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Safety, tolerability, pharmacokinetics, and efficacy of burosumab in infants with X-linked hypophosphataemia: an
Agnès Linglart1, Francesco Emma2, Justine Bacchetta3
1Paris Saclay University, INSERM, AP-HP, Bicêtre Paris Saclay Hospital, Le Kremlin Bicêtre Cedex, France.
Insights
Burosumab is safe and well-tolerated in infants under 12 months with X-linked hypophosphataemia (XLH). Early treatment with burosumab in infants shows no new safety concerns, supporting its use in this age group.
Area of Science:
- Pediatric Nephrology
- Rare Diseases
- Pharmacology
Background:
- X-linked hypophosphataemia (XLH) is a rare genetic disorder affecting phosphate metabolism.
- Burosumab, an anti-fibroblast growth factor 23 monoclonal antibody, is approved for XLH in patients aged one year and older.
- Early intervention in XLH may improve long-term clinical outcomes.
Purpose of the Study:
- To evaluate the safety and efficacy of burosumab in infants younger than 12 months with XLH.
- To assess treatment-emergent adverse events (TEAEs) and tolerability in this pediatric population.
Main Methods:
- An open-label, non-randomized, phase 1/2 study enrolled 16 infants aged less than 12 months with confirmed XLH.
- Participants received burosumab every two weeks for up to 48 weeks, with varying doses based on age cohorts.
- Safety and tolerability were assessed by monitoring TEAEs, with serum phosphate levels also evaluated.
Main Results:
- All 16 participants experienced TEAEs, most commonly pyrexia (75%).
- Four participants had treatment-related TEAEs, including one instance of increased parathyroid hormone.
- No TEAEs led to treatment discontinuation or death, and one participant developed antidrug antibodies.
Conclusions:
- Burosumab demonstrates safety and tolerability in infants under 12 months initiating treatment for XLH.
- Findings are consistent with previous studies, indicating no novel safety concerns in this younger population.
- Early treatment with burosumab in infants with XLH is supported by these safety and tolerability data.
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.
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