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1.
Brasília; CONITEC; out. 2019. graf, ilus, tab.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1024750

RESUMO

INTRODUÇÃO: a DP, ou glicogenose tipo II, pode ser classificada em DP precoce (idade de início dos sintomas ≤ 12 meses) e DP tardia (idade de início dos sintomas ≥ 12 meses). A DP é uma doença rara, grave, associada à alta morbimortalidade, e que não está incluída no Programa Nacional de Triagem Neonatal. Seu acometimento neuromuscular progressivo - frequentemente fatal nas formas mais graves ­ decorre de mutações patogênicas bialélicas no gene GAA, localizado no cromossomo 17q25.2-q25.3. A DP é uma glicogenose muscular, não associada à ocorrência de hipoglicemia, causada pela atividade deficiente da alfa glicosidase ácida (sinônimo: maltase ácida), enzima lisossômica que libera glicose a partir do glicogênio, conforme a demanda de energia celular. A atividade deficiente desta enzima leva ao acúmulo de glicogênio dentro dos lisossomos e do citoplasma das células da musculatura lisa, esquelética e cardíaca. Este acúmulo acaba danificando o funcionamento celular e destruindo as células, por hipertrofia e ruptura dos lisossomos. A prevenção das manifestações clínicas e o tratamento das manifestações já estabelecidas da DP pode ser realizada, quando indicado, com a terapia de reposição enzimática (TRE) com maltase ácida recombinante humana (alfaalglicosidase), produzida em células de ovário de hamster chinês. TECNOLOGIA: alfa-alglicosidase (myozyme®). PERGUNTA: O uso da alfa-alglicosidase é eficaz e seguro em pacientes com DP? EVIDÊNCIAS CIENTÍFICAS: Dada a existência de menos de 5 ensaios clínicos randomizados (ECR) incluindo uma, outra ou ambas as formas da doença, foram avaliados também ensaios clínicos abertos prospectivos que avaliaram os desfechos de interesse e cujo tamanho amostral era igual ou superior a 5. Assim, trinta e seis estudos foram incluídos, sendo que 13/36 avaliaram DP precoce (entre eles, uma revisão sistemática e um ECR) e 23/36 que avaliaram DP tardia (entre eles, duas revisões sistemáticas e um ECR). DP Precoce: Foi encontrada evidência de benefício da TRE para cardiomiopatia, tempo para início de ventilação mecânica, sobrevida, e segurança. Ressalta-se, contudo, que a maioria dos estudos incluiu pacientes que iniciaram TRE até um ano de idade e que não estavam em ventilação mecânica invasiva, sendo esta a população para a qual este tratamento deve ser indicado. DP Tardio: Foi encontrada evidência de benefício da TRE para capacidade vital forçada (CVF), teste de caminhada em 6 minutos, sobrevida/mortalidade, tempo de ventilação e segurança. AVALIAÇÃO ECONÔMICA: As análises de custo-efetividade resultaram em uma razão de custo efetividade incremental (RCEI) de R$ 1.521.942,46 por ano de vida livre de ventilação para o tratamento da DP precoce com alfa-alglicosidase mais cuidados de suporte em comparação a somente cuidados de suporte; e uma RCEI de R$ 5.306.919,17 por ano de vida ganho (AVG) no tratamento da DP tardia com alfa-alglicosidase mais cuidados de suporte em comparação a somente cuidados de suporte. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A estimativa dos gastos com a incorporação da alfaalglicosidase na perspectiva do SUS, dentro dos cenários propostos para o tratamento dos pacientes com DP precoce, variou de R$ 2,87 milhões a R$ 10,98 milhões no primeiro ano e entre R$ 15,7 milhões e R$ 78,9 milhões após transcorridos cinco anos. Para o tratamento dos pacientes com DP tardia, o impacto orçamentário variou de R$ 102,4 milhões a R$ 156,87 milhões no primeiro ano e entre R$ 613,78 milhões e R$ 1,02 bilhões após transcorridos cinco anos. Finalmente, para o tratamento de todos os pacientes com DP (precoce e tardia), o impacto orçamentário estimado variou de R$ 110,66 milhões a R$ 167,86 milhões no primeiro ano e entre R$ 663,34 milhões e R$ 1,1 bilhões após transcorridos cinco anos de incorporação no SUS. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Reveglucosidase alfa: há 3 ensaios clínicos concluídos, de fase 2, fase 3 e sua extensão, cuja intervenção é intitulada como BMN 701, GAA humana recombinante GILT-tagged, avaliada apenas para DP tardio, sem resultados disponíveis. RECOMENDAÇÃO INICIAL: A Conitec, em sua 76ª reunião ordinária, no dia 3 de abril de 2019, considerando o alto custo da terapia e o elevado impacto orçamentário, o Plenário da Conitec recomendou de forma preliminar a incorporação da alfa-aglicosidade para a forma precoce da doença devido aos ganhos nos desfechos de tempo para início de ventilação mecânica e sobrevida. CONSULTA PÚBLICA: A Consulta Pública nº 33 foi realizada entre os dias 05/06 e 24/06/2019. Foram recebidas 389 contribuições, 61 pelo formulário técnico-científico e 328 pelo formulário de experiência ou opinião sendo 52% concordando totalmente com a recomendação preliminar da Conitec. Foram levantadas questões sobre a utilização da TRE em pacientes com DP tardia, porém os estudos incluídos na CP não trouxeram novas evidências de benefício no tratamento da DP tardia e a proposta de risco compartilhado submetida pela empresa, nas condições apresentadas, não apresentava elementos suficientes para justifica-la. Assim, o plenário da Conitec entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 81ª reunião ordinária, no dia 5 de setembro de 2019, deliberaram, por unanimidade, por recomendar a incorporação no SUS da alfa-alglicosidase para o tratamento da forma precoce da doença de Pompe, conforme Protocolo Clínico do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 470/2019. DECISÃO: Incorporar a alfa-alglicosidase para a forma precoce da doença de Pompe, conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde, no âmbito do Sistema Único de Saúde ­ SUS. Dada pela Portaria nº 48, seção 1, página 65, em 17 de outubro de 2019.


Assuntos
Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Terapia de Reposição de Enzimas , Glicosídeo Hidrolases/uso terapêutico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
2.
Orphanet J Rare Dis ; 14(1): 78, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943998

RESUMO

BACKGROUND: Pompe disease is a rare, progressive, autosomal recessive lysosomal storage disorder caused by mutations in the acid α-glucosidase gene. This is the first report of Chinese patients from the global Pompe Registry. Chinese patients enrolled in the Registry ( ClinicalTrials.gov , NCT00231400) between Jan 2013 and 2 Sep 2016 with late onset Pompe disease (LOPD; presentation after 12 months of age or presentation at ≤12 months without cardiomyopathy) were included. Data analyses were descriptive. RESULTS: Of the 59 Chinese patients included, 86.4% had never received enzyme replacement therapy (ERT). The age at symptom onset and diagnosis was 14.9 (12.35) and 22.1 (10.08) years, which is younger than previous reports of LOPD patients from the rest of the world (28.4 [18.86] and 34.9 [20.03], respectively). The most common diagnosis methods were enzyme assay (79.7%) and/or DNA analysis (61.0%). Of the 36 patients diagnosed using DNA analysis, 31 had standardized variant data and among these patients the most common mutations were c.2238G > C (n = 18, 58.1%) and c.2662G > T (n = 5, 16.1%). Chinese LOPD patients appeared to have worse lung function versus patients from the rest of the world, indicated by lower forced vital capacity (37.2 [14.00]% vs. 63.5 [26.71]%) and maximal expiratory and inspiratory pressure (27.9 [13.54] vs. 51.0 [38.66] cm H2O, and 29.4 [12.04] vs. 70.5 [52.78] cm H2O). CONCLUSIONS: Compared with patients from the rest of the world, Chinese patients with LOPD appeared to have younger age at symptom onset and diagnosis, lower lung function, and the majority had not received ERT. The most common mutations were c.2238G > C and c.2662G > T.


