Ultragenyx’s hypophosphatemia drug succeeds in phase 3 study

Patients treated with burosumab demonstrated a statistically significant improvement in serum phosphorus levels, with 94% of patients achieving normal levels compared to 8% on placebo (p<0.0001).  Patients treated with burosumab also achieved a statistically significant improvement in stiffness and strong trends in improvements in physical function and pain.

Adverse events were consistent with what has been previously observed in open label studies in adults and children. Ultragenyx is conducting the study under a collaboration and license agreement with Kyowa Hakko Kirin. 

Burosumab is being developed by Ultragenyx, Kyowa Hakko Kirin and Kyowa Kirin International.

Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President of Ultragenyx. : "These data demonstrate a clinical improvement in patients treated with burosumab and support the potential for treatment of adults.

"When combined with a favorable safety profile and a strong serum phosphorus response, we believe these clinical data should support regulatory submissions in adults with XLH, and we look forward to discussing our filing plans with the U.S. FDA."

"This study provides valuable additional placebo controlled data to that already obtained from the global clinical development program for pediatric and adult patients with XLH." said Mitsuo Satoh, Executive Officer, Vice President, Head of Research and Development Division of Kyowa Hakko Kirin. "I believe burosumab has the potential to be an effective treatment option for patients with XLH."

"We are pleased that the data from this adult Phase 3 study supports the safety and efficacy of burosumab and look forward to progressing our discussions with the regulatory bodies in Europe and the US," said Dr. Tom Stratford, President and CEO of KKI.

Efficacy Results

The study enrolled 134 patients, randomized 1:1 to burosumab at a dose of 1 mg/kg or placebo every four weeks for 24 weeks.

The study met the primary endpoint of increasing serum phosphorus levels as 94% of patients treated with burosumab (n=68) achieved serum phosphorus levels above the lower limit of normal and maintained levels in the low normal range through 24 weeks, compared to 8%  in the placebo arm (n=66; p<0.0001).

There were three pre-specified key secondary endpoints, including stiffness and physical function, both measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and pain measured by the Brief Pain Inventory Question 3 (BPI Q3; pain at its worst in the last 24 hours).

At week 24 stiffness improved by a mean score of 7.87 points for patients treated with burosumab compared to a 0.25 point worsening among patients in the placebo group (mean difference of 8.12; p=0.0122).

Physical function improved by 3.11 points for patients treated with burosumab compared to a 1.79 point worsening among patients in the placebo group (mean difference of 4.90 points; p=0.0478). Pain score improved by 0.79 for patients treated with burosumab compared to a 0.32 improvement among patients in the placebo group (mean score difference of 0.46 points; p=0.0919).

Results were directionally consistent towards improvement across all three key secondary endpoints. After pre-planned multiplicity adjustment, the improvement in stiffness among patients treated with burosumab remained statistically significant at the less than the 0.0167 threshold, while physical function and pain scores demonstrated strong trends.

Safety Results

There was no difference in the overall frequency of treatment emergent adverse events, treatment related adverse events and serious adverse events between the two treatment groups. 

The most common (>10%) adverse events in patients treated with either burosumab or placebo were back pain (burosumab 15%, placebo 9%), nasopharyngitis (burosumab 13%, placebo 9%), tooth abscess (burosumab 13%, placebo 8%), injection site reactions (burosumab 12%, placebo 12%), headache (burosumab 12%, placebo 8%), restless legs syndrome (burosumab 12%, placebo 8%), dizziness (burosumab 10%, placebo 6%), nausea (burosumab 10%, placebo 9%), arthralgia (burosumab 9%, placebo 24%), pain in extremity (burosumab 7%, placebo 15%) and oropharyngeal pain (burosumab 2%, placebo 11%).

There was no evidence of hypersensitivity reactions to injections. There were two serious adverse events in each treatment group, none of which were considered treatment-related. No differences between groups were observed in serum intact parathyroid hormone levels or ectopic mineralization as assessed by renal ultrasounds or echocardiograms.

Of the 134 patients enrolled in the study, one patient in the burosumab arm discontinued treatment during the 24-week double-blind treatment period due to consent withdrawal. There have been no deaths in the study.