Objectives: Asfotase alfa (AA), an enzyme replacement therapy, is the only approved medical treatment for pediatric-onset hypophosphatasia (HPP), which is caused by deficient tissue-nonspecific alkaline phosphatase activity. We detail the long-term efficacy of AA observed from the pediatric clinical trial program.
Methods: Efficacy data collected to study completion were pooled from 3 open-label, multicenter investigations of children who manifested HPP signs/symptoms before age 6 months: ages ≤3 years (study 002/003 [NCT00744042/NCT01205152]; n=11), ≤5 years (010-10 [NCT01176266]; n=69), and 512 years (006/008 [NCT00952484/NCT01203826]; n=5). Key assessments included survival, Radiographic Global Impression of Change (RGI-C) score (−3=severe worsening, +3=complete/near-complete healing), Rickets Severity Scale (RSS) score (010 indicating increasing severity), and growth Z-scores.
Results: Data were from 85 patients (median [min, max]: age at enrollment, 1.3 [0, 12.4] y; average weekly total AA dose, 5.98 [4.0, 11.9] mg/kg; and treatment duration, 2.31 [0, 7.5] y). Probability of survival at 7 years from 002/003 and 01010 vs. historical controls was 87% vs. 27%. Significant improvement on the RGI-C was documented at Month 3, with the median (min, max) score reaching +2.0 (−1.0,+3.0; P<0.0001; n=78) at Month 6, and then sustained through Year 7 (+2.3 [+2.0,+3.0]; P=0.001; n=11). Median (min, max) RSS score improved similarly, decreasing from 4.8 (0, 10) at Baseline (n=82) to 1.0 (0, 10) at Month 6 (n=75) and to 0.5 (0, 5.5) at Year 7 (n=9). Growth improved significantly. Median (min, max) Baseline length/height Z-score was −2.91 (−10.1,+0.9; n=83), increasing +0.23 (−1.9,+6.1; P<0.05; n=76) at Month 6, and +1.01 (−3.2,+3.1; n=11) at Year 7. Median (min, max) Baseline weight Z-score was −2.50 (−23.8, 0; n=84), increasing +0.44 (−4.9,+6.4; P<0.05; n=77) at Month 6 and +1.67 (−2.9,+5.1; P<0.05; n=11) at Year 7. Functional outcomes assessed across various scales varied but generally showed cognitive and motor improvement.
Conclusions: In this pooled data analysis of 85 children manifesting signs/symptoms of HPP before age 6 months, AA improved survival, radiographic skeletal manifestations of HPP, and growth. Improvements were observed early on, and sustained over 7 years of treatment.
Disclosure: WH, CRG, MPW, and NB are clinical study investigators and have received honoraria, and/or institutional grant funding/research support, and/or speaker/consulting fees, and/or travel support from Alexion Pharmaceuticals, Inc. AP is an employee of, and may own stock/options, in Alexion Pharmaceuticals, Inc., which sponsored the study. SZ is an employee of Covance, Inc., and provided statistical services for this analysis under contract to Alexion Pharmaceuticals, Inc.