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Gerald F Cox - One of the best experts on this subject based on the ideXlab platform.
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Immune tolerance induction for Laronidase treatment in mucopolysaccharidosis I.
Molecular genetics and metabolism reports, 2017Co-Authors: Roberto Giugliani, Gerald F Cox, Susan Richards, Taiane Alves Vieira, Clarissa Gutierrez Carvalho, Maria-veronica Munoz-rojas, A. N. Semyachkina, Victoria Y. Voinova, Yong XueAbstract:Abstract Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with Laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of Laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose Laronidase infusions (0.058–0.29 mg/kg/week) was followed by an immune-challenge period with Laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-Laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of Laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving Laronidase treatment. Clinical Trial Registration: NCT00741338.
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Effect of anti-Laronidase antibodies on efficacy and safety of Laronidase enzyme replacement therapy for MPS I: A comprehensive meta-analysis of pooled data from multiple studies
Molecular genetics and metabolism, 2016Co-Authors: Yong Xue, Susan Richards, Asif Mahmood, Gerald F CoxAbstract:Enzyme replacement therapy (ERT) with Laronidase has an important role in the treatment of patients with mucopolysaccharidosis type I (MPS I). Laronidase is safe and has demonstrated effectiveness in terms of stabilizing or improving conventional clinical and laboratory markers of the disease. However, like most ERTs, Laronidase produces an anti-drug IgG antibody response in more than 90% of patients during the first few months of treatment. Preclinical data from the MPS I canine model suggest that anti-drug antibodies (ADA) impair enzyme uptake in target tissues. In patients, the effects on tissue glycosaminoglycan (GAG) clearance are difficult to assess directly but data from clinical studies have suggested an association between ADA and both a reduced pharmacodynamic response and hypersensitivity reactions. This comprehensive meta-analysis of pooled data from patients in three clinical studies of Laronidase (including one study with an extension) was undertaken to provide a more robust assessment of the relationship between the ADA response to Laronidase, clinical and laboratory markers of MPS I, and hypersensitivity reactions. The meta-analysis demonstrated an inverse relationship between the ADA response and the percent reduction in urinary GAG (uGAG) levels. However, no relationships between the ADA response and changes in percent predicted forced vital capacity and six-minute walk test were seen. The study also re-assayed stored serum samples from the original trials with a novel method to determine the inhibitory effect of ADA. Patients with higher ADA exposure over time were found to have higher inhibition of enzyme uptake into cells. High ADA exposure can result in a commensurate level of enzyme uptake inhibition that decreases the pharmacodynamic effect of the exogenously administered therapeutic enzyme, but with no clear effect on clinical efficacy.
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Successful pregnancy and breastfeeding in a woman with mucopolysaccharidosis type I while receiving Laronidase enzyme replacement. therapy.
Clinical and experimental obstetrics & gynecology, 2015Co-Authors: Mario Castorina, Gerald F Cox, Daniela Antuzzi, Susan Richards, Y XueAbstract:The authors describe the first mother-infant pair to complete an on-going, prospective, open-label, Phase 4 trial (ALIU) UU3, NCT00418821) determining the safety of Laronidase enzyme replacement therapy (ERT) in pregnant women with mucopolysaccharidosis type I (MPS I) and their breastfed infants. The mother, a 32-year-old with attenuated MPS I (Scheie syndrome), received Laronidase for three years and continued treatment throughout her second pregnancy and while lactating. A healthy 2.5 kg male was delivered by elective cesarean section at 37 weeks. He was breastfed for three months. No Laronidase was detected in breast milk. The infant never developed anti-Laronidase IgM antibodies, never had inhibitory antibody activity in a cellular uptake assay, and always had normal urinary glycosaminoglycan (GAG) levels. No drug-related adverse events were reported. At 2.5 years of age, the boy is healthy with normal growth and development. In this first prospectively monitored mother-infant pair, Laronidase during pregnancy and breastfeeding was uneventful.
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diagnosis and treatment trends in mucopolysaccharidosis i findings from the mps i registry
European Journal of Pediatrics, 2012Co-Authors: Kristin Daco, Pamela Arn, Lisa H Underhill, Lakshmi Rangachari, Gerald F Cox, Torayuki Okuyama, Roberto Giugliani, Frits A. Wijburg, Paige KaplanAbstract:Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with Laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler–Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since Laronidase became available in 2003 (gap during 2006–2009: Hurler—0.2 year, Hurler–Scheie—0.5 year, Scheie—1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler–Scheie and Scheie patients (gap during 2006–2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with Laronidase (42 out of 45 patients by 2009). Conclusions: Despite the availability of Laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler–Scheie and Scheie phenotypes, which can lead to a sub-optimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients.
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Source document verification in the Mucopolysaccharidosis Type I Registry.
Pharmacoepidemiology and drug safety, 2011Co-Authors: Karien Verhulst, Gerald F Cox, Michael Beck, Joe T.r. Clarke, Nathalie Guffon, Laura Artiles-carloni, Jordao Correa Neto, Paul M. Fernhoff, Yuan Kong, Ana Maria MartinsAbstract:Purpose The Mucopolysaccharidosis Type I (MPS I) Registry is an international observational database that tracks the natural history and the outcomes of patients with MPS I. The Registry was a regulatory requirement following the approval of Laronidase enzyme replacement therapy for MPS I in 2003. All data are collected voluntarily after informed consent from the patient or family. Data are checked through queries, monthly reviews, and electronic audits to identify missing, inconsistent, or invalid data. This analysis sought to determine overall data accuracy in the Registry through source document verification (SDV). Methods Two phases of SDV were performed. In each phase, Registry data were compared against source documents at sites in Europe, Latin America, and North America. Three patients were randomly selected for SDV at each of the selected sites among all patients enrolled ≥18 months and ever receiving Laronidase. Key parameters central to MPS I and its treatment were examined from the baseline and the last available assessments. Results Results indicate an overall source-to-database error rate in the MPS I Registry of 2.7% (47 discrepancies out of 1715 items; 95% confidence interval [2.2%, 3.5%]) in Phase 1 and 3.7% (64 discrepancies out of 1732 items; 95% confidence interval [2.9%, 4.7%]) in Phase 2. No systematic errors were found. Conclusions The overall error rates in both phases of SDV demonstrate acceptable data accuracy in the MPS I Registry within the data fields that were assessed. Copyright © 2011 John Wiley & Sons, Ltd.
Emil D Kakkis - One of the best experts on this subject based on the ideXlab platform.
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Long-term efficacy and safety of Laronidase in the treatment of mucopolysaccharidosis I.
Pediatrics, 2009Co-Authors: Lorne A Clarke, Gregory M. Pastores, Michael Beck, Edwin H Kolodny, Joseph Muenzer, David M Rapoport, Kenneth I Berger, Marisa Sidman, J. Edmond Wraith, Emil D KakkisAbstract:OBJECTIVE. Our goal was to evaluate the long-term safety and efficacy of recombinant human α-l-iduronidase (Laronidase) in patients with mucopolysaccharidosis I. PATIENTS AND METHODS. All 45 patients who completed a 26-week, double-blind, placebo-controlled trial of Laronidase were enrolled in a 3.5-year open-label extension study. Mean patient age at baseline was 16 (range: 6–43) years. All patients had attenuated disease (84% Hurler-Scheie, 16% Scheie phenotypes). Clinical, biochemical, and health outcomes measures were evaluated through the extension phase. Changes are presented as the mean ± SEM. RESULTS. All 40 patients (89%) who completed the trial received at least 80% of scheduled infusions. As shown in earlier trials, urinary glycosaminoglycan levels decreased within the first 12 weeks and liver volume decreased within the first year. Percent predicted forced vital capacity remained stable, with a linear slope of −0.78 percentage points per year. The 6-minute walk distance increased 31.7 ± 10.2 m in the first 2 years, with a final gain of 17.1 ± 16.8 m. Improvements in the apnea/hypopnea index (decrease of 7.6 ± 4.5 events per hour among the patients with significant baseline sleep apnea) and shoulder flexion (increase of 17.4° ± 3.6°) were most rapid during the first 2 years. Improvements in the Child Health Assessment Questionnaire/Health Assessment Questionnaire disability index (decrease of 0.31 ± 0.11, signifying a clinically meaningful improvement in activities of daily living) were gradual and sustained over the treatment period. Laronidase infusions were generally well tolerated except in 1 patient who experienced an anaphylactic reaction. Infusion-associated reactions, which occurred in 53% of the patients, were mostly mild, easily managed, and decreased markedly after 6 months. One patient died as a result of an upper respiratory infection unrelated to treatment. Antibodies to Laronidase developed in 93% of the patients; 29% of the patients were seronegative at their last assessment. CONCLUSIONS. This trial demonstrates the long-term clinical benefit and safety of Laronidase in attenuated patients with mucopolysaccharidosis I and highlights the magnitude and chronology of treatment effects. Prompt diagnosis and early treatment will maximize treatment outcomes.
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A dose-optimization trial of Laronidase (Aldurazyme) in patients with mucopolysaccharidosis I.
Molecular genetics and metabolism, 2008Co-Authors: Roberto Giugliani, Ana Maria Martins, Emil D Kakkis, Verónica Muñoz Rojas, Eugênia Ribeiro Valadares, Joe T.r. Clarke, José Eduardo Góes, Mary Alice Worden, Marisa Sidman, Gerald F CoxAbstract:Abstract Recombinant human α- l -iduronidase (Aldurazyme®, Laronidase) is approved as an enzyme replacement therapy to treat the lysosomal storage disorder, mucopolysaccharidosis type I (MPS I) at a dose of 0.58 mg/kg by once-weekly intravenous infusion. To assess whether alternate dosing regimens might provide a better reduction in lysosomal storage, a 26-week, randomized, open-label, multinational dose-optimization trial was conducted. The pharmacodynamic effect and safety of the approved Laronidase dose was compared to three alternative regimens (1.2 mg/kg every 2 weeks; 1.2 mg/kg every week; 1.8 mg/kg every 2 weeks) among 33 MPS I patients. The four treatment regimens showed no significant differences in the reduction of urinary glycosaminoglycan excretion or liver volume. Laronidase had an acceptable safety profile in all dose regimen groups. Infusion-associated reactions were the most common drug-related adverse events across dose regimens (by patient incidence), and included pyrexia (21%), vomiting (15%), rash (15%), and urticaria (12%). Patients in the approved dose group had the lowest incidence of drug-related adverse events (38% vs. 63–75%) and infusion-associated reactions (25% vs. 25–63%). There was one death: a patient with acute bronchitis died of respiratory failure 6 h after completing the first Laronidase infusion. The approved 0.58 mg/kg/week Laronidase dose regimen provided near-maximal reductions in glycosaminoglycan storage and the best benefit-to-risk ratio. The 1.2 mg/kg every 2 weeks regimen may be an acceptable alternative for patients with difficulty receiving weekly infusions, but the long-term effects of this regimen are unknown.
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Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression
American Journal of Medical Genetics Part A, 2008Co-Authors: Maria-veronica Munoz-rojas, Taiane Alves Vieira, Ronaldo Costa, Simone Fagondes, Angela John, Laura Bannach Jardim, Leonardo M Vedolin, Marcia Raymundo, Patricia I Dickson, Emil D KakkisAbstract:In mucopolysaccharidosis I, deficiency of α-L-iduronidase can cause spinal cord compression (SCC) due to storage of glycosaminoglycans (GAGs) within the cervical meninges. As intravenous enzyme replacement therapy (ERT) is not likely to provide enzyme across the blood–brain barrier, standard treatment for this complication is usually surgical, which has a high morbidity and mortality risk. We report on the use of intrathecal (IT) Laronidase in a MPS I patient with SCC who refused the surgical treatment. Assessments were performed at baseline, with clinical and biochemical evaluations, 4-extremity somatosensory evoked potentials, 12 min walk test and MRI studies of the CNS. Changes on these parameters were evaluated after 4 IT infusions of Laronidase administered monthly via lumbar puncture. To our knowledge, this was the first MPS patient who received IT ERT. No major adverse events were observed. There were no clinically significant changes in serum chemistries. CSF GAG results revealed pretreatment values slightly above normal standards: 13.3 mg/L (NV
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enzyme replacement therapy in patients who have mucopolysaccharidosis i and are younger than 5 years results of a multinational study of recombinant human α l iduronidase Laronidase
Pediatrics, 2007Co-Authors: Edmond J Wraith, Michael Beck, Emil D Kakkis, Yong Xue, R Lane, Ans T Van Der Ploeg, Elsa Shapiro, Nathalie GuffonAbstract:OBJECTIVE. Our objective was to evaluate the safety, pharmacokinetics, and efficacy of Laronidase in young, severely affected children with mucopolysaccharidosis I. METHODS. This was a prospective, open-label, multinational study of 20 patients who had mucopolysaccharidosis I and were <5 years old (16 with Hurler syndrome, 4 with Hurler-Scheie syndrome) and were scheduled to receive intravenous Laronidase at 100 U/kg (0.58 mg/kg) weekly for 52 weeks. Four patients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary glycosaminoglycan levels at week 22. RESULTS. Laronidase was well tolerated at both dosages. Investigators reported improved clinical status in 94% of patients at week 52. The mean urinary glycosaminoglycan level declined by ∼50% at week 13 and was sustained thereafter. A more robust decrease in urinary glycosaminoglycan was observed in patients with low antibody levels and those who were receiving the 200 U/kg dosage. On examination, the liver edge was reduced by 69.5% in patients with a palpable liver at baseline and week 52 (n = 10). The proportion of patients with left ventricular hypertrophy decreased from 53% to 17%. Global assessment of sleep studies showed improvement or stabilization in 67% of patients, and the apnea/hypopnea index decreased by 5.8 events per hour (-8.5%) in those with abnormal baseline values. The younger patients with Hurler syndrome (<2.5 years) and all 4 patients with Hurler-Scheie syndrome showed normal mental development trajectories during the 1-year treatment period. CONCLUSIONS. Laronidase seems to be well tolerated and to provide clinical benefit in patients who have severe mucopolysaccharidosis I and are <5 years old. Enzyme replacement therapy is not curative and may not improve all affected organs and systems in individuals when irreversible changes have developed. The long-term clinical outcome and effects of antibodies and Laronidase dosing on glycosaminoglycan reduction warrant additional investigation. Copyright
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Enzyme replacement therapy in patients who have mucopolysaccharidosis i and are younger than 5 years: Results of a multinational study of recombinant human α-L-iduronidase (Laronidase)
Pediatrics, 2007Co-Authors: J. Edmond Wraith, Michael Beck, Emil D Kakkis, Yong Xue, R Lane, Ans T Van Der Ploeg, Elsa Shapiro, Nathalie GuffonAbstract:OBJECTIVE. Our objective was to evaluate the safety, pharmacokinetics, and efficacy of Laronidase in young, severely affected children with mucopolysaccharidosis I. METHODS. This was a prospective, open-label, multinational study of 20 patients who had mucopolysaccharidosis I and were
Ana Maria Martins - One of the best experts on this subject based on the ideXlab platform.
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CASE SERIES OF PATIENTS UNDER BIWEEKLY TREATMENT WITH Laronidase: A REPORT OF A SINGLE CENTER EXPERIENCE.
Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo, 2019Co-Authors: Sandra Obikawa Kyosen, Leny Toma, Helena B. Nader, Marion Coting Braga, Vanessa Gonçalves Pereira, Sueli Canossa, João Bosco Pesquero, Vânia D'almeida, Ana Maria MartinsAbstract:OBJECTIVE To report the stabilization of urinary glycosaminoglicans (GAG) excretion and clinical improvements in patients with mucopolysaccharidosis type I (MPS I) under an alternative dose regimen of Laronidase of 1.2 mg/kg every other week. METHODS We participated in a dose-optimization trial for Laronidase in MPS-I patients using four alternative regimens: 0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every week and 1.8 mg/kg every other week (EOW). After the trial ended, the patients resumed the recommended dose and regimen of 0.58 mg/kg every week. Under this regimen, some patients presented difficulties in venous access and were unable to commute weekly to the treatment center. Therefore, we used an alternative regimen that consisted of 1.2 mg/kg EOW in eight patients. A retrospective study of medical records of MPS-I patients who underwent both enzyme replacement therapy (ERT) regimens, of 0.58 mg/kg every week and 1.2 mg/kg EOW, was done. RESULTS Patients remained clinically stable under the alternative regimen, did not present elevation of urinary GAG nor any adverse event.Conclusions: The switch of dose regimen to 1.2 mg/kg EOW of Laronidase was safe, and did not cause any clinical worsening in patients who had been previously under standard dose ERT.
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The impact of Laronidase treatment in otolaryngological manifestations of patients with mucopolysaccharidosis
Brazilian journal of otorhinolaryngology, 2015Co-Authors: Ana Paula Fiuza Funicello Dualibi, Ana Maria Martins, Gustavo Antonio Moreira, Marisa Frasson De Azevedo, Reginaldo Raimundo Fujita, Shirley Shizue Nagata PignatariAbstract:Abstract Introduction Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by deficiency of α- l -iduronidase. The otolaryngological findings include hearing loss, otorrhea, recurrent otitis, hypertrophy of tonsils and adenoid, recurrent rhinosinusitis, speech disorders, snoring, oral breathing and nasal obstruction. Objective To evaluate the impact of enzymatic replacement therapy with Laronidase (Aldurazyme®) in patients with mucopolysaccharidosis (MPS I), regarding sleep and hearing disorders, and clinical manifestations in the upper respiratory tract (URT). Methods Nine patients with MPS I (8 Hurler-Scheie, and 1 Scheie phenotypes) of both sexes, ages ranging between 3 and 20 years, were included in this study. Patients were evaluated between seven and 11 months before the treatment and between 16 and 22 months after the onset of the enzymatic replacement. They were all submitted to a clinical and otolaryngological evaluation, including nasofibroscopical, polysomnographic and audiologic exams. Results The results’ data showed decreasing of the frequency of ear, nose and throat infections, with improvement of the rhinorrhea and respiratory quality. No remarkable changes were observed regarding macroglossia and tonsil and adenoid hypertrophy. Audiometric and polysomnographic evaluations did not show statistical significance. Conclusion Enzymatic replacement therapy in patients with mucopolysaccharidosis I provides control of recurrent URT infections, rhinorrhea and respiratory quality, however it is does not seem to improve audiologic and polisomnographic parameters, with no effect on adenoid and tonsils hypertrophy and macroglossia.
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early treatment with Laronidase improves clinical outcomes in patients with attenuated mps i a retrospective case series analysis of nine sibships
Orphanet Journal of Rare Diseases, 2015Co-Authors: Nouriya Alsannaa, Luisa Bay, Deborah S Barbouth, Youssef Benhayoun, Cyril Goizet, Norberto Guelbert, Sandra Obikawa Kyosen, Ana Maria Martins, Simon A Jones, Chanika PhornphutkulAbstract:Enzyme replacement therapy (ERT) with Laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with Laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. These findings suggest early initiation of Laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.
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Laronidase hypersensitivity and desensitization in type I mucopolysaccharidosis: a case report.
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 2014Co-Authors: Luis Felipe Ensina, Ana Maria Martins, Carolina Aranda, Alex Eustáquio De Lacerda, Inês Cristina Camelo-nunes, Dirceu Solé, Mariana CastellsAbstract:Universidade Federal de São Paulo, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilHarvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy,Dept Med, Boston, MA 02115 USAUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Clin Immunol & Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilWeb of Scienc
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Source document verification in the Mucopolysaccharidosis Type I Registry.
Pharmacoepidemiology and drug safety, 2011Co-Authors: Karien Verhulst, Gerald F Cox, Michael Beck, Joe T.r. Clarke, Nathalie Guffon, Laura Artiles-carloni, Jordao Correa Neto, Paul M. Fernhoff, Yuan Kong, Ana Maria MartinsAbstract:Purpose The Mucopolysaccharidosis Type I (MPS I) Registry is an international observational database that tracks the natural history and the outcomes of patients with MPS I. The Registry was a regulatory requirement following the approval of Laronidase enzyme replacement therapy for MPS I in 2003. All data are collected voluntarily after informed consent from the patient or family. Data are checked through queries, monthly reviews, and electronic audits to identify missing, inconsistent, or invalid data. This analysis sought to determine overall data accuracy in the Registry through source document verification (SDV). Methods Two phases of SDV were performed. In each phase, Registry data were compared against source documents at sites in Europe, Latin America, and North America. Three patients were randomly selected for SDV at each of the selected sites among all patients enrolled ≥18 months and ever receiving Laronidase. Key parameters central to MPS I and its treatment were examined from the baseline and the last available assessments. Results Results indicate an overall source-to-database error rate in the MPS I Registry of 2.7% (47 discrepancies out of 1715 items; 95% confidence interval [2.2%, 3.5%]) in Phase 1 and 3.7% (64 discrepancies out of 1732 items; 95% confidence interval [2.9%, 4.7%]) in Phase 2. No systematic errors were found. Conclusions The overall error rates in both phases of SDV demonstrate acceptable data accuracy in the MPS I Registry within the data fields that were assessed. Copyright © 2011 John Wiley & Sons, Ltd.
Roberto Giugliani - One of the best experts on this subject based on the ideXlab platform.
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Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I
BioDrugs, 2018Co-Authors: William M. Pardridge, Roberto Giugliani, Ruben J. Boado, Mathias SchmidtAbstract:Background Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α- l -iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood–brain barrier (BBB). Human IDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI. Methods The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI. Results Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3–3 mg/kg with a stable plasma elimination half-life ( t _½). The plasma pharmacokinetic parameters for valanafusp alpha overlapped with the same parameters previously reported for recombinant human IDUA (Laronidase). The majority of the tested subjects had been receiving Laronidase ERT for years, and some showed high levels of anti-drug antibodies (ADAs). However, the presence of these ADAs did not generally alter the rate of plasma clearance of valanafusp alpha in MPSI. The infusion of 0.3–6 mg/kg doses of valanafusp alpha had no effect on plasma glucose for up to 24 h after the drug infusion. Conclusion The plasma clearance of valanafusp alpha is increased four-fold in children with MPSI compared with adult subjects at a dose of 1–3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1–3 mg/kg, is comparable to that of Laronidase in children with MPSI.
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Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I.
BioDrugs : clinical immunotherapeutics biopharmaceuticals and gene therapy, 2018Co-Authors: William M. Pardridge, Roberto Giugliani, Ruben J. Boado, Mathias SchmidtAbstract:Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the α-L-iduronidase (IDUA) lysosomal enzyme and the majority of MPSI patients have severe central nervous system (CNS) involvement. Enzyme replacement therapy (ERT) with recombinant IDUA does not treat the CNS, due to the lack of transport of the enzyme across the blood-brain barrier (BBB). Human IDUA has been re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb domain binds the endogenous insulin receptor on the human BBB to trigger receptor-mediated transport across the BBB, and acts as a molecular Trojan horse to ferry the fused IDUA into the brain of patients with MPSI. The present investigation describes the initial dosing, plasma pharmacokinetics, and plasma glucose response to the intravenous infusion of doses of valanafusp alpha ranging from 0.3 to 3 mg/kg in five adults and from 1 to 6 mg/kg in 13 pediatric subjects with MPSI. Valanafusp alpha plasma clearance is increased four-fold in children, and shows a linear pharmacokinetic response over the dose range of 0.3-3 mg/kg with a stable plasma elimination half-life (t½). The plasma pharmacokinetic parameters for valanafusp alpha overlapped with the same parameters previously reported for recombinant human IDUA (Laronidase). The majority of the tested subjects had been receiving Laronidase ERT for years, and some showed high levels of anti-drug antibodies (ADAs). However, the presence of these ADAs did not generally alter the rate of plasma clearance of valanafusp alpha in MPSI. The infusion of 0.3-6 mg/kg doses of valanafusp alpha had no effect on plasma glucose for up to 24 h after the drug infusion. The plasma clearance of valanafusp alpha is increased four-fold in children with MPSI compared with adult subjects at a dose of 1-3 mg/kg. The plasma pharmacokinetic profile of valanafusp alpha, at a dose of 1-3 mg/kg, is comparable to that of Laronidase in children with MPSI.
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Immune tolerance induction for Laronidase treatment in mucopolysaccharidosis I.
Molecular genetics and metabolism reports, 2017Co-Authors: Roberto Giugliani, Gerald F Cox, Susan Richards, Taiane Alves Vieira, Clarissa Gutierrez Carvalho, Maria-veronica Munoz-rojas, A. N. Semyachkina, Victoria Y. Voinova, Yong XueAbstract:Abstract Enzyme replacement therapy (ERT) can produce anti-drug antibody (ADA) responses that reduce efficacy or lead to hypersensitivity reactions. Six patients with severe mucopolysaccharidosis type I (MPS I/Hurler syndrome) who did not receive hematopoietic stem cell transplantation underwent an immunosuppression regimen prior to initiating ERT with Laronidase. The primary endpoint for immune tolerance induction was the number of patients with an ADA titer ≤ 3200 after 24 weeks of Laronidase at the labeled dose. Cyclosporine levels were measured weekly and doses adjusted to maintain trough levels above 400 mg/mL. A 6-week (Cohort 1) or 12-week (Cohort 2) immune tolerance induction period with cyclosporine (initial dose: 15 or 20 mg/kg/day), azathioprine (initial dose: 2.5 or 5 mg/kg/day) and low-dose Laronidase infusions (0.058–0.29 mg/kg/week) was followed by an immune-challenge period with Laronidase infusions at the labeled dose (0.58 mg/kg/week) for 24 weeks. Anti-Laronidase IgG titers were determined following treatment. There were 147 treatment-emergent adverse events reported, most of which were mild and not related to the study treatment. While there was no evidence of immune tolerance in 3 of 3 patients in Cohort 1, there were some indications of immune tolerance induction in 2 of 3 patients in Cohort 2. Patients with lower ADA titers showed greater reductions in urinary glycosaminoglycan excretion. Routine monitoring of plasma cyclosporine parent-compound levels by high pressure liquid chromatography proved difficult for clinical practice. The evolving clinical management of MPS I and a better understanding of the clinical impact of Laronidase-related immunogenicity require reassessment of immune modulation strategies in patients with MPS I receiving Laronidase treatment. Clinical Trial Registration: NCT00741338.
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Alternative Laronidase dose regimen for patients with mucopolysaccharidosis I: a multinational, retrospective, chart review case series
Orphanet journal of rare diseases, 2016Co-Authors: Dafne Dain Gandelman Horovitz, Roberto Giugliani, Angelina Xavier Acosta, Anna Hlavatá, Katarina Hlavatá, Michel Tchan, Anneliese Lopes Barth, Laercio Cardoso, Emília Katiane Embiruçu De Araújo Leão, Ana Carolina EspositoAbstract:Background Enzyme replacement therapy (ERT) with Laronidase (recombinant human α-L-iduronidase, Aldurazyme®) is indicated for non-neurological signs and symptoms of mucopolysaccharidosis type I (MPS I). The approved Laronidase dose regimen is weekly infusions of 0.58mg/kg, however, patients and caregivers may have difficulty complying with the weekly regimen. We examined clinical outcomes, tolerability, compliance, and satisfaction in a series of patients who switched to every other week infusions.
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Effects of enzyme replacement therapy started late in a murine model of mucopolysaccharidosis type I.
PloS one, 2015Co-Authors: Gabriela Pasqualim, Roberto Giugliani, Guilherme Baldo, Talita Giacomet De Carvalho, Angela Maria Vicente Tavares, Ursula Da Silveira MatteAbstract:Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don’t receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6–8mo) with 1.2mg Laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-Laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible.
Patricia I Dickson - One of the best experts on this subject based on the ideXlab platform.
