Introduction: Hypophosphatasia (HPP) is caused by inactivating mutation(s) within the gene for tissue nonspecific alkaline phosphatase (TNSALP). Patients with the perinatal and infantile forms of HPP suffer rickets, poor growth, and delayed gross motor function. In 2012, we detailed significant improvement in skeletal mineralization and respiratory function in such patients treated for 1 year with asfotase alfa, a bone-targeted recombinant human TNSALP,1 and recently for up to 3 years.2 We now report functional and height measures from these patients up to 3 years.
Methods: Multinational, phase II, open-label trial of asfotase alfa (13 mg/kg, 3×/week, s.c.). Height/length at each time point was the mean of three repeat measures and Z-scores were calculated according to population-appropriate growth standards. Motor development was assessed using the Gross Motor Subscale of the Bayley Scales of Infant Development III (BSID-III) for patients aged 042 months and the Locomotion Subscale of the Peabody Developmental Motor Scales 2nd edition (PDMS-2) for patients ≥43 months. BSID-III scores are presented as scaled scores (SS) relative to healthy peers. The mean (S.D.) BSID-III SS for healthy, same-age peers is 10 (3), thus increases in SS would indicate accelerated acquisition of skills.
Results: Eleven patients enrolled with a median age (min, max) of 6.8 months (2.9 weeks, 3 years)1. One patient died (sepsis unrelated to study drug) and 1 withdrew, thus nine patients were studied long-term. At baseline (BL), median (min, max) Z-score for height was −3.7 (−9.2, −0.7; n=11) and increased by a median change from BL (min, max) of +1.2 (−1.0, +1.9; n=9), +1.5 (−1.5, +3.8; n=9), and +2.3 (−1.4, +4.1; n=8) at 48, 96, and 144 weeks, respectively. Median BSID-III Gross Motor SS (min, max) increased from 1 (1, 8; n=11) at first assessment to 2 (1, 5; n=7 patients with data available), 5 (1, 7; n=6), and 6 (6, 7; n=3) at 48, 96, and 144 weeks, respectively. Two patients transitioned to the PDMS-2 at week 72 and continued to demonstrate gross motor improvements at week 144.
Conclusion: Profound delays in growth and gross motor function in pediatric patients with severe HPP improved substantially during treatment with asfotase alfa for up to 3 years, consistent with accompanying skeletal improvement.1,2
20 - 22 Sep 2014
European Society for Paediatric Endocrinology