Bone Abstracts

Objectives: Asfotase alfa (AA), an enzyme replacement therapy, is the only approved treatment for pediatric-onset hypophosphatasia (HPP). We evaluated the safety profile of AA from the clinical trial program spanning pediatric and adult patients.

Methods: Safety data were pooled from 4 open-label, multicenter studies in children aged ≤3 years (study 002/003 [NCT00744042/NCT01205152]; n=11) and ≤5 years (study 010-10 [NCT01176266]; n=69) with HPP presenting before age 6 months; children aged 5–12 years with HPP (study 006/008 [NCT00952484/NCT01203826]; n=13); and adolescents/adults aged 13–65 years with HPP presenting at any age (study 009 [NCT01163149]; n=19). Safety events after the studies ended were not included.

Results: Overall, 112 patients (median [min, max] age at enrollment: 3.2 [0, 66.5] y; female: 51%) had a median (min, max) treatment duration of 2.7 years (1 d, 7.5 y) and average weekly total dose of 5.95 (2.1, 11.9) mg/kg. Adverse events (AEs) occurred in all patients; 26% of events were considered treatment-related; 74% were mild, and 21% were moderate. ISRs were the most common treatment-related AEs (73%). Ten (9%) patients experienced serious treatment-related AEs. Serious AEs of special interest were craniosynostosis (25%), injection-associated reactions (5%), injection site reactions (ISRs; 2%), ectopic calcifications (2%), and liver abnormalities/disease (2%). Ten infants with severe HPP (aged 1 d–20 mo at enrollment) died, four of pneumonia/sepsis and 1 each of respiratory failure and cerebral death, HPP-related complications, severe respiratory failure, cardiopulmonary arrest, severe cardiopulmonary insufficiency, and transtentorial and cerebellar tonsillar herniation from cerebral edema. Most deaths were considered related to underlying HPP. One death, attributed to pneumonia, was reported as possibly related to AA. AEs leading to withdrawal occurred in 11 (10%) patients; pneumonia and respiratory failure were reported in ≥2 patients. During treatment, 97/109 (89%) patients tested positive for anti-AA immunoglobulin G (IgG) antibodies, and 55 (57%) of these showed presence of neutralizing antibodies (NAbs). No relationship between patient anti-AA IgG/NAb status and treatment-emergent AEs was observed.

Conclusions: In this pooled analysis of mostly prepubescent children (84%) receiving AA for up to 7 years, ISRs were the most common treatment-related AEs.

Disclosure: MPW, NB, CH, WH, CRG, and PSK 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. JH and VS are employees 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.