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

x linked rickets

Thomas O. Carpenter 1. Erik A. Imel 2. Mary D. Ruppe 3. Thomas J. Weber 4. Mark A. Klausner 5. Margaret M. Wooddell 5. Tetsuyoshi Kawakami 5. Takahiro Ito 5. Xiaoping Zhang 5. Jeffrey Humphrey 5. Karl L. Insogna 1 and Munro Peacock 2

1 Yale Center for X-Linked Hypophosphatemia, Yale University School of Medicine, New Haven, Connecticut, USA. 2 Indiana University School of Medicine, Indianapolis, Indiana, USA. 3 The Methodist Hospital, Houston, Texas, USA. 4 Duke Clinical Bone Laboratories, Duke University Medical Center, Durham, North Carolina, USA. 5 Kyowa Hakko Kirin Pharma Inc. Princeton, New Jersey, USA.

Address correspondence to: Thomas O. Carpenter, Department of Pediatrics (Endocrinology), Yale University School of Medicine, 333 Cedar Street, PO Box 208064, New Haven, Connecticut 06520-8064, USA. Phone: 203.785.6526; Fax: 203.737.4290; E-mail: thomas.carpenter@yale.edu.

First published February 24, 2014

Submitted: August 21, 2013; Accepted: December 17, 2013.

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 t1/2 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.

Trial registration. Clinicaltrials.gov NCT00830674.

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-

Category: Rickets

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