Dataset Information

Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y.

ABSTRACT: Previous studies have shown that elosulfase alfa has a favorable efficacy/safety profile in Morquio A patients aged ?5 y. This study evaluated safety and impact on urine keratan sulfate (uKS) levels and growth velocity in younger patients.Fifteen Morquio A patients aged <5 y received elosulfase alfa 2.0?mg/kg/week for 52?wk during the primary treatment phase of a phase II, open-label, multinational study. Primary endpoint was safety and tolerability; secondary endpoints were change in uKS and growth velocity over 52?wk.All 15 patients completed the primary treatment phase. Six of 743 infusions (0.8%) administered led to adverse events (AEs) requiring infusion interruption and medical intervention. Eleven patients (73.3%) had ?1 study drug-related AE, mostly infusion-associated reactions. Mean z-score growth rate per year numerically improved from -0.6 at baseline to -0.4 at week 52. Comparison to untreated subjects of similar age in the Morquio A Clinical Assessment Program study showed a smaller decrease in height z-scores for treated than for untreated patients. Mean percent change from baseline in uKS was -30.2% at 2?wk and -43.5% at 52?wk.Early intervention with elosulfase alfa is well-tolerated and produces a decrease in uKS and a trend toward improvement in growth.

SUBMITTER: Jones SA

PROVIDER: S-EPMC4700045 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y.

Jones Simon A SA Bialer Martin M Parini Rossella R Martin Ken K Wang Hui H Yang Ke K Shaywitz Adam J AJ Harmatz Paul P

Pediatric research 20150902 6

<h4>Background</h4>Previous studies have shown that elosulfase alfa has a favorable efficacy/safety profile in Morquio A patients aged ≥5 y. This study evaluated safety and impact on urine keratan sulfate (uKS) levels and growth velocity in younger patients.<h4>Methods</h4>Fifteen Morquio A patients aged <5 y received elosulfase alfa 2.0 mg/kg/week for 52 wk during the primary treatment phase of a phase II, open-label, multinational study. Primary endpoint was safety and tolerability; secondary ...[more]

PMID: 26331768

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Project description:Managed access agreements provide a crucial mechanism whereby real-world data can be collected systematically to reduce uncertainty around available clinical and economic data, whilst providing the opportunity to identify patient sub-populations who are most likely to benefit from a new treatment. This manuscript aims to share learnings from the first managed access agreement, which was initiated following positive conditional approval in 2015 from the National Institute for Health and Care Excellence (NICE) for elosulfase alfa, an enzyme replacement therapy for the treatment of mucopolysaccharidosis type IVA (MPS IVA). This managed access agreement enabled the collection of comprehensive real-world data for patients with MPS IVA, with results demonstrating that patients starting elosulfase alfa treatment showed gains similar to those seen in the pivotal trial for outcomes including endurance, respiratory and cardiac function, pain, quality of life measures and urinary keratan sulfate levels. In addition, former trial patients continued to see benefits in both clinical assessments and quality of life/activities of daily living nine years after beginning treatment. Key strengths of the process included recruitment of a high proportion of MPS IVA patients treated in England (72/89 known eligible patients) with a wide range of ages (2-58 years). Participation of a patient organisation (the MPS society) ensured that the patient voice was present throughout the process, whilst a contract research organisation (Rare Disease Research Partners) ensured that patients were represented when interpreting agreement criteria and during patient assessment meetings. Longer-term follow-up will be required for several MPS IVA outcomes (e.g. skeletal measures) to further reduce uncertainty, and continued follow-up of patients who had stopped treatment was found to be challenging. The burden associated with this managed access agreement was found to be high for patients, physicians, patient organisations, NHS England and the manufacturer, therefore costs and benefits of future agreements should be considered carefully before initiation. Through evaluation of the strengths and limitations of this process, it is hoped that learnings from this managed access agreement can be used to inform future agreements.

Project description:Mucopolysaccharidosis (MPS) IVA is a rare lysosomal storage disorder with multiple skeletal and non-skeletal abnormalities requiring multiple surgical interventions. It is well known that patients with MPS IVA suffer from tachycardia, but cardiac and hemodynamic alterations have not been reported to date. We investigated the cardiovascular and hemodynamic alterations in patients with MPS IVA and developed a possible patho-mechanism for cardiovascular deterioration during anesthesia.In this observational study, serial cardiac examinations were performed in 54 patients with MPS IVA who were followed at the Children's Hospital of the Mainz Medical University (Mainz, Germany) between 1991 and 2014 (follow-up 1-24 years; median 5.8 years). Results were compared with data from a large central European cohort of more than 2000 healthy infants and children.None of the patients had arterial hypertension, but 4% had evidence of increased pulmonary artery pressure. Patients developed aortic root extension up to 6.9 standard deviations above normal. Left-sided valve leaflet thickening occurred in 26 patients (five with valve disease). Patients had lower left ventricular dimensions (z: -1.02±0.1), lower stroke volumes (z: -2.3±0.17), lower left ventricular mass (z: -1.5±0.21), but higher wall thickness (z: +0.8±0.16), and higher work index (z: +2.5±0.2) compared to healthy control subjects. Cardiac output was preserved by an increase in heart rate of 21%. Sixty % of patients showed impaired diastolic filling; heart rate (99.0±1.8 vs. 92.0±2.1 bpm), age (18.0±1.8 vs. 14.2±1 years), and cardiothoracic ratio (61.6±3.6% vs. 55±4.2%) of these patients were higher compared to those with normal filling.The results of this study suggest an age-progressive disproportion of the intra-thoracic organs of patients with MPS IVA, which is accompanied by aortic root extension and thickened left ventricles, with reduced stroke volumes, impaired diastolic filling patterns, and increased heart rates.

Dataset Information

Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y.

Publications

Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y.

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