Imel Erik A, Zhang Xiaoping, Ruppe Mary D, Weber Thomas J, Klausner Mark A, Ito Takahiro, Vergeire Maria, Humphrey Jeffrey S, Glorieux Francis H, Portale Anthony A, Insogna Karl, Peacock Munro, Carpenter Thomas O
Indiana University School of Medicine (E.A.I., M.P.), Indianapolis, Indiana 46202; Kyowa Hakko Kirin Pharma Inc (X.Z., M.A.K., T.I., M.V., J.S.H.), Princeton, New Jersey 08540; Houston Methodist Hospital (M.D.R.), Houston, Texas 77030; Duke University Medical Center (T.J.W.), Durham, North Carolina 27710; Shriners Hospital for Children (F.H.G.), Montreal, Quebec H3G 1A6, Canada; University of California (A.A.P.), San Francisco, California 94143; and Yale Center for X-Linked Hypophosphatemia (K.I., T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520.
J Clin Endocrinol Metab. 2015 Jul;100(7):2565-73. doi: 10.1210/jc.2015-1551. Epub 2015 Apr 28.
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.
The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH.
Two sequential open-label phase 1/2 studies were done.
Six academic medical centers were used.
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).
KRN23 was injected sc every 28 days.
The main outcome measure was the proportion of subjects attaining normal serum Pi and safety.
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.
Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.
在X连锁低磷血症（XLH）中，成纤维细胞生长因子23（FGF23）升高会降低肾小管磷的最大重吸收率/肾小球滤过率（TmP/GFR）和血清无机磷（Pi），导致佝偻病和/或骨软化症。
目的是检验每月注射KRN23（抗FGF23抗体）可安全改善成年XLH患者血清Pi的假设。
进行了两项连续的开放标签1/2期研究。
使用了六个学术医学中心。
28名成年XLH患者参加了为期4个月的剂量递增研究（0.05 - 0.6 mg/kg）；22名进入了为期12个月的扩展研究（0.1 - 1 mg/kg）。
每28天皮下注射一次KRN23。
主要观察指标是血清Pi恢复正常的受试者比例和安全性。
基线时，平均TmP/GFR、血清Pi和1,25 - 二羟维生素D [1,25(OH)2D]分别为1.6±0.4 mg/dL、1.9±0.3 mg/dL和36.6±14.3 pg/mL。在剂量递增期间，TmP/GFR、Pi和1,25(OH)2D升高，TmP/GFR和Pi在7天达到峰值，1,25(OH)2D在3 - 7天达到峰值，谷值时保持在（TmP/GFR、Pi）高于或[1,25(OH)2D]接近给药前水平。在四次递增剂量后的每次给药后，分别有14.8%、37.0%、74.1%和88.5%的受试者的峰值Pi在2.5至4.5 mg/dL之间。在12个月的扩展期内，57.9% - 85.0%的受试者的峰值Pi在正常范围内，≥25%的受试者的谷值Pi水平维持在正常范围内。任何受试者的血清Pi均未超过4.5 mg/dL。虽然1,25(OH)2D水平短暂升高，但血清和尿钙平均值仍保持正常。KRN23治疗增加了骨转换生物标志物，且安全性良好。
每月注射KRN23可使所有受试者的血清Pi、TmP/GFR和1,25(OH)2D显著升高。KRN23具有有效治疗XLH的潜力。