Assuntos
Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/genética , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Adolescente , Adulto , China , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Doenças por Armazenamento dos Lisossomos/enzimologia , Doenças por Armazenamento dos Lisossomos/genética , Masculino , Pressões Respiratórias Máximas , Mutação/genética , Sistema de Registros , Capacidade Vital/fisiologia , Adulto Jovem , alfa-Glucosidases/genética
5.
Clin Immunol ; 200: 66-70, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30711607

RESUMO

In Pompe disease, anti-drug antibodies (ADA) to acid alpha-glucosidase (GAA) enzyme replacement therapy contribute to early mortality. Assessing individual risk for ADA development is notoriously difficult in (CRIM-positive) patients expressing endogenous GAA. The individualized T cell epitope measure (iTEM) scoring method predicts patient-specific risk of developing ADA against therapeutic recombinant human GAA (rhGAA) using individualized HLA-binding predictions and GAA genotype. CRIM-negative patients were six times more likely to develop high ADA titers than CRIM-positive patients in this retrospective study, whereas patients with high GAA-iTEM scores were 50 times more likely to develop high ADA titers than patients with low GAA-iTEM scores. This approach identifies high-risk IOPD patients requiring immune tolerance induction therapy to prevent significant ADA response to rhGAA leading to a poor clinical outcome and can assess ADA risk in patients receiving replacement therapy for other enzyme or blood factor deficiency disorders.


Assuntos
Anticorpos/imunologia , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/genética , Cadeias HLA-DRB1/genética , alfa-Glucosidases/genética , alfa-Glucosidases/imunologia , Simulação por Computador , Reações Cruzadas/imunologia , Mapeamento de Epitopos , Epitopos de Linfócito T/imunologia , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Tolerância Imunológica/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lactente , Metotrexato/uso terapêutico , Proteínas Recombinantes , Medição de Risco , Rituximab/uso terapêutico , alfa-Glucosidases/uso terapêutico
7.
Genet Med ; 21(4): 887-895, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30214072

RESUMO

PURPOSE: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients. METHODS: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone. RESULTS: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators. CONCLUSION: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/imunologia , Tolerância Imunológica/genética , Metotrexato/administração & dosagem , Idade de Início , Reações Cruzadas/imunologia , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Lactente , Recém-Nascido , Masculino , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/genética
8.
Lima; IETSI; 2019.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1009850

RESUMO

INTRODUCCIÓN: El presente dictamen expone la actualización de la evaluación de tecnología sanitaria de la seguridad y eficacia del uso de AA en pacientes con EPIT realizada en abril del 2016. La enfermedad de Pompe de inicio tardío (EPIT) es una enfermedad rara de depósito del glucógeno tipo II originada por la deficiencia de la enzima alfa-1,4-glucosidasa ácida (GAA). Dicha deficiencia conlleva a la acumulación de glucógeno en los lisosomas en el citoplasma, lo que resulta en la destrucción de los tejidos (i.e. músculo esquelético y cardíaco). Clínicamente, se caracteriza por debilidad proximal progresiva, dolor y fatiga, que a largo plazo conlleva a que el paciente requiera el uso de silla de ruedas y/o apoyo respiratorio. De acuerdo con la historia natural de la enfermedad, la insuficiencia respiratoria corresponde a la principal causa de muerte en personas con EPIT. Aunque a la fecha no se ha encontrado una cura para la EPIT, el tratamiento específico consiste en la provisión exógena de la enzima deficiente. En abril del 2016, el Instituto de Evaluación de Tecnologías en Salud (IETSI) emitió el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 027-SDEPFyOTS-DETS-IETSI-2016 "Seguridad y eficacia de alglucosidasa alfa en el tratamiento de pacientes con enfermedad de Pompe de inicio tardío" donde se aprobó el uso de alglucosidasa alfa (AA) para el tratamiento de pacientes mayores de 8 años con diagnóstico confirmado de EPIT. Dado que, de acuerdo con la evidencia identificada en dicho dictamen, el tratamiento con AA se asoció a efectos beneficiosos sobre variables funcionales (medidas mediante la prueba de la distancia caminada en 6 minutos (DC6M) y el porcentaje de la capacidad vital forzada (CVF) predicha, la sobrevida y la calidad de vida. OBJETIVO: Incluir nueva evidencia que haya surgido a la fecha considerando además los criterios para inicio y suspensión de tratamiento. TECNOLOGÍA SANITARIA DE INTERÉS: Los aspectos más relevantes de la tecnología de interés se encuentran descritos en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 027-SDEPFyOTS-DETS-IETSI-2016. Brevemente, la alglucosidasa alfa (AA) 50mg (Myozyme 50mg®) se obtiene mediante tecnología ADN recombinante a partir del cultivo de células de mamíferos procedentes de ovario de hámster chino. Se piensa que el mecanismo de acción de la AA es a través de su unión a los receptores de manosa 6-fosfato en la superficie de las células, enzima que luego es internalizada y transportada a los lisosomas donde se activa la actividad lisosómica para aumentar la división del glucógeno, dando como resultados la estabilización o el restablecimiento de la función cardiaca y del músculo esquelético (incluyendo los músculos respiratorios). METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de AA para el tratamiento de EPIT. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (PubMed-Medline) y Health Systems Evidence. Adicionalmente, se amplió la búsqueda revisando revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) como la Cochrane Group, The National Institute for Health and Care Excellence (NICE), the Agency for Health Care Research and Quality (AHRQ), The Canadian Agency for Drugs and Technologies in Health (CADTH) y The Scottish Medicines Consortium (SMC). RESULTADOS: Así en el presente dictamen de actualización se identificaron cuatro guías de práctica clínica (GPC) nuevas, ninguna evaluación de tecnologías sanitarias (ETS) nueva, una revisión sistemática (RS), y dos estudios observacionales nuevos. Luego de revisarlos, se concluye que el tratamiento con AA muestra alguna evidencia de beneficio en los pacientes con EPIT. De acuerdo con las recomendaciones internacionales identificadas, para optimizar la efectividad del tratamiento de pacientes con EPIT, es necesario delimitar algunos aspectos prácticos del uso de AA como establecer los criterios de inicio y de suspensión de tratamiento. En ese sentido, se deben identificar a las subpoblaciones o grupos existentes entre los pacientes con EPIT (por ejemplo, sintomáticos versus asintomáticos, pacientes severamente comprometidos, etc.). Así, de acuerdo con las recomendaciones internacionales, se debe iniciar tratamiento en los pacientes que presentan síntomas, pues la evidencia existente a la fecha proviene de este grupo de pacientes. En cambio, la evidencia es insuficiente para emitir recomendaciones sobre el inicio de terapia de reemplazo enzimático (TRE) en pacientes asintomáticos. La recomendación de inicio de la TRE se basa en los resultados obtenidos en un ECA que mostró mejoría en la función muscular y estabilización del deterioro de la función respiratoria. Cabe resaltar que la sola estabilización de los resultados del tratamiento se considera como respuesta al tratamiento, pues es lo contrario a lo esperado de acuerdo a la historia natural de la condición (i.e. deterioro progresivo). CONCLUSIONES: En el presente dictamen de actualización se identificaron cuatro GPC nuevas, ninguna ETS nueva, una RS, y dos estudios observacionales nuevos. Las GPC recomiendan el uso de AA en pacientes con diagnóstico confirmado de EPIT bajo las siguientes consideraciones: 1) criterios de inicio: pacientes sintomáticos (i.e. debilidad muscular detectable en el examen físico o alteraciones en biopsia muscular, reducción de la CVF mayor a 10% y/o dificultad para realizar actividades de la vida diaria), que no estén severamente comprometidos (i.e. que no se encuentren en estadio avanzado de EPIT o que ya no cuenten con función muscular o respiratoria); 2) criterios de suspensión: considerar suspender el tratamiento con AA en aquellos pacientes que a pesar del tratamiento luego de uno a dos años muestran deterioro progresivo de la función muscular y respiratoria; en pacientes con esperanza de vida estimada corta; en pacientes con reacciones adversas severas relacionadas con la infusión de la AA; en pacientes con bajo nivel de adherencia al tratamiento. En relación con el seguimiento las GPC recomiendan evaluación anual de la efectividad de la AA en los pacientes con EPIT y monitoreo de los niveles de anticuerpos IgG cada tres meses. En pacientes asintomáticos, las GPC recomiendan un seguimiento cercano cada 6 meses para determinar el momento de aparición de los síntomas y el inicio de la TRE. Schoser et al 2017, realizaron una RS y un MA de Poisson (de estudios observacionales) para evaluar el efecto de la AA sobre la sobrevida, función motora y función respiratoria en pacientes con EPIT, donde reportaron que los pacientes que recibieron tratamiento con AA tenían 5 veces menor tasa de mortalidad que los pacientes no tratados (razón de tasa: 0.21; IC 95% creíble: 0.11- 0.41). Asimismo, reportaron una mejoría en la DC6M durante los primeros meses de tratamiento con estabilización en los años siguientes; y una estabilización del deterioro de la función respiratoria. Dos estudios observacionales de Ripolone 2017 y van der Ploeg 2016 incluidos en el presente dictamen reportaron luego de 6 meses de seguimiento que en los pacientes con EPIT que inician tratamiento con AA se observó una mejoría en la función motora medida a través de la DC6M y una estabilización del deterioro de la función pulmonar. Los hallazgos reportados en este dictamen son consistentes con el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 027-SDEPFyOTS-DETS-IETSI-2016, es decir que existe evidencia de baja calidad de beneficio en desenlaces críticos como la sobrevida; evidencia de moderada calidad sobre beneficio en otro desenlace importante como la función motora (medida a través de la DC6M) en los primeros meses de tratamiento; y evidencia de moderada calidad sobre la estabilización del deterioro de la función respiratoria (medida a través de la CVF). El Instituto de Evaluación de Tecnologías en Salud e Investigación- IETSI ratifica la aprobación de uso de alglucosidasa alfa en el tratamiento de pacientes con enfermedad de Pompe de inicio tardío, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.


