Abstract
ContextLong-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.ObjectiveTo evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.DesignPhase 2 open-label study (July 2010 to September 2016).SettingTwenty-two sites; 12 countries.ParticipantsSixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.InterventionAsfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.Main Outcome MeasuresPrimary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [−3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).ResultsDuring median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (−1.7, +3.0)], Year 1 [+2.0 (−2.3, +3.0)], and Last Assessment [+2.3 (−2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.ConclusionsMost infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
Highlights
Responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health (NIH). 49 50 Trial Registration: ClinicalTrials.gov Identifier: NCT01176266. 53 Conflict of interest disclosures CEH has been an investigator and advisor/consultant and has received research support, speaker/consulting fees, and travel support from Alexion Pharmaceuticals, Inc
[word count limit: none; current count: 4793] INTRODUCTION Hypophosphatasia (HPP) is the rare, inherited, systemic, metabolic disease characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), which leads to extracellular accumulation of its substrates, mainly inorganic pyrophosphate (PPi) and pyridoxal 5'-phosphate (PLP) [1,2,3,4]
Reduced dephosphorylation of PLP, the circulating form of vitamin B6, by TNSALP has been associated with vitamin B6-responsive seizures in infants with HPP [3,5]. 121 Clinical presentation of HPP varies with age at onset, from in utero to adulthood [2,6]. Characteristic signs, symptoms, and complications of perinatal and infantile HPP that are potentially life-threatening include respiratory failure, vitamin B6-responsive seizures, chest deformity, and craniosynostosis; other manifestations include severe hypercalcemia, nephrocalcinosis, poor growth, osteomalacia, and bowing of the long bones [2,5,7,8,9,10,11]
Summary
Responsibility of the authors and do not necessarily represent the official views of the NIH. 49 50 Trial Registration: ClinicalTrials.gov Identifier: NCT01176266 (https://clinicaltrials.gov/ct2/show/NCT01176266). 53 Conflict of interest disclosures CEH has been an investigator and advisor/consultant and has received research support, speaker/consulting fees, and travel support from Alexion Pharmaceuticals, Inc. Conclusions: Most infants/young children treated with asfotase alfa showed early radiographic and clinical improvement that was sustained up to 6 years; radiographic “nonresponders” had more severe underlying disease and more frequent neutralizing antibodies at Last Assessment. Characteristic signs, symptoms, and complications of perinatal and infantile HPP that are potentially life-threatening include respiratory failure, vitamin B6-responsive seizures, chest deformity, and craniosynostosis; other manifestations include severe hypercalcemia, nephrocalcinosis, poor growth, osteomalacia, and bowing of the long bones [2,5,7,8,9,10,11]. In an open-label study of 11 infants and young children (aged ≤3 y) 134 with life-threatening HPP, treatment with asfotase alfa for up to 7 years improved HPP135 related skeletal abnormalities seen on radiograph, respiratory function, growth, and cognitive and motor function [17,18]. We report the long-term safety and efficacy of asfotase alfa in the largest study to date of infants and children aged ≤5 years with manifestations of HPP before age 6 months
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