Data from Pharmawand - Curated by Marshall Pearce - Date added 05 December 2017

Ultragenyx Pharmaceutical Inc., Kyowa Hakko Kirin Co., Ltd. and Kyowa Kirin International PLC announced positive 48-week data from the randomized, double-blind, placebo-controlled Phase III study of burosumab (KRN 23) in adults with X-linked hypophosphatemia (XLH). Treatment with burosumab for 48 weeks showed sustained maintenance of normal serum phosphorus levels and further improvement in stiffness, physical function and pain. Patients who crossed over from placebo to burosumab after 24 weeks showed normalization of serum phosphorus and improvement in stiffness, pain and physical functioning.

An increased rate of fracture healing, in favor of burosumab treated patients, was observed during the first 24 weeks of burosumab treatment and this increased up to 48 weeks of treatment. Placebo patients who crossed over to burosumab showed a similar increased rate of fracture healing. The safety profile was consistent with what has been previously observed in this study and in other open label studies of burosumab in adults and children. Burosumab is being developed by Ultragenyx, Kyowa Hakko Kirin and Kyowa Kirin International.

48-Week 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 a 24-week double blind period. After 24 weeks, patients from both treatment arms continued on to an open-label period, during which they all received 1mg/kg of burosumab every four weeks.From 24 to 48 weeks of treatment, 84% of patients who had received burosumab since the beginning of the study (n=68) achieved and maintained serum phosphorus levels above the lower limit of normal (2.5 mg/dL). 89% of patients who crossed over from placebo to burosumab after 24 weeks (n=66) achieved and maintained serum phosphorus levels above the lower limit of normal. Patients treated with burosumab showed continued improvement in stiffness and physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). For patients treated with burosumab, stiffness further improved from a mean change of 7.42 points at 24 weeks to 16.03 points at 48 weeks. Patients who crossed over from placebo to burosumab treatment had a mean change of 15.82 points from 24 to 48 weeks. Physical function also further improved from a mean change of 2.78 points at 24 weeks to 7.76 points at 48 weeks. For patients in the crossover group, physical function improved by a mean change of 8.18 points from 24 to 48 weeks.

Burosumab was associated with a reduction in pain measured by the Brief Pain Inventory Question 3 (BPI Q3; pain at its worst in the last 24 hours), as well as a reduction in the use of pain medication. For patients treated with burosumab, pain scores further improved from a mean change of 0.81 points at 24 weeks to 1.09 points at 48 weeks. Patients who crossed over from placebo to burosumab treatment had a mean change of 1.18 points from 24 to 48 weeks. The patient frequency of reported opioid use decreased by 76% from 17 patients (25%) at baseline to four patients (6%) at week 48 in the burosumab group, and by 70% from 13 patients (20%) to four patients (6%) in the crossover group. The patient frequency of reported nonsteroidal anti-inflammatory drugs (NSAIDs) use decreased by 72% from 47 patients (69%) at baseline to 13 patients (19%) at week 48 in the burosumab group, and by 74% from 43 patients (65%) to 11 patients (17%) in the crossover group. Burosumab treatment resulted in increased healing of fractures (active fractures and pseudofractures) compared to placebo at week 24, and this improvement continued through 48 weeks. When evaluating follow-up X-rays in the 52% of patients with identified fractures or pseudofractures at baseline, the 43% rate of fracture healing observed at 24 weeks on burosumab increased to 63% at 48 weeks. In the crossover group which had an 8% rate of fracture healing at 24 weeks, the rate increased to 35% at week 48. The crossover patient group fracture healing result was consistent with the effect observed in the first 24 weeks of the burosumab group treatment.

Safety Results- There was no difference in the overall frequency of treatment emergent serious and non-serious adverse events, treatment related adverse events and serious adverse events between the group who received burosumab for the 48-week period compared to the group who received placebo for the 24-week double-blind period and then crossed over to burosumab. The safety profile at 48 weeks was generally similar to that observed at 24 weeks.

Comment:Ultragenyx is conducting a second open-label bone quality Phase III study in 14 adult XLH patients evaluating the improvement in osteomalacia, the underlying bone pathology of XLH, via bone biopsy. The bone quality study complements the phosphate and patient symptom data from the larger Phase III XLH study by evaluating the effect of burosumab more directly on the bone.

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