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://ichgcp.net/clinical-trials-registry/NCT00952484) and NCT01203826 (https://ichgcp.net/clinical-trials-registry/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Figures

Figure 1. Study design and patient participation.

During the 6-month initial phase involving 13 participants, 1 child withdrew for elective surgery after 1 month of treatment. The remaining 12 were assessed up to 5 years (60 months) of treatment and continue on study. Data were pooled across these 2 phases for analysis. The radiographic findings were contrasted to 2-year experience with 16 historical control patients. *ClinicalTrials.gov: NCT00952484, NCT01203826. LOCF, last observation carried forward.

Figure 2. Skeletal features of untreated hypophosphatasia.

Untreated, the radiographic features of hypophosphatasia in children (e.g., patient 7) include, as in the wrist pictured, osteopenia, metaphyseal fraying, metaphyseal flaring, and metadiaphyseal sclerosis, and as in the knee pictured, characteristic “tongues” of radiolucency, irregularity of the provisional zone of calcification, distal metaphyseal demineralization, transverse subphyseal band of lucency, and apparent physeal widening.

Figure 3. Skeletal improvements during treatment with asfotase alfa.

Changes in RGI-C scores during 6 months and 2 years of treatment with asfotase alfa. Individual dots illustrate the distribution of individual patient scores at each time point. Boxes represent the median RGI-C scores and represent first and third quartiles. Whisker lines above and below the boxes represent the end-range of patient scores. The RGI-C is scored on a scale ranging from –3 to +3, with 0 representing no change. Negative values represent worsening, and positive values represent improvement or healing. A score of +3 indicates nearly complete or complete healing. Median RGI-C scores for the historical controls and asfotase alfa were 0 and 2, respectively, at 6 months and 2 years. The number of patients assessed at each time point is shown below each bar. P ≤ 0.0001 by Wilcoxon signed-rank test at all time points compared with no change.

Figure 4. Representative radiographic changes.

Radiographic changes were documented in 12 treated patients and are illustrated in the Supplemental Methods. Patient 7, a 6-year-old boy at enrollment, is shown. RGI-C, Radiographic Global Impression of Change; RSS, Rickets Severity Score. Note the improvements at 6 months of treatment that persist after 5 years of therapy.

Figure 5. Growth during treatment with asfotase alfa.

Growth was assessed by Z scores for (A) weight, (B) height, and (C) BMI. For all graphs, individual dots indicate individual patient scores at each time point. Median, min, max, and n values are given below each panel. P values at 5 years from Wilcoxon signed-rank test.

Figure 6. Functional assessment during treatment with asfotase alfa.

(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.