aficamten (CK-274) / Cytokinetics, CORXEL, Bayer - LARVOL DELTA

Cas13-Mediated RNA Base Editing Using mxABE Restores Heart Function in a Humanized Hypertrophic Cardiomyopathy Model (ASGCT 2025) - "Current treatments, such as Aficamten and Mavacamten, do not address the underlying genetic cause and have significant side effects. This study demonstrates the successful application of mxABE, a CRISPR-Cas13-based RNA base editor being developed for HCM treatment by correcting the MYH7 mutation. The AAV-mxABE therapy effectively prevented heart remodeling and restored heart function in a humanized Myh6 hR403Q/+ mouse model, highlighting its potential as a safe and targeted therapeutic strategy for hereditary cardiomyopathies. Disease Focus of Abstract:Other Other: Genetic Heart Disease"

Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertrophic Cardiomyopathy • Immunology • MYH7

Concomitant Aficamten and Disopyramide in Symptomatic Obstructive Hypertrophic Cardiomyopathy. (PubMed, JACC Heart Fail) - P2, P2/3, P3 | "In this cohort of patients with symptomatic oHCM with persistent LVOT obstruction, combination therapy with aficamten and disopyramide was safe and well tolerated but did not enhance clinical efficacy vs aficamten alone. For such oHCM patients, aficamten treatment may be considered with an option to discontinue disopyramide. (Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM [REDWOOD-HCM]; NCT04219826) (Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [SEQUOIA-HCM]; NCT05186818) (Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Aficamten in Adults With HCM [FOREST-HCM]; NCT04848506)."

Journal • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Cardiac myosin inhibition in hypertrophic cardiomyopathy: review of the evolving evidence base. (PubMed, Expert Rev Cardiovasc Ther) - "Mavacamten and aficamten are the first 2 drugs in this class with high-quality phase III randomized clinical trial data (Based on PUBMED search, last query April 2025). There is a growing body of evidence based on high-quality scientific investigation that are broadening the therapeutic options for patients with this condition. However, as different drugs emerge in the same class, it is crucial to appreciate clinically meaningful class-based effects vs. specific drug differences."

Clinical • Journal • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

SEQUOIA­HCM: Effect of aficamten treatment on patients with hypertrophic obstructive cardiomyopathy by geographical region (HEART FAILURE 2025) - No abstract available

Clinical • Late-breaking abstract • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Efficacy and safety of aficamten in patients with obstructive hypertrophic cardiomyopathy and mild symptoms (HEART FAILURE 2025) - No abstract available

Clinical • Late-breaking abstract • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Efficacy of aficamten in obstructive hypertrophic cardiomyopathy: A systematic review and meta-analysis. (PubMed, Am Heart J Plus) - "The small sample sizes, diverse study designs and single-arm analysis limit our findings. More robust trials with larger sample sizes are required to establish conclusive evidence."

Journal • Retrospective data • Review • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Clinical Evaluation of the Effect of Aficamten on QT/QTc Interval in Healthy Participants. (PubMed, Clin Transl Sci) - P3 | "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. 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."

Clinical • Journal • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy

SAFETY AND OUTCOMES OF CONCOMITANT AFICAMTEN AND DISOPYRAMIDE USE AND WITHDRAWAL IN PATIENTS WITH OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY: AN ANALYSIS OF REDWOOD-HCM COHORT 3, SEQUOIA-HCM, AND FOREST-HCM TRIALS - Ahmad Masri (ACC 2025) - "The addition of aficamten to diso for a selected group of oHCM patients with persistent LVOT obstruction was safe and effective. Furthermore, withdrawal of diso did not compromise efficacy of aficamten."

Clinical • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

ATRIAL AND VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY TREATED WITH CARDIAC MYOSIN INHIBITORS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CLINICAL TRIALS - Luis Rene Puglla Sanchez (ACC 2025) - "In this meta-analysis of RCTs among patients with HCM, there was no difference in the incidence of supraventricular or ventricular arrhythmias in patients treated with CMI or placebo over a mean follow-up of 23 weeks."

Retrospective data • Review • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy

EFFECT OF AFICAMTEN TREATMENT FOR UP TO 72 WEEKS ON CARDIAC STRUCTURE AND FUNCTION IN PATIENTS WITH OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY: THE SEQUOIA-HCM AND FOREST-HCM CMR SUB-STUDIES - Ahmad Masri (ACC 2025) - "Longer-term treatment with aficamten over 48-72 weeks resulted in favorable cardiac remodeling with reduction in LV mass, LA volume, and MR while myocardial fibrosis remained stable."

