RESUMEN
O AZD7442 ou Evusheld, produzido pela AstraZeneca, é uma combinação de dois anticorpos monoclonais humanos de ação longa denominados tixagevimab (AZD8895 ou COV2-2196) e cilgavimab (AZD1061 ou COV2-2130), clonados a partir de linfócitos B isolados de células mononucleares de sangue periférico de pacientes convalescentes de COVID-19 (CONITEC, 2021). Seu uso é indicado para profilaxia pré-exposição ao SARS-CoV-2 em indivíduos adultos e pediátricos que, em decorrência de diferentes condições clínicas, não podem se vacinar ou não desenvolvem defesas adequadas após a imunização contra a COVID-19 (ASTRAZENECA, 2022). Foram revisadas as avaliações do uso do Evusheld pela Agência Europeia de Medicamentos, Estados Unidos, Israel, Canadá, Austrália e pelo Brasil. Até o momento, segundo a Comissão Nacional de Incorporação de Tecnologias no SUS (CONITEC), não há evidências suficientes a respeito da eficácia e segurança do uso do medicamento em questão no tratamento ou profilaxia da COVID-19.
AZD7442 or Evusheld, produced by AstraZeneca, is a combination of two long-acting human monoclonal antibodies called tixagevimab (AZD8895 or COV2-2196) and cilgavimab (AZD1061 or COV2-2130), cloned from B lymphocytes isolated from mononuclear cells of peripheral blood of patients convalescent from COVID-19 (CONITEC, 2021). Its use is indicated for pre-exposure prophylaxis to SARS-CoV-2 in adult and pediatric individuals who, due to different clinical conditions, cannot be vaccinated or do not develop adequate defenses after immunization against COVID-19 (ASTRAZENECA, 2022). ). Evaluations of the use of Evusheld by the European Medicines Agency, the United States, Israel, Canada, Australia and Brazil were reviewed. To date, according to the National Commission for the Incorporation of Technologies in the SUS (CONITEC), there is not enough evidence regarding the efficacy and safety of using the drug in question in the treatment or prophylaxis of COVID-19.
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Adulto Joven , Anticuerpos Monoclonales/administración & dosificación , COVID-19/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Monoclonal antibodies (mAbs) have been a valuable tool to elucidate several biological processes, such as stem cell differentiation and cancer, and contributed to virtually all areas of biomedical sciences. Yet, it remains a challenge to obtain mAbs specific to poorly expressed epitopes, or to epitopes that are actually involved in important biological phenomena, such as cell differentiation and metastasis. Drug-induced subtractive immunization, and recently the multiple tolerization subtractive immunization (MTSI) technique, reported by our group, have the potential to level up the field, as they direct the host´s immune response towards these epitopes. However, due to cyclophosphamide (CY) treatment, high mice mortality can be observed, and only a few data are available on how these techniques affect the immune system of mice. Tolerogen and immunogen cells, RWPE-1 and PC-3 cells, respectively, were individually seeded at 2 × 104 cells/cm2, and then adjusted to 2 × 106 cells per mouse before immunization, which was conducted in a subtractive approach (MTSI) with CY. Immunosuppression of mice was recorded via total white blood counting, as well the reactivity of circulating polyclonal antibodies (pAbs). General parameters, including weight, physical appearance, and behavior on mice subjected to three different concentrations of CY were recorded. mAbs were obtained using classical hybridoma techniques, using the spleen of immunized mice. After purification, antibodies were characterized by Western blotting, and Indirect immunofluorescence. In conclusion, all CY dosage were efficient in creating an immunosuppression state, but only the 100 mg/kg body weight was feasible, as the others resulted in extensive mice mortality. pAbs obtained in the peripheral blood of mice showed more reactivity towards tumor cells. MAbs 2-7A50 and 2-5C11 recognized antigens from tumor cells, but not from their non-tumor counterparts, as shown in western blotting and immunofluorescence assays. MTSI technique was successful in generating mAbs that recognize tumor-specific antigens.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Ciclofosfamida/administración & dosificación , Terapia de Inmunosupresión/métodos , Inmunosupresores/administración & dosificación , Animales , Especificidad de Anticuerpos , Línea Celular , Epítopos/inmunología , Humanos , Recuento de Leucocitos , Masculino , Ratones Endogámicos BALB CRESUMEN
Hemolytic Uremic Syndrome (HUS) associated with Shiga-toxigenic Escherichia coli (STEC) infections is the principal cause of acute renal injury in pediatric age groups. Shiga toxin type 2 (Stx2) has in vitro cytotoxic effects on kidney cells, including human glomerular endothelial (HGEC) and Vero cells. Neither a licensed vaccine nor effective therapy for HUS is available for humans. Recombinant antibodies against Stx2, produced in bacteria, appeared as the utmost tool to prevent HUS. Therefore, in this work, a recombinant FabF8:Stx2 was selected from a human Fab antibody library by phage display, characterized, and analyzed for its ability to neutralize the Stx activity from different STEC-Stx2 and Stx1/Stx2 producing strains in a gold standard Vero cell assay, and the Stx2 cytotoxic effects on primary cultures of HGEC. This recombinant Fab showed a dissociation constant of 13.8 nM and a half maximum effective concentration (EC50) of 160 ng/mL to Stx2. Additionally, FabF8:Stx2 neutralized, in different percentages, the cytotoxic effects of Stx2 and Stx1/2 from different STEC strains on Vero cells. Moreover, it significantly prevented the deleterious effects of Stx2 in a dose-dependent manner (up to 83%) in HGEC and protected this cell up to 90% from apoptosis and necrosis. Therefore, this novel and simple anti-Stx2 biomolecule will allow further investigation as a new therapeutic option that could improve STEC and HUS patient outcomes.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Síndrome Hemolítico-Urémico/prevención & control , Fragmentos Fab de Inmunoglobulinas/inmunología , Toxina Shiga II/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Apoptosis/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Humanos , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Glomérulos Renales/citología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Proteínas Recombinantes , Toxina Shiga I/inmunología , Toxina Shiga I/toxicidad , Toxina Shiga II/toxicidad , Escherichia coli Shiga-Toxigénica/inmunología , Células VeroRESUMEN
INTRODUCCIÓN: La enfermedad por coronavirus 2019 (COVID-19), causada por el coronavirus 2 del Síndrome respiratorio agudo grave (SARS-CoV-2) fue inicialmente reportada en Wuhan, China en diciembre de 2019 (2). El espectro de la enfermedad es amplio e incluye desde cuadros leves y autolimitados hasta neumonía atípica severa y progresiva, falla multiorgánica y muerte (3,4). La Organización Mundial de la Salud (OMS) al 29 de junio de 2021 reportó 2.6 millones de casos nuevos en la última semana, con más de 57 mil nuevas muertes reportadas (5). Desde la identificación inicial del SARS-CoV-2, hasta el momento de este reporte, la OMS ha identificado cuatro como variantes cuya patogenicidad es preocupante (Alpha: B.1.1.7, Beta: B.1.351, Gamma: P.1 y Delta: B.1.617.2) y que podrían modificar el curso de la pandemia (6). Casirivimab e Imdevimab son anticuerpos monoclonales tipo inmunoglobulina G1 (IgG1) humana, ambos se administran en conjunto y que se dirigen contra el virus SARS-CoV-2 que causa la COVID-19, ya que se unen a los epítopos no competitivos del dominio de unión al receptor (RBD) de la proteína espiga (S) del SARS-CoV-2. La combinación de estos anticuerpos monoclonales, denominada REGEN COV, ha recibido la Autorización de uso de emergencia (EUA) por la Administración de Alimentos y Medicamentos de los Estados Unidos (FDA) (7). La presente nota técnica tiene como objetivo describir la evidencia científica publicada respecto a la eficacia y efectividad de la combinación de los anticuerpos monoclonales Casirivimab e Imdevimab (REGEN COV) en la prevención de COVID-19. MÉTODOS: Se realizó una búsqueda sistemática hasta el 10 de setiembre de 2021 en las bases de datos científicas MEDLINE/PubMed, LILACS/Biblioteca virtual en salud (BVS) y L.OVE/Epistemonikos, incluyendo términos en lenguaje natural y lenguaje estructurado (Tesauros) según cada base de datos para el fármaco de interés: "REGEN-COV", "casirivimab", "imdevimab", "REGN10933" y "REGN10987"; "SARS-CoV-2", "COVID-19". Se incluyeron publicaciones de ensayos clínicos o en etapa de pre-impresión (manuscritos no certificados por una revisión por pares) que reporten resultados para al menos uno de los desenlaces. Se consideraron publicaciones en idioma: inglés, español o portugués. Adicionalmente, se incluyeron estudios de ensayos de neutralización que trataban de la efectividad del fármaco de interés frente a las variantes del SARS-CoV-2. Se excluyeron estudios realizados en animales. La selección de los estudios y extracción de los datos no fue pareada. No se hizo evaluación de riesgo de sesgo de las publicaciones incluidas. RESULTADOS: En la Revisión Rápida N° 04-2021 de UNAGESP, se realizó una búsqueda sistematizada hasta el 28 de junio de 2021 (1); en esta búsqueda se recuperaron 02 reportes correspondientes a las 02 partes de un ensayo clínico aleatorizado del fármaco de interés (Casirivimab e Imdevimab) para la prevención de infección sintomática por SARS-CoV-2. Adicionalmente, se realizó una búsqueda sistematizada hasta el 10 de setiembre en la que se recuperaron 04 documentos sobre la efectividad de este fármaco sobre las variantes de preocupación (VOC) del SARS-CoV-2. CONCLUSIONES: El objetivo de esta nota técnica fue describir la evidencia científica publicada respecto a la eficacia y efectividad de la combinación de los anticuerpos monoclonales Casirivimab e Imdevimab (REGEN COV) en la prevención de COVID-19. La intervención evaluada para la prevención de COVID-19 fue la combinación de anticuerpos monoclonales REGEN-COV (Casirivimab (REGN 10933) 600mg e Indevimab (REGN 10987) 60mg) que es administrada por vía subcutánea. Se identificó un ensayos clínicos aleatorizados (ECA) realizado en partes (parte A y B) que evaluaron la eficacia de la combinación REGEN COV (Casirivimab/Imdevimab) para prevenir infección sintomática por SARS-CoV-2 (COVID-19); no se identificó ningún estudio que evaluara la efectividad de este fármaco para la prevención de COVID-19. Se identificaron 4 estudios que evaluaron la capacidad de neutralización de estos anticuerpos frente a las variantes Alpha, Beta, Gamma y Delta del SARS-CoV-2 en estudios in vitro. La combinación REGEN COV (Casirivimab 600mg/Imdevimab 600mg) administrada por vía subcutánea, en pacientes con PCR negativo y exposición a un contacto intradomiciliario con infección por SARS-CoV-2, redujo el riesgo de desarrollar COVID-19 en un 81.4% en relación al riesgo de los que recibieron placebo (1.5% vs 7.8%, RR: 0.186, IC 95% 0.09 0.35). En relación a los eventos adversos, en la parte A del ECA revisado se reportaron 265/1311 (20.2%) eventos adversos en el grupo de intervención y 379/1306 (29%) en el grupo placebo. Los eventos adversos más frecuentes fueron cefalea y reacción en el lugar de inyección. La frecuencia de eventos adversos serios (EAS) fue de 10/1311 (0.8%) en el grupo intervención y de 15/1306 (1.1%) en el grupo placebo. Ninguno de los EAS fueron atribuidos a la vacuna. En el grupo de intervención no se reportó ningún evento de especial interés. Se reportaron 4 fallecimiento después del término del seguimiento, 2 en cada brazo, de los cuales ninguno fue atribuido a la vacunación. En cuanto a la capacidad de neutralización frente a las variantes de preocupación (VOC) del SARS-CoV-2, los estudios revisados informaron que la combinación REGEN COV (Casirivimab/Imdevimab) mantuvo la capacidad de neutralización contra la variante Alpha (B.1.1.7) y Delta (B.1.617.1 y B.1.617.2), y mantuvo parcialmente la capacidad de neutralización contra la variante Beta (B.1.351) y Gamma (P.1), probablemente debido a mutaciones K417N y E484K resistentes a Casirivimab.
Asunto(s)
Humanos , SARS-CoV-2/efectos de los fármacos , COVID-19/prevención & control , Anticuerpos Monoclonales/administración & dosificación , Eficacia , Análisis Costo-Beneficio , Combinación de MedicamentosRESUMEN
ANTECEDENTES: La enfermedad por coronavirus 2019 (COVID-19), causada por el virus SARS-CoV-2 sigue produciendo millones de casos y muertes a nivel global hasta la fecha. Si bien ya existen vacunas eficaces para prevenir dicha enfermedad, algunos medicamentos han mostrado tener un rol terapéutico, como son los anticuerpos monoclonales específicos para proteínas del virus SARS-CoV-2. Por esta razón, se elaboró la presente Revisión Rápida con el fin de identificar y evaluar la evidencia disponible sobre este tema. OBJETIVO: El objetivo de esta revisión es identificar y sistematizar la evidencia disponible sobre la eficacia de los anticuerpos monoclonales específicos para SARS-CoV-2 previniendo el desarrollo de COVID-19, o mejorando los desenlaces clínicos de los pacientes con dicha enfermedad. METODOLOGÍA: Se realizó una revisión rápida basada en dos preguntas: a) En pacientes sin COVID-19 sintomático, ¿el uso de anticuerpos monoclonales específicos para SARS-CoV-2 comparado con no uso o placebo, es eficaz previniendo el desarrollo de COVID-19 sintomático? b) En pacientes con infección confirmada por SARS-CoV-2, ¿el uso de anticuerpos monoclonales específicos para SARS-CoV-2 comparado con no uso o placebo, es eficaz mejorando los desenlaces clínicos de los pacientes? Sólo se incluyeron ensayos clínicos aleatorizados o no. Para ello, se realizó una búsqueda sistemática en las bases de datos MEDLINE/PubMed, EMBASE/Ovid, LILACS, la Biblioteca Cochrane, MedRxiv, y BioRxiv. Luego de eliminar duplicados, fueron seleccionaron los ítems que cumplieran con la pregunta de investigación. No se evaluó riesgo de sesgo ni la calidad de la evidencia identificada. RESULTADOS: Se identificaron 14 estudios, 4 sobre prevención post exposición COVID-19, y 10 sobre eficacia mejorando desenlaces clínicos en pacientes con la enfermedad. De estos, 2 fueron en pacientes hospitalizados sin enfermedad crítica, y 8 en ambulatorios. Solo 5 de los 14 estudios fueron publicaciones científicas revisadas por pares. Los estudios encontrados evaluaron los anticuerpos monoclonales: Bamlanivimab (LY-CoV555), Bamlanivimab/Etesevimab (LY-CoV555+LY-CoV016), la combinación Casirivimab/Imdevimab (REGN10933+REGN10987), Sotrovimab (GSK4182136), Regdanvimab (CT-P59), y la combinación Cilgavimab/Tixagevimab (AZD7442, AZD8895+AZD1061). Respecto al desenlace de Prevención de infección sintomática post-exposición, Bamlanivimab 4200mg IV tendría una eficacia a las 8 semanas del 44%. Casirivimab/Imdevimab 600mg/600mg SC tendría una eficacia de 81.4% a los 28 días en pacientes PCR negativos al momento de recibir la medicación, y 31.5% en pacientes PCR positivos. Cilgavimab/Tixagevimab 300mg IM no tendría efecto significativo 30 a 180 días post-exposición, excepto en aquellos con PCR negativo basal, con una eficacia de 73%. Respecto a los desenlaces clínicos en pacientes hospitalizados con COVID-19, ni el estudio ACTIV-3 evaluando Bamlanivimab 7000mg IV, ni el estudio RECOVERY evaluando Casirivimab/Imdevimab 4000 mg/4000 mg IV, encontraron eficacia; ya sea mejorando la recuperación clínica, o disminuyendo muertes/ventilación mecánica, respectivamente. Sobre eficacia del tratamiento en pacientes ambulatorios, los tres reportes del estudio BLAZE-1 concluyen que Bamlanivimab IV combinado con Etesevimab (2800mg/2800mg) reduce la proporción de hospitalizaciones o visita a emergencia o muerte a los 29 días entre un 70% y 84%. El estudio de Regeneron® con Casirivimab/Imdevimab IV 1200mg/1200mg, y 4000mg/4000mg, muestra reducción significativa en atenciones médicas hasta el día 29 de 57% en general, 65% si tenían anticuerpos negativos basales, y 71% con factores de progresión. Otro reporte muestra reducción en hospitalizaciones o muerte de 71.3% (1200/1200mg) y 70.4% (600mg/600mg). Sotrovimab 500mg IV redujo hospitalización o muerte hasta el día 29 en 85%; y Regdanvimab IV redujo hospitalización o necesidad de oxígeno a los 28 días en 54% (40mg/Kg), y en 44% (80mg/Kg). Los tres reportes del estudio BLAZE-1 concluyen que Bamlanivimab IV no reduce la carga viral a los 11 días; en cambio, Bamlanivimab/Etesevimab 2800mg/2800mg IV si reduce la carga a los 7 y 11 días. Los reportes de Regeneron® concluyen que Casirivimab/Imdevimab IV reduce la carga viral al día 7. Regdanvimab no muestra diferencias significativas en la velocidad de negativización del PCR. Ningún estudio mostró diferencias en la proporción de eventos adversos o eventos adversos serios. CONCLUSIONES: Existe evidencia basada en ensayos clínicos, en su mayoría no revisados por pares, que los anticuerpos monoclonales serian medicamentos seguros y eficaces para prevenir enfermedad sintomática luego de exposición, sobre todo en aquellos con PCR negativo para SARS-CoV-2; y también mejorando los desenlaces clínicos (incluyendo hospitalización o muerte) en pacientes ambulatorios con COVID-19. No tendrían eficacia en el tratamiento de pacientes con COVID-19 ya hospitalizados.