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Data from subjects receiving intrathecal Laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I
Data in brief, 2015Co-Authors: Patricia I Dickson, Agnes H. Chen, Paul Harmatz, Ilkka Kaitila, Anton Mlikotic, Alla Victoroff, Merry Passage, Jacqueline Madden, David E. NaylorAbstract:Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal Laronidase in a 4-month pilot study and/or a 12-month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects.
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Safety of Laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I
Molecular Genetics and Metabolism, 2015Co-Authors: Patricia I Dickson, Agnes H. Chen, Paul Harmatz, Ilkka Kaitila, Anton Mlikotic, Alla Victoroff, Merry Passage, Jacqueline Madden, David E. NaylorAbstract:Enzyme replacement therapy with Laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal Laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.
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Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression.
American journal of medical genetics. Part A, 2008Co-Authors: Maria-veronica Munoz-rojas, Taiane Vieira, Ronaldo Costa, Simone Fagondes, Angela John, Laura Bannach Jardim, Leonardo M Vedolin, Marcia Raymundo, Patricia I Dickson, Emil KakkisAbstract:In mucopolysaccharidosis I, deficiency of alpha-L-iduronidase can cause spinal cord compression (SCC) due to storage of glycosaminoglycans (GAGs) within the cervical meninges. As intravenous enzyme replacement therapy (ERT) is not likely to provide enzyme across the blood-brain barrier, standard treatment for this complication is usually surgical, which has a high morbidity and mortality risk. We report on the use of intrathecal (IT) Laronidase in a MPS I patient with SCC who refused the surgical treatment. Assessments were performed at baseline, with clinical and biochemical evaluations, 4-extremity somatosensory evoked potentials, 12 min walk test and MRI studies of the CNS. Changes on these parameters were evaluated after 4 IT infusions of Laronidase administered monthly via lumbar puncture. To our knowledge, this was the first MPS patient who received IT ERT. No major adverse events were observed. There were no clinically significant changes in serum chemistries. CSF GAG results revealed pretreatment values slightly above normal standards: 13.3 mg/L (NV < 12 mg/L) which after IT Laronidase infusions were within normal levels (10.3 mg/L). 12MWT presented a 14% improvement, with better performance on stability and gait control. Maximum voluntary ventilation showed 55.6% improvement considering the percentage of predicted (26.7% at baseline compared to 41.9%); Maximum Inspiration Pressure improved 36.6% of predicted (26.8% at baseline to 36.7%); Pulmonary diffusion improved 17.6% of predicted %. In conclusion, although the improvement observed in this case with IT Laronidase should be confirmed in further patients, this procedure seems to be a safe treatment for SCC in MPS I.
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Intrathecal enzyme replacement therapy in a patient with mucopolysaccharidosis type I and symptomatic spinal cord compression
American Journal of Medical Genetics Part A, 2008Co-Authors: Maria-veronica Munoz-rojas, Taiane Alves Vieira, Ronaldo Costa, Simone Fagondes, Angela John, Laura Bannach Jardim, Leonardo M Vedolin, Marcia Raymundo, Patricia I Dickson, Emil D KakkisAbstract:In mucopolysaccharidosis I, deficiency of α-L-iduronidase can cause spinal cord compression (SCC) due to storage of glycosaminoglycans (GAGs) within the cervical meninges. As intravenous enzyme replacement therapy (ERT) is not likely to provide enzyme across the blood–brain barrier, standard treatment for this complication is usually surgical, which has a high morbidity and mortality risk. We report on the use of intrathecal (IT) Laronidase in a MPS I patient with SCC who refused the surgical treatment. Assessments were performed at baseline, with clinical and biochemical evaluations, 4-extremity somatosensory evoked potentials, 12 min walk test and MRI studies of the CNS. Changes on these parameters were evaluated after 4 IT infusions of Laronidase administered monthly via lumbar puncture. To our knowledge, this was the first MPS patient who received IT ERT. No major adverse events were observed. There were no clinically significant changes in serum chemistries. CSF GAG results revealed pretreatment values slightly above normal standards: 13.3 mg/L (NV
