Pharmacological management of X-linked hypophosphataemia

Abstract

The most common heritable disorder of renal phosphate wasting, X-linked hypophosphataemia (XLH), was discovered to be caused by inactivating mutations in the phosphate regulating gene with homology to endopeptidases on the X-chromosome (PHEX) gene in 1995. Although the exact molecular mechanisms by which PHEX mutations cause disturbed phosphate handling in XLH remain unknown, focus for novel therapies has more recently been based upon the finding that the bone-produced phosphaturic hormone fibroblast growth factor-23 is elevated in XLH patient plasma. Previous treatment strategies for XLH were based upon phosphate repletion plus active vitamin D analogues, which are difficult to manage, fail to address the primary pathogenesis of the disease, and can have deleterious side effects. A novel therapy for XLH directly targeting fibroblast growth factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA, henceforth referred to just as burosumab) has emerged as an effective, and recently approved, pharmacological treatment for both children and adults. This review will provide an overview of the clinical manifestations of XLH, the molecular pathophysiology, and summarize its current treatment.

Keywords: PHEX; X-linked hypophosphataemia; burosumab-twza; fibroblast growth factor 23.

Figure 1

Data from a 24‐week randomized, placebo‐controlled trial of burosumab 1 mg kg^–1 vs. placebo in adults with X‐linked hypophosphataemia are shown. (A) Mean serum phosphorus is within the normal range at the midpoint of dosing interval during treatment with burosumab, compared with placebo treated subjects, whose phosphorus remained low. (B) Active fractures or pseudofractures were more likely to heal during 24 weeks of burosumab compared with placebo. Adapted and reproduced from Figures 1A and 3A of Insogna et al. J Bone Miner Res 2018;33:1383–1393; (Reference [21]); Wiley Publishers, https://doi.org/10.1002/jbmr.3475. Creative Commons Attribution License (CC BY 4.0, https://creativecommons.org/licenses/by/4.0)