Safety, tolerability, pharmacokinetics, and efficacy of burosumab in infants with X-linked hypophosphataemia: an open-label, multicentre, non-randomised study

Abstract

Background: Burosumab, a human anti-fibroblast growth factor 23 monoclonal antibody, is approved in Europe for treating X-linked hypophosphataemia (XLH) in patients aged at least 1 year. Early initiation might further improve clinical outcomes. This study investigated the safety and efficacy of administering burosumab to patients younger than 12 months.

Methods: This open-label, non-randomised, phase 1/2 study included infants from clinical sites in Austria, France, Italy, Spain and the UK. Key eligibility criteria were age less than 12 months, presence of a pathogenic or likely pathogenic variant, or variant of uncertain importance in the PHEX gene in either the participant or a directly related family member with appropriate X-linked inheritance, and hypophosphataemia. Participants received burosumab every 2 weeks for up to 48 weeks: cohorts 1 and 2 (infants aged from 6 to less than 12 months with starting doses 0·4 or 0·8 mg/kg) and cohort 3 (infants younger than 6 months with starting dose 0·4 mg/kg). The primary endpoint was safety and tolerability assessed in the full-analysis set of all participants who received at least one dose of burosumab and had at least one serum phosphate measurement after treatment, was safety, with a focus on treatment-emergent adverse events (TEAEs). The study is registered with ClinicalTrials.gov (NCT04188964) and is completed.

Findings: Study recruitment was initiated on Feb 26, 2020, and the study was completed on March 6, 2024. Of 17 participants assessed for eligibility, 16 were enrolled and assigned to cohorts 1, 2, and 3, which included three, nine, and four participants, respectively (n=16); seven of 16 were female, 15 of 16 completed the study, one discontinued and transitioned to receive burosumab in a local hospital. All participants had TEAEs with no differences in incidence across cohorts; four had at least one treatment-related TEAE, one developed antidrug antibodies. No TEAEs led to treatment discontinuation or death. The most common TEAE was pyrexia, reported in 12 (75%) of 16 (95% CI 47·6-92·7) participants. The most common treatment-related TEAE was blood parathyroid hormone increase, reported in three (19%) of 16 (4·0-45·6) participants.

Interpretation: This study confirms the safety and tolerability of burosumab in patients with XLH initiating treatment aged less than 12 months and is consistent with previous reports with no new safety concerns.

Funding: Kyowa Kirin Pharmaceutical Development.