medwireNews: Burosumab treatment for X-linked hypophosphataemia (XLH) may begin in the first year of life, suggest phase 2 trial findings published in The Lancet Diabetes & Endocrinology.
The human anti-fibroblast growth factor-23 monoclonal antibody has already been approved in Europe for children with XLH aged 12 months and older, explain Emilia Quattrocchi (Kyowa Kirin Pharmaceutical Development, Marlow, UK) and co-authors.
Hypothesising that initiating treatment earlier might improve clinical outcomes, the team recruited 16 children (seven girls) with XLH aged less than 12 months. All the participants carried a pathogenic, likely pathogenic, or variant of unknown importance in the PHEX gene and had an affected parent.
Infants aged between 6 and 12 months were assigned to receive burosumab 0.4 mg/kg (cohort 1, n=3) or 0.8 mg/kg (cohort 2, n=9) every 2 weeks for up to 48 weeks, while four infants aged less than 6 months were given treatment at 0.4 mg/kg (cohort 3).
Overall, 15 of the 16 children completed the study, and one patient discontinued the study but continued to receive burosumab at a local hospital. The average exposure to burosumab was 11.1 months over 26.1 cycles; 69% of children received at least one dose increase following low serum phosphate levels, giving mean maximum doses in cohort 1, 2 and 3 of 1.5, 0.9 and 1.3 mg/kg, respectively.
Quattrocchi et al report that the treatment was “well tolerated, with no safety concerns” at both dose levels, with a similar incidence of treatment-emergent adverse events (TEAEs) across the three cohorts, none of which required treatment interruption or discontinuation.
The most frequent TEAEs were pyrexia (75%), nasopharyngitis (44%), rhinitis (44%), upper respiratory tract infection (38%) and COVID-19 (31%), all of which are “common for infants,” the investigators say. Constipation, elevated blood parathyroid hormone (PTH), decreased 25-hydroxy vitamin D levels and cough were each experienced by a quarter of patients.
Four patients were thought to have TEAEs linked to treatment, namely three cases of elevated PTH in cohort 1 (94 pg/mL) and cohort 2 (84 and 68 pg/mL), and one case of dermatitis acneiform in cohort 2. Another patient in cohort 2 required surgery for grade 3 craniosynostosis but this was judged to be a known complication of XLH.
Adverse events of special interest included one (6%) patient with antidrug antibodies, who did not experience hypersensitivity or injection site reactions, one (6%) case of ectopic mineralisation, five (31%) cases of hypersensitivity, and one (6%) injection site reaction, as well as the three (19%) PTH elevations.
The authors also report that mean serum phosphate concentrations increased over treatment, from a baseline average of 3.10 mg/dL to 3.71 mg/dL at the end of treatment, at which point they were within normal range. This was accompanied by an increase in serum 1,25(OH)2 D levels from 65.2 to 73.3 pg/mL, and a decrease in serum total alkaline phosphatase from 714 to 387 U/L, with two patients showing normal alkaline phosphatase levels by week 48, as did four of 11 patients who were followed up to week 56.
In addition, 87% of 15 patients responded to treatment based on improvements in Radiographic Global Impression of Change (RGI-C) global score, and 33% responded in terms of their RGI-C long leg score, while 85% of 13 assessed participants responded to treatment according to their Rickets Severity Score. Knee radiographs from one patient showed an improvement in rickets from baseline at week 48.
“Similar to the findings from a study in children aged 1–4 years […] burosumab did not improve height or weight Z scores of participants in the current study,” the investigators report.
However, acknowledging the “difficulties in accurately measuring height in infants”, they say that “[a] larger study with longer treatment duration is required to fully establish whether burosumab treatment can normalise growth when initiated in patients younger than 1 year.”
The team concludes that “there is a need to further explore how early burosumab initiation can alleviate disease symptoms and burden in patients with XLH. This could be achieved with a larger cohort size, longer study duration, and collection of real-world data.”
By Lynda Williams
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