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1.
Neurology ; 92(18): e2109-e2117, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31036580

RESUMO

OBJECTIVE: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. METHODS: UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. RESULTS: Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. CONCLUSIONS: Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

2.
Lancet ; 393(10189): 2416-2427, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31104833

RESUMO

BACKGROUND: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia. METHODS: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. FINDINGS: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. INTERPRETATION: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Feminino , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Bone ; 122: 76-81, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30772600

RESUMO

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.

4.
Lancet Diabetes Endocrinol ; 7(3): 189-199, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30638856

RESUMO

BACKGROUND: Children with X-linked hypophosphataemia have high concentrations of circulating phosphatonin fibroblast growth factor 23 (FGF23), which causes renal phosphate wasting and hypophosphataemia, rickets, skeletal deformities, and growth impairment. Burosumab, a human monoclonal antibody against FGF23, improves phosphate homoeostasis and rickets in children aged 5-12 years with X-linked hypophosphataemia. We aimed to assess the safety and efficacy of burosumab in younger children with X-linked hypophosphataemia. METHODS: In this open-label, phase 2 trial at three hospitals in the USA, children (aged 1-4 years) with X-linked hypophosphataemia received burosumab (0·8 mg/kg) via subcutaneous injection every 2 weeks for 64 weeks. The dose was increased to 1·2 mg/kg if two consecutive pre-dose serum phosphorus concentrations were below 1·03 mmol/L (3·2 mg/dL), serum phosphorus had increased by less than 0·16 mmol/L (<0·5 mg/dL) from baseline, and a dose of burosumab had not been missed. Participants could continue to receive burosumab for up to an additional 96 weeks during the extension period. Key inclusion criteria were age 1-4 years at the time of informed consent; fasting serum phosphorus concentration of less than 0·97 mmol/L (3·0 mg/dL); serum creatinine 8·8-35·4 µmol/L (0·1-0·4 mg/dL); radiographic evidence of rickets (at least five participants were required to have a Thacher Rickets Severity Score of ≥1·5 at the knee); and a confirmed PHEX mutation or a variant of unknown significance in the patient or direct relative also affected with X-linked hypophosphataemia. Conventional therapy was stopped upon enrolment. The coprimary endpoints were safety and change from baseline to week 40 in fasting serum phosphorus concentrations. Changes in rickets severity from baseline to weeks 40 and 64 (assessed radiographically using Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change), and recumbent length or standing height, were key secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02750618, and is ongoing. FINDINGS: Between May 16, 2016, and June 10, 2016, we enrolled 13 children with X-linked hypophosphataemia. All 13 children completed 64 weeks of treatment and were included in the efficacy and safety analysis; none exceeded 70 weeks of treatment at the time of analysis. Serum phosphorus least squares mean increase from baseline to week 40 of treatment was 0·31 mmol/L (SE 0·04; 95% CI 0·24-0·39; 0·96 mg/dL [SE 0·12]; p<0·0001). All patients had at least one adverse event. 14 treatment-related adverse events, mostly injection site reactions, occurred in five children. One serious adverse event considered unrelated to treatment (tooth abscess) occurred in a child with a history of tooth abscess. All other adverse events were mild to moderate, except a severe food allergy considered unrelated to treatment. No instances of nephrocalcinosis or noteworthy changes in the results of a standard safety chemistry panel emerged. Total Thacher Rickets Severity Score decreased by a least squares mean of -1·7 (SE 0·1; p<0·0001) from baseline to week 40 and by -2·0 (SE 0·1; p<0·0001) by week 64. The Radiographic Global Impression of Change score also indicated significant improvement, with a least squares mean score of +2·3 (SE 0·1) at week 40 and +2·2 (0·1) at week 64 (both p<0·0001). Mean length or standing height Z score was maintained from baseline to week 64. INTERPRETATION: Burosumab had a favourable safety profile, increased serum phosphorus, and improved rickets and prevented early declines in growth in children aged 1-4 years with X-linked hypophosphataemia. These findings could substantially alter the treatment of young children with X-linked hypophosphataemia. FUNDING: Ultragenyx Pharmaceutical and Kyowa Kirin International.

5.
Value Health ; 21(8): 973-983, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30098676

RESUMO

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by renal phosphate wasting and defective bone mineralization. Symptoms include bone pain, joint pain, stiffness, and fatigue. Published evidence regarding the patient experience of XLH is sparse and no XLH-specific outcome measures have been validated. OBJECTIVES: To understand the symptoms, impacts, and patient experience of XLH and to evaluate the face and content validity of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) and the Brief Pain Inventory Short Form (BPI-SF) for use as end points in XLH clinical trials. METHODS: Face-to-face, qualitative, semistructured interviews were conducted with 18 adults with XLH in the United States using concept elicitation and cognitive debriefing techniques. Open-ended questioning elicited spontaneous concepts focusing on XLH-associated symptoms and functional limitations. Cognitive debriefing of the WOMAC® and BPI-SF assessed the relevance and patient understanding of item wording, recall period, and response options. RESULTS: Various distinct symptom concepts were elicited including pain symptoms, dental symptoms, sensory symptoms, tiredness/fatigue symptoms, and musculoskeletal symptoms. Participants reported experiencing significant bone and joint pain, stiffness, mobility limitations, and an impact on their ability to work. Cognitive interviewing found both instruments to be relevant and well understood by most patients. CONCLUSIONS: The interviews generated rich, qualitative insights into the patient experience of XLH. Cognitive debriefing of the BPI-SF and WOMAC® supported their value as XLH clinical trial end points. Future research will assess the psychometric properties of these instruments for use in the XLH population.


Assuntos
Raquitismo Hipofosfatêmico Familiar/psicologia , Satisfação do Paciente , Adulto , Feminino , Humanos , Entrevistas como Assunto/métodos , Masculino , Pessoa de Meia-Idade , Dor/etiologia , Psicometria/instrumentação , Psicometria/métodos , Pesquisa Qualitativa , Índice de Gravidade de Doença
6.
N Engl J Med ; 378(21): 1987-1998, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29791829

RESUMO

BACKGROUND: X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. METHODS: In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. RESULTS: The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS: In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/metabolismo , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Crescimento/efeitos dos fármacos , Humanos , Túbulos Renais/metabolismo , Articulação do Joelho/diagnóstico por imagem , Masculino , Manejo da Dor , Fósforo/sangue , Radiografia , Índice de Gravidade de Doença
7.
Neuromuscul Disord ; 28(2): 158-168, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29305133

RESUMO

GNE myopathy is a rare distal myopathy, caused by mutations in the GNE gene, affecting sialic acid synthesis. Clinical presentation varies from asymptomatic early stage patients to severely debilitating forms. This first report describes clinical presentations and severity of the disease, using data of 150 patients collected via the on-line, patient-reported registry component of the GNE Myopathy Disease Monitoring Program (GNEM-DMP). Disease progression was prospectively analysed, over a 2-year period, using the GNE myopathy functional activity scale (GNEM-FAS). The average annual rates of decline in function were estimated at -9.6% and -3.2% in ambulant and non-ambulant patients respectively. 4.3% of participants became non-ambulant within one year. The mean time from onset to required use of a wheelchair was 11.9 years. Mean delay of genetic diagnosis from symptom onset was 5.2 years. Mutation specific analysis demonstrated genotype-phenotype relationships; i.e. p.Ala662Val may be associated with a more severe phenotype, compared to p.Val727Met. Patients with compound heterozygous mutation in epimerase and kinase domain appeared to have a more severe phenotype compared to patients with both mutations located within one domain. Acknowledging the limitations of the study, these findings suggest that the severity of the GNE mutations affects disease severity. The GNEM-DMP is a useful data collection tool, prospectively measuring the progression of GNE myopathy, which could play an important role in translational and clinical research and further understanding of genotype-phenotype correlations.

8.
J Comp Eff Res ; 7(4): 381-395, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29139300

RESUMO

AIM: GNE myopathy, a rare, severe, progressive myopathy, presents with lower extremity distal muscle weakness. The GNE myopathy functional activity scale (GNEM-FAS) evaluates the impact of GNE myopathy on functioning in adults. This paper presents the psychometric validation of the GNEM-FAS. PATIENTS & METHODS: Validation of the GNEM-FAS was performed using data from a randomized, double-blind, placebo-controlled Phase-II study (n = 46). RESULTS: Domain score distributions were acceptable. Moderate inter-item correlations (typical range, 0.40-0.70), strong item convergent and discriminant validity and high internal consistency reliability (α = 0.88-0.92) supported the instrument structure. Test-retest reliability was strong (ICC range: 0.87-0.95). Scale scores distinguished among subjects with differing disease severity (p < 0.05). CONCLUSION: This study provides preliminary evidence of the GNEM-FAS as a valid, reliable assessment.

9.
J Clin Neuromuscul Dis ; 19(1): 19-26, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28827485

RESUMO

OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.


Assuntos
Força Muscular/genética , Debilidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Miosite de Corpos de Inclusão/congênito , Adolescente , Adulto , Idoso , Feminino , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Pessoa de Meia-Idade , Atividade Motora/genética , Miosite de Corpos de Inclusão/complicações , Miosite de Corpos de Inclusão/genética , Ácido N-Acetilneuramínico/genética , Adulto Jovem
10.
PLoS One ; 12(3): e0173261, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28267778

RESUMO

GNE myopathy (GNEM), also known as hereditary inclusion body myopathy (HIBM), is a late- onset, progressive myopathy caused by mutations in the GNE gene encoding the enzyme responsible for the first regulated step in the biosynthesis of sialic acid (SA). The disease is characterized by distal muscle weakness in both the lower and upper extremities, with the quadriceps muscle relatively spared until the late stages of disease. To explore the role of SA synthesis in the disease, we conducted a comprehensive and systematic analysis of both free and total SA levels in a large cohort of GNEM patients and a mouse model. A sensitive LC/MS/MS assay was developed to quantify SA in serum and muscle homogenates. Mean serum free SA level was 0.166 µg/mL in patients and 18% lower (p<0.001) than that of age-matched control samples (0.203 µg/mL). In biopsies obtained from patients, mean free SA levels of different muscles ranged from 0.046-0.075 µg/µmol Cr and were markedly lower by 72-85% (p<0.001) than free SA from normal controls. Free SA was shown to constitute a small fraction (3-7%) of the total SA pool in muscle tissue. Differences in mean total SA levels in muscle from patients compared with normal controls were less distinct and more variable between different muscles, suggesting a small subset of sialylation targets could be responsible for the pathogenesis of GNEM. Normal quadriceps had significantly lower levels of free SA (reduced by 39%) and total SA (reduced by 53%) compared to normal gastrocnemius. A lower SA requirement for quadriceps may be linked to the reported quadriceps sparing in GNEM. Analysis of SA levels in GneM743T/M743T mutant mice corroborated the human study results. These results show that serum and muscle free SA is severely reduced in GNEM, which is consistent with the biochemical defect in SA synthesis associated with GNE mutations. These results therefore support the approach of reversing SA depletion as a potential treatment for GNEM patients.


Assuntos
Miopatias Distais/metabolismo , Músculo Esquelético/metabolismo , Ácido N-Acetilneuramínico/deficiência , Adolescente , Adulto , Idoso , Animais , Biomarcadores , Biópsia , Cromatografia Líquida , Modelos Animais de Doenças , Miopatias Distais/sangue , Miopatias Distais/patologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Ácido N-Acetilneuramínico/sangue , Espectrometria de Massas em Tandem , Adulto Jovem
11.
J Neuromuscul Dis ; 3(1): 49-66, 2016 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-27854209

RESUMO

BACKGROUND: GNE Myopathy (GNEM) is a progressive adult-onset myopathy likely caused by deficiency of sialic acid (SA) biosynthesis. OBJECTIVE: Evaluate the safety and efficacy of SA (delivered by aceneuramic acid extended-release [Ace-ER]) as treatment for GNEM. METHODS: A Phase 2, randomized, double-blind, placebo-controlled study evaluating Ace-ER 3 g/day or 6 g/day versus placebo was conducted in GNEM subjects (n = 47). After the first 24 weeks, placebo subjects crossed over to 3 g/day or 6 g/day for 24 additional weeks (dose pre-assigned during initial randomization). Assessments included serum SA, muscle strength by dynamometry, functional assessments, clinician- and patient-reported outcomes, and safety. RESULTS: Dose-dependent increases in serum SA levels were observed. Supplementation with Ace-ER resulted in maintenance of muscle strength in an upper extremity composite (UEC) score at 6 g/day compared with placebo at Week 24 (LS mean difference +2.33 kg, p = 0.040), and larger in a pre-specified subgroup able to walk ≥200 m at Screening (+3.10 kg, p = 0.040). After cross-over, a combined 6 g/day group showed significantly better UEC strength than a combined 3 g/day group (+3.46 kg, p = 0.0031). A similar dose-dependent response was demonstrated within the lower extremity composite score, but was not significant (+1.06 kg, p = 0.61). The GNEM-Functional Activity Scale demonstrated a trend improvement in UE function and mobility in a combined 6 g/day group compared with a combined 3 g/day group. Patients receiving Ace-ER tablets had predominantly mild-to-moderate AEs and no serious adverse events. CONCLUSIONS: This is the first clinical study to provide evidence that supplementation with SA delivered by Ace-ER may stabilize muscle strength in individuals with GNEM and initiating treatment earlier in the disease course may lead to better outcomes.


