Bone Abstracts

Objective: To evaluate safety and efficacy after 5 years of treatment with asfotase alfa in adolescents and adults with hypophosphatasia (HPP) in a Phase 2, open-label, randomized, dose-ranging study (NCT01163149).

Methods: Treatment with subcutaneous asfotase alfa 0.3 or 0.5 mg/kg per d was compared with no treatment (control) for 6 months in patients aged 13–66 years. After 6 months, all patients (treatment and control groups) received active treatment at 0.5 mg/kg per d; dose was increased after 6–12 months to 1 mg/kg 6x/wk (lowest approved dose). The primary safety outcome was tolerability. Coprimary efficacy outcomes included median change at 6 months in plasma inorganic pyrophosphate (PPi) and pyridoxal-5’-phosphate (PLP) levels. Other measures included 6-Minute Walk Test (6MWT) and Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2). Data from treatment groups were pooled and reported below as median (min, max).

Results: The study randomized 19 patients (6 aged 13–18 years; 13 aged ≥18 years); 15/19 (79%) completed 5 years of treatment. One patient withdrew due to injection-site hypersensitivity and anaphylactoid reaction (1 episode each). No deaths occurred. The most common treatment-emergent adverse events were injection-site reactions. Decreases in PPi were numerically greater and decreases in PLP were statistically significantly greater at 6 months in treated patients (n=13) vs controls (n=6): PPi, −2.2 μM (−4.4, 0.3) vs −0.2 (−6.8, 1.1; P=0.0715); PLP, −255 ng/ml (−1467, −17) vs 11 (−374, 346; P=0.0285). Decreases were sustained through 5 years (n=16): PPi, −3.0 μM (−5.2, 7.8); PLP, −284 ng/ml (−1580, −25). Distance walked in 6MWT improved from 355 m (10, 620; n=19) before treatment to 450 m (280, 707; n=13) after 5 years of treatment with asfotase alfa, increasing from 76% predicted (42, 101; n=15) to 88% predicted (62, 137; n=11). BOT-2 Running Speed and Agility total point score was 6.5 (0, 39; n=16) before treatment and improved by 4.0 (−5, 18; n=11) after 5y, and BOT-2 Strength total point score was 13.5 (0, 33; n=18) before treatment and improved by 3.5 (−9, 9; n=12) after 5y.

Conclusion: Asfotase alfa was generally well tolerated, numerically decreased circulating PPi and PLP, and improved physical function in adolescents and adults with HPP.

Disclosure: This study was sponsored by Alexion Pharmaceuticals, Inc. PSK is a clinical trial investigator and has received honoraria and travel support from Alexion Pharmaceuticals, Inc., for consulting and participation on advisory boards. AED and SM are employees.