Background: In children with X-linked hypophosphatemia (XLH), sometimes called vitamin D resistant rickets, high circulating levels of fibroblast growth factor 23 (FGF23) cause hypophosphatemia with consequent rickets, lower limb deformities, and growth impairment. Conventional therapy requires multiple daily oral phosphate and active vitamin D (Pi/D) doses. Burosumab, a fully human IgG1 monoclonal antibody to FGF23, is U.S. FDA approved for the treatment of XLH in adult and pediatric patients ≥6 months of age.
Aims: To compare efficacy and safety of burosumab vs Pi/D in children with XLH.
Methods: This was a phase 3, randomized, active-controlled study (CL301; NCT02915705) in 61 children with XLH (1-12 years old). Subjects were randomized 1:1 to open-label subcutaneous burosumab starting at 0.8 mg/kg Q2W or Pi/D (dosing individually tailored by investigator per established guidelines). Eligibility criteria included total Rickets Severity Score (RSS) ≥2.0 and prior treatment with Pi/D. The primary endpoint was the Radiographic Global Impression of Change (RGI-C) Global Score (GS) for rickets at Week 40.
Results: Week 40 standing height Z-score change from baseline was significantly greater (p=0.04) in burosumab-treated subjects, with a least square (LS) mean (SE) of 0.16 (0.05) vs 0.03 (0.03) in Pi/D-treated subjects. Week 40 mean (SE) growth velocity was 7.2 (0.4) centimeters/year in burosumab-treated subjects vs 6.1 (0.2) centimeters/year in Pi/D-treated subjects. At Week 40, the RGI-C GS was significantly higher with burosumab vs Pi/D (LS mean ±SE: +1.9 ±0.1 vs +0.8 ±0.1; p<0.0001). More burosumab subjects had substantial healing (RGI-C ≥+2.0), compared with Pi/D subjects (21/29 [72%] vs 2/32 [6%]; p<0.0001). Burosumab was well-tolerated. Adverse events (AEs) of interest, including injection site reactions, hypersensitivity reactions, and gastrointestinal events, were more frequent in the burosumab vs the Pi/D group, all mild to moderate in severity. All subjects completed the study and no subjects discontinued treatment.
Conclusions: In this phase 3, randomized, controlled trial, burosumab administration significantly improved rickets and standing height Z-score compared with conventional therapy in children with XLH.