Burosumab Phase 3 Produces Positive Results

Burosumab (Crysvita) was approved by the US FDA to treat adults and children ages 1 year and older with x-linked hypophosphatemia (XLH), a rare genetic variation of rickets. Phase 3 study results help explain why.

Last week, Ultragenyx announced positive Phase 3 results from the first head-to-head trial comparing burosumab (Crysvita) to conventional therapy in children with X-Linked Hypophosphatemia (XLH).

Traditionally, children with XLH are treated with oral phosphate and active vitamin D. The randomized, open-label phase 3 clinical study exhibited that patients receiving burosumab were 10 times more likely than patients receiving the previous standard of care to have substantial healing of rickets, an important measure for children with XLH. The drug was approved by the FDA for the treatment of XLH last month.

Additionally, burosumab had a rapid and profound effect on the underlying disease — an outcome never previously achieved with conventional therapy.

Sixty-one patients aged 1 through 12 were enrolled in the study in the US, Europe, Canada, Australia, Japan, and Korea, and efficacy and safety of burosumab (n=32) were compared to that of conventional therapy (n=29). The change in rickets at 40 weeks, assessed by 3 independent blinded pediatric radiologists using the radiographic global impression of change (RGI-C) scale, served as the primary endpoint for the study.

Patients in the burosumab treatment group were administered an initial dose of 0.8 mg/kg subcutaneously every other week with dose increases up to 1.2 mg/kg implemented in 5 patients. Patients in the conventional therapy arm received the local standard regimen based on expert guidelines with ongoing optimization by each patient’s physician.

The study met its primary endpoint, exhibiting that the drug significantly improved rickets versus conventional therapy, as assessed by 3 independent blinded pediatric radiologists using the RGI-C scale. Further, substantial healing (RGI-C ≥ +2.0) was seen in 72% of patients receiving burosumab compared to 6% of patients receiving conventional therapy.

“This is the first study that directly compares Crysvita to conventional therapy for XLH, and we have now clearly demonstrated that Crysvita has a rapid and profound effect on the underlying disease, an outcome that was not achieved with conventional therapy,” said Camille L. Bedrosian, MD Chief Medical Officer of Ultragenyx. “These data reinforce the results seen in our earlier Phase 2 studies, and we believe that Crysvita will transform the treatment of XLH in children.”

Secondary endpoints included additional rickets assessments using the RGI-C scale and the Thacher Rickets Severity Scoring (RSS) system, pharmacodynamic assessments, changes in growth velocity and height, walking ability, patient-reported outcomes assessing pain, fatigue and physical function, and safety.

At baseline, patients in both arms had mean serum phosphorus levels and mean renal phosphate reabsorption levels below the lower limits of normal. In the burosumab arm, mean serum phosphorus and renal phosphate reabsorption levels post-baseline through Week 40 were in the normal range. In the conventional therapy arm, mean serum phosphorus and renal phosphate reabsorption levels stayed below the lower limits of normal over the 40-week period.

“The results of this important controlled study demonstrate the value of directing therapy at the mechanism of renal phosphate wasting in XLH,” said the lead study investigator, Erik Imel, MD, Associate Professor of Medicine and Pediatrics at Indiana University School of Medicine. “While prior conventional therapy fails to improve renal phosphate wasting, Crysvita works to improve serum phosphorus by correcting the renal phosphate wasting. The differences in mechanism are clearly important to outcomes as demonstrated in this study. By comparing XLH patients treated with Crysvita to patients treated with conventional therapy, we are finally able to demonstrate the magnitude of benefit on parameters of serum phosphorus, bone metabolism, and improvements in the skeleton.”

The safety profile observed in this study was generally consistent with that seen in previous pediatric XLH studies of burosumab. There were no treatment discontinuations and no deaths reported in the study; however, 3 serious adverse events (AEs) in the burosumab arm and 1 serious AE in the conventional therapy arm occured. None of these AEs were considered treatment-related. This phase 3 pediatric study was not required for the regulatory application in the US; it will serve as a confirmatory study in Europe.

Ultragenyx has made clear its intentions to present full results at an upcoming medical meeting.

For more from the rare disease community, subscribe to RDR’s e-newsletter.