Assuntos
Anticorpos Monoclonais Humanizados/economia , Arteriosclerose/prevenção & controle , LDL-Colesterol/sangue , Atenção à Saúde/economia , Indústria Farmacêutica/economia , Hipolipemiantes/economia , Infarto do Miocárdio/prevenção & controle , Inibidores de PCSK9 , Má Conduta Profissional , Acidente Vascular Cerebral/prevenção & controle , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Arteriosclerose/sangue , Arteriosclerose/complicações , Arteriosclerose/economia , Ensaios Clínicos como Assunto , Controle de Custos , Análise Custo-Benefício , Gerenciamento Clínico , Custos de Medicamentos , Uso de Medicamentos , Humanos , Hipolipemiantes/classificação , Hipolipemiantes/uso terapêutico , Estilo de Vida , Infarto do Miocárdio/etiologia , Seleção de Pacientes , Honorários por Prescrição de Medicamentos , Pró-Proteína Convertase 9/imunologia , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Estados Unidos , United States Food and Drug AdministrationRESUMO
Acquisition costs and cost-effectiveness have limited access and recommendations to use proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibiting monoclonal antibodies (mAbs). Recently, prices were reduced by 60% for alirocumab and evolocumab. This statement systematically reviewed subgroup analyses from statin and PCSK9 mAb trials to identify higher risk groups for which PCSK9 mAbs at the new price could be considered a reasonable (Assuntos
Anticorpos Monoclonais/uso terapêutico
, Doenças Cardiovasculares/tratamento farmacológico
, Pró-Proteína Convertase 9/imunologia
, Anticorpos Monoclonais/economia
, Anticorpos Monoclonais Humanizados/uso terapêutico
, Doenças Cardiovasculares/complicações
, Doenças Cardiovasculares/patologia
, Doenças Cardiovasculares/prevenção & controle
, LDL-Colesterol/sangue
, Análise Custo-Benefício
, Humanos
, Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
, Hipercolesterolemia/complicações
, Hipercolesterolemia/tratamento farmacológico
, Hipercolesterolemia/patologia
, Hiperlipoproteinemia Tipo II/complicações
, Hiperlipoproteinemia Tipo II/tratamento farmacológico
, Hiperlipoproteinemia Tipo II/patologia
, Pró-Proteína Convertase 9/genética
, Qualidade de Vida
, Fatores de Risco
, Índice de Gravidade de Doença
, Sociedades Científicas
RESUMO
INTRODUCTION: Evolocumab is fully human monoclonal antibody which binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), and prevents its blocking effect on recycling of liver low-density lipoprotein (LDL) receptors. Areas covered: The aim of this review is to assess efficacy, safety, and cost-effectiveness of evolocumab in adult patients with high cardiovascular risk. Major research databases MEDLINE, EBSCO, and CENTRAL were systematically searched for relevant study reports. Expert commentary: Even when given in full doses, statins augmented with ezetimibe and cholesterol-binding resins could not reduce cholesterol baseline level for more than 66%, while evolocumab reduces cholesterol level for 75% or even more. Up to now, evolocumab showed good safety profile, and patents tolerate it very well. The abovementioned advantages of evolocumab made it almost ideal drug for hypercholesterolemia, and probably in the future the best drug for secondary prevention of major cardiovascular events. Evolocumab is borderline cost-effective for the treatment of patients with high cardiovascular risk in European countries, while in the U.S.A. it is under debate where the underlying assumption (risk of cardiovascular disease events) determine the true value.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Hipercolesterolemia/tratamento farmacológico , Adulto , Anticorpos Monoclonais/economia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/economia , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/economia , Doenças Cardiovasculares/etiologia , Análise Custo-Benefício , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/economia , Pró-Proteína Convertase 9/imunologia , Fatores de Risco , Prevenção Secundária/métodosAssuntos
Anticorpos/imunologia , Patentes como Assunto/legislação & jurisprudência , Pró-Proteína Convertase 9/imunologia , Anticorpos/química , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Biotecnologia/economia , Biotecnologia/legislação & jurisprudência , Humanos , Modelos Moleculares , Inibidores de PCSK9 , Pró-Proteína Convertase 9/química , Estados Unidos , Universidades/economia , Universidades/legislação & jurisprudênciaRESUMO
