ESPE Abstracts (2018) 89 FC10.1

Burosumab Improved Rickets, Phosphate Metabolism, and Clinical Outcomes Compared to Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH) - A Randomized Controlled Phase 3 Study

Ola Nilssona,b, Michael P. Whytec, Erik A. Imeld, Craig Munnse, Anthony A. Portalef, Leanne Wardg, Jill H. Simmonsh, Raja Padidelai, Noriyuki Nambaj,k, Hae Il Cheongl, Meng Maom, Alison Skrinarm, Chao-Yin Chenm, Javier San Martinm & Francis Glorieuxn

aKarolinska Institutet, Stockholm, Sweden; bÖrebro University, Örebro, Sweden; cShriners Hospitals for Children, St Louis, Missouri, USA; dIndiana University School of Medicine, Indianapolis, Indiana, USA; eThe Children’s Hospital at Westmead, Sydney, Australia; fUniversity of California, San Francisco, California, USA; gUniversity of Ottawa, Ottawa, Ontario, Canada; hVanderbilt University School of Medicine, Nashville, Tennessee, USA; iRoyal Manchester Children’s Hospital, Manchester, UK; jOsaka Hospital, Japan Community, Healthcare Organization, Osaka, Japan; kOsaka University Graduate School of Medicine, Osaka, Japan; lSeoul National University Children’s Hospital, Seoul, Democratic People’s Republic of Korea; mUltragenyx Pharmaceutical Inc., Novato, California, USA; nShriners Hospital for Children-Canada, McGill University, Montreal, Canada

In children with XLH, high circulating levels of FGF23 cause hypophosphatemia with consequent rickets, skeletal deformities, and growth impairment. Conventional therapy consists of multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab is a fully human monoclonal antibody against FGF23 indicated for the treatment of XLH. In the active-control study CL301 (NCT02915705), 61 children with XLH (1–12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (Q2W) or Pi/D as prescribed by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 and prior receipt of Pi/D. The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C). At Week 40, burosumab significantly improved rickets compared with Pi/D (RGI-C global score least squares [LS] mean ± SE: +1.92±0.11 vs +0.77±0.11; P<0.0001). More subjects in the burosumab group had substantial healing (RGI-C ≧+2.0) at Week 40, compared with the Pi/D group (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, P<0.0001). Additional evidence for improvement of rickets included decreased Total RSS (LS mean ± SE change, burosumab vs Pi/D: −2.04±0.145 vs −0.71±0.138; P<0.0001), decreased alkaline phosphatase (−131±13 vs −35±19; P<0.0001), and improved RGI-C lower limb deformity score (+0.62±0.12 vs +0.21±0.12; P=0.020). At Week 40, increases in serum phosphorous (P<0.0001) and TmP/GFR (P<0.0001) were significantly greater with burosumab compared with Pi/D. Standing height Z-score increased in both treatment groups from baseline to Week 40 with an LS mean change of +0.15 (95% CI: 0.05, 0.25) for burosumab and +0.08 (−0.02, 0.19) for Pi/D. Percent predicted distance walked in six minutes increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reaction, were higher in the burosumab group, but were mild to moderate in severity overall, with no discontinuations. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved. In this randomized Phase 3 clinical trial, burosumab Q2W resulted in significantly greater improvements in rickets and phosphate metabolism compared with conventional therapy in 1–12 year-old children with XLH.