Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks. X-linked hypophosphatemia (XLH) is a heritable disorder with key clinical features caused by low phosphate levels in children, including rickets, poor growth, and leg bowing. Traditionally, XLH has been treated with multiple daily doses of phosphate and an active form of vitamin D. "Burosumab" is a novel antibody therapy that blocks a phosphate-wasting hormone called FGF23. Over 64 weeks,this therapy has shown to be better able to restore normal phosphate levels, heal rickets, and improve growth and leg bowing compared with traditional therapy in children 1-12 years of age. In the current study, children originally treated with burosumab or conventional therapy for 64 weeks with underwent a further study up to 88 weeks. Here, improvements from baseline in rickets continued between 64 and 88 weeks among children who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing, affirming the findings of the pivotal 64-week trial. As in the initial 64-week trial, burosumab was well tolerated in children who continued burosumab through 88 weeks, and in those who crossed over from conventional therapy. These data provide additional support for the use of burosumab to treat pediatric XLH. Graphical AbstractFollowing the 64-week, open-label, phase 3 study of burosumab vs conventional therapy in children aged 1-12 years with X-linked hypophosphatemia (NCT02915705), participants could enter the 22-week extension period in which all participants received burosumab treatment. Both those who continued to receive burosumab (top panel) and those who started burosumab during the extension period (bottom panel) showed improvements in Knee Rickets Severity Scores from burosumab initiation. These improvements were supported by similar changes in Radiographic Global Impression of Change Rickets Total score, height Z-score, and serum phosphorus and alkaline phosphatase levels.