OR13-4 Safety Profile of Asfotase Alfa Treatment of Patients with Hypophosphatasia: A Pooled Analysis

Abstract

Asfotase alfa (AA), an enzyme replacement therapy, is the only approved medical treatment for pediatric-onset hypophosphatasia (HPP). We report the safety profile of AA in patients from the clinical trial program. Safety data were pooled from 4 open-label, multicenter studies in children age ≤3 years (study 002/003 [NCT00744042/NCT01205152]; n=11) and age ≤5 years (study 010-10 [NCT01176266]; n=69) with onset of HPP symptoms before age 6 months, children age 5-12 years with HPP and open growth plates (study 006/008 [NCT00952484/NCT01203826]; n=13), and adolescents and adults age 13-65 years with onset of HPP at any age (study 009 [NCT01163149]; n=19). AA doses varied between studies; data were available for up to 7 years from studies 002/003, 010-10, and 006/008 and for up to 5 years from study 009. Safety events after the studies ended were not included. In total, data were available for 112 patients (median [min, max] age at enrollment: 3.2 [0, 66.5] y; female: 51%; white: 84%). Median (min, max) treatment duration was 2.7 years (1 d, 7.5 y). The average weekly total dose ranged from 2.1 to 11.9 mg/kg. All patients experienced adverse events (AEs); 26% of events were considered related to treatment and were mild (74%) or moderate (21%) in severity. Serious treatment-related AEs were reported in 10 (9%) patients. Serious AEs of special interest were craniosynostosis (25%; including increased intracranial pressure), injection-associated reactions (5%; including hypersensitivity), injection site reactions (ISRs) (2%; including erythema), ectopic calcifications (2%; including nephrolithiasis), and liver abnormalities or disease (2%; including chronic hepatitis). Overall, ISRs were the most common treatment-related AEs (73%). Ten deaths occurred among patients with severe HPP who entered the studies as infants (1 day to 20 months). Four of these deaths were attributed to pneumonia/sepsis, and 1 death each was attributed to respiratory failure and cerebral death; HPP-related complications; severe respiratory failure; cardiopulmonary arrest; severe cardiopulmonary insufficiency; and transtentorial and cerebellar tonsillar herniation due to cerebral edema. The majority of deaths were considered related to underlying HPP; one of the deaths, attributed to pneumonia, was reported by the investigator as being possibly related to AA. AEs leading to AA withdrawal were reported in 11 (10%) patients; those reported in ≥2 patients included pneumonia and respiratory failure. Anti-AA antibody data were available for 109 patients; 97 (89%) tested positive, and 55 (57%) of these showed presence of neutralizing antibodies at some time during the studies. In this pooled analysis of mostly prepubescent children (84%) treated with AA for up to 7 years, ISRs were the most frequently reported treatment-related AEs. Funding: This study was sponsored by Alexion Pharmaceuticals, Inc.