Assuntos
Miopatias Distais/tratamento farmacológico , Ácido N-Acetilneuramínico/farmacologia , Avaliação de Resultados (Cuidados de Saúde) , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/administração & dosagem , Ácido N-Acetilneuramínico/efeitos adversos , Adulto Jovem
12.
Mol Genet Metab ; 118(2): 65-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27132782

RESUMO

Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.


Assuntos
Testes de Estado Mental e Demência/normas , Erros Inatos do Metabolismo/tratamento farmacológico , Avaliação de Resultados (Cuidados de Saúde) , Doenças Raras/tratamento farmacológico , Cuidadores , Criança , Desenvolvimento Infantil , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , National Institutes of Health (U.S.) , Pais , Tecnologia de Sensoriamento Remoto , Estados Unidos , United States Food and Drug Administration
13.
N Engl J Med ; 366(10): 904-13, 2012 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-22397652

RESUMO

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).


Assuntos
Fosfatase Alcalina/uso terapêutico , Terapia de Reposição de Enzimas , Hipofosfatasia/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Raquitismo/tratamento farmacológico , Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/farmacologia , Disponibilidade Biológica , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Pré-Escolar , Terapia de Reposição de Enzimas/efeitos adversos , Feminino , Humanos , Hipofosfatasia/complicações , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Lactente , Recém-Nascido , Infusões Intravenosas , Injeções Subcutâneas/efeitos adversos , Masculino , Radiografia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Raquitismo/diagnóstico por imagem , Raquitismo/etiologia , Resultado do Tratamento
14.
N Engl J Med ; 362(15): 1396-406, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20393176

RESUMO

BACKGROUND: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease. METHODS: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Adolescente , Adulto , Idade de Início , Idoso , Análise de Variância , Criança , Hipersensibilidade a Drogas/etiologia , Feminino , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Imunoglobulina G/sangue , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Capacidade Vital/efeitos dos fármacos , Caminhada , Adulto Jovem , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/imunologia
15.
Genet Med ; 11(3): 210-9, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19287243

RESUMO

PURPOSE: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease. METHODS: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort. RESULTS: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns. CONCLUSIONS: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Estatura , Peso Corporal , Pré-Escolar , Tosse/induzido quimicamente , Ecocardiografia , Ensaio de Imunoadsorção Enzimática , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/metabolismo , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Imunoglobulina G/sangue , Lactente , Estimativa de Kaplan-Meier , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Dermatopatias/induzido quimicamente , Fatores de Tempo , Resultado do Tratamento , alfa-Glucosidases/efeitos adversos , alfa-Glucosidases/imunologia
16.
Muscle Nerve ; 38(4): 1236-45, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18816591

RESUMO

The objective of this 12-month study was to describe the clinical features of late-onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6-min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness.


Assuntos
Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/fisiopatologia , Paralisia Respiratória/diagnóstico , Paralisia Respiratória/fisiopatologia , Adulto , Idade de Início , Idoso , Biomarcadores/análise , Doença Crônica/terapia , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Músculo Esquelético/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Músculos Respiratórios/fisiopatologia , Índice de Gravidade de Doença
17.
Mol Genet Metab ; 90(4): 449-52, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17270480

RESUMO

The enzymatic defect in Pompe disease is insufficient lysosomal acid alpha-glucosidase (GAA) activity which leads to lysosomal glycogen accumulation. We recently introduced a simple and reliable method to measure GAA activity in dried blood spots using Acarbose, a highly selective alpha-glucosidase inhibitor, to eliminate isoenzyme interference. Here we demonstrate that this method efficiently detects late-onset Pompe patients who are frequently misdiagnosed by conventional methods due to residual GAA activity in other tissue types.


Assuntos
Doença de Depósito de Glicogênio Tipo II/diagnóstico , alfa-Glucosidases/sangue , Acarbose/farmacologia , Adulto , Coleta de Amostras Sanguíneas/métodos , Células Cultivadas , Fibroblastos/enzimologia , Fluorometria/métodos , Inibidores de Glicosídeo Hidrolases , Humanos , Himecromona/análogos & derivados , Himecromona/metabolismo , Isoenzimas/sangue , Especificidade por Substrato
18.
Dev Med Child Neurol ; 48(7): 576-81, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16780627

