ESPE Abstracts (2014) 82 FC2.1

Asfotase Alfa: Sustained Improved Growth and Function with Extended Treatment in Children with Hypophosphatasia

Katherine Madsona, Cheryl Rockman-Greenbergb, Agustin Melianc, Scott Moseleyd, Tatjana Odrljind, Amy Reevesa & Michael Whytea

aShriners Hospitals for Children, St Louis, Missouri, USA; bUniversity of Manitoba, Winnipeg, Manitoba, Canada; cAlexion Pharmaceuticals, Cheshire, Connecticut, USA; dAlexion Pharmaceuticals, Cambridge, Massachusetts, USA

Introduction: Hypophosphatasia (HPP) is the rare, inherited, metabolic disease with broad-ranging severity caused by inactivating mutation(s) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. In the childhood form of HPP, there are mineralization defects of the bones and teeth, often with impaired physical function, muscle weakness, and decreased growth. We previously reported sustained radiographic improvement in rickets compared to historical controls in 5–12 year old patients (pts) receiving treatment with asfotase alfa, a bone-targeted recombinant human TNSALP, for up to 3 years.1 Here we report improvement in physical function and growth in these children.

Methods: In this randomized, multinational, open-label extension study of asfotase alfa, changes from baseline (BL) in physical function (6-min walk test, 6MWT), strength and agility (Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition, BOT-2), muscle strength (dynamometry), and height (z-score) were assessed.

Results: 12/13 patients (one withdrew: elective surgery) received ≥3 years of treatment. By parental report, all pts at BL had abnormal gaits and 8 (62%) had muscle weakness. Mean 6MWT improved from BL (345 m) 59% predicted to 76% at 3 months (n=11) and to 89% at 3 years (n=7), both: P<0.0001. The other four patients, evaluated at 3.5 years, had 6MWT of 71, 75, 96, and 99% predicted. Mean strength and agility standard score (healthy normal=50) improved from 27 (BL) to 35 at 3 months (P=0.0035) and to 48 at 3 years (P<0.0002, n=7). The other four patients, evaluated at 3.5 years, had BOT-2 scores of 36, 38, 52, and 58. Right hip abductor muscle strength best effort 13 lbs, 43% predicted, (n=12) at BL increased to 54% at 3 months (n=11) and to 80% at 3 years (P=0.0124, n=6). The other four patients improved to 57, 64, 92, and 93% predicted. Median height z-score was −1.26 at BL and −0.74 (P=0.0538) at 3 years.

Conclusion: Children with HPP and difficulty walking, muscle weakness, and significant rickets at baseline1, then treated with asfotase alfa, showed gains in height with rapid and sustained improvement in strength, agility, and function.

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