RESUMEN
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
El uso de Idursulfasa como tratamiento del síndrome de Hunter o Mucopolisacaridosis tipo II, genera beneficios a los pacientes, relacionados a la capacidad de desempeñar algunas funciones como caminar y mejoría en el tamaño del bazo y el hígado que podrían producir molestias al paciente. Se recomienda la cobertura del medicamento Idursulfasa como tratamiento del síndrome de Hunter o Mucopolisacaridosis tipo II, bajo la modalidad de cobertura con generación de evidencia.(AU)
Asunto(s)
Mucopolisacaridosis II/tratamiento farmacológico , Iduronato Sulfatasa/administración & dosificación , Calidad de Vida , Evaluación de la Tecnología BiomédicaRESUMEN
PURPOSE: The primary objective of this study was to determine the safety of idursulfase in Hunter syndrome patients aged 5 years or younger. METHODS: Idursulfase (0.5 mg/kg) was administered intravenously on a weekly basis (52 infusions per patient) in an open-label study. Safety monitoring included adverse events, anti-idursulfase antibodies, vital signs, physical examination, 12-lead electrocardiogram, concomitant medications or procedures, and laboratory testing (clinical chemistry, hematology, and urinalysis). The following exploratory efficacy outcomes were assessed at baseline and at weeks 18 or 36 or 53: urinary glycosaminoglycan levels, liver or spleen size, developmental milestones, and growth indices. Pharmacokinetic parameters were assessed at week 27. RESULTS: Twenty-eight boys aged 1.4-7.5 years were enrolled (one discontinued for noncompliance) in the study. All the patients reported adverse events (16 patients (57%) reported possibly or probably treatment-related adverse events). The only severe adverse event was sleep apnea (two patients); others were mild or moderate. Sixteen patients had infusion-related adverse events, a similar proportion as previously reported. Thirteen patients (46%) experienced at least one serious adverse event: pyrexia and bronchopneumonia were the most common (three patients each). No clinically important drug-related changes in laboratory parameters or vital signs or electrocardiograms were reported. Nineteen patients (68%) developed anti-idursulfase immunoglobulin G antibodies. Growth rates remained within normal age-related ranges. Developmental quotients were lower than normal but remained stable. By week 18, organ size and urinary glycosaminoglycan levels decreased as compared with baseline and remained stable throughout the study. CONCLUSION: Idursulfase safety, tolerability, and efficacy were similar to that previously reported in males ≥5 years.
Asunto(s)
Iduronato Sulfatasa/uso terapéutico , Mucopolisacaridosis II/tratamiento farmacológico , Anticuerpos Antiidiotipos , Niño , Preescolar , Terapia de Reemplazo Enzimático , Estudios de Seguimiento , Glicosaminoglicanos/orina , Humanos , Iduronato Sulfatasa/administración & dosificación , Iduronato Sulfatasa/efectos adversos , Iduronato Sulfatasa/inmunología , Lactante , Hígado/efectos de los fármacos , Masculino , Bazo/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disease caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyses a step in the catabolism of glycosaminoglycans. The glycosaminoglycans accumulate within tissues affecting multiple organs and physiologic systems. The clinical manifestations include neurologic involvement, severe airways obstruction, skeletal deformities and cardiomyopathy. The disease has a variable age of onset and variable rate of progression. In those with severe disease, death usually occurs in the second decade of life, whereas those patients with less severe disease may survive into adulthood. Enzyme replacement therapy with intravenous infusions of idursulfase has emerged as a new treatment for mucopolysaccharidosis type II. OBJECTIVES: To evaluate the effectiveness and safety of enzyme replacement therapy with idursulfase compared to other interventions, placebo or no intervention, for treating mucopolysaccharidosis type II. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register (date of last search 01 September 2011).We also searched EMBASE, PubMed and the Literature Latino-Americana e do Caribe em Ciências da Saúde (LILACS) (date of last search October 2009). SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of enzyme replacement therapy with idursulfase compared to no intervention, placebo or other options (e.g. behavioral strategies, transplantation). DATA COLLECTION AND ANALYSIS: Two authors independently screened the trials identified, appraised quality of papers and extracted data. MAIN RESULTS: One study (96 patients) met the inclusion criteria, although the primary outcome of this review - z score for height and weight, was not assessed in the study. Following 53 weeks of treatment, patients in the weekly idursulfase 0.5 mg/kg group demonstrated a significant improvement rate compared with placebo for the primary outcome: distance walked in six minutes on the basis of the sum of ranks of change from baseline, mean difference 37.00 (95% confidence interval 6.52 to 67.48). The every-other-week idursulfase 0.5 mg/kg group also showed an improvement, which was not significant compared with placebo, mean difference 23.00 (95% confidence interval -4.49 to 50.49). After 53 weeks, there was no statistical significance difference in per cent predicted forced vital capacity between the three groups and absolute forced vital capacity was significantly increased from baseline in the weekly dosing group compared to placebo, mean difference 0.16 (95% confidence interval CI 0.05 to 0.27). No difference was observed between the every-other-week idursulfase 0.5 mg/kg group and placebo.In addition, liver and spleen volumes and urine glycosaminoglycan excretion were significantly reduced from baseline by both idursulfase dosing regimens. Idursulfase was generally well tolerated, but infusion reactions did occur. Idursulfase antibodies were detected in 31.7% of patients at the end of the study and they were related to a smaller reduction in urine glycosaminoglycan levels. AUTHORS' CONCLUSIONS: The current evidence is limited. While the randomised clinical trial identified was considered to be of good quality, it failed to describe important outcomes. It has been demonstrated that enzyme replacement therapy with idursulfase is effective in relation to functional capacity (distance walked in six minutes and forced vital capacity), liver and spleen volumes and urine glycosaminoglycan excretion in patients with mucopolysaccharidosis type II compared with placebo. There is no available evidence in the included study and in the literature on outcomes such as improvement in growth, sleep apnoea, cardiac function, quality of life and mortality. More studies are needed to obtain more information on the long-term effectiveness and safety of enzyme replacement therapy.