Improvements in the 6-Minute Walk Test and Correlation with Quality-of-Life Measures in Children and Adults with Hypophosphatasia Treated with Asfotase Alfa

Presentation Number: MON 334
Date of Presentation: April 3rd, 2017

Ioannis C. Tomazos*1, Scott Moseley1, Gilbert L’Italien1, Hugo Gomes Da Silva1 and Dawn Phillips2
1Alexion Pharmaceuticals, Inc., New Haven, CT, 2University of North Carolina, Chapel Hill, NC


Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low serum alkaline phosphatase activity and poor skeletal mineralization resulting from mutations within the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). HPP symptoms (eg, rachitic-like deformities, fractures, musculoskeletal complications, muscle weakness, pain) can negatively affect ambulation, activities of daily living, and health-related quality of life (HRQOL). The 6‑Minute Walk Test (6MWT), a widely used test of functional exercise capacity in patients (pts) with chronic disabling conditions (eg, Duchenne muscular dystrophy), has been shown to correlate with HRQOL-related measures in pts with HPP (eg, EQ-5D) (1). Asfotase alfa (AA) is a human recombinant TNSALP approved for treatment of HPP. This analysis evaluated 6MWT results from 23 HPP pts enrolled in 2 Phase 2, randomized, open-label studies of AA. In the first study/extension (NCT00952484/NCT01203826), 13 children (aged 6‒12 y) received AA. In the second study (NCT01163149), 19 adolescents and adults (aged 13‒65 y) received AA or no treatment (control) for an initial 6 mo; all eligible pts then received AA in an open-label extension (this analysis includes 10 adults with confirmed pediatric-onset HPP [AA n=7; control n=3]). Median (SD) meters walked is reported. Distribution-based analyses using the 1/3 baseline SD method (2) at screening/baseline (BL) estimated that the minimum clinically important difference (MCID) for the 6MWT in HPP is 31 m for children and adults. Distance walked by children treated with AA (n=13) increased significantly from 350 (90.5) at BL to 482 (98.1) at Month 6 (M6); 524 (84.4) at Year 1 (Y1); 516 (44.2) at Y2; 588 (37.7) at Y4; and 568 (61.7) at Y5 (P<0.0001 all). Increases from BL (M6: 124 [65.9]; Y1: 161 [56.7]; Y2: 180 [62.4]; Y4: 203 [90.6]; Y5: 221 [82.2]) were 4–7 times the 30-m MCID. Increases in 6MWT correlated with HRQOL improvements measured by the Childhood Health Assessment Questionnaire Disability Index (r=−0.57; P<0.001) and the Pediatric Outcomes Data Collection Instrument global function (r=0.76; P<0.001), transfer/basic mobility (r=0.69; P<0.001), and sports/physical functioning (r=0.78; P<0.001) subscales. For adults with pediatric-onset HPP treated with AA in the initial 6 months (n=7), distance walked improved from 334 (104.9) at BL to 417 (96.6) at M6 (change: 40 [57.0]); for nontreated pts (n=3), distance walked decreased from 401 (240.1) at BL to 355 (218.7) at M6 (change: −20 [26.5]). At Y3 of AA exposure (n=8), distance walked was 453 (91.6; change: 90.5 [72.8]), reflecting improvement of nearly 3 times the 31-m MCID. Children and adults with pediatric-onset HPP sustained clinically meaningful improvements in physical function during treatment with AA. Correlations between 6MWT and HRQOL measures indicated that AA increased QOL in pts with HPP regardless of age.


Disclosure: ICT: Employee, Alexion Pharmaceuticals, Inc.. SM: Employee, Alexion Pharmaceuticals, Inc.. GL: Employee, Alexion Pharmaceuticals, Inc.. HG: Employee, Alexion Pharmaceuticals, Inc.. DP: Consultant, Alexion Pharmaceuticals, Inc..