Assuntos
Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Avaliação da Tecnologia Biomédica , Análise Custo-Eficiência
9.
PLoS One ; 13(12): e0208854, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532252

RESUMO

The majority of children and adults with Pompe disease in the population of European descent carry the leaky splicing GAA variant c.-32-13T>G (IVS1) in combination with a fully deleterious GAA variant on the second allele. The phenotypic spectrum of this patient group is exceptionally broad, with symptom onset ranging from early infancy to late adulthood. In addition, the response to enzyme replacement therapy (ERT) varies between patients. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) has been suggested to be a modifier of disease onset and/or response to ERT. Here, we have investigated the effect of the ACE I/D polymorphism in a relatively large cohort of 131 children and adults with Pompe disease, of whom 112 were followed during treatment with ERT for 5 years. We assessed the use of wheelchair and mechanical ventilation, muscle strength assessed via manual muscle testing and hand-held dynamometry (HHD), distance walked on the six-minute walk test (6MWT), forced vital capacity (FVC) in sitting and supine position and daily-life activities assessed by R-PAct. Cross sectional analysis at first visit showed no differences between the genotypes with respect to age at first symptoms, diagnosis, wheelchair use, or ventilator use. Also response to ERT over 5 years assessed by linear mixed model analyses showed no significant differences between ACE groups for any of the outcome measures. The patient cohort contained 24 families with 54 siblings. Differences in ACE genotype could neither explain inter nor intra familial differences. We conclude that the ACE I/D polymorphism does not explain the large variation in disease severity and response to ERT observed among Pompe patients with the same c.-32-13T>G GAA variant.


Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II , Modelos Biológicos , Peptidil Dipeptidase A , Polimorfismo Genético , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Feminino , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/enzimologia , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Força Muscular , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/uso terapêutico , Caminhada
10.
J Pediatr Endocrinol Metab ; 31(12): 1343-1347, 2018 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-30433875

RESUMO

Background With conventional enzyme replacement therapy (ERT), the clinical prognosis of classic Pompe disease is often unsatisfactory. About half the patients treated with ERT at the recommended dosage (20 mg/kg every other week) require ventilatory support within the first years of life. The heterogeneous response to ERT has been related to different factors, including cross-reactive immunologic material (CRIM) status and age at ERT initiation. Early treatment with a standard dosage of ERT improves clinical outcome and avoids mechanical ventilation in CRIM-positive patients detected at newborn screening, not preventing persistent hyperCKemia and muscle weakness. Later treatment with higher dosages of ERT was shown to provide similar benefits in CRIM-positive patients. Here, we report the clinical and biochemical outcomes of six patients with classic Pompe disease treated with different dosages of alglucosidase alpha at different ages. Methods A standard dosage of ERT was employed in five patients, sharing a poor prognosis after transient clinical improvements, even in the case of early treatment (four died at 22.2±11.9 months and one survived but required tracheostomy and gastrostomy). Early higher dosage of alglucosidase alpha (40 mg/kg/week from 14 days) was administered to one CRIM-positive patient with fetal persistent bradycardia. Results Early higher dosage of alclucosidase alpha not only achieved normal neuromotor development but also the full correction of biochemical markers of muscle damage until 3 years of age, an unmet target with the standard dosage. Speech delay was not prevented by this approach. Conclusions We suggest that early treatment with a higher dosage of ERT may further improve clinical prognosis in classic Pompe disease.


Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/administração & dosagem , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Masculino , Metotrexato/uso terapêutico , Prognóstico , Rituximab/uso terapêutico , Resultado do Tratamento , alfa-Glucosidases/uso terapêutico
11.
Neuromuscul Disord ; 28(11): 965-968, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30314719

RESUMO

Clinical data regarding the use of enzyme replacement therapy (ERT) during pregnancy in late-onset Pompe disease (LOPD) is still scarce. We present the clinical case of a 32-year-old female patient with LOPD, on enzyme replacement therapy (ERT) since the age of 29 years old, who had treatment interrupted after her second week of pregnancy with subsequent deterioration of her muscle condition. ERT was resumed by week 20 with clear clinical improvement. The pregnancy and delivery was otherwise uneventful and there were no problems during the neonatal period. After one-year follow-up the mother was clinically stable and the child had a normal development. A review of the existing literature shows that maintaining ERT during pregnancy may be of crucial importance for LOPD patients without adding obvious risks to the foetus. However, more data needs to be collected to address safety for the foetus and exclude potential teratogenicity.


Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Adulto , Feminino , Humanos , Gravidez , Resultado do Tratamento
12.
J Neurol ; 265(12): 2783-2788, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30232608

RESUMO

INTRODUCTION: Although not curative, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase enzyme has shown to be effective in the treatment of late-onset Pompe disease (LOPD). For this potentially life-long treatment, little is known on the clinical effect of cessation and resuming ERT. Due to a Swiss supreme court decision on ERT reimbursement, a temporary stop of ERT occurred in our study population. The aim of this study was to report the 36-months follow-up assessments after resuming ERT. METHODS: After resuming ERT, seven patients suffering from genetically and enzymatically confirmed LOPD had periodic, mandatory, prospective assessments of pulmonary function tests, muscle strength summary scores, distances walked in timed walking tests, and patient-reported questionnaires. Data were statistically analyzed for significant differences between time points at ERT cessation, at ERT resuming, and 36 months thereafter. RESULTS: After resuming ERT forced vital capacity (p = 0.007) and distance walked in the 6 min walk test (6-MWT, p = 0.011) significantly increased at 36 months. Compared to before ERT cessation, distance walked in 6-MWT at 36 months still remained significantly lower (p = 0.005). Self-reported scores in the fatigue severity scale significantly declined at 36 months after resuming ERT (p = 0.019). No other functional or reported parameter significantly changed at 36 months after resuming ERT. CONCLUSIONS: Our data suggests that long-term interruption of ERT in LOPD may lead to deterioration of clinical meaningful parameters and quality of life. In addition, a clinical restoration after ERT cessation is possible for most of the LOPD patients within a 36 months follow-up.


Assuntos
Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Feminino , Seguimentos , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Masculino , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Suíça , Resultado do Tratamento
13.
Eur J Paediatr Neurol ; 22(6): 1103-1109, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30166092

RESUMO

BACKGROUND: Pompe disease (PD) is a rare condition caused by mutations in gene encoding for the enzyme alpha-glucosidase, resulting in an abnormal intracellular accumulation of glycogen. The disease clinical spectrum ranges from severe infantile forms to adult-onset forms with minor limitations. Since 2000 enzyme replacement therapy (ERT) is available and disease natural history has changed, with prolonged survival and evidence of myopathic features. METHODS: In this study, we monitored disease progression up to three years in eight young patients with PD. Based on the literature data and the long term personal experience, we selected validated functional scales for neuromuscular disorders and compared the results to identify a simple and reliable protocol for the follow-up of children with PD. Moreover, we evaluated cognitive functions using developmental/cognitive tests. RESULTS: Based on study results, we suggest that motor functions in children with PD could be better assessed by Chop Intend, MFM20 (Motor Function Measure Scale for Neuromuscular Diseases 20) and NSAA (North Star Ambulatory Assessment), according to age and functional level. Evaluation should be completed with ROM (Range Of Motion) measurement, MRC (Medical Research Council) evaluation and 6MWT (6 Minute Walk test) when possible. CONCLUSIONS: The proposed protocol seems to be reliable and should be done every six months, because of the progressive natural history of the disease, the rapid changes typical of developmental age and the need to document ERT effects. About cognitive functions, additional tests to classical intelligence scales (WISC, WPPSI) should be useful to better describe specific neuropsychological profile.


Assuntos
Progressão da Doença , Doença de Depósito de Glicogênio Tipo II/complicações , /métodos , Criança , Pré-Escolar , Cognição , Terapia de Reposição de Enzimas/métodos , Feminino , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Lactente , Masculino , Fenótipo , Padrão de Cuidado
14.
Mol Ther ; 26(9): 2304-2314, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30025991

RESUMO

This 52-week, phase I/II double-blind, randomized, placebo-controlled study investigated the novel use of clenbuterol in late-onset Pompe disease (LOPD) stably treated with ERT. Eleven of thirteen participants completed the study. No serious adverse events were related to clenbuterol, and transient minor adverse events included mild elevations of creatine kinase, muscle spasms, and tremors. At week 52, the 6-min walk test distance increased by a mean of 16 m (p = 0.08), or a mean of 3% of predicted performance (p = 0.03), and the maximum inspiratory pressure increased 8% (p = 0.003) for the clenbuterol group. The quick motor function test score improved by a mean of seven points (p = 0.007); and the gait, stairs, gower, chair test improved by a mean of two points (p = 0.004). Clenbuterol decreased glycogen content in the vastus lateralis by 50% at week 52. Transcriptome analysis revealed more normal muscle gene expression for 38 of 44 genes related to Pompe disease following clenbuterol. The placebo group demonstrated no significant changes over the course of the study. This study provides initial evidence for safety and efficacy of adjunctive clenbuterol in patients with LOPD (NCT01942590).


Assuntos
Clembuterol/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Adulto , Idoso , Método Duplo-Cego , Feminino , Glicogênio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Quadríceps/efeitos dos fármacos , Músculo Quadríceps/metabolismo
15.
Int J Cardiol ; 269: 104-110, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30049495

RESUMO

BACKGROUND: Cardiac failure is the main cause of death in untreated classic infantile Pompe disease, an inheritable metabolic myopathy characterized by progressive hypertrophic cardiomyopathy. Since the introduction of enzyme replacement therapy (ERT), survival has increased significantly due to reduced cardiac hypertrophy and improved cardiac function. However, little is known about ERT's long-term effects on the heart. METHODS: Fourteen patients were included in this prospective study. Cardiac dimensions, function, conduction and rhythm disturbances were evaluated at baseline and at regular intervals thereafter. RESULTS: Treatment duration ranged from 1.1 to 13.9 years (median 4.8 years). At baseline, all patients had increased left ventricular mass index (LVMI) (median LVMI 226 g/m2, range 98 to 599 g/m2, Z-score median 7, range 2.4-12.4). During the first four weeks, LVMI continued to increase in six patients. Normalization of LVMI was observed in 13 patients (median 30 weeks; range 3 to 660 weeks). After clinical deterioration, LVMI increased again slightly in one patient. At baseline, PR interval was shortened in all patients; it normalized in only three. A delta-wave pattern on ECG was seen in six patients and resulted in documented periods of supraventricular tachycardias (SVTs) in three patients, two of whom required medication and/or ablation. One patient had severe bradycardia (35 beats/min). CONCLUSION: This study shows that ERT significantly reduced LVMI, and sustained this effect over a period of 13.9 years. The risk for rhythm disturbances remains. Regular cardiac evaluations should be continued, also after initially good response to ERT.


Assuntos
Terapia de Reposição de Enzimas/tendências , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Cardiopatias/diagnóstico por imagem , Cardiopatias/tratamento farmacológico , alfa-Glucosidases/administração & dosagem , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/métodos , Eletroencefalografia/tendências , Terapia de Reposição de Enzimas/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
17.
Orphanet J Rare Dis ; 13(1): 82, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29788986

RESUMO

BACKGROUND: Pompe disease is a rare metabolic myopathy. In adult patients, progressive weakness of limb-girdle and respiratory muscles often leads to wheelchair and respirator dependency. Clinical studies have shown enzyme replacement therapy (ERT) to positively affect motor and respiratory outcomes. Here we investigate whether ERT reduces patients' risk of needing a wheelchair or respirator. METHODS: Data were collected as part of a prospective international survey, the IPA/Erasmus MC Pompe survey, which was conducted annually between 2002 and 2016. We excluded patients who were already using a wheelchair or respirator, those under 18 at survey entry, and those who had missing information. Time-dependent Cox proportional hazard models were used. RESULTS: The inclusion criteria for analyzing the risk of wheelchair use were met by 189 patients (median age 47 years; range 18-75). During follow-up, 126 (67%) started ERT. Over 1120 person-years of follow-up (median 5 years), 46 became wheelchair dependent, 16 of whom used ERT. After adjustment for disease duration, sex and country, ERT reduced the risk for wheelchair use (HR 0.36; 95% CI 0.17-0.75). For analyses of respirator use, 177 patients met the inclusion criteria (median age 46 years; range 18-73). Over 1190 person-years of follow-up (median 6 years), 125 patients (71%) were treated and 48 started respiratory support, 28 of whom received ERT. We found no association between ERT and the risk for respirator use (HR 1.23; 95% CI 0.61-2.47). CONCLUSIONS: Our study found that ERT reduced the risk for wheelchair dependency. We could not demonstrate an effect on respiratory support.


Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Dispositivos de Proteção Respiratória/estatística & dados numéricos , Cadeiras de Rodas/estatística & dados numéricos , Adulto Jovem
18.
Genet Med ; 20(10): 1284-1294, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29565424

RESUMO

PURPOSE: Pompe disease results from lysosomal acid α-glucosidase (GAA) deficiency and its associated glycogen accumulation and muscle damage. Alglucosidase alfa (recombinant human GAA (rhGAA)) received approval in 2006 as a treatment for Pompe disease at the 160 L production scale. In 2010, larger-scale rhGAA was approved for patients up to 8 years old without cardiomyopathy. NCT01526785 evaluated 4,000 L rhGAA efficacy/safety in US infantile- or late-onset Pompe disease (IOPD, LOPD) patients up to 1 year old transitioned from 160 L rhGAA. METHODS: A total of 113 patients (87 with IOPD; 26 with LOPD) received 4,000 L rhGAA for 52 weeks dosed the same as previous 160 L rhGAA. Efficacy was calculated as the percentage of patients stable/improved at week 52 (without death, new requirement for invasive ventilation, left ventricular mass z-score increase >1 if baseline was >2, upright forced vital capacity decrease ≥15% predicted, or Gross Motor Function Measure-88 decrease ≥8 percentage points). Safety evaluation included an extension ≤20 months. RESULTS: Week 52 data was available for 104 patients, 100 of whom entered the extension. At week 52, 87/104 (83.7%) were stable/improved. Overall survival was 98.1% overall, 97.6% IOPD, 100% LOPD; 92.4% remained invasive ventilator-free (93.4% IOPD, 88.7% LOPD). Thirty-five patients had infusion-associated reactions. Eight IOPD patients died of drug-unrelated causes. CONCLUSIONS: Most Pompe disease patients were clinically stable/improved after transitioning to 4,000 L rhGAA. Safety profiles of both rhGAA forms were consistent.


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , alfa-Glucosidases/administração & dosagem , Idade de Início , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Proteínas Recombinantes/efeitos adversos , alfa-Glucosidases/efeitos adversos
19.
J Pediatr ; 195: 236-243.e3, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29428273

RESUMO

OBJECTIVE: To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha-glucosidase (rhGAA) in patients with classic infantile Pompe disease. STUDY DESIGN: Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme-linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator-free) survival, reduction in left ventricular mass index, and improvement of motor function. RESULTS: Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. CONCLUSIONS: Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.


Assuntos
Anticorpos/sangue , Terapia de Reposição de Enzimas , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Imunomodulação , alfa-Glucosidases/imunologia , alfa-Glucosidases/uso terapêutico , Linfócitos B/metabolismo , Biomarcadores/sangue , Pré-Escolar , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Lactente , Masculino , Metotrexato/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento
20.
Orphanet J Rare Dis ; 13(1): 32, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422078

RESUMO

BACKGROUND: Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. METHODS: A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). RESULTS: Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. CONCLUSIONS: These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Itália , Masculino , Proteínas Recombinantes , Estudos Retrospectivos , alfa-Glucosidases/administração & dosagem
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