Plasma neurofilament analysis in VITALITY-ALS.

Objective: To evaluate correlations between neurofilament (Nf) concentrations and clinical characteristics and disease progression using a large longitudinal dataset from VITALITY-ALS (ClinicalTrials.gov identifier: NCT02496767), a 48-week, randomized, double-blind, placebo-controlled clinical trial of in people with ALS (pALS).

Methods: Plasma was collected at baseline and every 8 weeks thereafter.

Standard-of-Care Medication Withdrawal in Patients With Obstructive Hypertrophic Cardiomyopathy Receiving Aficamten in FOREST-HCM.

Background: Standard-of-care (SoC) medications for the treatment of obstructive hypertrophic cardiomyopathy (oHCM) are recommended as first-line therapy despite the lack of evidence from controlled clinical trials and well known off-target side effects.

Objectives: We describe the impact of SoC therapy downtitration and withdrawal in patients already receiving aficamten in FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in Hypertrophic Cardiomyopathy; NCT04848506).

Methods: Patients receiving SoC therapy (beta-blocker, nondihydropyridine calcium-channel blocker, and/or disopyramide) were eligible for protocol-guided SoC downtitration and withdrawal at the discretion of the investigator and after achieving a stable dose of aficamten for ≥4 weeks.

Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

Background: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined.

Objectives: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten.

Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

Background: A primary goal in treating obstructive hypertrophic cardiomyopathy (oHCM) is to improve patients' health status: their symptoms, function, and quality of life. The health status benefits of aficamten, a novel cardiac myosin inhibitor, have not been comprehensively described.

Objectives: This study sought to determine the effect of aficamten on patient-reported health status, including symptoms of fatigue, shortness of breath, chest pain, physical and social limitations, and quality of life.

Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy.

Background: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events.

Objectives: This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy.

Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

Background: Aficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study.

Objectives: The authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM.

Methods: Serial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF).

Safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy: A 36-week analysis from FOREST-HCM.

Aims: The aim of this study was to report safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) over 36 weeks in the ongoing FOREST-HCM trial.

Methods And Results: Patients were started on aficamten 5 mg daily, with doses adjusted in 5-mg increments (5-20 mg) at ≥2-week intervals according to site-read left ventricular ejection fraction (LVEF). Aficamten dose was increased if LVEF ≥55%, maintained if LVEF 50-54%, decreased if LVEF 40-<50%, and temporarily interrupted if LVEF <40%.

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

Background: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility.

Methods: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results.

Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM Baseline Characteristics and Study Design.

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).

Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial.

Objective: To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial.

Methods: In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5).

Health utilities and quality-adjusted life years for patients with amyotrophic lateral sclerosis receiving or placebo in FORTITUDE-ALS.

Aims: To estimate the health utilities and quality-adjusted life years (QALYs) in patients with amyotrophic lateral sclerosis (ALS) receiving versus placebo in FORTITUDE-ALS.

Materials And Methods: We performed a post hoc analysis of clinical trial data from FORTITUDE-ALS (NCT03160898). This Phase IIb, double-blind, randomized, dose-ranging, placebo-controlled, parallel-group, 12-week trial evaluated in patients with ALS.

Phase 2 Study of Aficamten in Patients With Obstructive Hypertrophic Cardiomyopathy.

Background: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.

Objectives: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.

Efficacy of omecamtiv mecarbil in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide level: insights from the GALACTIC-HF trial.

Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF).

Methods And Results: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death.

MiToS and King's staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial.

Objective: To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS.

Methods: This was a analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16.

Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial.

Importance: Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies.

Objective: To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF.

Design, Setting, And Participants: Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted.

Developments in Exercise Capacity Assessment in Heart Failure Clinical Trials and the Rationale for the Design of METEORIC-HF.

Heart failure with reduced ejection fraction (HFrEF) is a highly morbid condition for which exercise intolerance is a major manifestation. However, methods to assess exercise capacity in HFrEF vary widely in clinical practice and in trials. We describe advances in exercise capacity assessment in HFrEF and a comparative analysis of how various therapies available for HFrEF impact exercise capacity.

Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial.

: To evaluate the possible effect of , a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed.

Noninvasive ventilation use by patients enrolled in VITALITY-ALS.

To evaluate the prescribing practices of noninvasive ventilation (NIV) and patient compliance during VITALITY-ALS. VITALITY-ALS enrolled patients with a slow vital capacity (SVC) ≥70% of predicted who were not using NIV at screening. Physicians prescribed NIV without restriction following randomization.