Aficamten: First Approval.

A industria brasileira, apos intenso processo de crescimento e consolidacao durante seu periodo de industrializacao substitutiva de importacoes (1956-1979), passou a sofrer, dentro de um contexto de mudanca de paradigma produtivo, um constante processo de defasagem quanto a incorporacao de tecnologias a partir dos anos 80. Esse atraso se manifestou tanto na obsolescencia das maquinas e equipamentos, quanto nos modelos administrativos e nas relacoes capital-trabalho, devido principalmente ao Estado, principal fomentador do desenvolvimento da economia e da industria ter perdido a capacidade de realizar politicas industriais (PI) e tecnologicas (PT) que promovessem uma rearticulacao interna das forcas produtivas. Nesse sentido, na presente pesquisa se concentrou a discussao na apresentacao dos determinantes fundamentais do atraso tecnologico da industria brasileira decisivamente a partir dos anos 80, analisando-se, para isso, as condicionantes politicas, economicas e ideologicas, tendo-se como foco as politicas industriais e tecnologicas promovidas pelo Estado brasileiro que, mesmo fomentando um crescimento industrial acelerado da economia com base no paradigma da producao em massa, basicamente prezou pelo desenvolvimento de uma industria voltada para a capacidade produtiva. Nesse sentido, quando se tornou premente uma transicao para o novo paradigma de producao flexivel, esta embasada na geracao de capacidade tecnologica, emergiram inumeras barreiras a essa mudanca. Mesmo a economia tendo buscado desenvolver um nucleo de pesquisa e desenvolvimento e ciencia e tecnologia proprios, esses nao foram suficientemente dinâmicos o bastante a ponto de colocar o pais em movimentos de catching up tecnologico constante como ocorria nos paises mais desenvolvidos, buscando-se direcionar o desenvolvimento da economia para o novo paradigma produtivo. De outro lado, quanto as PI e PT adotadas no desenvolvimento da Coreia do Sul, o fomento do processo de catching up produtivo e tecnologico possibilitou a esse pais absorver de forma dinâmica a “janela de oportunidade” que se abriu com o surgimento do novo paradigma, possibilitando ao pais, que teve um processo de industrializacao tardia como o Brasil, desenvolvesse uma das principais industrias do mundo no que tange a geracao de produtos intensivos em alta tecnologia, votados ao mercado internacional, levando a economia coreana a se situar proximo ou sobre a fronteira tecnologica em expansao do novo paradigma. Assim, o estudo parte do referencial teorico da abordagem schumpeteriana a fim apontar alguns dos elementos que levaram a estrutura industrial brasileira a se conformar com um dinamismo relativamente lento no seu processo de desenvolvimento tecnologico formando uma estrutura com pouca competitividade nos setores mais dinâmicos da industria, os de alta tecnologia e que representam, atualmente o segmento chave da competicao empresarial internacional. Este cenario contrasta com o caso oposto da Coreia do Sul onde esse setor da economia, atualmente, se mostra bastante dinâmico em termos de geracao e disseminacao das inovacoes tecnologicas.

Successful alcohol septal ablation in a pregnant patient with symptomatic hypertrophic obstructive cardiomyopathy

Background: While most current treatments can improve symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), they may be poorly tolerated and do not target the underlying pathophysiology. Mavacamten is the first and only cardiac myosin inhibitor approved for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive HCM but has not been evaluated in a pediatric age group. SCOUT-HCM (Study of MavaCamten in AdOlescents with Symptomatic ObstrUcTive HCM; NCT06253221) will evaluate the efficacy, safety, and pharmacokinetics of mavacamten in adolescents with symptomatic obstructive HCM. Methods: SCOUT-HCM is a randomized, double-blind, placebo-controlled, international phase 3 clinical trial that will enroll 40 adolescents (age 12 to <18 years) with obstructive HCM (Figure). Patients will receive mavacamten or placebo during the first 28 weeks, followed by a 28-week double-blind active treatment period. Inclusion criteria include a diagnosis of HCM with presence of symptoms and left ventricular outflow tract (LVOT) obstruction. Patients with HCM phenocopies, LVEF <50% at rest in the past 6 months, planned escalation in HCM therapy or upcoming intervention (eg, major cardiac surgery) will be excluded. The primary endpoint is change in Valsalva LVOT gradient from baseline to week 28. Key secondary endpoints include other echocardiographic parameters, safety, pharmacokinetics, and exercise capacity. Conclusions: SCOUT-HCM is the first randomized controlled trial evaluating a targeted myosin inhibitor in adolescents with symptomatic obstructive HCM. The results will inform the utility of mavacamten in adolescent patients with symptomatic obstructive HCM.

Molecular targets in diseased cells and tissues are the basis for precision medicine that stratifies patients into specific subgroups to develop targeted therapies. Myosin heavy chain (MHC) gene isoforms encode the proteins that form the thick filaments in muscle that enable muscle contraction. Management of familial hypertrophic cardiomyopathy has relied on surgical and symptomatic medical (pharmacological) treatment. However, in April 2022, the US Food and Drug Administration (FDA) approved a small molecule that selectively but reversibly inhibits sarcomeric myosin, mavacamten (MYK-461, Camzyos) for adults with symptomatic hypertrophic cardiomyopathy, New York Heart Association (NYHA) class II–III. Mavacamten is a first-in-class, precision medicine for patients with symptomatic hypertrophic obstructive cardiomyopathy that inhibits cardiac myosin and reduces actin-myosin interactions to reduce left ventricular outflow tract obstruction, improve exercise capacity, and reduce symptoms. This editorial aims to introduce how understanding the genetic and molecular basis of hypertrophic cardiomyopathy has resulted in a novel approach to precision medicine in cardiovascular disease.

Efficacy and Safety of Mavacamten in the Treatment of Hypertrophic Cardiomyopathy: A Systematic Review.

Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy. A comparison of clinical, haemodynamic and exercise outcomes.

Dual Chamber Pacing for Patients With Hypertrophic Obstructive Cardiomyopathy: A Clinical Perspective in 2000

Introduction: Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder involving the cardiac sarcomere. Mavacamten is the first-in-class oral cardiac myosin inhibitor approved for treating HCM in adults targeting sarcomere hypercontractility. We aimed to evaluate the efficacy and safety of mavacamten in symptomatic obstructive HCM. Methods: We conducted a systematic literature search in Embase, PubMed, Scopus, and Web of Science databases from inception until March 05, 2023. Results: After screening 349 studies, our final analysis included 5 studies with 843 obstructive HCM patients and an average follow-up of 27.2 weeks. A fixed effects model was used to calculate risk ratios (RRs). Our meta-analysis revealed a significant improvement in NYHA functional class from baseline in patients on mavacamten compared to placebo [RR, 4.59 (95% CI: 2.94-7.16), p<0.00001]. Mavacamten use in obstructive HCM patients also resulted in significantly lower rates of septal reduction therapy (SRT) or patients who were guideline-eligible for SRT versus placebo [RR, 0.29 (95% CI: 0.22-0.39), p<0.00001]. There was no significant effect of mavacamten use on the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (p = 0.22). Also, no significant difference was observed in the occurrence of ≥1 serious adverse event (p = 0.77), atrial fibrillation (p = 0.98), and non-sustained ventricular tachycardia (p = 0.44) between mavacamten and placebo group. Conclusions: A substantial improvement in NYHA functional class without any serious adverse events, and a significant reduction in the number of patients requiring SRT, makes mavacamten a promising drug for obstructive HCM.

Objectives:To examine whether percutaneous alcohol septal ablation affects coronary flow reserve (CFR) in patients with hypertrophic cardiomyopathy (HCM).Methods:CFR was measured immediately before and after septal ablation in patients with symptomatic...

Long-Term Favorable Cardiac Remodeling in Obstructive Hypertrophic Cardiomyopathy Patients Treated With Mavacamten for Up to 128 Weeks: Insights From the VALOR-HCM Trial.

To provide a contemporary review of data regarding patient selection and outcomes for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) undergoing septal reduction therapy with alcohol septal ablation (ASA). This review focuses on recent guideline updates from the USA and Europe, multiple recently published large multicenter, multinational registries of patients being treated with ASA, and a recent review of “real world” outcomes of ASA and surgical myectomy (SM) treated in hospitals in the USA. Recent data have demonstrated that ASA is a safe procedure and is effective for the reduction of symptoms associated with obstructive HCM. Both short-and long-term outcomes after ASA appear similar to outcomes in patients undergoing SM and medical treatment. Outcomes in a real-world setting evaluating ASA and SM outside of high volume centers specializing in treatment of HCM show that ASA is increasing in use and that outcomes are fairly consistent across centers performing the procedure.

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BackgroundBeta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown.MethodsWe conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index.ResultsA total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and −1.2 ml per kilogram per minute (95% CI, −1.7 to −0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups.ConclusionsAmong patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms. (Funded by Cytokinetics; MAPLE-HCM ClinicalTrials.gov number, NCT05767346.)

BACKGROUND:Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality in children, but treatment options are limited. Aficamten, a next-in-class cardiac myosin inhibitor, directly targets the hypercontractility underlying HCM. Aficamten improved exercise capacity, health status, and symptoms in adults with obstructive HCM in the pivotal, phase 3 SEQUOIA-HCM trial (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM; NCT05186818).METHODS:CEDAR-HCM (Clinical Evaluation of dosing With Aficamten to Reduce Obstruction in Pediatric Population With HCM) is an international, multicenter, randomized, double-blind, placebo-controlled trial followed by an open-label extension to evaluate the efficacy, safety, and pharmacokinetics of aficamten in pediatric participants with symptomatic obstructive HCM. The trial will enroll ≈55 adolescents (12 to <18 years) and subsequently expand to include at least 10 children (6 to <12 years) with nonsyndromic obstructive HCM, left ventricular ejection fraction ≥60%, Valsalva left ventricular outflow tract gradient ≥50 mm Hg, and New York Heart Association functional class ≥II. Participants will be randomized 2:1 to aficamten or placebo in addition to standard of care therapy or as monotherapy, with echocardiogram-guided dose adjustments targeting a Valsalva left ventricular outflow tract gradient <30 mm Hg while maintaining left ventricular ejection fraction ≥50%. The primary end point is the change in Valsalva left ventricular outflow tract gradient from baseline to week 12. Secondary end points include change in resting left ventricular outflow tract gradient, cardiac biomarkers, New York Heart Association functional class, and assessment of pharmacokinetics. After completing the 12-week randomized period, eligible participants will continue into a long-term open-label extension.RESULTS:The trial is currently enrolling.CONCLUSIONS:Results of CEDAR-HCM will provide insight into the safety and efficacy of aficamten in adolescents and in children as young as 6 years of age.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06412666.

PurposeThe aim of the study was to project the long-term net health benefits of mavacamten for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM) in the United States. MethodsA Markov model with 4 mutually exclusive health states (New York Heart Association [NYHA] functional classes I, II, and III/IV and death) was developed to project the life-years (LYs) and quality-adjusted life-years (QALYs) over a lifetime horizon for patients with symptomatic obstructive HCM receiving mavacamten with or without β-blocker (BB) or calcium channel blocker (CCB) monotherapy or placebo with or without BB or CCB monotherapy. The model simulated a patient cohort with a starting age of 59 years and 41% women. Transition probabilities across NYHA functional classes were estimated using data from the Phase III Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM) and the EXPLORER long-term extension (EXPLORER-LTE) cohort from the Long-term Safety Extension Study of Mavacamten in Adults who Have Completed MAVERICK-HCM or EXPLORER-HCM (MAVA-LTE) trial and were extrapolated after week 30. The mortality risks of NYHA functional class I were assumed to be the age- and sex-specific mortality risks of the US general population. The mortality risks for NYHA class II and III/IV were estimated using those for class I in conjunction with the relative mortality risks derived using patients with obstructive HCM from a large real-world registry. Health state utilities for each treatment were estimated from EXPLORER-HCM. Both LYs and QALYs were aggregated over a lifetime for each treatment arm, discounted at 3% annually, and compared between the 2 arms. Sensitivity analyses were conducted to evaluate the robustness of the model findings. FindingsOver a lifetime, treatment with mavacamten with or without BB or CCB monotherapy was associated with 3.67 incremental LYs compared with placebo with or without BB or CCB monotherapy (13.00 vs 9.33 LYs). Compared with individuals in the placebo group, patients in the mavacamten group were projected to spend 6.17 additional LYs in NYHA functional class I and 0.04 and 2.46 fewer LYs in NYHA functional classes II and III/IV, respectively. With utilities incorporated, mavacamten with or without BB or CCB monotherapy was associated with 4.17 additional QALYs compared with placebo with or without BB or CCB monotherapy (11.74 vs 7.57 QALYs). In the sensitivity analyses, incremental benefits ranged from 1.55 to 6.21 LYs and from 2.48 to 6.19 QALYs across the scenarios. ImplicationsThis model projected substantial net health benefits associated with mavacamten for symptomatic obstructive HCM owing to improved patient survival and quality of life. The projected QALY gain underscored the likely long-term clinical value of mavacamten in symptomatic obstructive HCM.