Asunto(s)
Humanos , SARS-CoV-2/inmunología , COVID-19/prevención & control , COVID-19/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Eficacia , Análisis Costo-BeneficioRESUMEN
Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Antivirales/administración & dosificación , Arenavirus del Nuevo Mundo/fisiología , Glicoproteínas/inmunología , Fiebre Hemorrágica Americana/prevención & control , Receptores de Transferrina/inmunología , Células A549 , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Fiebre Hemorrágica Americana/inmunología , Fiebre Hemorrágica Americana/virología , Humanos , Estructura Terciaria de Proteína , Receptores de Transferrina/química , Receptores de Transferrina/genéticaRESUMEN
In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Terapia de Reemplazo Enzimático/métodos , Iduronato Sulfatasa/administración & dosificación , Mucopolisacaridosis II/tratamiento farmacológico , Receptores de Transferrina/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/administración & dosificación , Adolescente , Adulto , Brasil/epidemiología , Niño , Quimioterapia Combinada , Femenino , Humanos , Masculino , Mucopolisacaridosis II/epidemiología , Mucopolisacaridosis II/genética , Mucopolisacaridosis II/patología , Receptores de Transferrina/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
In the phase III CASTOR trial, daratumumab, bortezomib and dexamethasone (D-Vd) significantly extended progression-free survival compared with bortezomib and dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Here, we present patient-reported outcomes (PROs) from the CASTOR trial. PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire. Treatment effects through Cycle 8 were measured by a repeated measures mixed-effects model. After Cycle 8, PROs were only collected for patients in the D-Vd group who continued on daratumumab monotherapy. Compliance rates for PRO assessments were high and similar between treatment groups. Mean changes from baseline were generally similar between treatment groups for EORTC QLQ-C30 global health status (GHS), functioning and symptoms, and did not exceed 10 points for either treatment group. Subgroup analyses were consistent with the results observed in the overall population. There was no change in patients' health-related quality of life for the first eight cycles of therapy; thereafter, patients treated with daratumumab over the long-term reported improvements in GHS and pain. These results complement the significant clinical benefits observed with D-Vd in patients with RRMM and support its use in this patient population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Modelos Biológicos , Mieloma Múltiple , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Bortezomib/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Tasa de SupervivenciaRESUMEN
BACKGROUND: Spending on drugs provided by the Brazilian Public Health System (BPHS) for the treatment of rheumatoid arthritis (RA) increased substantially with the beginning of the supply of biological disease-modifying anti-rheumatic drugs (bDMARD). This study aims to perform a cost-utility analysis of the most used biological drugs for the treatment of RA in Brazil. METHODS: a Markov model was used to carry out the cost-utility analysis. The data were obtained from a prospective cohort of RA patients using adalimumab, etanercept, and golimumab in Brazil. The BPHS perspective was adopted and the time horizon was five years. Deterministic and probabilistic sensitivity analyses were performed to evaluate the uncertainty. RESULTS: golimumab was the most cost-effective drug. Etanercept was dominated by golimumab. Adalimumab presented an incremental cost-utility ratio (ICUR) of $95,095.37 compared to golimumab in five years of follow-up. These results were confirmed by sensitivity analyses. CONCLUSION: the utility among adalimumab, etanercept, and golimumab was similar and the cost was the component that most impacted the economic model. Therefore, depending on the agreed price with the drug manufacturers, the incremental cost-utility ratio may vary among them.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Modelos Económicos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , Adalimumab/administración & dosificación , Adalimumab/economía , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/economía , Antirreumáticos/economía , Artritis Reumatoide/economía , Brasil , Estudios de Cohortes , Análisis Costo-Beneficio , Etanercept/administración & dosificación , Etanercept/economía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Cadenas de Markov , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores del Factor de Necrosis Tumoral/economíaRESUMEN
BACKGROUND: List prices of tumor necrosis factor (TNF) inhibitors drastically increased during the last decade, but previous research has shown that half of these increases were offset by rising manufacturer discounts. It remains unclear to what extent manufacturers' discounts have offset increases in list prices of each self-administered injectable TNF inhibitor. Evaluating trends in net prices and discounts at the product level will be paramount in understanding the role of competition in the biologic market. OBJECTIVES: To (a) describe product-level changes in net prices of each self-administered injectable TNF inhibitor available in 2007-2019 and (b) quantify to what extent manufacturer discounts have offset increases in list prices. METHODS: We obtained 2007-2019 pricing data for etanercept, adalimumab, certolizumab, and golimumab from the investment firm SSR Health, which uses company-reported sales to estimate net prices and discounts for brand products manufactured by publicly traded companies. For each drug and year, we calculated annual costs of treatment for patients with rheumatoid arthritis based on list and net prices and discounts in Medicaid and other payers. RESULTS: From 2007-2019, list prices of etanercept and adalimumab increased by 293% and 295%, respectively; however, discounts offset 47% and 45% of these increases, leading to net price increases of 171% and 203%. List prices of golimumab and certolizumab increased by 183% and 182%, respectively, but with discounts offsetting 58% and 59% of these increases, net prices increased by 103% and 109%. Net prices of golimumab started to decrease after 2016, while net prices of adalimumab and certolizumab experienced their first drop in 2019. Across the study period, discounts in Medicaid and in other payers increased, respectively, from 21% to 85% and 6% to 32% for etanercept; from 26% to 88% and 19% to 35% for adalimumab; from 28% to 63% and 22% to 46% for golimumab; and from 29% to 83% and 27% to 47% for certolizumab. CONCLUSIONS: Despite growing manufacturer discounts, net prices of self-administered injectable TNF inhibitors still increased at a mean annual rate of 9.6% in 2007-2019. This led to net prices tripling for adalimumab and more than doubling for etanercept, golimumab, and certolizumab. DISCLOSURES: This study was funded by the Myers Family Foundation. Hernandez is funded by the National Heart, Lung and Blood Institute (grant number K01HL142847). Funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Hernandez has served on Pfizer's scientific advisory board. The other authors have nothing to disclose.
Asunto(s)
Antirreumáticos/uso terapéutico , Costos de los Medicamentos/tendencias , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/administración & dosificación , Adalimumab/economía , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/economía , Antirreumáticos/administración & dosificación , Etanercept/administración & dosificación , Etanercept/economía , Humanos , Inyecciones , Autoadministración , Estados UnidosRESUMEN
MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à la réévaluation du produit TakhzyroMC (lanadélumab), un anticorps monoclonal pour injection sous-cutanée toutes les 2 semaines (avec possibilité de réduire à 4 semaines), indiqué pour la prévention systématique des crises d'angiÅdème héréditaire (AOH) chez les adultes et les adolescents âgés de 12 ans et plus. TakhzyroMC n'est pas destiné au traitement des crises d'AOH aiguës. Lors de la première évaluation, publiée en août 2019, l'INESSS recommandait de ne pas ajouter TakhzyroMC à la Liste des produits du système du sang du Québec puisque la valeur thérapeutique n'avait pas été reconnue, et ce, principalement pour les raisons suivantes : Les données probantes étaient encore trop immatures pour garantir l'innocuité à plus long terme d'un produit qui fait partie d'une nouvelle classe d'agents thérapeutiques dans le traitement de l'AOH. L'ampleur du gain clinique (efficacité) reste difficile à déterminer en l'absence d'étude de comparaison directe avec des produits activement utilisés dans la pratique clinique. Le traitement alors prescrit était considéré comme efficace pour la grande majorité des patients atteints d'AOH de types 1 et 2. De plus, son usage historique dans la prise en charge de l'AOH suggérait un profil d'innocuité favorable. DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du lanadélumab. Des données expérientielles et contextuelles issues de la consultation d'experts sont présentées. La collecte de données permettant de capter la perspective des patients effectuée lors de la première évaluation a été bonifiée au moyen de questionnaires. BESOIN DE SANTÉ: L'angiÅdème héréditaire est une maladie génétique autosomique dominante rare, typiquement causée par un déficit quantitatif (type 1) ou fonctionnel (type 2) de l'inhibiteur de la C1-estérase (C1-INH). Elle se caractérise par la survenue d'Ådèmes non inflammatoires, transitoires et récidivants affectant les tissus du visage, des membres, des voies respiratoires supérieures, du système digestif ou du système urogénital. L'évolution de la maladie de l'AOH est douloureuse, imprédictible et potentiellement mortelle, et s'accompagne d'une diminution de la qualité de vie due à l'imprévisibilité des crises, leur fréquence et la détresse physique et émotionnelle. La prise en charge a pour objectif de prévenir ou de réduire la fréquence et la gravité des crises d'AOH et, ainsi, d'améliorer la qualité de vie. La prophylaxie à long terme est généralement proposée aux patients lorsque les traitements sur demande ne sont pas suffisants pour obtenir une qualité de vie adéquate. Les traitements disponibles au Québec comprennent un concentré plasmatique de C1-INH (BerinertMC) inscrit à la Liste des produits du système du sang du Québec en thérapie de remplacement ainsi qu'un antagoniste de la voie kinine-kallicréine (FirazyrMC) inscrit aux Listes de médicaments Médicament d'exception, pour le traitement des crises aiguës. Depuis février 2020, HaegardaMC est distribué dans certains centres du Québec et permet l'administration d'un concentré plasmatique de C1-INH par la voie sous-cutanée. Au Québec, on estime qu'entre 120 et 150 personnes seraient atteintes d'AOH et qu'une centaine d'entre elles seraient diagnostiquées. Bien que la maladie soit généralement bien contrôlée, la prise en charge thérapeutique s'accompagne d'un fardeau important, qu'il s'agisse de l'administration du traitement (problèmes d'accès veineux), de la fréquence et de la durée des injections, ou encore du matériel à transporter par les patients durant leurs déplacements. Résultats: Les données disponibles montrent que la prophylaxie par le lanadélumab à la dose de 300 mg à toutes les 2 semaines a permis de réduire le taux mensuel de crises d'angiÅdème au cours de 3 études cliniques : de 73 % à 87 % par rapport au placebo dans un essai clinique randomisé pivot de 26 semaines; de 82 % à 92 % par rapport au niveau de base dans la prolongation non contrôlée de l'étude de phase 3 et % par rapport au niveau de base dans une étude de cohorte menée en France. Une exposition au lanadélumab d'environ 18 mois au cours de l'étude de prolongation, qui s'ajoute aux 26 semaines de traitement de l'étude pivot pour certains patients, suggère que l'efficacité du lanadélumab en prévention des crises d'angiÅdème héréditaire peut se maintenir dans le temps. Le risque de biais est cependant élevé et l'étude de prolongation est toujours en cours. Cette efficacité a été similairement observée dans l'analyse d'autres paramètres, tels que le recours au traitement sur demande, le taux de crises d'intensité modérée ou élevée et le taux de crises avec morbidité élevée (diminution de 73 % à 87 % par rapport au placebo et de 91 % à 96 % par rapport au niveau de base). Finalement, une proportion importante de patients n'a rapporté aucune crise dans le cadre des différentes études (de 31 % à 44 %, excluant l'étude de cohorte française). Une analyse de comparaison indirecte soumise par le fabricant évaluant en parallèle l'efficacité du lanadélumab et celles des produits comparateurs. Cette analyse n'a pas été retenue puisque le choix de modèles à effets fixes diminue la plausibilité des résultats de comparaison indirecte en ne permettant pas de prendre en considération l'hétérogénéité significative observée entre les études. DÉLIBÉRATION SUR L'ENSEMBLE DES CRITÈRES: Les membres du Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription sont majoritairement d'avis que la valeur thérapeutique du lanadélumab (TakhzyroMC) est démontrée pour la prévention systématique des crises d'angiÅdème héréditaire chez les adultes et les adolescents. Conséquemment, les membres sont majoritairement d'avis qu'il est responsable, juste et équitable d'inscrire le lanadélumab (TakhzyroMC) sur la Liste des produits du système du sang du Québec à condition qu'une atténuation du fardeau économique soit mise en place. DÉLIBÉRATION SUR L'ENSEMBLE DES CRITÈRES: Les membres du Comité délibératif ont également exprimé la préoccupation suivante relativement à l'ajout de ce produit à la Liste des produits du système du sang du Québec : Les membres sont préoccupés par l'ampleur des coûts liés à la prise en charge de ces patients. Ils se questionnent notamment sur la justesse du prix de ces produits et sur l'utilisation équitable des ressources qui en découle. RECOMMANDATION DE l'INESSS TakhzyroMC: Ajout du produit TakhzyroMC à la Liste des produits du système du sang du Québec pour la prévention systématique des crises d'angiÅdème héréditaire chez l'ensemble des adultes et adolescents atteints d'AOH de types 1 et 2. TakhzyroMC n'est pas destiné au traitement des crises d'AOH aiguës.
MANDATE: The Institut national d'excellence en santé et en services sociaux (INESSS) reassessed Takhzyroï (lanadelumab), a monoclonal antibody for subcutaneous injection every 2 weeks (with the option of reducing the frequency to every 4 weeks) indicated for the routine prevention of attacks of hereditary angioedema (HAE) in adults and adolescents 12 years of age and older. Takhzyro™ is not intended for the treatment of acute HAE attacks. In the initial evaluation, published in August 2019, INESSS recommended that Takhzyro™ not be added to the Liste des produits du système du sang du Québec (blood products list) since its therapeutic value had not been recognized, primarily for the following reasons: The evidence was still too immature to guarantee the longer-term safety of a product that is in a new class of therapeutic agents for the treatment of HAE; The extent of the clinical gain (efficacy) is difficult to determine in the absence of studies involving a direct comparison with products actively used in clinical practice. The standard treatment available at the time was considered efficacious for the vast majority of patients with type 1 or 2 HAE, and its past use in the management of HAE pointed to a favourable safety profile. RESULTS: The available data show that prophylaxis with lanadelumab at a dose of 300 mg every 2 weeks reduced the monthly angioedema attack rate in three clinical studies: by 73% to 87% compared to placebo in a 26-week pivotal randomized clinical trial; by 82% to 92% relative to baseline in the uncontrolled extension of the Phase 3 study; and X% relative to baseline in a French cohort study. Exposure to lanadelumab for approximately 18 months during the extension study, in addition to the 26 weeks of treatment in the pivotal study for certain patients, suggests that lanadelumab's efficacy in preventing hereditary angioedema attacks can be maintained over time. However, the risk of bias is high, and the extension study is still ongoing. This efficacy was similarly observed in the analysis of other endpoints, such as the use of on-demand therapy, the rate of moderate to severe attacks, and the rate of high-morbidity attacks (a decrease of 73% to 87% compared to placebo and of 91% to 96% relative to baseline). Lastly, a significant proportion of the patients in the different studies did not report any attacks (31% to 44%, excluding the French cohort study). An indirect comparative analysis submitted by the manufacturer and evaluating the efficacy of lanadelumab in parallel with that of the comparators. This analysis was not included because the choice of fixed-effects models reduces the plausibility of the indirect comparison results in that these models ignore the significant heterogeneity observed between studies. DELIBERATION ON ALL THE CRITERIA: The majority of members of the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription are of the opinion that the therapeutic value of lanadelumab (Takhzyro™) has been demonstrated for the routine prevention of hereditary angioedema attacks in adults and adolescents. Consequently, the majority of the members are of the opinion that it is responsible, fair and equitable to enter lanadelumab (Takhzyro™) on the Liste des produits du système du sang du Québec, provided that a measure to mitigate the economic burden is put in place. DELIBERATION ON ALL THE CRITERIA: The members are concerned about the high costs associated with managing these patients. In particular, they question the fairness of the price of these products and the equitableness of the use of the resources involved. INESSS'S RECOMMENDATION - TAKHZYRO™: The addition of Takhzyro™ to the Liste des produits du système du sang du Québec for the routine prevention of hereditary angioedema attacks in all adults and adolescents with type 1 or 2 HAE. Takhzyro™ is not intended for the treatment of acute HAE attacks.
