The data demonstrated that serum phosphorus levels, rickets, growth rates, and other functional outcomes improved with burosumab, and these treatment effects were sustained through 64 weeks of treatment. In addition, interim 24-week data from the separate pediatric Phase 2 study in patients aged one to five years demonstrated that burosumab increased serum phosphorus levels into the low normal range.
Adverse events were consistent with what has been previously observed for burosumab for the treatment of XLH. Ultragenyx is conducting the studies under a collaboration and license agreement with Kyowa Hakko Kirin to develop and commercialize burosumab.
Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President of Ultragenyx said: "These data support the potential for burosumab to treat XLH in pediatric patients, and show that treatment with burosumab can improve bone health and growth in children who have this debilitating disease.
"The first results in the younger under-5 year old group are consistent with what we have seen in older children, supporting the potential value of early treatment initiation."
Dr. Tom Stratford, President and CEO of KKI said: "The data from these pediatric studies are encouraging and support our aim to contribute to the health and wellbeing of people through innovative drug discovery and commercialization of medicinal products.
"We are confident that burosumab has the potential to address a clear unmet medical need in the treatment of XLH."
Phase 2 XLH Study in Five to 12 Year Olds
The randomized, multicenter, open-label, dose-finding study enrolled 52 patients between five and 12 years old, 49 of whom had been on currently available therapy (oral phosphate/active vitamin D therapy) for an average of approximately seven years prior to entering the study.
All patients have completed the full 64-week dose-titration and treatment period. A subset of these patients (n=34) were pre-specified as having higher RSS scores, defined by baseline total RSS scores of > 1.5.
Metabolic Measures
Patients demonstrated increases in mean serum phosphorus, renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels through 64 weeks of treatment.
Patients in both dosing groups had mean serum phosphorus levels in the low normal range through 64 weeks of treatment, demonstrating that phosphate wasting, the underlying cause of the disease, improved and patients were able to maintain increased serum phosphorus levels.
Bone Disease Results
Thacher Rickets Severity Scoring (RSS)
Rickets severity was assessed using the RSS scoring system. There was a statistically significant improvement in rickets scores in all groups at 64 weeks, with the greatest improvements in patients with higher baseline rickets scores (RSS ≥1.5) who received bi-weekly dosing of burosumab. Overall, patients (n=52) had a 51% reduction in RSS score (p < 0.0001).
Patients with higher baseline rickets scores (n=34) had a 59% reduction in RSS score (p < 0.0001). Patients who were dosed bi-weekly (n=26) had a 58% reduction in RSS score (p < 0.0001). Patients with higher baseline rickets scores who were dosed bi-weekly (n=17) had a 62% reduction in RSS score (p < 0.0001).
Radiographic Global Impression of Change (RGI-C) Scale
The change in the severity of rickets was assessed by the RGI-C score. Data show significant improvement in rickets in all groups at 64 weeks. Overall, all patients (n=52) experienced a mean improvement in RGI-C score of +1.57 (p< 0.0001) and those patients with higher baseline rickets scores (n=34) experienced a mean improvement of +1.98 (p< 0.0001).
Within the higher severity subset, 77% (26/34) experienced substantial healing (score >2).
Patients who were dosed bi-weekly (n=26) experienced a mean improvement in RGI-C score of +1.62 (p< 0.0001). Patients with higher baseline rickets scores who were dose bi-weekly (n=17) showed a mean improvement of +2.08 (p< 0.0001) (substantial healing) and 82% experienced substantial healing.
Growth Velocity
Patients with higher baseline rickets scores showed more growth impairment (baseline height percentile= 5.84), and these patients demonstrated greater improvement in growth. Among all patients (n=52), growth velocity improved by a mean of +0.55 cm/year (p=0.0376), and there was 0.15 change in height z-score (p<0.0001).
Patients with higher baseline rickets scores had a +0.86 cm/year improvement in growth velocity (p=0.0175) and a 0.17 change in height z-score (p=0.0016). Patients who were dosed bi-weekly (n=26) experienced a +0.73 cm/year change in growth velocity (p=0.0160) and a 0.18 change in height z-score (p=0.0002).
Patients with higher baseline rickets scores who were dosed bi-weekly (n=17) had a +1.11 cm/year change in growth velocity (p=0.0076) and a 0.18 change in height z-score (p=0.0063).
Functional Measurements: 6 Minute Walk Test (6MWT) and Patient Reported Outcomes (PROs)
Patients with walking impairment at baseline (defined by < 80% predicted normal walk distance in 6MWT) in the bi-weekly dosing group (n=14) achieved a mean increase of 85 meters (p<0.0001).
Functional disability scores were measured with the Pediatric Orthopedic Society North America/Pediatric Outcome Data Collection Instrument (POSNA/PODCI).
When evaluating the Global score of all five domains in those patients with substantial impairment at baseline (n= 28), defined as baseline scores < 40 or one standard deviation below the normalized score of 50), a mean improvement of +14.1 (p< 0.0001) was observed.
Though the magnitude of these changes in functional measurements are substantial, any conclusions must be tempered by the fact that these data are from an uncontrolled, open-label study.
Safety and Tolerability
Approximately 65% of patients had injection site reactions, all of which were considered mild. There was one previously reported serious adverse event considered possibly treatment-related. This was a patient with fever and muscle pain who improved without complication and is still in the study.
There have been no deaths or discontinuations from the study.
No clinically meaningful changes were observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone. None of the patients had serum phosphorus levels above the upper limit of normal at any time point.
No clinically significant changes were observed in renal ultrasounds pre- and post-treatment.
Phase 2 XLH Study in One to Five Year Olds
The multicenter, open-label Phase 2 study enrolled 13 children between the ages of one and five years old (mean age 2.9 years), all of whom have previously been on oral phosphate/active vitamin D therapy.
The 64-week study is assessing the safety, pharmacodynamics, and efficacy of burosumab administered every 2 weeks at a starting dose of 0.8mg/kg, which can be increased to 1.2mg/kg at any time during the study.
All patients have completed 24 weeks of treatment. Patients demonstrated increases in mean serum phosphorus, and maintained levels in the low normal range through 24 weeks of treatment. Patients also demonstrated increases in serum 1,25 dihydroxy vitamin D levels, and significant decreases in alkaline phosphatase levels.
Adverse events were consistent with what has been previously observed for burosumab for the treatment of XLH. Approximately 23% of patients had injection-site reactions, all of which were considered mild. There have been no deaths or discontinuations from the study.