A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants

Malik, Fady I.; Robertson, Laura; Armas, Danielle; Robbie, Edward P; Osmukhina, Anna; Xu, Donghong; Li, Hanbin; Solomon, Scott D.

doi:10.1016/j.jacbts.2022.04.008

Cited by 22 publications

(15 citation statements)

References 16 publications

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“…CMIs have been recently developed as a therapy for HCM to directly reduce the myocardial hypercontractility that underlies the pathophysiology of HCM. CMIs target the myofilament apparatus to decrease the number of actin-myosin cross-bridges, thus resulting in dose-dependent reduction in contractility [ 38 , 39 ]. As CMIs are a targeted disease-specific therapy, they promise less side-effects compared to non-targeted therapy [ 38 , 40 ].…”

Section: Cardiac Myosin Inhibitors (Cmis) Developmentmentioning

confidence: 99%

“…In a phase I clinical trial in healthy adults, aficamten was well tolerated, adverse events were generally mild and comparable in frequency to those seen with placebo [ 39 ]. The double-blind, placebo-controlled, dose-finding Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM (REDWOOD-HCM) phase 2 trial enrolled a total of 95 patients across 4 cohorts.…”

Section: Cardiac Myosin Inhibitors (Cmis) Developmentmentioning

confidence: 99%

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Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?

Lee,

Masri

2023

Curr Heart Fail Rep

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Purpose of Review Cardiac myosin inhibitors (CMIs) and activators are emerging therapies for hypertrophic cardiomyopathy (HCM) and heart failure with reduced ejection fraction (HFrEF), respectively. However, their effects on cardiac troponin levels, a biomarker of myocardial injury, are incompletely understood. Recent Findings In patients with HCM, CMIs cause substantial reductions in cardiac troponin levels which are reversible after stopping treatment. In patients with HFrEF, cardiac myosin activator (omecamtiv mecarbil) therapy cause modest increases in cardiac troponin levels which are reversible following treatment cessation and not associated with myocardial ischaemia or infarction. Summary Transient changes in cardiac troponin levels might reflect alterations in cardiac contractility and mechanical stress. Such transient changes might not indicate cardiac injury and do not appear to be associated with adverse outcomes in the short to intermediate term. Longitudinal changes in troponin levels vary depending on the population and treatment. Further research is needed to elucidate mechanisms underlying changes in troponin levels.

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Section: Cardiac Myosin Inhibitors (Cmis) Developmentmentioning

confidence: 99%

Section: Cardiac Myosin Inhibitors (Cmis) Developmentmentioning

confidence: 99%

Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?

Lee,

Masri

2023

Curr Heart Fail Rep

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“…10 Aficamten is metabolized via CYP2D6, although no formal dosing guidance exists for management of concurrent drug interactions with CYP2D6 inducers, inhibitors, or substrates. 14 CYP2D6 phenotype did not affect the pharmacokinetics of aficamten. In pharmacokinetic analyses, the presence of food did not appear to impact the bioavailability of aficamten, suggesting it may be taken in either a fasted or fed state.…”

Section: Pharmacologymentioning

confidence: 84%

Cardiac Myosin Inhibitors: Expanding the Horizon for Hypertrophic Cardiomyopathy Management

et al. 2023

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Objective: To review the current literature on the efficacy and safety of cardiac myosin inhibitors (CMIs) for the treatment of hypertrophic cardiomyopathy (HCM). Data Sources: A literature search was conducted on PubMed from origin to April 2023, using the search terms “MYK-461,” “mavacamten,” “CK-3773274,” and “aficamten.” Studies were limited to English-based literature, human subjects, and clinical trials resulting in the inclusion of 13 articles. ClinicalTrials.gov was also used with the same search terms for ongoing and completed trials. Study Selection and Data Extraction: Only phase II and III studies were included in this review except for pharmacokinetic studies that were used to describe drug properties. Data Synthesis: CMIs enable cardiac muscle relaxation by decreasing the number of myosin heads that can bind to actin and form cross-bridges. Mavacamten, the first Food and Drug Administration (FDA)-approved drug in this class, has been shown to improve hemodynamic, functional, and quality of life measures in HCM with obstruction. In addition, aficamten is likely to become the next FDA-approved CMI with promising phase II data and an ongoing phase III trial expected to release results in the next year. Relevance to Patient Care and Clinical Practice in Comparison with Existing Drugs: CMIs provide a novel option for obstructive hypertrophic cardiomyopathy, particularly in those not suitable for septal reduction therapy. Utilization of these agents requires knowledge of drug interactions, dose titration schemes, and monitoring parameters for safety and efficacy. Conclusions: CMIs represent a new class of disease-specific drugs for treatment of HCM. Cost-effectiveness studies are needed to delineate the role of these agents in patient therapy.

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“…In contrast with mavacamten, it has a shorter half-life and fewer drug–drug interactions and has shown promise in preliminary results from its initial phase II clinical trial program. 63 , 64 The REDWOOD-HCM trial evaluated the safety and tolerability of aficamten in patients with symptomatic obstructive HCM and demonstrated that compared with placebo, treatment with aficamten resulted in rapid and sustained reduction in LVOT gradients, improvement in NYHA class, and decrease in cardiac biomarkers. 65 Importantly, there were no serious adverse events related to aficamten and no treatment interruptions or discontinuations due to adverse events.…”

Section: Managementmentioning

confidence: 99%

Familial Hypertrophic Cardiomyopathy: Diagnosis and Management

Litt¹,

Ali²,

Reza³

2023

VHRM

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Hypertrophic cardiomyopathy (HCM) is widely recognized as one of the most common inheritable cardiac disorders. Since its initial description over 60 years ago, advances in multimodality imaging and translational genetics have revolutionized our understanding of the disorder. The diagnosis and management of patients with HCM are optimized with a multidisciplinary approach. This, along with increased safety and efficacy of medical, percutaneous, and surgical therapies for HCM, has afforded more personalized care and improved outcomes for this patient population. In this review, we will discuss our modern understanding of the molecular pathophysiology that underlies HCM. We will describe the range of clinical presentations and discuss the role of genetic testing in diagnosis. Finally, we will summarize management strategies for the hemodynamic subtypes of HCM with specific emphasis on the rationale and evidence for the use of implantable cardioverter defibrillators, septal reduction therapy, and cardiac myosin inhibitors.

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A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants

Cited by 22 publications

References 16 publications

Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?

Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?

Cardiac Myosin Inhibitors: Expanding the Horizon for Hypertrophic Cardiomyopathy Management

Familial Hypertrophic Cardiomyopathy: Diagnosis and Management

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