Background: Hypophosphatasia (HPP) is the rare inherited metabolic disorder resulting from loss-of-function mutation(s) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. TNSALP deficiency can cause a spectrum of complications in children including premature deciduous tooth loss, rickets, poor growth, and compromised physical function. We previously reported that children, 512 years old, with HPP and treated with asfotase alfa, a recombinant bone-targeted human TNSALP, experienced rapid improvement in skeletal mineralization and physical function, sustained through 3 years (Madson, JBMR 2014).
Objectives: Report data following 5 years of asfotase alfa treatment in these children.
Methods: Phase II, open-label, ongoing extension study of asfotase alfa (6 mg/kg per week; SC). Outcomes include change in rickets severity (7-point Radiographic Global Impression of Change (RGI-C) scale; −3=severe worsening, +3=near-complete/complete healing); functional ability (6-Minute Walk Test (6MWT):normal range=80120% predicted for healthy peers; Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) Strength and Agility score:mean (S.D.) for healthy peers=50 (10); Child Health Assessment Questionnaire (CHAQ) Disability Index:03, 0=no disability); and safety. Data are presented as median (min, max).
Results: 12 patients who entered the extension study were treated ≧5 years. At baseline, 6MWT was 61%(29%, 82%) predicted, BOT-2 was 28(20, 37), and CHAQ was 1(0, 2.25). Rapid and significant improvement in rickets was sustained through 5 years (RGI-C: +2.2(+1.7,+2.7); P=0.0005). Normalization of physical function was also sustained: 83%(70%, 104%) predicted (P=0.0002) on the 6MWT, and normal BOT-2 (46(33, 64); P<0.0001). Most patients continued to report no detectable disability on CHAQ (0(0,1); P=0.0002). Most common AEs were mild-to-moderate injection site reactions in all patients (eg erythema, macule, and lipohypertrophy; 1 injection site atrophy assessed as severe). There were no deaths or AEs leading to withdrawal.
Conclusion: Normalization of HPP-related skeletal manifestations and functional ability is sustained through 5 years of asfotase alfa treatment in children with HPP. Treatment was well tolerated.
Declaration of interest: TO and SM are employees of Alexion, which sponsored the study. KLM received honoraria from Alexion. MPW has received honoraria, grants, and travel fee from Alexion. CRG is clinical trials investigator and received honoraria and travel fee from Alexion.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology