ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2016) 45 OC5.1 | DOI: 10.1530/endoabs.45.OC5.1

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

Raja Padidela1, William van’t Hoff2, Wolfgang Högler3, Anthony Portale4, Erik Imel5, Annemieke Boot6, Agnès Linglart7, Michael Whyte8, Alison Skrinar9, Javier San Martin9 & Thomas Carpenter10

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

In XLH, high circulating FGF23 causes hypophosphatemia, rickets, and short stature. In our Phase 2 study, 52 XLH children (ages 5–12 years, ≤Tanner 2) were randomized to receive KRN23 subcutaneously biweekly (Q2W) or monthly (Q4W). Serum phosphate (Pi) was measured biweekly. KRN23 dose was titrated (maximum 2 mg/kg) targeting age-appropriate serum Pi concentrations.

The first 36 subjects had a mean 6.6 years of standard-of-care treatment before washout. Serum Pi increased 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 rickets, assessed by the Thacher Rickets Severity Score (RSS), with greater improvements seen with Q2W dosing (44% reduction; P=0.0126) and particularly in higher-severity rickets patients (baseline RSS ≥1.5) (59% reduction; P<0.0001). Using the Radiographic Global Impression of Change (RGI-C; −3=worsening; +3=complete healing), Q2W dosing improved rickets by +1.6 (P<0.0001) with the higher-severity rickets subset showing substantial healing (+2.0; P<0.0001). Alkaline phosphatase, a marker of rickets severity, decreased. Most treatment-related adverse events (AE) were mild, most commonly a transient injection site reaction (39%). One child experienced a serious AE and was hospitalized for fever/muscle pain that improved and continues in the trial. No clinically significant changes occurred in serum or urine calcium, serum iPTH, or renal ultrasound. In summary, KRN23 improved phosphorus homeostasis and rickets in children with XLH, with an acceptable benefit-risk profile.

All PatientsPatients with Baseline Total 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, # P<0.001, comparing Wk 40 to baseline.