ESPE Abstracts (2016) 86 FC2.6

Effect of KRN23, a Fully Human Anti-FGF23 Monoclonal Antibody, on Rickets in Children with X-linked Hypophosphatemia (XLH): 40-week Interim Results from a Randomized, Open-label Phase 2 Study

Agnès Linglarta, Thomas Carpenterb, Erik Imelc, Annemieke Bootd, Wolfgang Höglere, Raja Padidelaf, William van’t Hoffg, Michael Whyteh, Chao-Yin Cheni, Alison Skrinari, Sunil Agarwali, Javier San Martini & Anthony Portalej

aAPHP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; bYale University School of Medicine, New Haven, Connecticut, USA; cIndiana University School of Medicine, Indianapolis, Indiana, USA; dUniversity of Groningen, Groningen, The Netherlands; eBirmingham Children’s Hospital, Birmingham, UK; fRoyal Manchester Children’s Hospital, Manchester, UK; gGreat Ormond Street Hospital, London, UK; hShriners Hospital for Children, St. Louis, Missouri, USA; iUltragenyx Pharmaceutical Inc., Novato, California, USA; jUniversity of California, San Francisco, California, USA

Background: In XLH, high circulating FGF23 causes hypophosphatemia, rickets, and short stature.

Objective and hypotheses: To evaluate KRN23 effects on serum phosphate (Pi) level and rickets severity in XLH children in a Phase 2 study.

Method: 52 XLH children (ages 5–12 years, ≤Tanner 2) received KRN23 subcutaneously biweekly (Q2W) or monthly (Q4W). Serum Pi was measured at 2-week intervals. KRN23 dose was titrated (maximum 2 mg/kg) targeting age-appropriate serum Pi concentrations. Rickets severity was assessed by the Thacher Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C; −3=worsening; +3=complete healing).

Results: The first 36 subjects had a mean 6.6 years of standard-of-care treatment before washout. KRN23 increased serum Pi from baseline in all subjects to near normal levels (mean increase 0.30 mmol/l at 38 weeks; P<0.001) and was more stable with Q2W dosing; hyperphosphatemia did not occur. KRN23 significantly improved RSS with greater improvements seen with Q2W dosing (44% reduction; P=0.0126) and particularly in higher-severity subjects (baseline RSS ≥1.5) (59% reduction; P<0.0001). Q2W dosing improved RGI-C by +1.6 (P<0.0001) with higher-severity subjects showing substantial healing (+2.0; P<0.0001). Most treatment-related adverse events (AE) were mild; transient injection site reactions occurred most frequently (39%). One child experienced a serious AE (fever/muscle pain) that improved and the child continues in the trial. No clinically meaningful changes occurred in serum/urine calcium, serum iPTH, or renal ultrasound.

Table 1. (for abstract FC2.6)
All PatientsPatients with Baseline RSS ≥1.5
BaselineWk 40BaselineWk 40
Mean Total RSSAll (N=36)1.41.0*All (N=18)2.31.2*
Q2W (N=18)1.50.9*Q2W (N=9)2.41.0*
Q4W (N=18)1.31.1Q4W (N=9)2.21.4*
Mean RGI-CAll (N=36)+1.4*All (N=18)+1.9*
Q2W (N=18)+1.6*Q2W (N=9)+2.0*
Q4W (N=18)+1.2*Q4W (N=9)+1.7*
*P<0.05, comparing Wk 40 to baseline.

Conclusion: KRN23 improved phosphorus homeostasis and rickets in children with XLH.