Efficacy of Burosumab in Children with X-linked Hypophosphatemia (XLH)

Annemieke M. Boot, on behalf of the international XLH study group

Background: XLH is an X-linked dominant rare disease. The PHEX mutation, which causes XLH, results in high FGF23 levels, which leads to defective bone mineralization and rickets.

Objective: to evaluate the efficacy and safety of burosumab, an anti-FGF23 monoclonal antibody, in children with XLH.

Methods: Two phase 2 studies have been done. In CL201, 52 children with XLH (5-12 years old, Tanner <=2) were randomized 1:1 to receive burosumab subcutaneously every two (Q2W) or every 4 weeks (Q4W). In CL205, 13 children with rickets total severity score (RSS) >=2 (aged 1-4 years) received burosumab Q2W. In a randomized controlled phase 3 (CL301) study 61 children (1-12 years) with XLH and RSS >=2 were randomized to receive Burosumab Q2W or Pi/D as prescribed by investigators.

Results: In the Q2W treated subjects total RSS was reduced by 58% in CL201 and 69% in CL205 (both p<0.0001) at week 64. Mean serum phosphorus increased from 0.8 (0.1) at baseline to 1.1 (0.1) mmol/l at week 64. Mean alkaline phosphatase decreased from 462 U/l at baseline to 354 U/l at week 64 in CL201 (P<0.0001) and from 549 to 334 U/l in CL205 (p<0.0001). One subject per study experienced a serious adverse event (AE); hospitalization for fever/muscle pain that resolved with a day (CL201) and a dental abscess (CL205).

In the phase 3 study the RSS decreased more in the burosumab group than the Pi/D group (-2.04 vs -0.71; p<0.0001) with greater increases in serum phosphorus levels and decreases of alkaline phosphatase (-131 vs -35 p<0.0001), at week 40. In study CL301 there were 3 serious adverse events (3 burosumab, 1 Pi/D), none were treatment related and all resolved.

Conclusion: Burosumab Q2W improves serum phosphorus and rickets in children aged 1-12 yrs with XLH and severe rickets and results in greater improvements in clinical outcome than conventional treatment.