Asfotase alfa therapy for children with hypophosphatasia
Michael P. Whyte, … , Tatjana Odrljin, Cheryl Rockman-Greenberg
Michael P. Whyte, … , Tatjana Odrljin, Cheryl Rockman-Greenberg
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e85971. https://doi.org/10.1172/jci.insight.85971.
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Clinical Medicine Bone biology

Asfotase alfa therapy for children with hypophosphatasia

Abstract

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP.

Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6–12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients.

Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti–asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance.

Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP.

Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826).

Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Authors

Michael P. Whyte, Katherine L. Madson, Dawn Phillips, Amy L. Reeves, William H. McAlister, Amy Yakimoski, Karen E. Mack, Kim Hamilton, Kori Kagan, Kenji P. Fujita, David D. Thompson, Scott Moseley, Tatjana Odrljin, Cheryl Rockman-Greenberg

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Figure 6

Functional assessment during treatment with asfotase alfa.

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Functional assessment during treatment with asfotase alfa. (A) Percent p...
(A) Percent predicted 6MWT distance median achieves the normal range after 6 months of treatment and is sustained at 5 years of therapy. P ≤ 0.0005 by paired t test for the mean difference between each time point and baseline. (B) Gross motor function, assessed using the BOT-2 Running Speed and Agility subtest (17), shows median scores reaching the normal range (gray area) by 1 year of treatment that were sustained. Median, min, max, and n values are given within the figure. (C) Disability assessment using the CHAQ (24) shows patient improvement. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 mean difference for each time point compared with baseline by paired t test. Median, min, max, and n values are given below each figure. For all graphs, individual dots indicate individual patient scores at each time point. Gray area represents the normal range.