Hypophosphatasia (HPP) is the rare inherited metabolic bone disorder resulting from deficiency in tissue-nonspecific alkaline phosphatase (TNSALP). HPP can cause a spectrum of sequelae in children, including muscle weakness and compromised physical function. 512 year-old children treated ≥3 years with asfotase alfa, a recombinant bone-targeted human TNSALP, had improved skeletal mineralisation, growth, and physical function. Here, we report muscle strength and the individual subtests of the Bruininks Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) in these children. This ongoing Phase II open-label extension study (6 mg/kg per week subcutaneous asfotase alfa) assessed bilateral hip and knee extension and flexion, hip abduction, and grip strength by hand-held dynamometry (HHD), reported as percent predicted (%P; right side) for matched, healthy peers. Physical function was evaluated using the BOT-2 Strength subtest (e.g. long jumps, push-ups, etc.), and running speed/agility subtest (e.g. shuttle runs, one-legged hop, etc.). 11/12 patients in the extension study participated in functional testing with last assessment (LA) at 3 years (n=7) or 3.5 years (n=4). Right-side strength (%P) ranged from median (min-max) 32 (953; hip extensor) to 60 (21149; grip) at baseline. Strength in all right-side muscle groups improved at 3 months (P<0.05) except grip, and continued to improve to LA (median 5998%P, hip and knee extensor, respectively) (P<0.05). Left side results were similar. BOT-2 Strength scaled score (mean(S.D.) for healthy peers: 15(5)) improved from median (minmax) 4 (113) at baseline to 15 (1024) at LA (P<0.0001). Median Running speed/agility scaled score improved from 3 (19) at baseline to 12 (719) at LA (P<0.0001). Performance on all BOT-2 subscales improved significantly. These children with HPP had substantial muscle weakness and impaired function at baseline. With asfotase alfa treatment, rapid and continued improvements in strength contributed to significant gains in physical function, which impact ability to perform activities of daily living.
Disclosure: S Moseley, T Odrljin, and K P Fujita are employees of Alexion Pharmaceuticals, Inc. D Phillips receives consulting fees from Alexion. K L Madson, C Rockman-Greenberg, and M P Whyte have received honoraria, travel support, and research grant support from Alexion. Editorial support was provided by Fishawack Communications, GmbH, Basel, Switzerland, and was funded by Alexion Pharmaceuticals, Inc., Cheshire, CT, USA.