants |
| title_fullStr | Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants |
| title_full_unstemmed | Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants |
| title_short | Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants |
| title_sort | clinical evaluation of the effect of aficamten on qt qtc interval in healthy participants |
| topic | cardiovascular disease phase 1 QT QTc interval safety |
| url | https://doi.org/10.1111/cts.70218 |
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