Pediatric Study Demonstrated Improvements in Rickets Severity, Growth, Pain and Physical Activity in Children with Debilitating, Lifelong Hereditary Disease
Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), Kyowa Hakko Kirin Co. Ltd, and Kyowa Kirin International PLC today announced that the results of a pediatric Phase 2 clinical trial of Crysvita® (burosumab) for the treatment of X-linked hypophosphatemia (XLH) in children aged 5 to 12 years were published online by the New England Journal of Medicine (NEJM). The results demonstrated that Crysvita improved rickets severity, growth, pain and physical function, and increased serum phosphorus and renal phosphate reabsorption. Adverse events were consistent with those previously observed for Crysvita for the treatment of XLH in children. Topline results from this study were previously announced in April 2017.
XLH is a rare, chronic progressive musculoskeletal disorder that affects children and adults. Crysvita is the first treatment to target the underlying pathophysiology of XLH – excess production of fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate excretion and active vitamin D production by the kidney. In the NEJM article entitled “Burosumab Therapy in Children with X-Linked Hypophosphatemia” the authors state, “Inhibition of FGF-23 activity with burosumab, a recombinant human lgG1 monoclonal antibody, was associated with an increase in renal tubular phosphate reabsorption and the correction of hypophosphatemia in children with X-linked hypophosphatemia. The improvement in phosphate metabolism corresponded to a decrease in the severity of rickets. The healing of rickets probably contributed to concurrent improvements in growth and physical activity and a reduction in pain.”
“This study was the natural extension of recent discoveries related to disease mechanisms in XLH, and in particular FGF23’s role as a mediator of renal phosphate metabolism,” said Tom Carpenter, M.D., the lead study investigator, Director of the Yale Center for X-Linked Hypophosphatemia, and Professor of Pediatric Endocrinology at Yale University School of Medicine. “The therapeutic approach taken, to directly inhibit FGF23’s renal actions, demonstrates the potential advantages to therapy of metabolic disease when targeting a central disease mechanism. Sustained improvements in serum phosphorus resulted, with corresponding improvement in skeletal abnormalities. The approach should prove to be an important advance in the therapy of XLH.”
On April 17, 2018 the U.S. Food and Drug Administration (FDA) approved Crysvita for the treatment of XLH in adult and pediatric patients 1 year of age and older. On February 23, 2018 Crysvita received a positive European Commission decision granting conditional marketing authorization to Crysvita for the treatment of XLH with radiographic evidence of bone disease in children 1 year of age and older and adolescents with growing skeletons. Data from this Phase 2 study were included in both the U.S. and European regulatory applications.
“I am delighted that these results have been accepted by the New England Journal of Medicine, a world-leading medical journal with a mission to publish “ground breaking” research,” said Mitsuo Satoh, Ph.D., Executive Officer, Vice President Head of R&D Division of Kyowa Hakko Kirin. “We will continue our R&D activities that strengthens the clinical evidence base for burosumab to contribute to patients all over the world.”
Phase 2 Study Design
The randomized, multicenter, open-label, dose-finding Phase 2 study enrolled 52 children aged 5 to 12 years with XLH at nine sites in the United States and EU. Patients were randomized to receive Crysvita subcutaneously either every two or four weeks for 64 weeks. The primary endpoint was the change in rickets severity as measured by Rickets Severity Score and the Radiographic Global Impression of Change. Secondary endpoints included changes in: metabolic measures including serum phosphorus, 1,25 dihydroxy vitamin D, and serum alkaline phosphatase; growth; physical ability; patient-reported pain and functional disability; and safety.
About X-Linked Hypophosphatemia (XLH)
XLH is a rare, hereditary, progressive and lifelong skeletal disorder characterized by renal phosphate wasting caused by excess FGF23 production. It affects both children and adults. In children, XLH causes rickets that leads to lower-extremity deformity, delayed growth and decreased height. Adults with XLH have an increased risk of fractures.