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1.
Ter Arkh ; 92(7): 77-84, 2020 Sep 01.
Artigo em Russo | MEDLINE | ID: mdl-33346448

RESUMO

Currently, the main pathogenetic method for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) is the treatment with recombinant monoclonal antibodies that block the C5 component of the complement system. Eculizumab is the first biotechnological drug, which is a monoclonal antibody, with proven clinical efficacy and safety for the treatment of patients with PNH, which is used in world clinical practice. In Russia, in the framework of the state program Development of the pharmaceutical and medical industry for 20132020 was developed Elizaria (JSC GENERIUM) the first biosimilar of the original drug eculizumab. AIM: To evaluate the pharmacokinetic and pharmacodynamic parameters, as well as safety and immunogenicity parameters of the drug Elizara in the induction phase of therapy in previously untreated patients with PNH. MATERIALS AND METHODS: The study included 11 patients with PNH aged 26 to 75 years who had not previously received eculizumab. Each of the study participants was injected with the studied drug Elizaria at a dose of 600 mg intravenously once a week for 4 weeks. RESULTS: During the clinical study, it was noted that the concentration of the studied drug significantly increased by the time the infusion was completed and then gradually decreased to a minimum at the end of the dosing interval. The average concentration of eculizumab 5 minutes before the administration of the study drug at all visits exceeded 35 g/ml, the minimum concentration sufficient to completely inhibit intravascular hemolysis in patients with PNH. The pharmacodynamic efficacy of the drug Elizaria was confirmed by a decrease in the concentration of the membrane-attack complex (MAC) after the first infusion of the drug was maintained at stable levels until visit 5. A persistent decrease in the level of MAC and a four-fold decrease in the average values of lactate dehydrogenase to visit 5 from 1286.4 to 280.9 U/l demonstrated a marked decrease in activity and stabilization of the hemolytic process against the background of the induction of therapy with Elizaria at a dose of 600 mg once a week and confirmed the effecacy of the study drug. Among the 9 adverse events, only 5 had a relationship with the studied drug, including one serious adverse event in the form of an allergic reaction, which, according to the researcher, had a possible cause-effect relationship with the infusion of the studied drug. In 2 patients, low-titer binding anti-drug antibodies were detected without neutralizing activity during treatment with the studied drug, which may indicate its low immunogenicity. CONCLUSION: The study evaluated the pharmacokinetic and pharmacodynamic properties of the drug Elizaria in the regimen of induction therapy in previously untreated patients with PNH, confirming its efficacy. The study demonstrated the safety and low immunogenicity of the study drug.


Assuntos
Medicamentos Biossimilares , Hemoglobinúria Paroxística , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Medicamentos Biossimilares/efeitos adversos , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Federação Russa
2.
Int J Hematol ; 112(4): 466-476, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32869125

RESUMO

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab's efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab's efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Hemoglobinúria Paroxística/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Transfusão de Sangue/estatística & dados numéricos , Peso Corporal , Esquema de Medicação , Feminino , Hemoglobinúria Paroxística/diagnóstico , Humanos , Japão , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Segurança , Resultado do Tratamento
3.
Am J Case Rep ; 21: e927418, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32917848

RESUMO

BACKGROUND Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. CASE REPORT Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. CONCLUSIONS We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/metabolismo , Infecções por Coronavirus/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Pneumonia Viral/complicações , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Betacoronavirus , Complemento C5/efeitos dos fármacos , Complemento C5/imunologia , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/epidemiologia , Feminino , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/imunologia , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Microangiopatias Trombóticas/complicações , Microangiopatias Trombóticas/imunologia
4.
Rinsho Ketsueki ; 61(8): 929-936, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32908057

RESUMO

Treatment with eculizumab (Soliris®), a humanized anti-C5 monoclonal antibody improves the quality of life of patients with paroxysmal nocturnal hemoglobinuria (PNH), remarkably reduces hemolysis, improves symptoms associated with hemolysis, and prevents thrombosis. Because eculizumab therapy is not a curative treatment, it is necessary to continue infusion every two weeks, which has been an issue from the viewpoint of convenience. In recent years, an improved version of eculizumab, ravulizumab (Ultomiris®), which relies on the technology of recycling antibodies has been developed and can be administered every 8 weeks. Crovalimab (SKY59), which can be administered subcutaneously every four weeks, is also under development, and therefore, the convenience for patients with PNH is improving. However, many issues still persist, and several new anti-complement drugs are currently under development. Hopefully, a better drug will be developed by thorough examination of what drug is best for the patient by considering not only its efficacy and safety but also its convenience.


Assuntos
Anticorpos/uso terapêutico , Hemoglobinúria Paroxística , Proteínas do Sistema Complemento , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Qualidade de Vida , Radioimunoterapia
5.
PLoS One ; 15(9): e0237497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32886668

RESUMO

BACKGROUND: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. OBJECTIVE: The aim of this study was to assess patient preference for ravulizumab or eculizumab. METHODS: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. RESULTS: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). CONCLUSION: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Preferência do Paciente , Qualidade de Vida , Adulto Jovem
6.
Ann Hematol ; 99(10): 2303-2313, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856141

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by a deregulated complement system, chronic Coombs-negative, intravascular hemolysis, and a variable clinical course with substantial risk to develop thromboembolic events. We analyzed diagnostic and prognostic parameters as well as clinical endpoints in 59 adult patients suffering from PNH in 5 hematology centers in Austria (observation period: 1978-2015). Median follow-up time was 5.6 years. The median clone size at diagnosis amounted to 55% and was higher in patients with classical PNH (81%) compared to patients with PNH associated with aplastic anemia (AA) or myelodysplastic syndromes (MDS) (50%). The clone size also correlated with lactate dehydrogenase (LDH) levels. In one patient, anemia improved spontaneously and disappeared with complete normalization of LDH after 16 years. Seventeen patients received therapy with eculizumab. The rate of thromboembolic events was higher in the pre-eculizumab era compared with eculizumab-treated patients but did not correlate with the presence of age-related clonal hematopoiesis or any other clinical or laboratory parameters. Peripheral blood colony-forming progenitor cell counts were lower in PNH patients compared with healthy controls. Only two patients with classical PNH developed MDS. Overall, 7/59 patients died after 0.5-32 years. Causes of death were acute pulmonary hypertension, Budd-Chiari syndrome, and septicemia. Overall survival (OS) was mainly influenced by age and was similar to OS measured in an age-matched healthy Austrian control cohort. Together, compared with previous times, the clinical course and OS in PNH are favorable, which may be due to better diagnosis, early recognition, and eculizumab therapy.


Assuntos
Hemoglobinúria Paroxística/epidemiologia , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Adulto , Anemia Aplástica/epidemiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Áustria/epidemiologia , Medula Óssea/patologia , Causas de Morte , Células Clonais/patologia , Ensaio de Unidades Formadoras de Colônias , Terapia Combinada , Inativadores do Complemento/uso terapêutico , Creatinina/sangue , Progressão da Doença , Feminino , Seguimentos , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/epidemiologia , Prognóstico , Tromboembolia/etiologia
9.
Am J Hematol ; 95(8): 944-952, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32311169

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement-mediated intravascular hemolysis and thrombosis. The increased incidence of PNH-driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement-mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti-thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in-part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/líquido cefalorraquidiano , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Inativadores do Complemento/farmacologia , Feminino , Voluntários Saudáveis , Hemoglobinúria Paroxística/complicações , Humanos , Masculino , Fenótipo
10.
PLoS One ; 15(3): e0230869, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218584

RESUMO

INTRODUCTION: Ravulizumab (ALXN1210) is a long-lasting recycling IgG monoclonal antibody with an increased affinity for the neonatal Fc receptor (FcRn). The FcRn is essential for regulating IgG homeostasis. Saturation of the FcRn pathway is seen under high IgG doses as they compete with endogenous IgG to bind the FcRn by their Fc regions, resulting in enhanced IgG clearance. PATIENTS/METHODS: Between Jan 2016 and Jun 2019 (median observation time 21.6 months (6-37.7 months)) serum IgG concentrations and IgG1-4 subclasses were evaluated over a longitudinal course (post-hoc analysis) in 12 ravulizumab-treated adult patients with paroxysmal nocturnal hemoglobinuria (PNH) (58% (7/12) males, median age 50 years (yrs) (18-70 yrs)). All patients were enrolled in one of the three ravulizumab-PNH-related trials (201-, 301-, or 302-study) at the University Hospital Essen. RESULTS: Baseline IgG concentrations were documented in 11 out of the 12 patients prior to ravulizumab treatment (median IgG 9.9 g/L (5-13.5 g/L)). In two female patients a clinically not relevant hypogammaglobulinemia with an associated IgG1 or a combined IgG1/IgG2 deficiency prior to treatment was documented. The data were further stratified with regard to various treatment intervals as multiple analyses were obtained. Throughout observation time IgG concentrations remained within physiologic ranges with no evidence of a treatment-related IgG depletion (median IgG at study endpoint 10.1 g/L (6-13.4 g/L)). CONCLUSION: In ravulizumab-treated PNH patients, IgG and IgG subclass levels which are regulated by the FcRn remained unaffected. Therefore, no treatment associated hypogammaglobulinemia is to be feared under chronic ravulizumab therapy.


Assuntos
Agamaglobulinemia/complicações , Anticorpos Monoclonais Humanizados/uso terapêutico , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Hemoglobinúria Paroxística/sangue , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem
11.
Blood ; 135(12): 912-920, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31978221

RESUMO

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Biomarcadores , Complemento C5/imunologia , Inativadores do Complemento/farmacologia , Monitoramento de Medicamentos , Feminino , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento
15.
Am J Hematol ; 95(11): 1334-1343, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33464651

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, life-threatening hematologic disease characterized by chronic complement-mediated hemolysis and thrombosis. Despite treatment with eculizumab, a C5 inhibitor, 72% of individuals remain anemic. Pegcetacoplan (APL-2), a PEGylated C3 inhibitor, has the potential to provide more complete hemolysis control in patients with PNH. This open-label, phase Ib study was designed to assess the safety, tolerability, and pharmacokinetics of pegcetacoplan in subjects with PNH who remained anemic during treatment with eculizumab. Pharmacodynamic endpoints were also assessed as an exploratory objective of this study. Data are presented for six subjects in cohort 4 who received treatment for up to 2 years. In total, 427 treatment-emergent adverse events (TEAEs) were reported, 68 of which were possibly related to the study drug. Eight serious TEAEs occurred in two subjects; three of these events were considered possibly related to the study drug. Pegcetacoplan pharmacokinetic concentrations accumulated with repeated dosing, and steady state was reached at approximately 6-8 weeks. Lactate dehydrogenase levels were well controlled by eculizumab at baseline. Pegcetacoplan increased hemoglobin levels and decreased both reticulocyte count and total bilirubin in all six subjects. Improvements were observed in Functional Assessment of Chronic Illness Therapy Fatigue scores. Two subjects discontinued for reasons unrelated to pegcetacoplan. All four subjects who completed the study transitioned to pegcetacoplan monotherapy following eculizumab discontinuation and avoided transfusions. In this small study, pegcetacoplan therapy was generally well-tolerated, and resulted in an improved hematological response by achieving broad hemolysis control, enabling eculizumab discontinuation.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C3/antagonistas & inibidores , Hemoglobinúria Paroxística/tratamento farmacológico , Adulto , Anemia Hemolítica/tratamento farmacológico , Anemia Hemolítica/etiologia , Anemia Hemolítica/prevenção & controle , Anticorpos Monoclonais Humanizados/efeitos adversos , Bilirrubina/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Complemento C5/antagonistas & inibidores , Substituição de Medicamentos , Feminino , Febre/induzido quimicamente , Hemoglobinas/análise , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/imunologia , Hemólise/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Pancreatite/induzido quimicamente , Estudos Prospectivos , Contagem de Reticulócitos
16.
Transfus Med Rev ; 33(4): 256-265, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31703946

RESUMO

Dysregulation of the complement system underlies the pathophysiology of many diseases. Renewed interest in complement occurred with the recognition that its therapeutic inhibition was possible. Terminal complement blockade with the anti-C5 monoclonal antibody eculizumab significantly changed management and clinical outcomes of patients with paroxysmal nocturnal hemoglobinuria, and served as a proof of concept for other complement-mediated diseases. Eculizumab is also approved for atypical hemolytic uremic syndrome and myasthenia gravis. Multiple new disease indications have been identified, and novel complement inhibitors are in various stages of development, with several currently in human trials. Beyond C5, these new drugs block proximal complement, pathway-specific targets, convertase activity, and anaphylatoxin function. Though monoclonal antibodies are still common, peptides, RNAi, and small molecule inhibitors provide the opportunity for different administration routes and schedules. Several challenges still exist or will soon present themselves, including mitigation of infection risk, effective monitoring strategies, and how to choose between therapeutics when more than one is available. In this review, we will describe the lessons learned from the "eculizumab era," present many of the novel therapeutics currently or soon to be in trials, and highlight some of the challenges that will require attention as the field progresses.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/fisiologia , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Miastenia Gravis/tratamento farmacológico , Microangiopatias Trombóticas/tratamento farmacológico
17.
Brasília; CONITEC; nov. 2019.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1120623

RESUMO

TECNOLOGIA: Vacina meningocócica ACWY (conjugada) (Menactra®, Nimenrix® e Menveo®) e vacina adsorvida meningocócica B (recombinante) (Trumenba® e Bexsero®). CONTEXTO: A hemoglobinúria paroxística noturna (HPN) é um distúrbio hematológico clonal crônico. Trata-se de uma doença rara, a incidência anual é estimada em 1,3 casos por um milhão de indivíduos. O tratamento da HPN inclui abordagens farmacológicas e não farmacológicas, e tem como objetivo a atenuação da anemia e dos episódios tromboembólicos. Uma das opções terapêuticas é o medicamento eculizumabe, um anticorpo monoclonal. No entanto, o uso de eculizumabe está associado a risco de 1.000 a 2.000 vezes maior na incidência de doença meningocócica em pessoas que recebem o medicamento. O fabricante do medicamento orienta que todos os pacientes sejam vacinados contra a doença meningocócica (causada pela bactéria Neisseria meningitidis), para os sorogrupos A, C, Y, W135 e B, pelo menos duas semanas antes de receber o eculizumabe. Atualmente, o calendário vacinal contempla a vacina meningocócica C, num esquema vacinal de três doses (aos 3 e 5 meses de idade, com reforço aos 12 meses, podendo ser aplicado até os 4 anos). PERGUNTA: Qual a eficácia, segurança e impacto orçamentário da vacina meningocócica ACWY (conjugada) e vacina adsorvida meningocócica B (recombinante) para pacientes com HPN que utilizem eculizumabe? EVIDÊNCIAS CIENTÍFICAS: Foram realizadas buscas sistematizadas nas bases de dados Medline (via PubMed), Embase, Cochrane Library, Biblioteca Virtual em Saúde (BVS) e Lilacs (via Bireme). A busca das evidências resultou em 74 referências, destas nove preenchiam os critérios de elegibilidade. A qualidade da evidência foi avaliada pela metodologia GRADE, para o principal desfecho avaliado, doença meningocócica, a qualidade global da evidência foi muito baixa. De acordo com os estudos incluídos, os pacientes em tratamento com o eculizumabe desenvolveram a doença meningocócica, mesmo estando vacinados. Nos Estados Unidos, durante o período de 2008 a 2016, foram identificados 16 casos de doença meningocócica em pacientes que utilizam eculizumabe; entre estes, 11 casos foram causados por N. meningitidis não-agrupável. Quatorze pacientes tinham registro de recebimento de pelo menos uma dose de vacina meningocócica antes do início da doença (12). Geralmente, cepas de meningococo não-agrupável não causam doença invasiva em indivíduos saudáveis (12,32,37). Foram selecionados sete relatos de caso, de pacientes em uso do medicamento, que haviam sido vacinados, e desenvolveram doença meningocócica invasiva por diferentes sorogrupos (18­24), no entanto os pacientes não haviam recebido vacinação contra a cepa específica de sua infecção. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO (AIO): Os custos assumidos nesta análise foram restritos aos de aquisição da vacina meningocócica ACWY (conjugada) e vacina adsorvida meningocócica B; os preços foram consultados no Banco de Preços em Saúde (BPS) e na lista de preços de medicamentos da Câmara de Regulação do Mercado de Medicamentos (CMED). Considerou-se a população acima de 14 anos de idade com HPN em uso de eculizumabe, com a prevalência de 1,6/100.000 indivíduos no primeiro ano e nos anos subsequentes foi estimado com base na incidência 1,3/1.000.000 de indivíduos por ano. Foram considerados dois cenários, o primeiro assumindo-se um market share de 100% desde o primeiro ao último ano e outro considerando um market share inicial de 50%, chegando a 100% no quinto ano. Dessa forma, com base nos dois distintos cenários de market share, o impacto orçamentário em cinco anos após a incorporação da vacina meningocócica ACWY (conjugada) para pacientes com HPN que utilizem eculizumabe, pode variar de R$ 455.766,29 à R$ 581.829,30. E para a vacina adsorvida meningocócica B (recombinante), para a mesma população e ao final de cinco anos, o impacto orçamentário pode variar de R$ 1.728.264,50 à R$ 2.206.295,10. Se as duas vacinas fossem incorporadas ao SUS, este montante poderia variar entre R$ 2.184.030,78 e R$ 2.788.124,40. CONSIDERAÇÕES FINAIS: A maioria dos casos de infecção por Neisseria meningitidis ocorreu em pacientes que tinham recebido pelo menos uma dose de vacina meningocócica antes do início do tratamento, no entanto os pacientes não haviam recebido vacinação contra a cepa específica de sua infecção. Em nenhum dos casos houve infecção meningocócica devido à falha da vacina. Destaca-se que o uso das vacinas meningocócicas ACWY e B pode aumentar os sinais e sintomas de HPN, como hemólise (31), no entanto não foram identificados estudos que avaliassem desfechos de piora clínica ou outras complicações relacionadas ao uso das vacinas. Também não foi avaliado desfechos relacionados a adesão da vacina para esta população específica. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Pelo exposto, a Conitec, em sua 81ª reunião ordinária, no dia 06 de setembro de 2019, recomendou a incorporação no SUS da vacina meningocócica ACWY (conjugada) para os pacientes com hemoglobinúria paroxística noturna que fazem o uso do eculizumabe e a não incorporação da vacina adsorvida meningocócica B (recombinante). A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: Foram recebidas 18 contribuições, sendo duas pelo formulário para contribuições técnico-científicas e 16 pelo formulário para contribuições sobre experiência ou opinião. Das duas contribuições recebidas de cunho técnico-científico, uma foi a favor da recomendação preliminar, no entanto não houve justificativa e a outra contribuição foi parcialmente favorável a recomendação preliminar. Esta última oriunda da empresa Alexion (fabricante do medicamento eculizumabe). O laboratório reforça os dizeres em bula quanto a recomendação para vacinação do sorogrupo B juntamente com os sorogrupos ACWY e acrescenta dois estudos que demonstram que a prevalência do sorogrupo B de meningococo no Brasil é muito relevante. Entre as 16 (dezesseis) contribuições de experiência ou opinião, todas favoráveis à recomendação preliminar, 14 (quatorze) não continham nenhuma informação ou abordavam temas diferentes, restando 02 (duas) contribuições. Estas contribuições, uma da Sociedade Brasileira de Transplantes de Medula Óssea e a outra da Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH), foram favoráveis à recomendação da vacina meningocócica ACWY, mas reforçavam a necessidade da incorporação da vacina meningocócica B para os pacientes com hemoglobinúria noturna que fazem uso do eculizumabe. Após apreciação das contribuições encaminhadas pela Consulta Pública, o plenário da Conitec entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 82ª reunião ordinária, no dia 10 de outubro de 2019, deliberaram, por unanimidade, recomendar a incorporação da vacina meningocócica ACWY para pacientes com hemoglobinúria paroxística noturna que fazem o uso do eculizumabe e pela não incorporação da vacina meningocócica B. Foram assinados os Registros de Deliberação nº 480/2019 e nº 481/2019, respectivamente. DECISÃO: Incorporar a vacina meningocócica ACWY (conjugada) para os pacientes com hemoglobinúria paroxística noturna que fazem uso do eculizumabe e de não incorporar a vacina adsorvida meningocócica B (recombinante) para os pacientes com hemoglobinúria paroxística noturna que fazem uso do eculizumabe, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 60, publicada no Diário Oficial da União nº 224, seção 1, página 79, em 20 de novembro de 2019.


