Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P < 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P < 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities.