ECTS2014 Poster Presentations Bone development/growth and fracture repair (55 abstracts)
A randomized, double-blind, placebo-controlled, ascending, single-dose study of a human monoclonal anti-FGF23 antibody (KRN23) in X-linked hypophosphatemia
Thomas Carpenter 1 , Erik Imel 2 , Mary Ruppe 3 , Thomas Weber 4 , Mark Klausner 5 , Margaret Wooddell 5 , Tetsuyoshi Kawakami 5 , Takahiro Ito 5 , Xiaoping Zhang 5 , Jeffrey Humphrey 5 , Karl Insogna 1 & Munro Peacock 2
1Yale University School of Medicine, New Haven, Connecticut, USA; 2Indiana University School of Medicine, Indianapolis, Indiana, USA;
3The Methodist Hospital at Houston, Houston, Texas, USA;
4Duke University Medical Center, Durham, North Carolina, USA;
5Kyowa Hakko Kirin Pharma, Inc., Princeton, New Jersey, USA.
Purpose: In X-linked hypophosphatemia (XLH), elevated serum FGF23 causes low serum phosphorus (Pi) and inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. We report safety, tolerability and biochemistry markers following single ascending dose administration of KRN23 in adults with XLH.
Methods: 38 XLH subjects with baseline FGF23≥30 pg/ml were randomized to receive single doses of KRN23 (K) or placebo (P) either (0.003–0.3 mg/kg) or (0.1–1.0 mg/kg). Biochemistry and immunogenicity were assessed at baseline and at various time points up to day 50.
Results: 22 subjects were in the i.v. cohort (17K, 5P), and 16 in the s.c. cohort (12K, 4P). At baseline, demographic characteristics were comparable in all groups Serum Pi and renal threshold maximum for phosphate reabsorption (TmP/GFR) were lower than reference ranges in all subjects. At the higher doses, both i.v. and s.c. KRN23 increased serum Pi, TmP/GFR and 1,25(OH)2D; peak serum Pi occurred later with s.c. (8–15 days) than with i.v. dosing (4–5 days). Duration of effect on Pi was dose-related and longer with s.c. than i.v., persisting beyond 29 days with s.c. Adverse events (AEs) occurred with higher frequency in patients receiving KRN23 (82% i.v., 83% s.c.) compared to those receiving placebo (40% i.v., 50% s.c.). AEs related to the study drug occurred in six patients. Single-dose administration of KRN23 was well-tolerated as assessed by AEs, laboratory parameters, vital signs, calcium homeostasis, renal ultrasonography, and ECGs. No patient had an increase in nephrocalcinosis or developed hypercalciuria, hypercalcemia or a rise in serum parathyroid hormone. No anti-KRN23 antibody was detected in any patients.
Conclusions: Blocking FGF23 activity with KRN23 is a promising treatment for XLH. Single i.v. or s.c. doses increased serum TmP/GFR, serum Pi and 1,25(OH)2D with effects lasting for more than 4 weeks with s.c. dosing.
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Bone Abstracts
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