Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study.

ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.ResultsAt week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95 % CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation.ConclusionsElosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile

Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients

Mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 μg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided

Long-Term Velaglucerase Alfa Treatment in Children with Gaucher Disease Type 1 Naïve to Enzyme Replacement Therapy or Previously Treated with Imiglucerase

Background Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). Methods Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30–60 U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. Results The study included 24 pediatric patients. Fifteen patients were naïve to ERT on entry into the preceding trials TKT032 (12-month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for \u3e 30 months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8 years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24 months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naïve patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. Conclusion The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults

Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N=173), analyses were also performed for a modified per-protocol (MPP) population (N=124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3)m and 39.9 (10.1)m for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study (N=56) and 15.1 (7.1)m and 31.7 (6.8)m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0)stairs/min for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3)stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was -59.4 (1.8)% and -62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P<0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified

Mucopolysaccharidoses in northern Brazil: Targeted mutation screening and urinary glycosaminoglycan excretion in patients undergoing enzyme replacement therapy

Mucopolysaccharidoses (MPS) are rare lysosomal disorders caused by the deficiency of specific lysosomal enzymes responsible for glycosaminoglycan (GAG) degradation. Enzyme Replacement Therapy (ERT) has been shown to reduce accumulation and urinary excretion of GAG, and to improve some of the patients’ clinical signs. We studied biochemical and molecular characteristics of nine MPS patients (two MPS I, four MPS II and three MPS VI) undergoing ERT in northern Brazil. The responsiveness of ERT was evaluated through urinary GAG excretion measurements. Patients were screened for eight common MPS mutations, using PCR, restriction enzyme tests and direct sequencing. Two MPS I patients had the previously reported mutation p.P533R. In the MPS II patients, mutation analysis identified the mutation p.R468W, and in the MPS VI patients, polymorphisms p.V358M and p.V376M were also found. After 48 weeks of ERT, biochemical analysis showed a significantly decreased total urinary GAG excretion in patients with MPS I (p < 0.01) and MPS VI (p < 0.01). Our findings demonstrate the effect of ERT on urinary GAG excretion and suggest the adoption of a screening strategy for genotyping MPS patients living far from the main reference centers