Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23

Abstract

Context: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia.

Objective: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH.

Design: Two sequential open-label phase 1/2 studies were done.

Setting: Six academic medical centers were used.

Participants: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg).

Intervention: KRN23 was injected sc every 28 days.

Main outcome measure: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety.

Results: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile.

Conclusions: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.

Trial registration: ClinicalTrials.gov NCT01340482 NCT01571596.

Figures

Figure 1.

CONSORT diagram for the dose-escalation and extension studies. Twenty-eight adult subjects with XLH entered the 4-month dose-escalation trial, and 22 subjects who had completed the dose-escalation study entered the 12-month extension trial. Two subjects withdrew early during the dose-escalation trial, and three subjects withdrew early during the extension trial. *, One subject in a planned bone substudy (see Supplemental Data).

Figure 2.

Effect of KRN23 on serum Pi (A), TmP/GFR (B), and 1,25(OH)2D (C) in adults with XLH. KRN23 administration (arrow) occurred every 28 days. Data are presented as mean ± SD. *, P values remaining <.05 after Bonferroni adjustment for multiple comparisons were considered significantly different from the baseline value. An asterisk over a horizontal line with arrowheads indicates that all values shown under that line were different from baseline (P < .05). The horizontal broken lines indicate baseline level. The vertical broken lines demarcate the 4-month dose-escalation study from the 12-month extension study; n = 28 for the dose-escalation study; n = 22 for the extension study.

Figure 3.

Effect of multiple-dose administration of KRN23 in adults with XLH on serum calcium (A), 2-hour urine calcium/creatinine ratio (B), 24-hour urinary calcium excretion (C), and PTH (D). Arrows indicate day for KRN23 administration (every 28 days). Data are presented as mean ± SD. *, P values remaining <.05 after Bonferroni adjustment for multiple comparisons were considered significantly different from the baseline value. An asterisk over a horizontal line with arrowheads indicates that all values shown under that line were different from baseline (P < .05). The vertical broken lines demarcate the 4-month dose-escalation study from the 12-month extension study; n = 28 for the dose-escalation study; n = 22 for the extension study.