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Bone Abstracts (2017) 6 OC26 | DOI: 10.1530/boneabs.6.OC26

ICCBH2017 Oral Communications (1) (26 abstracts)

A randomized, open-label Phase 2 study of KRN23, an investigational fully human Anti-FGF23 monoclonal antibody, in children with X-linked Hypophosphatemia (XLH)

Wolfgang Högler 1 , Anthony Portale 2 , Erik Imel 3 , Annemieke Boot 4 , Agnès Linglart 5 , Raja Padidela 6 , William van’t Hoff 7 , Michael Whyte 8 , Meng Mao 9 , Alison Skrinar 9 , Javier San Martin 9 & Thomas Carpenter 10

1Birmingham Children’s Hospital, Birmingham, UK; 2University of California, San Francisco, CA, USA; 3Indiana University School of Medicine, Indianapolis, IN, USA; 4University of Groningen, Groningen, Netherlands, The Netherlands; 5Hôpital Bicêtre, Le Kremlin-Bicêtre, France; 6Royal Manchester Children’s Hospital, Manchester, UK; 7Great Ormond Street Hospital, London, UK; 8Shriners Hospital for Children, St Louis, MO, USA; 9Ultragenyx Pharmaceutical Inc., Novato, CA, USA; 10Yale University School of Medicine, New Haven, CT, USA.

Objectives: In XLH, FGF23-mediated hypophosphatemia leads to defective bone mineralization and rickets. Investigational product KRN23 binds FGF23 and inhibits its activity. The objective of this Phase 2 study was to evaluate the safety and efficacy of KRN23 in 52 children with XLH (ages 5–12 years, ≤Tanner 2).

Methods: Patients were randomized to receive KRN23 biweekly (Q2W) or monthly (Q4W) by SC injection. KRN23 dose was titrated (maximum 2 mg/kg) to achieve age-appropriate serum phosphate (Pi) concentrations which were measured Q2W. Efficacy endpoints included change in rickets severity (Thacher Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C); −3= severe worsening; 0= no change; +3=complete healing), pharmacodynamic parameters, and growth. The primary analysis was at Week (Wk) 40; extended analysis was at Wk64.

Results: Rickets was evident at baseline (mean RSS 1.8) despite ~7 years of prior oral phosphate/active vitamin D therapy. Serum Pi increased in all patients to near normal levels (mean increase from baseline to Wk38 was 0.33 mmol/l; P<0.001) and was more stable in Q2W group. No hyperphosphataemia occurred. At Wk40, mean RSS improved by 61% for the Q2W group, 37% for Q4W, and 50% overall (P<0.001 all groups). In subjects with higher-severity rickets (baseline RSS ≥1.5; N=34), mean RSS improved by 71% for Q2W, 48% for Q4W, and 61% overall (P<0.0001 all groups). At Wk40, mean RGI-C scores of +1.72 for Q2W, +1.41 for Q4W, and +1.56 overall (P<0.0001 all groups) also indicated improvement. In the subset with baseline RSS ≥1.5, substantial healing of rickets was observed with a mean RGI-C+2.04 for Q2W; +1.78 for Q4W, and +1.91 overall (P<0.0001 all groups). Efficacy was sustained at Wk64. Most treatment-related adverse events (AEs) were mild. Transient injection site reactions (33%) were most frequent. One child experienced a serious AE, was hospitalized for fever/muscle pain that resolved, and continues in the trial. No clinically meaningful changes occurred in serum or urine calcium, serum iPTH, or renal ultrasounds.

Summary: KRN23 improved serum Pi and rickets in children with XLH, and was generally safe and well tolerated.

Hogler: travel and consulting fees from Ultragenyx; Portale: travel and advisory panel for Ultragenyx; Carpenter: grant support and travel from Ultragenyx; Imel, Boot, Linglart, van’t Hoff: travel and consulting fees from Ultragenyx; Padidela: consulting.

Volume 6

8th International Conference on Children's Bone Health


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