Asunto(s)
Humanos , Angioedemas Hereditarios/prevención & control , Anticuerpos Monoclonales/administración & dosificación , Eficacia , Análisis Costo-Beneficio/economíaRESUMEN
Daratumumab is an anti-CD38 monoclonal antibody approved for use in multiple myeloma in 2015 and under investigation for use in light-chain amyloidosis. We report a case of a patient with amyloidosis who developed bilateral, acute secondary angle closure during an infusion of daratumumab. Ultrasound biomicroscopy obtained 3 days after the onset of her symptoms demonstrated the cause to be bilateral choroidal effusions. Taken together with several previous case reports, the evidence suggests that, like topiramate, daratumumab is associated with the idiosyncratic reaction of choroidal effusions, resulting in a spectrum of clinical outcomes from myopic shift to acute angle closure. The treating oncologist and eye care provider should be aware of these adverse outcomes in any patient undergoing treatment with this medication, as swift recognition and intervention may be vision-saving.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Glaucoma de Ángulo Cerrado/inducido químicamente , Administración Oftálmica , Amiloidosis/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Efusiones Coroideas/diagnóstico por imagen , Efusiones Coroideas/tratamiento farmacológico , Ciclopentolato/uso terapéutico , Combinación de Medicamentos , Oftalmopatías/tratamiento farmacológico , Femenino , Glaucoma de Ángulo Cerrado/diagnóstico por imagen , Glaucoma de Ángulo Cerrado/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Gonioscopía , Humanos , Infusiones Intravenosas , Presión Intraocular/efectos de los fármacos , Microscopía Acústica , Persona de Mediana Edad , Antagonistas Muscarínicos/uso terapéutico , Prednisolona/uso terapéuticoRESUMEN
Treatment with anti-CD20, used in many diseases in which B cells play a pathogenic role, has been associated with susceptibility to intracellular infections. Here, we studied the effect of anti-CD20 injection on CD8+ T cell immunity using an experimental model of Trypanosoma cruzi infection, in which CD8+ T cells play a pivotal role. C57BL/6 mice were treated with anti-CD20 for B cell depletion prior to T. cruzi infection. Infected anti-CD20-treated mice exhibited a CD8+ T cell response with a conserved expansion phase followed by an early contraction, resulting in a strong reduction in total and parasite-specific CD8+ T cell numbers at 20 days postinfection. Anti-CD20 injection increased the frequency of apoptotic CD8+ T cells, decreased the number of effector and memory CD8+ T cells, and reduced the frequency of proliferating and cytokine-producing CD8+ T cells. Accordingly, infected anti-CD20-treated mice presented lower cytotoxicity of T. cruzi peptide-pulsed target cells in vivo All of these alterations in CD8+ T cell immunity were associated with increased tissue parasitism. Anti-CD20 injection also dampened the CD8+ T cell response, when this had already been generated, indicating that B cells were involved in the maintenance rather than the induction of CD8+ T cell immunity. Anti-CD20 injection also resulted in a marked reduction in the frequency of interleukin-6 (IL-6)- and IL-17A-producing cells, and recombinant IL-17A (rIL-17A) injection partially restored the CD8+ T cell response in infected anti-CD20-treated mice. Thus, anti-CD20 reduced CD8+ T cell immunity, and IL-17A is a candidate for rescuing deficient responses either directly or indirectly.IMPORTANCE Monoclonal antibody targeting the CD20 antigen on B cells is used to treat the majority of non-Hodgkin lymphoma patients and some autoimmune disorders. This therapy generates adverse effects, notably opportunistic infections and activation of viruses from latency. Here, using the infection murine model with the intracellular parasite Trypanosoma cruzi, we report that anti-CD20 treatment affects not only B cell responses but also CD8+ T cell responses, representing the most important immune effectors involved in control of intracellular pathogens. Anti-CD20 treatment, directly or indirectly, affects cytotoxic T cell number and function, and this deficient response was rescued by the cytokine IL-17A. The identification of IL-17A as the cytokine capable of reversing the poor response of CD8+ T cells provides information about a potential therapeutic treatment aimed at enhancing defective immunity induced by B cell depletion.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antígenos CD20/inmunología , Linfocitos T CD8-positivos/inmunología , Enfermedad de Chagas/inmunología , Interleucina-17/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Enfermedad de Chagas/prevención & control , Femenino , Inyecciones Intraperitoneales , Interleucina-17/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Trypanosoma cruziRESUMEN
Envenoming due to Loxosceles spider bites still remains a neglected disease of particular medical concern in the Americas. To date, there is no consensus for the treatment of envenomed patients, yet horse polyclonal antivenoms are usually infused to patients with identified severe medical conditions. It is widely known that venom proteins in the 30-35 kDa range with sphingomyelinase D (SMasesD) activity, reproduce most of the toxic effects observed in loxoscelism. Hence, we believe that monoclonal antibody fragments targeting such toxins might pose an alternative safe and effective treatment. In the present study, starting from the monoclonal antibody LimAb7, previously shown to target SMasesD from the venom of L. intermedia and neutralize its dermonecrotic activity, we designed humanized antibody V-domains, then produced and purified as recombinant single-chain antibody fragments (scFvs). These molecules were characterized in terms of humanness, structural stability, antigen-binding activity, and venom-neutralizing potential. Throughout this process, we identified some blocking points that can impact the Abs antigen-binding activity and neutralizing capacity. In silico analysis of the antigen/antibody amino acid interactions also contributed to a better understanding of the antibody's neutralization mechanism and led to reformatting the humanized antibody fragment which, ultimately, recovered the functional characteristics for efficient in vitro venom neutralization.
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Anticuerpos Monoclonales , Antivenenos , Anticuerpos de Cadena Única , Venenos de Araña/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Antígenos/inmunología , Antivenenos/administración & dosificación , Antivenenos/inmunología , Eritrocitos/efectos de los fármacos , Hemólisis/efectos de los fármacos , Humanos , Modelos Moleculares , Pruebas de Neutralización , Anticuerpos de Cadena Única/administración & dosificación , Anticuerpos de Cadena Única/inmunología , Picaduras de Arañas/terapia , Venenos de Araña/efectos adversos , Arañas/inmunologíaRESUMEN
Human respiratory syncytial virus (hRSV) is the most important etiological agent causing hospitalizations associated with respiratory diseases in children under 5 years of age as well as the elderly, newborns and premature children are the most affected populations. This viral infection can be associated with various symptoms, such as fever, coughing, wheezing, and even pneumonia and bronchiolitis. Due to its severe symptoms, the need for mechanical ventilation is not uncommon in clinical practice. Additionally, alterations in the central nervous system -such as seizures, encephalopathy and encephalitis- have been associated with cases of hRSV-infections. Furthermore, the absence of effective vaccines or therapies against hRSV leads to elevated expenditures by the public health system and increased mortality rates for the high-risk population. Along these lines, vaccines and therapies can elicit different responses to this virus. While hRSV vaccine candidates seek to promote an active immune response associated with the achievement of immunological memory, other therapies -such as the administration of antibodies- provide a protective environment, although they do not trigger the activation of the immune system and therefore do not promote an immunological memory. An interesting approach to vaccination is the use of virus-neutralizing antibodies, which inhibit the entry of the pathogen into the host cells, therefore impairing the capacity of the virus to replicate. Currently, the most common molecule targeted for antibody design against hRSV is the F protein of this virus. However, other molecular components of the virus -such as the G or the N hRSV proteins- have also been explored as potential targets for the control of this disease. Currently, palivizumab is the only monoclonal antibody approved for human use. However, studies in humans have shown a protective effect only after the administration of at least 3 to 5 doses, due to the stability of this vaccine. Furthermore, other studies suggest that palivizumab only has an effectiveness close to 50% in high-risk infants. In this work, we will review different strategies addressed for the use of antibodies in a prophylactic or therapeutic context and their ability to prevent the symptoms caused by hRSV infection of the airways, as well as in other tissues such as the CNS.
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Anticuerpos Monoclonales/uso terapéutico , Desarrollo de Medicamentos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Virus Sincitial Respiratorio Humano/inmunología , Anticuerpos Monoclonales/administración & dosificación , Desarrollo de Medicamentos/métodos , Humanos , Programas de Inmunización , Inmunización Pasiva , Inmunoglobulina A Secretora/inmunología , Inmunoglobulina G/inmunología , Premedicación , Infecciones por Virus Sincitial Respiratorio/inmunología , Infecciones por Virus Sincitial Respiratorio/virologíaRESUMEN
BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.
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Anticuerpos Monoclonales/administración & dosificación , Bortezomib/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Prednisona/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Asia , Bortezomib/efectos adversos , Supervivencia sin Enfermedad , Esquema de Medicación , Quimioterapia Combinada/efectos adversos , Europa (Continente) , Femenino , Humanos , Quimioterapia de Mantención , Masculino , Melfalán/efectos adversos , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , América del Norte , Prednisona/efectos adversos , América del Sur , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Since its first isolation in 1983, over 77 million people became infected with the human immunodeficiency virus (HIV), and only one case has been reported in which the virus was completely removed from the body. A recent second case was reported that remains to be confirmed. Antiretroviral therapy (ART) manages to control blood viral replication and, consequently, to restore -at least partially- the functions of the immune system, with a notable positive impact on the morbidity and mortality associated with the virus. However, given the difficulty in eliminating the virus from the body, treatment should be given for life. This long-term exposure to antiretroviral drugs implies the risk of generating intolerance, toxic effects, gaps in adherence and the potential selection of resistance mutations. Another limitation is the high cost of treating 37 million persons living with HIV, most of whom are living in resource-limited countries and relying on international aid initiatives. Having these challenges in mind, there is general agreement that new approaches for preventing and treating HIV infection are needed to control the epidemic, while vaccine development efforts continue. In this regard, new generation broadly neutralising monoclonal antibodies (bnMAbs) against the HIV viral envelope protein can prevent virus acquisition, reduce viremia, enhance immunity, and induce the killing of infected cells in animal models of HIV infection. Most importantly, some clinical trials have shown that bnMAbs could effectively d ecrease viremia and delay viral rebound in people chronically infected with HIV.
Desde su primer aislamiento en 1983, el virus de la inmunodeficiencia humana (HIV) ha infectado a más de 77 millones de personas y solo se ha documentado un caso en el cual el virus fue removido completamente del organismo; aún resta confirmar un segundo caso informado recientemente. El tratamiento antirretroviral logra controlar la replicación viral en el plasma y en consecuencia recuperar (al menos parcialmente) la actividad del sistema inmune, con una notable reducción de la morbilidad y la mortalidad asociadas a la infección por HIV. Sin embargo, ante la dificultad para eliminar completamente el virus del organismo, es necesario continuar el tratamiento de por vida. Esto implica la exposició n a largo plazo a drogas antirretrovirales con riesgo de generar intolerancia, efectos tóxicos, brechas en la adherencia y selección de mutantes resistentes. Otro aspecto a considerar es la carga económica que implica tratar a 37 millones de personas infectadas con HIV, la mayoría de ellas en países que solo pueden afrontar esos costos con ayuda internacional. Por ello, hasta tanto se disponga de una vacuna capaz de prevenir la infección de todas las formas circulantes del HIV, es necesario desarrollar nuevas herramientas terapéuticas capaces de complementar y potenciar los efectos del tratamiento antirretroviral. Diversos ensayos preclínicos sugieren que la administración pasiva de anticuerpos monoclonales dirigidos contra la glicoproteína de envoltura viral podría prevenir la infección, reducir la carga viral, estimular la respuesta inmune y favorecer la eliminación de células infectadas con HIV.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Neutralizantes/administración & dosificación , Infecciones por VIH/prevención & control , Infecciones por VIH/terapia , Animales , Quimioterapia Combinada , VIH-1/inmunología , Humanos , Carga ViralRESUMEN
Los anticuerpos monoclonales que inhiben los puntos de control PD-1 y CTLA-4 se usan actualmente en el tratamiento del melanoma y cáncer metastásico de pulmón de células no pequeñas, entre otros. Se refiere el caso de una paciente con cáncer de pulmón en tratamiento con pembrolizumab. La paciente se presentó con edema facial y parálisis facial periférica. En el laboratorio se observó la hormona tirotrofina (TSH) elevada y se llegó al diagnóstico de hipotiroidismo por pembrolizumab. Inició tratamiento con levotiroxina con mejoría clínica. Se presenta este caso por el importante papel del dermatólogo en el manejo multidisciplinario del paciente oncológico. (AU)
Monoclonal antibodies that inhibit PD-1 and CTLA-4 control points are currently used in the treatment of melanoma and metastatic non-small cell lung cancer, among others. The case of a patient, with lung cancer being treated with Pembrolizumab. The patient was presented with facial edema and peripheral facial paralysis and in the laboratory the elevated hormone Tyrotrophin (TSH) was observed, the diagnosis of pembrolizumab hypothyroidism was reached. She started treatment with levothyroxine with clinical improvement. This case is presented by the important role of the dermatologist in the multidisciplinary management of the cancer patient. (AU)
Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Inmunoterapia/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Tiroxina/uso terapéutico , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/tratamiento farmacológico , Tirotropina/análisis , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas Supresoras de Tumor/efectos de los fármacos , Dermatología , Traumatismos Faciales , Parálisis Facial , Antígeno CTLA-4/efectos de los fármacos , Antígeno CTLA-4/fisiología , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Receptor de Muerte Celular Programada 1/fisiología , Pemetrexed/administración & dosificación , Melanoma/complicaciones , Melanoma/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Metástasis de la Neoplasia/tratamiento farmacológicoRESUMEN
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.