Clinical • Cardiomyopathy • Cardiovascular • Fibrosis • Hypertrophic Cardiomyopathy • Immunology • Obstructive Hypertrophic Cardiomyopathy

EVALUATION OF CYTOCHROME P450 2C9, 2C19, AND 2D6 INHIBITION ON THE PHARMACOKINETICS OF AFICAMTEN IN HEALTHY PARTICIPANTS - Neha Maharao (ACC 2025) - "AFI was given alone and with multiple daily doses (≥9 days before AFI dosing) of fluconazole (FLZ; strong CYP2C19 and moderate CYP 2C9/3A inhibitor), paroxetine (PRX; strong selective CYP2D6 inhibitor), and fluoxetine (FLX; strong CYP 2C19/2D6 inhibitor). AFI was primarily eliminated by CYP2C9 (fraction metabolized [fm]=50%), with contributions from CYPs 3A (fm=26%, historical data), 2D6 (fm=21%), and 2C19 (fm=3%). Weak DDIs are likely from strong inhibition of any one pathway and only moderate DDIs are expected with moderate to strong multi-pathway inhibitors."

Clinical • PK/PD data • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • CYP2C19 • CYP2C9

CARDIAC MYOSIN INHIBITORS FOR HYPERTROPHIC CARDIOMYOPATHY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS - Adeel Ahmad (ACC 2025) - "CMIs can contribute to improving key efficacy outcomes for patients withhypertrophic cardiomyopathy while reducing the incidence of SRT."

Retrospective data • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy

UNDERSTANDING THE IMPACT OF PLACEBO ON PATIENT-REPORTED HEALTH STATUS: AN ANALYSIS FROM SEQUOIA-HCM - Charles Sherrod (ACC 2025) - P3 | "Background: Given that patient-reported outcomes are often considered particularly susceptible to placebo effects and their growing importance in obstructive hypertrophic cardiomyopathy (oHCM), clinicians need to understand how much changes in placebo-assigned patients' health status may be due to a 'placebo effect' rather than more intensive care at specialized oHCM centers, changes in treatment adherence, or regression to the mean. In the SEQUOIA-HCM study (NCT05186818), patients with symptomatic oHCM were randomized to aficamten or placebo and treated for 24 weeks, followed by blinded treatment withdrawal... In SEQUOIA-HCM, about one-third of the KCCQ-OSS improvement in those treated with placebo was due to placebo effects, and the residual improvement was due to other unmeasured effects. These findings suggest that changes in health status following placebo treatment should not be completely ascribed to placebo effects."

Clinical • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Can Generative AI Conduct Evidence Gap Analysis in HEOR? A Case Study of Hypertrophic Cardiomyopathy Using ValueGen.AI (ISPOR 2025) - "Generative AI can rapidly and effectively identify literature gaps, as demonstrated by ValueGen.AI in revealing deficiencies in epidemiological data across diverse populations and limited real-world evidence on patient-reported outcomes and costs in HCM."

Case study • Clinical • HEOR • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy

A Characterization of the Nonclinical Pharmacology and Toxicology of Aficamten, a Reversible Allosteric Inhibitor of Cardiac Myosin. (PubMed, Int J Toxicol) - "These findings were largely reversible and consistent with excessive on-target pharmacology associated with cardiac myosin inhibition. The reversible nature of aficamten-associated adverse effects is supportive of its clinical safety as this property suggests that these findings, should they occur in humans, may also be reversible, limiting long-term human cardiac risk."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy

Effect of Aficamten Treatment for Up to 72 Weeks on Cardiac Structure and Function in Patients with Obstructive Hypertrophic Cardiomyopathy: The SEQUOIA-HCM and FOREST-HCM CMR Sub-studies (964-09) (GlobeNewswire) - P3 | N=282 | SEQUOIA-HCM (NCT05186818) | P2/3 | N=900 | FOREST-HCM (NCT04848506) | Sponsor: Cytokinetics | "Longer-term treatment with aficamten resulted in statistically significant improvements (mean ±SD) in measures of cardiac structure and function including left ventricular mass index (-9.8 g/m2 ±18.1, p<0.0001), maximum left ventricular septal wall thickness (-2.4 mm ±2.3, p<0.0001), left atrial volume (-17.9 ml ±28.3, p<0.0001) and mitral regurgitant volume (-18.1 ml ±19.2, p<0.0001) and fraction (-14.2% ±15.6, p<0.0001). These changes were accompanied by stable replacement fibrosis (late gadolinium enhancement mass = -0.3 g ±5.0, p=0.51) and reduced interstitial fibrosis (global extracellular volume (ECV) = -1.2 % ±2.8, p = 0.002; Native T1 = -36.6 ms ±55.7, p<0.0001)."

P2/3 data • P3 data • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Understanding the Impact of Placebo on Patient-Reported Health Status: An Analysis from SEQUOIA-HCM (1029-176) (GlobeNewswire) - P3 | N=282 | SEQUOIA-HCM (NCT05186818) | Sponsor: Cytokinetics | "In patients randomized to placebo in SEQUOIA-HCM, the change in KCCQ-OSS was evaluated from baseline to Week 24 and following blinded treatment withdrawal from Week 24 to Week 28. Among the 140 (47%) patients on placebo, the median KCCQ-OSS at baseline was 67.2 (95% CI: 62.9, 71.5) and the median improvement at Week 24 was 5.7 points (95% CI: 3.2, 8.3; p<0.01). After withdrawal from Week 24 to Week 28, the median score decreased by only 2.1 points (95% CI: -3.5, -0.7; p<0.01)."

P3 data • Patient reported outcomes • Obstructive Hypertrophic Cardiomyopathy

Safety and Outcomes of Concomitant Aficamten and Disopyramide Use and Withdrawal in Patients with Obstructive Hypertrophic Cardiomyopathy: An Analysis of REDWOOD-HCM Cohort 3, SEQUOIA-HCM, and FOREST-HCM Trials (411-06) (GlobeNewswire) - "Combination therapy with aficamten and disopyramide was well-tolerated; the analysis suggests that combination of disopyramide with aficamten did not result in lower left ventricular outflow tract (LVOT) gradients compared to treatment with aficamten alone. The analysis suggests that withdrawal of disopyramide while receiving aficamten did not reduce the efficacy of aficamten and further that withdrawal of aficamten while on disopyramide resulted in the return of LVOT obstruction and symptoms, with an increase in NT-proBNP. There were no safety events reported with either aficamten or disopyramide withdrawal, and no episodes of atrial fibrillation after disopyramide withdrawal were reported."

Retrospective data • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Safety and Efficacy of Mavacamten and Aficamten in Patients With Hypertrophic Cardiomyopathy. (PubMed, J Am Heart Assoc) - "Mavacamten and aficamten represent effective medications for the treatment of symptomatic oHCM."

Journal • Atrial Fibrillation • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertrophic Cardiomyopathy • Non-obstructive Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Advances in Cardiovascular Pharmacotherapy. I. Cardiac Myosin Inhibitors. (PubMed, J Cardiothorac Vasc Anesth) - "In this article, the authors review the molecular mechanisms of action of cardiac myosin inhibitors, discuss in detail the most recent data from mavacamten and aficamten clinical trials, describe future planned studies designed to address unanswered questions about their clinical utility in HCM phenotypes, and comment on their potential application to patients with other forms of heart failure with preserved ejection fraction. The possible anesthetic implications of mavacamten and aficamten are also discussed because it is highly likely that patients who are treated with these medications will begin to present for perioperative care with increasing regularity."

Journal • Review • Anesthesia • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertrophic Cardiomyopathy • Immunology

The evolving landscape of hypertrophic cardiomyopathy management: a review of the updated AHA/ACC/multisociety guidelines (PubMed, G Ital Cardiol (Rome)) - "Therapeutic options for the treatment of hypertrophic obstructive cardiomyopathy have recently expanded with the introduction of myosin inhibitors, mavacamten and aficamten, which demonstrated a remarkable effect on functional capacity and symptoms of patients with left ventricular outflow tract obstruction. In recent years, there has also been a change in the approach to physical exercise in patients with hypertrophic cardiomyopathy, which now also includes the possibility of participating in high-intensity and competitive sports for selected patients with a low-risk profile. In this review, we explore the main innovations of the American College of Cardiology/American Heart Association guidelines on hypertrophic cardiomyopathy, we highlight the differences with the guidelines on the management of cardiomyopathies of the European Society of Cardiology, and we highlight some important unresolved issues in the management of the disease."

Journal • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Efficacy of cardiac myosin inhibitors mavacamten and aficamten in hypertrophic cardiomyopathy: a systematic review and meta-analysis of randomised controlled trials. (PubMed, Open Heart) - "According to our meta-analysis, cardiac myosin inhibitors significantly improve the resting and post-Valsalva LVOT gradient, reduce the LVEF and improve the NYHA class and cardiac biomarkers when compared with the placebo."

Clinical • Journal • Retrospective data • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • TNNI3

Aficamten vs Metoprolol for Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM Rationale, Study Design, and Baseline Characteristics. (PubMed, JACC Heart Fail) - P3 | "The authors describe the rationale, design, and baseline characteristics of patients in this study. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM [MAPLE-HCM]; NCT05767346)."

Clinical • Journal • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy

Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten. (PubMed, Clin Pharmacokinet) - "No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment."

Journal • PK/PD data • Cardiomyopathy • Cardiovascular • Hepatology • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy • Renal Disease

Efficacy and safety of cardiac myosin inhibitors for symptomatic hypertrophic cardiomyopathy: a meta-analysis of randomized controlled trials. (PubMed, Front Cardiovasc Med) - "Cardiac myosin inhibitors such as mavacamten and aficamten present potential new treatment options. They offer a promising alternative to current treatments, with a safety profile comparable to placebo. Further research is needed to confirm long-term benefits."

Journal • Retrospective data • Review • Cardiomyopathy • Cardiovascular • Hypertrophic Cardiomyopathy • Obstructive Hypertrophic Cardiomyopathy