ABSTRACT
CONTEXTO: La degeneración macular asociada a la edad (DMAE) es una de las principales causas de ceguera en el mundo, siendo su prevalencia en adultos mayores de 50 años del 5,6%, seguida de retinopatia diabética (2,5%). En los países de Latinoamérica se calcula una prevalencia en la población general del 10% y se estima que aproximadamente 39 millones de latinoamericanos padecerán alguna forma de DMAE para el 2040. Se trata de una enfermedad de la retina progresiva, crónica y multifactorial que lleva al deterioro de la visión y ceguera afectando principalmente personas mayores de 60 años. Afecta la mácula (porción central de la retina) resultando en la pérdida de la visión central lo que impediría conducir, leer y realizar actividades habituales de la vida diaria. Progresa desde estadíos iniciales a formas tardías y se puede subdividir en dos formas: neo vascular (húmeda) o atrofia geográfica no neo vascular (seca). A pesar de que a solo el 20% de los pacientes se les diagnostica la forma húmeda, esta es la responsable del 90% de los casos de pérdida de la visión y su evolución es más aguda. TECNOLOGÍA: Brolucizumab es un fragmento variable humanizado de cadena única inhibidor de factor de crecimiento endotelial A. Un fragmento variable de cadena única es un agente de unión autónomo que compromete sólo los dominios variables del anticuerpo monoclonal responsables de unirse a su receptor. Al ser un fragmento de cadena único es pequeño (peso molecular 26 kDa) y le falta la porción cristalizable de su dominio proveyéndole la probable ventaja de mayor biodisponibilidad e inmunogenicidad reducida. Se encuentra indicado como primera línea en el tratamiento de la degeneración macular neo vascular asociada a la edad. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de brolucizumab en pacientes com degeneración macular neo vascular asociada a la edad. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron dos ECAs, una RS, dos estudios observacionales, una GPC, una evaluación económica, cuatro evaluaciones de tecnologías sanitarias y 15 informes de políticas de cobertura de brolucizumab en degeneración macular neo vascular asociada a la edad. CONCLUSIONES: Evidencia de moderada calidad sugiere que brolucizumab presenta un beneficio considerable em pacientes con degeneración macular neo vascular asociada a la edad en relación a la mejora en la agudeza visual y modificaciones anatómicas (reducción del grosor de la mácula y neo vascularización coroidea) al igual que el ranibizumab o aflibercept. En términos de seguridad la evidencia sugiere que brolucizumab presenta una mayor tasa de eventos adversos serios no oculares (eventos trombo embólicos arteriales: infarto de miocardio no fatal, accidente cerebrovascular no fatal y muerte por causa vascular) y oculares (endoftalmitis), aunque los mismos fueron poco frecuentes y de manera no significativa, en comparación con ranibizumab y aflibercept. Evidencia de moderada calidad sugiere que brolucizumab presenta una eficacia menor que bevacizumab fraccionado/fuera de prospecto en pacientes con degeneración macular neo vascular asociada a la edad, dada la mayor tasa significativa de eventos adversos serios no oculares (eventos trombo embólicos arteriales: infarto de miocardio no fatal, accidente cerebrovascular no fatal y muerte por causa vascular), aunque los mismos fueron poco frecuentes. La mayoría de las guías de práctica clínica desarrolladas para esta patología identificadas son de fecha de publicación previa a la autorización de comercialización de brolucizumab por las principales aseguradoras europeas y latinoamericanas. Agencias financiadoras públicas de Canadá, Reino Unido y algunas instituciones aseguradoras privadas de Estados Unidos cubren esta tecnología. Algunas evaluaciones de tecnologías sanitarias y económicas europeas (Alemania y EUnetHTA) mostraron que brolucizumab no fue costo efectivo dado que no se pudo demostrar el beneficio agregado de esta tecnología en relación con los comparadores. La agencia canadiense de evaluación de tecnologías sanitarias consideró que se debe realizar una reducción de precio significativa en caso de contarse con bevacizumab fraccionado/fuera de prospecto como opción terapéutica. En otros países, aunque no se encuentra aprobado para esta indicación, el uso de bevacizumab fraccionado/fuera de prospecto es ampliamente utilizado. Los financiadores latinoamericanos relevados no mencionan esta tecnología. No existen evaluaciones económicas que estudien el impacto de esta droga em Argentina, sin embargo, dado el frecuente uso de bevacizumab fraccionado/fuera de prospecto, se debe considerar que el costo de brolucizumab sería considerablemente mayor al mismo.
Subject(s)
Humans , Endothelial Growth Factors/antagonists & inhibitors , Macular Degeneration/drug therapy , Health Evaluation/economics , Cost-Benefit Analysis/economicsABSTRACT
PURPOSE: To investigate efficacy and safety of repeated dexamethasone (DEX) implants over 24 months, in diabetic macular edema (DME) eyes that were treatment naive compared with eyes refractory to anti-vascular endothelial growth factor treatment, in a real-life environment. METHODS: This multicenter international retrospective study assessed best-corrected visual acuity and central subfield thickness (CST) of naive and refractory eyes to anti-vascular endothelial growth factor injections treated with dexamethasone implants. Safety data (intraocular pressure rise and cataract surgery) were recorded. RESULTS: A total of 130 eyes from 125 patients were included. Baseline best-corrected visual acuity and CST were similar for naive (n = 71) and refractory eyes (n = 59). Both groups improved significantly in vision after 24 months (P < 0.001). However, naive eyes gained statistically significantly more vision than refractory eyes (+11.3 ± 10.0 vs. 7.3 ± 2.7 letters, P = 0.01) and were more likely to gain ≥10 letters (OR 3.31, 95% CI 1.19-9.24, P = 0.02). At 6, 12, and 24 months, CST was significantly decreased compared with baseline in both naive and refractory eyes; however, CST was higher in refractory eyes than in naive eyes (CST 279 ± 61 vs. 313 ± 125 µm, P = 0.10). CONCLUSION: Over a follow-up of 24 months, vision improved in diabetic macular edema eyes after treatment with dexamethasone implants, both in eyes that were treatment naive and eyes refractory to anti-vascular endothelial growth factor treatment; however, improvement was greater in naive eyes.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Dexamethasone/administration & dosage , Diabetic Retinopathy/drug therapy , Drug Resistance , Macula Lutea/pathology , Macular Edema/drug therapy , Visual Acuity , Aged , Diabetic Retinopathy/complications , Diabetic Retinopathy/physiopathology , Drug Implants , Endothelial Growth Factors/antagonists & inhibitors , Female , Follow-Up Studies , Glucocorticoids/administration & dosage , Humans , Intraocular Pressure/physiology , Intravitreal Injections , Macular Edema/etiology , Macular Edema/physiopathology , Male , Retrospective Studies , Time Factors , Tomography, Optical Coherence , Treatment OutcomeSubject(s)
Humans , Neovascularization, Pathologic/physiopathology , Endothelial Growth Factors/physiology , Neovascularization, Pathologic/drug therapy , Endothelial Growth Factors/antagonists & inhibitors , Neovascularization, Physiologic/physiology , Neoplasms/blood supply , Antibodies, Monoclonal/therapeutic useABSTRACT
Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Endothelial Growth Factors/antagonists & inhibitors , Lymphokines/antagonists & inhibitors , Neoplasms, Experimental/drug therapy , Neovascularization, Pathologic/drug therapy , Phthalazines/pharmacology , Pyridines , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Growth Factor/antagonists & inhibitors , Animals , Drug Screening Assays, Antitumor , Endothelium, Vascular/drug effects , Humans , Mice , Mice, Nude , Receptors, Vascular Endothelial Growth Factor , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.