Purpose: In X-linked hypophosphatemia (XLH), elevated serum FGF23 causes low serum phosphorus (Pi) and inappropriately normal 125-dihydroxyvitamin D (125(OH)2D) levels. We report PK and PD of KRN23 following single ascending dose administration in adults with XLH.
Methods: 38 XLH patients with baseline FGF23≥30 pg/ml were randomized to receive a single dose of KRN23 (K) or placebo (P) either i.v. (0.0030.3 mg/kg) or s.c. (0.11.0 mg/kg). PK and PD samples were obtained from baseline through day 50. A validated ELISA method was used for PK and commercial assay kits were used for PD assays.
Results: 22 subjects participated in the i.v. cohort (17K, 5P), and 16 in the s.c. cohort (12K, 4P). Baseline age, sex, weight, and height of all groups were comparable in all groups. Mean KRN23 terminal half-life was shorter for i.v. (1112 days) than for s.c. (1319 days) administration. Absolute bioavailability was ~100% with s.c. dosing. There was a dose-proportional increase in serum KRN23 levels in both i.v. and s.c. cohorts. Following s.c. administration, peak serum KRN23 and Pi occurred at the same time. Area under the curve (AUClast) for changes from baseline in serum Pi, 125(OH)2D, and TmP/GFR were linearly correlated with AUCinf for serum KRN23. s.c. dosing exhibited a slower absorption profile (peak time: 811 days) and a more sustained effect than i.v. dosing as indicated by the delayed time to reach maximum mean serum Pi level (peak time: 815 vs 0.54 days) and longer time to return to baseline (50 vs 29 days).
Conclusions: KRN23 is a promising treatment for XLH patients. Complete absorption, sustained effect on serum Pi beyond 4 weeks, and a direct linear relationship between PK and PD effects supports a s.c. treatment regimen of once every 4 weeks for KRN23 in adults with XLH.
17 May 2014 - 20 May 2014