PURPOSE: Clinical trials of statins and other lipid-lowering therapies (LLTs) often report large inter-individual variations in their effects on low-density lipoprotein cholesterol (LDL-C). We evaluated apparent hyporesponsiveness to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab (defined as < 15% LDL-C reduction from baseline at all timepoints) using data from 10 Phase 3 trials (3120 hypercholesterolemic patients). METHODS: This report assessed the LDL-C percent reduction from baseline at weeks 4-104 (depending on study), and alirocumab serum levels and antidrug antibodies, in patients with apparent hyporesponsiveness. RESULTS: Among the 3120 patients evaluated, 98.9% responded to alirocumab, and 33 (1.1%) had < 15% LDL C reduction at all measured timepoints. Pharmacokinetics data indicated that 13/33 apparent hyporesponders had not received alirocumab; no pharmacokinetics data were available for 14/33, and 6/33 had detectable alirocumab. For the six patients with confirmed alirocumab receipt, the degree of adherence to pre-study concurrent LLTs could not be determined after study start; one of these patients had persistent antidrug antibodies. CONCLUSIONS: Apparent hyporesponsiveness to alirocumab appeared to be due to lack of receipt of alirocumab determined by serum alirocumab levels, possible lack of adherence to concurrent LLTs, a theoretical and rare possibility of biological non-responsiveness due to persistent antidrug antibodies, or other causes, as yet unidentified.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hipercolesterolemia/tratamento farmacológico , Inibidores de PCSK9 , Inibidores de Serina Proteinase/uso terapêutico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/farmacocinética , Biomarcadores/sangue , Ensaios Clínicos Fase III como Assunto , Regulação para Baixo , Resistência a Medicamentos , Quimioterapia Combinada , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Adesão à Medicação , Pró-Proteína Convertase 9/imunologia , Pró-Proteína Convertase 9/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Serina Proteinase/farmacocinética , Resultado do TratamentoAssuntos
Anticorpos/uso terapêutico , Asma/tratamento farmacológico , Engenharia de Proteínas , Anticorpos/genética , Anticorpos/imunologia , Asma/genética , Indústria Farmacêutica , Humanos , Inibidores de PCSK9 , Pró-Proteína Convertase 9/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologiaRESUMO
BACKGROUND AND OBJECTIVE: Heterozygous familial hypercholesterolemia and dyslipidemia are the predominant causes for cardiovascular disease (CVD). Clinical guidelines for lowering CVD risk have advocated that low density lipoprotein-cholesterol (LDL-C) must be reduced. The primary choice of therapy for controlling lipidemia has been statins, which are not completely effective. Proprotein convertase subtilisin/kexin type-9 (PCSK9), which interferes with LDL clearance from circulation, inversely relates to the LDL-C levels. The loss of statin efficacy is likely due to increased circulating PCSK9 and antibody therapy against PCSK9 has been found to be efficacious in lowering LDL-C. In this study, we evaluated the efficacy of PCSK9-mAbs for lowering LDL-C, in statin non-responsive hypercholesterolemia patients. STUDY DESIGN AND METHODS: PubMed, EMBASE, Scholar, Web of Science and Scopus databases were searched to identify randomized controlled trials of PCSK9 antibody-statin combination vs statin, published till 2015. Two reviewers independently screened the articles, and a collective decision was reached about the included studies in the metaanalysis. Parameters analyzed: change from baseline in LDL-C, high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC); ApoB and ApoA1 levels. RESULTS: A total of 12 studies with 4909 patients were selected. Overall, add-on therapy with PCSK9-mAb to the ongoing statin therapy was found to achieve greater reduction in LDL-C, ApoB, TC, compared to statin therapy. There were no major treatment emergent adverse effects due to PCSK9-mAb therapy. CONCLUSIONS: In adult patients with heterozygous familial hypercholesterolemia and dyslipidemia, PCSK9-mAb therapy in combination with statins was able to achieve the goal of lowering LDL-C.
Assuntos
Anticorpos Monoclonais/farmacologia , Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipoproteinemia Tipo III , Pró-Proteína Convertase 9/imunologia , LDL-Colesterol/metabolismo , Quimioterapia Combinada/métodos , Humanos , Hiperlipoproteinemia Tipo III/tratamento farmacológico , Hiperlipoproteinemia Tipo III/metabolismo , Hipolipemiantes/farmacologia , Conduta do Tratamento Medicamentoso , Resultado do TratamentoRESUMO
BACKGROUND: Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. AIMS: To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. METHODS: A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. CONCLUSIONS: The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).