RESUMO

The purpose of this article is threefold: (1) to describe the development, reliability, and validity of a revised physical performance measure for individuals with mucopolysaccharidosis type I (MPS I); (2) to standardize the test on a normal sample; and (3) to compare results from a selected sample of individuals with MPS I with age-based centiles. The MPS Physical Performance Measure (MPS-PPM) is composed of eight timed functional tasks (FT-8) and two endurance tasks with a modified Energy Expenditure Index for comfortable walking (CW) and fast walking (FW) speeds. Age norms were derived from a convenience sample of 150 typically developing children and adolescents (75 males, 75 females; mean age 11y 2mo [SD 4y 5mo]; range 5-22y). Using a Rasch model for speed tests and confirmatory factor analysis, we established the unidimensionality of the FT-8. Interrater reliability of the FT-8 (intraclass correlation [ICC]=0.98) and test-retest reliability of the FT-8 (ICC=0.96), CW (ICC=0.91), and FW (ICC=0.83) were good. Results of the age-based profiles in 10 individuals with MPS I (five males, five females; mean age 14y 2mo [SD 7y 6mo]; range 6-29y) indicate that the amount of time needed to perform functional tasks is severely affected by the disease, and most individuals were at or below the fifth centile for their age. The patterns of limitations in endurance were more varied. These results suggest the utility of using this revised MPS-PPM to identify the extent of limitation in age-expected physical performance. Implications for using the MPS-PPM for monitoring physical performance changes during clinical interventions are discussed.


Assuntos
Avaliação da Deficiência , Teste de Esforço/métodos , Destreza Motora , Mucopolissacaridose I/diagnóstico , Resistência Física , Atividades Cotidianas , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Determinação de Ponto Final , Metabolismo Energético , Análise Fatorial , Feminino , Humanos , Masculino , Mucopolissacaridose I/complicações , Mucopolissacaridose I/terapia , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Caminhada
19.
Pediatr Phys Ther ; 17(2): 128-39, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16357663

RESUMO

PURPOSE: The purposes of this article are to describe the pathology, medical implications, and typical impairments of individuals with various lysosomal storage diseases (LSDs), summarize results of recent clinical trials on medical interventions relevant to physical therapy practice, report new advances in functional measurement, and suggest a framework for physical therapy management and intervention. SUMMARY OF KEY POINTS: Medical and surgical interventions are enabling individuals with LSDs to not only survive but to improve their daily functioning and quality of life. This is likely to become an increasing area of emphasis in pediatric physical therapy, as the intervention emphasis for some individuals will shift from maintenance to restorative programs. RECOMMENDATIONS: We recommend that pediatric physical therapists become familiar with new LSD therapeutics, play a major role in evaluating impairment and functional limitation changes in individuals with LSDs, and become knowledgeable about the indications and precautions for restorative physical therapy programs.


Assuntos
Doenças por Armazenamento dos Lisossomos/reabilitação , Fisioterapia , Papel Profissional , Pessoal Técnico de Saúde , Administração de Caso , Criança , Crianças com Deficiência/reabilitação , Humanos , Doenças por Armazenamento dos Lisossomos/classificação , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/reabilitação , Desempenho Psicomotor
20.
Dev Med Child Neurol ; 47(2): 113-20, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15707234

RESUMO

The purpose of this article is to demonstrate: (1) the accuracy and (2) the reduction in amount of time and effort in assessing physical functioning (self-care and mobility domains) of children and adolescents using computer-adaptive testing (CAT). A CAT algorithm selects questions directly tailored to the child's ability level, based on previous responses. Using a CAT algorithm, a simulation study was used to determine the number of items necessary to approximate the score of a full-length assessment. We built simulated CAT (5-, 10-, 15-, and 20-item versions) for self-care and mobility domains and tested their accuracy in a normative sample (n=373; 190 males, 183 females; mean age 6y 11mo [SD 4y 2m], range 4mo to 14y 11mo) and a sample of children and adolescents with Pompe disease (n=26; 21 males, 5 females; mean age 6y 1mo [SD 3y 10mo], range 5mo to 14y 10mo). Results indicated that comparable score estimates (based on computer simulations) to the full-length tests can be achieved in a 20-item CAT version for all age ranges and for normative and clinical samples. No more than 13 to 16% of the items in the full-length tests were needed for any one administration. These results support further consideration of using CAT programs for accurate and efficient clinical assessments of physical functioning.


Assuntos
Desenvolvimento Infantil/fisiologia , Sistemas de Computação , Atividade Motora/fisiologia , Avaliação de Resultados (Cuidados de Saúde)/métodos , Atividades Cotidianas , Adolescente , Fatores Etários , Criança , Pré-Escolar , Simulação por Computador , Intervalos de Confiança , Demografia , Feminino , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Indicadores Básicos de Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Reprodutibilidade dos Testes , Autocuidado , Sensibilidade e Especificidade
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