OR14-3 Randomized, Open-Label, Dose-Finding, Phase 2 Study of KRN23, a Human Monoclonal Anti-FGF23 Antibody, in Children with X-Linked Hypophosphatemia (XLH)

Program: Abstracts - Orals, Poster Previews, and Posters
Session: OR14-Disorders of Phosphate Metabolism and Metabolic Bone Disease
Saturday, April 2, 2016: 11:45 AM-1:15 PM
Presentation Start Time: 12:15 PM
Room 104 (BCEC)
Thomas O Carpenter*1, Erik Imel2, Annemieke Boot3, Wolfgang Högler4, Agnes Linglart5, Raja Padidela6, William van't Hoff7, Michael P Whyte8, Yi Zhou9, Alison Skrinar9, Javier San Martin9 and Anthony A Portale10
1Yale University School of Medicine, New Haven, CT, 2Indiana University School of Medicine, Indianapolis, IN, 3University of Groningen, Groningen, Netherlands, 4Birmingham Children's Hospital, Birmingham, United Kingdom, 5Le Kremlin BicĂȘtre, Paris, France, 6Manchester Royal Children's Hospital, Manchester, United Kingdom, 7Great Ormond Street Hospital, London, United Kingdom, 8Shriners Hospitals for Children, St. Louis, MO, 9Ultragenyx Pharmaceutical Inc., Novato, CA, 10University of CA - San Francisco, San Francisco, CA
XLH is caused by mutations in PHEX that lead to elevated circulating FGF23 levels, and consequently to hypophosphatemia, rickets, osteomalacia, short stature, and extra-skeletal abnormalities. KRN23 has been shown to increase circulating inorganic phosphate (Pi) and 1,25(OH)2D levels in affected adults.

In an ongoing Phase 2 study (CL201), we evaluated KRN23 administered to 52 children with XLH (ages 5-12 years, ≤Tanner 2). After screening, treatment with Pi and vitamin D analogues was stopped. Subjects were randomized to receive either biweekly (Q2W) or monthly (Q4W) subcutaneous KRN23 injections. Serum Pi was measured at 2-week intervals. KRN23 dose was titrated (maximum 2mg/kg) to achieve age-appropriate serum Pi concentrations (3.5 – 5.0 mg/dL) for an effective KRN23 dosing regimen. The primary analyses were the changes from baseline (BL) to week 40 in serum Pi and in the Thacher Rickets Severity Score (RSS) as evaluated by a blinded expert.

Interim 24-week data were available for 36 subjects, and 40-week data for 12 subjects. At study entry, median age was 9 years; 50% were girls. At week 24, serum Pi and 1,25(OH)2D had increased from BL in all subjects. In the Q2W group (n=18; mean dose: ~0.6 mg/kg), mean (SD) serum Pi increased from 2.48 (0.43) mg/dL to 3.16 (0.44) mg/dL, and remained stable throughout the dosing cycle. In the Q4W group (n=18; mean dose: ~1 mg/kg), mean serum Pi peaked at week 22 (2 weeks post-dose), increasing from 2.27 (0.33) mg/dL at BL to 3.27 (0.45) mg/dL, but declined to 2.75 (0.33) mg/dL at week 24 (4 weeks post-dose). Mean TmP/GFR and serum 1,25(OH)2D levels increased in both groups and mean alkaline phosphatase (ALP) levels decreased in the Q2W group. At week 40 (N=12; median age, 8.0 years), improvements in serum Pi, 1,25(OH)2D, TmP/GFR, and ALP were sustained, with the Q2W group maintaining the serum Pi increases.

RSS at BL and week 40 were available for 12 subjects. BL radiographs revealed rickets (RSS ≥0.5; range 0.5-3.5) in 11 subjects who had been on oral phosphate/vitamin D therapy for ~6 years prior to baseline assessment. After 40 weeks of KRN23 treatment, RSS improved in 8 of these 11 children. Rickets improved in all 5 Q2W subjects (100%); mean RSS decreased by 80% (1.5 at BL to 0.3 at week 40). Rickets improved in 3 of 6 subjects (50%) and mean RSS decreased by 38% (1.3 at BL to 0.8 at week 40) in the Q4W group.

To date, no serious adverse events (AEs) have been reported, and no subject has discontinued participation. The most common treatment-related AEs were injection site reactions (50% of subjects). AEs were mostly mild; 1 AE was reported as moderate. No changes were observed in serum or urinary calcium levels; small increases in serum intact PTH were observed. Serum Pi did not increase above the upper limit of normal in any subject.

Interim results suggest that inhibition of FGF23 with KRN23 may offer a novel treatment to improve phosphorus homeostasis and rickets in children with XLH.

Disclosure: TOC: Principal Investigator, Ultragenyx Pharmaceutical Inc., Principal Investigator, Ultragenyx Pharmaceutical Inc.. EI: Investigator, Ultragenyx Pharmaceutical Inc.. AB: Investigator, Ultragenyx Pharmaceutical Inc.. WH: Investigator, Ultragenyx Pharmaceutical Inc., Investigator, Ultragenyx Pharmaceutical Inc.. AL: Investigator, Ultragenyx Pharmaceutical Inc., Investigator, Ultragenyx Pharmaceutical Inc.. RP: Investigator, Ultragenyx Pharmaceuticals Inc., Investigator, Alexion. WV: Investigator, Ultragenyx Pharmaceuticals Inc.. MPW: Investigator, Ultragenyx Pharmaceutical Inc.. YZ: Employee, Ultragenyx Pharmaceutical Inc.. AS: Employee, Ultragenyx Pharmaceuticals Inc.. JS: Employee, Ultragenyx Pharmaceuticals Inc.. AAP: Advisory Group Member, Ultragenyx Pharmaceutical Inc..

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting/pr-resources-for-endo

Sources of Research Support: This study was supported by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Hakko Kirin Pharma, Inc.