Background: In X-linked Hypophosphatemia (XLH), abnormally elevated serum Fibroblast Growth Factor 23 (FGF23) results in low renal maximum threshold for phosphate reabsorption (TmP/GFR), low serum phosphorus (Pi), inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2D) and development of rachitic deformities.
Methods: Up to four SC KRN23 doses were given every 28 days to 28 adults with XLH (26 completed) according to a dose-escalation algorithm (0.050.10.3 to 0.6 mg/kg). The primary outcome was Pi response.
Results: At baseline, 96.3% of subjects had serum Pi <2.5 mg/dl. Mean KRN23 dose increased from 0.05 to 0.48 mg/kg. Serum Pi, TmP/GFR, and serum 1,25(OH)2D increased from baseline after all doses, more with each subsequent dose. Mean serum Pi and TmP/GFR peaked at day 7 (1,25(OH)2D at days 37) and all declined before the next dose. Peak serum Pi increased from 2.21±0.33 mg/dl after dose 13.03±0.42 mg/dl after dose 4. Pre-dose serum Pi increased from 1.89±0.33 at baseline to 2.54±0.37 mg/dl after dose 4. Peak serum Pi increased to 2.5≤3.5 mg/dl on day 7 in 14.8, 37.0, 74.1, and 70.4% of subjects after dose 1, 2, 3 and 4 respectively. Serum Pi reached 3.5≤4.5 mg/dl only after dose 4 in 14.8% of subjects and never exceeded 4.5 mg/dl. There were no clinically significant changes in PTH or serum or urinary calcium. The most common adverse events were nasopharyngitis and arthralgia. There were no serious adverse events, deaths, anti-KRN23 antibodies, or significant changes in electrocardiograms (including development of LVH) or renal ultrasound. One subject with a baseline coronary artery calcification score of 0 had a minor increase post-treatment.
Conclusions: Monthly injections of KRN23 blocked the pharmacodynamic effects of excessive FGF23 in adults with XLH. KRN23 has potential as a novel treatment for adult and paediatric XLH.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology