Burosumab Improves Outcomes in Children with XLH in Phase 2 Trial

In a recent phase 2 trial, investigators have found that Crysvita (Ultragenyx Pharmaceutical Inc., Kyowa Kirin International PLC), or burosumab, improved outcomes in children aged 5-12 with X-linked hypophosphatemia (XLH), a rare, genetic variation of rickets that is characterized by low phosphate levels in the blood.

For the open-label, phase 2 trial, the investigators sought to evaluate burosumab, a monoclonal antibody that received approval from the US Food and Drug Administration (FDA) in April 2018 for the treatment of adults and children with XLH who were 1 year of age or older.

According to Ultragenyx, burosumab is “the first and only therapy that addresses the underlying cause of XLH,” by targeting fibroblast growth factor 23 (FGF-23), which is a hormone that reduces serum levels of phosphorus and active vitamin D. By inhibiting this hormone, burosumab can increase phosphate and vitamin D.

The phase 2 trial has published in the New England Journal of Medicine.

For the trial, investigators looked at 52 children with XLH who were randomly assigned in a 1:1 ratio to receive either subcutaneous burosumab every 2 weeks or every 4 weeks. The investigators adjusted the dose to achieve a serum phosphorus level at the low end of normal range, according to study authors.

The primary endpoint for the trial was change from baseline to weeks 40 and 64 in the Thacher rickets severity total score, which ranges from 0 to 10, with greater disease severity equating to higher scores. The investigators also assessed rachitic changes from baseline to weeks 40 and 64 by using the Radiographic Global Impression of Change. Other endpoints included pharmacodynamic marker changes, linear growth, physical ability, patient-reported outcomes, and frequency of any adverse events.

The investigators found that with every-2-week dosing, the mean Thacher rickets severity total score dropped from 1.9 at baseline to 0.8 at week 40; with every-4-week dosing, they also noted a drop in the total score from 1.7 at baseline to 1.1 at week 40. At week 64, they noted that these improvements persisted.

Another notable finding was that after the first dose in both arms of the trial, the mean serum phosphate level went up, and over 50% of those enrolled in both arms had phosphate levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]). Patients with every-2-week dosing maintained these stable phosphate levels through week 64. Furthermore, an increase was also noted when it came to renal tubular phosphate reabsorption in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter) from baseline.

“Inhibition of FGF-23 activity with burosumab was associated with an increase in renal tubular phosphate reabsorption and the correction of hypophosphatemia in children with XLH,” the authors write. “The improvement in phosphate metabolism corresponded to a decrease in the severity of rickets. The healing of rickets probably contributed to concurrent improvements in growth and physical activity and a reduction in pain.”

Before the approval of burosumab, there were no approved therapies for this condition, one that poses a significant burden on children and their families. The phase 2 study showed that burosumab improved bone health and growth in children with XLH.

“We will continue our R&D activities that strengthen the clinical evidence base for burosumab to contribute to patients all over the world,” Mitsuo Satoh, PhD, executive officer and vice president head of the R&D division of Kyowa Hakko Kirin said in a recent statement.