Assuntos
Humanos , Vacinas Meningocócicas/administração & dosagem , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
18.
Front Immunol ; 10: 1639, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379839

RESUMO

Background: Eculizumab blocks the lytic complement pathway by inhibiting C5 and has become the standard of care for certain complement-mediated diseases. Previously, we have shown that strong complement activation in vitro overrides the C5 inhibition by Eculizumab, which accounts for residual terminal pathway activity. Results: Here we show that the levels of residual hemolysis in ex vivo assays differ markedly (up to 3.4-fold) across sera collected from different paroxysmal nocturnal hemoglobinuria (PNH) patients on Eculizumab treatment. This large variability of residual activity was also found in sera of healthy donors, thus cross-validating the findings in patients. While PNH patients with residual lytic activities of 11-30% exhibited hemolysis levels around the upper limit of normal (i.e., plasma LDH of ~250 u/L), as expected for PNH patients on Eculizumab therapy, we found sustained and markedly increased LDH levels of around 400 u/L for the patient with the highest residual activity of 37%. Furthermore, the clinical history of nine out of 14 PNH patients showed intravascular breakthrough hemolysis at the time of documented infections despite ample amounts of administered Eculizumab and/or experimentally determined excess over C5. Conclusion: The occurrence of extraordinary high levels of residual terminal pathway activity in PNH patients receiving Eculizumab is rare, but can impair the suppression of hemolysis. The commonly observed low levels of residual terminal pathway activity seen for most PNH patients can exacerbate during severe infections and, thus, can cause pharmacodynamic breakthrough hemolysis in PNH patients treated with Eculizumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos
19.
Front Immunol ; 10: 1157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258525

RESUMO

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Eritrócitos/imunologia , Hemoglobinúria Paroxística/tratamento farmacológico , Ativação do Complemento/efeitos dos fármacos , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Hemólise/efeitos dos fármacos , Humanos
20.
Medicine (Baltimore) ; 98(27): e16164, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277120

RESUMO

Thrombosis are severe complications of paroxysmal nocturnal hemoglobinuria (PNH), effectively reduced by eculizumab. Extracellular vesicles (EVs) may play a central role. The objective of this study was to assess the procoagulant activity of plasma isolated from PNH patients (treated or not by eculizumab) and to quantify their circulating EVs.We iteratively collected the platelet-free-plasma of 17 PNH patients and 16 matched healthy volunteers, quantified their circulating EVs by flow cytometry and evaluated their procoagulant activity by thrombin generation and STA-Procoag-procoagulant phospholipid (PPL) assays.A significant decrease of EVs from platelets (P = .024) and an increase of the STA-Procoag-PPL clotting time (P = .049) was observed after initiation of eculizumab and up to 11 weeks after. This reduction of prothrombotic biomarkers was not observed with the thrombin generation test due to a lack of sensitivity of this assay. Active hemolysis was observed in 90% of patients and elevated D-dimers in 41% of them. However, no significant difference was observed between patients and control subjects regarding the procoagulant activity, the EVs quantity, or the cellular origin. Lactate dehydrogenase (LDH) levels were lower in eculizumab-treated patients compared to nontreated patients (441 vs 2448 IU/L). D-dimers and LDH decreased after administration of eculizumab (mean decrease of 1307 ng/mL and 4159 IU/L, respectively).These observations suggest a decrease of the phospholipid-dependent procoagulant potential of EVs after eculizumab therapy in PNH patients. TRIAL REGISTRATION:: NUB: B039201214365.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Hemoglobinúria Paroxística/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Estudos de Casos e Controles , Citometria de Fluxo , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose/etiologia
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