Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia

Abstract

Background. X-linked hypophosphatemia (XLH) is Funding. Kyowa Hakko Kirin Pharma, Inc.Introduction X-linked hypophosphatemia (XLH), the most common heritable form of rickets or osteomalacia, occurs due to loss-of-function mutations in PHEX, which result in elevated blood levels of fibroblast growth factor 23 (FGF23) (1, 2). FGF23 decreases renal tubular reabsorption of phosphate by reducing the abundance and possibly the activity of sodium-phosphate cotransporters on the apical membrane of proximal tubular epithelium, thereby reducing serum phosphate (measured as inorganic phosphorus, Pi) concentrations (3-5). Elevated FGF23 also decreases renal 1-α-hydroxylase activity, leading to low or inappropriately normal blood levels of 1,25-dihydroxyvitamin D [1,25(OH) 2 D] (1, 2).

Serum calcitriol levels in a patient with X-linked hypophosphatemia complicated by autosomal dominant polycystic kidney disease

“…Thus, the markedly increased serum 1,25(OH) 2 D levels in this patient seem to be caused by the blocking of the conventional FGF23 actions. Actually, the 1,25(OH) 2 D level was comparable to or even more than levels reported in patients with XLH after the treatment with neutralizing antibody against FGF23 [3]. However, the rapid decrease of 1,25(OH) 2 D level after the offtherapy with 1aOHD 3 associated with conversion of 24,25(OH) 2 D 3 was not explained by the decreased action of FGF23.…”

“…1i) were within the normal range, while urinary excretion of Ca showed only a transient elevation (Fig. 1e) on the maximal dose of 1aOHD 3 (Fig. 1a).…”

“…This was an unexpected observation, because the serum 1,25(OH) 2 D levels in patients with XLH are usually at the low normal ranges. Elevated levels of FGF23 contribute to inhibit 25OHD-1a-hydroxylase in the kidney to decrease 1,25(OH) 2 D synthesis [3]. Thus, the markedly increased serum 1,25(OH) 2 D levels in this patient seem to be caused by the blocking of the conventional FGF23 actions.…”

“…One might argue that the extremely high levels of serum 1,25(OH) 2 D levels in this case were caused by the pharmacologically treated dose of 1aOHD 3 . It is possible that (Fig.…”

“…The responsible gene for XLH is the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) [2]. In XLH, serum calcitriol [1,25(OH) 2 D] levels were found to be low normal in the presence of hypophosphatemia due to increased serum levels of fibroblast growth factor 23 (FGF23) [3].…”