Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia
Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia
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DOI：
10.1172/jci72829
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Peacock, Munro
中科院分区：
文献类型：
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作者：
Carpenter, Thomas O.;Imel, Erik A.;Peacock, Munro
背景X连锁低磷血症（XLH）是佝偻病和骨软化症最常见的遗传形式。磷酸盐调节内肽酶（PHEX）的XLH相关突变导致血清FGF 23升高，肾磷酸盐重吸收减少，血清磷酸盐（无机磷，Pi）和1，25-二羟维生素D [1，25（OH）（2）D]浓度降低。KRN 23是一种人抗FGF 23抗体，开发用于XLH的潜在治疗。在此，我们评估了KRN 23在单次i. v.或s.c.剂量的KRN 23在成人与XLH。将38名XLH患者随机接受单剂量的KRN 23（0.003- 0.3mg/kg i. v.或0.1-lmg/kg s.c.）或安慰剂。对PK、PD、免疫原性、安全性和耐受性进行了长达50天的评估。与安慰剂组相比，KRN 23显著增加肾小管磷酸盐重吸收最大阈值（TmP/GFR）、血清Pi和1，25（OH）（2）D（P < 0.01）。最大血清Pi浓度出现在s.c.与静脉给药（0.5-4天）相比，静脉给药（8-15天）观察到的变化。效应持续时间与剂量相关，在接受s.c.局TmP/GFR、血清Pi和血清1，25（OH）（2）D较基线的变化与血清KRN 23浓度相关。KRN 23的平均t（1/2）为静脉给药后8- 1/2天，皮下给药后13-19天。局患者未表现出肾钙质沉着增加或出现高钙尿、高钙血症、抗KRN 23抗体或血清甲状旁腺激素（PTH）或肌酐升高。KRN 23增加TmP/GFR、血清Pi和血清1，25（OH）（2）D。KR 23对血清Pi的积极作用及其有利的安全性特征表明KRN 23在XLH患者中的效用。
Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH.Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days.Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)(2)D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)(2)D correlated with serum KRN23 concentrations. The mean t(1/2) of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine.Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)(2)D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients.