Clinical Trials

Date: 2015-06-04

Type of information: Results

phase: 2

Announcement: results

Company: Ultragenyx Pharmaceutical (USA - CA)

Product: burosumab - recombinant human monoclonal IgG1 antibody for fibroblast growth factor 23/KRN23

Action mechanism:

• monoclonal antibody. KRN23 is an investigational recombinant fully human monoclonal IgG1 antibody, discovered by Kyowa Hakko Kirin, against the phosphaturic hormone fibroblast growth factor 23 (FGF23). It is being developed to treat X- linked hypophosphataemia, a disease characterized by excess activity of FGF23. FGF23 is a hormone that reduces serum levels of phosphorus and vitamin D by regulating phosphate excretion and vitamin D production by the kidney. Phosphate wasting in XLH is caused by excessive levels and activity of FGF23. KRN23 is designed to bind to and thereby inhibit the excessive biological activity of FGF23. By blocking excess FGF23 in patients with XLH, KRN23 is intended to restore normal phosphate reabsorption from the kidney and increase the production of vitamin D, which enhances intestinal absorption of phosphate and calcium.
• Ultragenyx and Kyowa Hakko Kirin entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23.

Disease: X-linked hypophosphatemia (XLH)

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Country: France, The Netherlands, UK, USA

Trial details:

• The randomized, open-label, dose-finding Phase 2 study is evaluating safety and efficacy in 36 pediatric XLH patients ages 5 to 12. The study consists of a 16-week individual dose-titration period followed by a 48-week treatment period, for a total of 64 weeks. Patients are divided into three cohorts of escalating starting dose levels of KRN23 with either monthly (Q4W) or biweekly (Q2W) dosing regimens. Patients can continue to have their dose increased throughout the duration of the study to reach an individually-optimized dose (NCT02163577).
• Safety, changes in serum phosphorus, and other pharmacodynamic parameters were evaluated at the 16-week analysis. Additional data, including radiographic evidence of rickets severity, will be evaluated at the 40-week and 64-week analyses. The open-label, long-term extension study enrolled 20 adult patients with XLH who had previously participated in the phase 1 INT-001 or INT-002 studies of KRN23. All patients had at least a 12-month KRN23 treatment break before enrolling in the extension study. Patients who had resumed oral phosphate and active vitamin D therapy between studies (65%) completed a 21-day washout period. All patients began KRN23 treatment at the last dose received in the INT-001 or 002 study with an option to titrate during the first 12 weeks. An analysis of 24-week data is being presented.

Latest news:

• • On April 6, 2017, Ultragenyx Pharmaceutical and Kyowa Kirin International announced  64-week data from a pediatric Phase 2 study of burosumab for the treatment of X-linked hypophosphatemia in children aged five to 12 years of age. 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.
• 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. Patients with higher baseline rickets scores (n=34) had a 59% reduction in RSS score. Patients who were dosed bi-weekly (n=26) had a 58% reduction in RSS score. Patients with higher baseline rickets scores who were dosed bi-weekly (n=17) had a 62% reduction in RSS score. 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 and those patients with higher baseline rickets scores (n=34) experienced a mean improvement of +1.98. 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. Patients with higher baseline rickets scores who were dose bi-weekly (n=17) showed a mean improvement of +2.08 (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 .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.
• • On September 19, 2016, Ultragenyx Pharmaceutical announced positive interim data from the ongoing pediatric Phase 2 study of KRN23 for the treatment of X-linked hypophosphatemia (XLH), demonstrating that serum phosphorus levels, rickets, growth rates and other functional outcomes improved with continued KRN23 treatment. The bi-weekly dose regimen continued to show a better overall response than patients who were dosed every four weeks, and patients with higher rickets at baseline showed greater improvements in bone disease and growth velocity. Data were also presented from the adult Phase 2 study of KRN23 for the treatment of XLH, demonstrating a significant increase in serum phosphorus levels and evidence of clinical improvement in walking, mobility, pain and stiffness at 24 weeks of treatment. Adverse events were consistent with what has been previously observed for KRN23 for the treatment of XLH. Data from the two studies were presented at the American Society for Bone and Mineral Research (ASBMR) 2016 Annual Meeting.
• Phase 2 Pediatric Study: The randomized, multicenter, open-label, dose finding study enrolled 52 patients ages five through 12, 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. The first 36 patients enrolled in the study have completed the full 64-week dose-titration and treatment period. A subset of these patients (n=18) were pre-specified as having higher rickets (greater bone disease), defined by baseline total RSS scores of > 1.5. An additional 16 patients with higher rickets have completed 40 weeks of treatment.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 at 40 weeks (n=52) and 64 weeks (n=36) using the RSS scoring system. Rickets improved significantly in all groups, with the greatest improvements in patients with higher baseline rickets (RSS ?1.5) who received bi-weekly dosing of KRN23.
• Radiographic Global Impression of Change (RGI-C) ScaleThe change in the severity of rickets was also assessed at 40 and 64 w:eeks by the RGI-C score. Data show significant improvement in rickets in all groups. Substantial healing (RGIC score > 2) was observed in all but one patient with higher baseline rickets who received bi-weekly dosing. Growth Velocity:  Patients with higher baseline RSS scores > 1.5 showed more growth impairment (baseline height percentile for 40-week group = 5.8%; baseline height percentile for 64-week group = 3.9%), and these patients demonstrated greater improvement in growth velocity and height z-score. 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 achieved a mean increase of 84 meters (p<0.001) at 40 weeks (n=14), and 97 meters (p<0.001) at 64 weeks (n=7). 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 +17.5 (p< 0.0001) was observed at 40 weeks. 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: The most common treatment-related adverse events reported by preferred term was injection site reaction in 33% of patients. All of these reactions were considered mild. All other treatment-related adverse events were also considered mild. There was one serious adverse event considered possibly treatment-related. This was a previously reported patient with fever and muscle pain who improved without complication and is still in the trial. There have been no deaths or discontinuations from the study for any reason. 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. Metabolic Measures: Patients treated with KRN23 demonstrated increased serum phosphorus at 24 weeks of treatment, and maintained levels in the low normal range. Renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels also increased from baseline to 24 weeks. Patient-Reported Outcomes and Physical Function: At baseline, 19 of 20 patients had worst pain scores measured by the Brief Pain Inventory Question 3 (BPI-Q3) of > 4, classified as moderate to severe pain. The mean BPI-Q3 score was significantly reduced from baseline (p=0.0268; 1.1 point reduction from 6.6 at baseline to 5.5 at 24 weeks). These patients also demonstrated significant improvements in BPI pain interference (p=0.0009) and pain severity (p=0.0141) scores. WOMAC pain, stiffness and physical function domain scores were significantly reduced at 24 weeks in these patients. Patients demonstrating the greatest improvements in stiffness (WOMAC stiffness responders) and pain (BPI-SF worst pain responders) had greater improvements in mobility tests, including the Timed Up and Go (TUG test for balance and agility) and the 6MWT. Mean patient TUG scores improved by 2 seconds (p=0.04) at week 24. At baseline, nearly all patients (19/20) were impaired in walking (defined by < 80% predicted normal walk distance in 6MWT). The mean increase in distance walked was 25 meters (p=0.05) from baseline. Safety and Tolerability: The most common adverse events were arthralgia (30%), nasopharyngitis (25%), back pain (20%), injection site reaction (20%), and pain in extremity (20%). Treatment-related adverse events occurred in 40% of patients, and were all considered mild. None of the four serious adverse events were considered treatment-related. There have been no deaths or discontinuations from the study.
• • On December 2, 2015, Ultragenyx Pharmaceutical announced positive interim data through 40 weeks from the first 36 patients in the ongoing pediatric Phase 2 study of KRN23 for the treatment of X-linked hypophosphatemia (XLH). Ultragenyx is conducting the Phase 2 study under a collaboration and license agreement with Kyowa Hakko Kirin to develop and commercialize KRN23. The data demonstrated that rickets disease was improved when measured by both Thacher Rickets Severity Scoring (RSS) and Radiographic Global Impression of Change (RGI-C) scoring methods and were further supported by functional improvements measured by patient reported outcomes in more severely affected patients. The data also demonstrated that while both dose groups showed improvements, the bi-weekly dose regimen generally resulted in a better overall response than the monthly dose regimen. Importantly, patients with more severe disease at baseline had greater improvements on treatment with KRN23. Study Results: Patients in the study (n=36) were enrolled at experienced XLH centers, and 35 patients had previously been on standard of care (oral phosphate/Vitamin D therapy) for an average of approximately 7 years prior to entering the study. Patients began a bi-weekly or monthly regimen at low doses and were titrated up to target a low-normal range of serum phosphorus. The study included a 16-week individual dose-titration period followed by a 48-week treatment period, for a total of 64 weeks. Data reported today are from the first 36 patients through 40 weeks of treatment. A subset of patients (n=18) were pre-specified as having high rickets severity (greater bone disease) if their baseline total RSS scores were > 1.5. For the responder analysis using total RSS, responders were pre-defined as those patients who had baseline total RSS scores > 1.0 and had 1.0 or more reduction at Week 40 which is considered a significant improvement. Bone Disease Results - Thacher Rickets Severity Scoring (RSS): RSS is a scoring system originally developed to assess rickets severity in children with nutritional rickets but is used now in genetic bone diseases. In patients who were dosed bi-weekly (n=18), the mean total RSS score decreased from 1.53 at baseline to 0.86 at 40 weeks (-0.67 points; 44% reduction; p=0.0126), and 75% of the patients (9/12) were responders. In the high severity patients who were dosed bi-weekly (n=9), the mean total rickets score decreased from 2.44 at baseline to 1.00 at 40 weeks (-1.44 points; 59% reduction; p<0.0001), and 89% of these patients were responders (8/9). In patients who were dosed monthly (n=18), the mean total rickets score decreased from 1.33 at baseline to 1.14 at 40 weeks (-0.19 points; 14% reduction), and 46% of the patients (5/11) were responders. In the high severity patients who were dosed monthly (n=9), the mean total RSS score decreased from 2.17 at baseline to 1.44 at 40 weeks (-0.72; 33% reduction) and 56% of these patients (5/9) were responders. Overall, in all patients (n=36), the mean total RSS score decreased from 1.43 at baseline to 1.00 at 40 weeks (-0.43; 30% reduction; p=0.0076), and 61% of the patients (14/23) were responders. In all the high severity patients (n=18), the mean total rickets score decreased from 2.31 at baseline to 1.22 at 40 weeks (-1.08; 47% reduction; p<0.0001), and 72% of these patients were responders (13/18). Radiographic Global Impression of Change (RGI-C) Scale: The change in the severity of rickets from baseline to Week 40 was also assessed by the RGI-C score, a 7-point scale that rates changes in a specific list of abnormalities in the wrist, knee, and leg by taking the mean of three independent radiologist readings comparing X-rays before and after treatment. Unlike RSS, clinical significance is explicit in RGI-C. Ratings of -3, -2, and -1 indicate severe, moderate, and minimal worsening, respectively, and ratings of +1, +2 and +3, indicate minimal healing, substantial healing, or complete/near complete healing, respectively. Patients who were dosed bi-weekly (n=18) experienced a mean improvement in RGI-C score of +1.56 (p<0.0001). Those patients with high severity rickets (n=9) experienced a mean improvement of +2.00 (p<0.0001) at 40 weeks (substantial healing) and 89% (8/9) experienced substantial healing (score >2). Patients who were dosed monthly (n=18) experienced a mean improvement in RGI-C score of +1.20. The patients with high severity rickets (n=9) experienced a mean improvement of +1.70 at 40 weeks and 44% (4/9) experienced substantial healing (score >2). Overall, all patients (n=36) experienced a mean improvement in RGI-C score of +1.38 (p<0.0001) and those patients who were severe (n=18) experienced a mean improvement of +1.85 (p<0.0001) at 40 weeks. Within the high severity subset, 67% (12/18) experienced substantial healing (score >2). Functional measurements: 6 Minute Walk Test (6MWT) and Patient Reported Outcomes (PRO's). The overall patient population (n=36) demonstrated a modest increase in meters walked in the 6MWT at Week 40 as many patients were not impaired in walking at baseline. Patients with walking impairment at baseline (defined by < 80% predicted normal walk distance in 6MWT; n=14) achieved a mean increase of 80 meters (~20% increase from baseline) at Week 40. 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=14, defined as baseline scores < 40, or one standard deviation below the normalized score of 50) or with severe rickets at baseline (n=18), a substantial mean improvement was observed of about one standard deviation or greater (~10 points) in both dose groups. The Pain/Comfort and Sports/Physical Function domains were the most affected at baseline and also substantially improved in these severely affected subjects treated in both dose groups. 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. Metabolic Measures: All patients demonstrated increases in serum phosphorus that were consistent with what had been observed previously reaching the low normal or just below normal range. Across both dose groups there were mean increases in both the renal phosphate reabsorption (TmP/GFR) and in serum 1,25 dihydroxy vitamin D levels through 40 weeks of treatment. Safety and Tolerability: The most common treatment-related adverse event reported by preferred term was injection site reaction in 39% of patients. All of these reactions were considered mild. All other treatment-related adverse events were considered mild. There was one 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 trial. There have been no deaths or discontinuations from the study for any reason. 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. Ultragenyx and Kyowa Hakko Kirin plan to file for a conditional marketing authorization in the EU on the basis of these data and on prior feedback from the EMA suggesting that we could do so if the data indicated a positive benefit-to-risk profile. In addition, we plan to proceed with a pediatric Phase 3 study in 2016. The exact design details are yet to be determined but will likely utilize RGI-C as the primary endpoint and would include a standard of care reference arm. This study is expected to be required for potential approval in the US and could also serve as a confirmatory study in the EU if a conditional marketing authorization were granted. • On July 9, 2015, Ultragenyx Pharmaceutical announced positive interim data from the first 12 patients in the ongoing pediatric Phase 2 study for KRN23 against fibroblast growth factor 23 (FGF23) for the treatment of X-linked hypophosphatemia (XLH). An improvement in mean rickets score was observed after 40 weeks of treatment with investigational KRN23 in these patients. Ultragenyx is conducting the Phase 2 study under a collaboration and license agreement with Kyowa Hakko Kirin to develop and commercialize KRN23.
• Bone Disease Efficacy: Eleven of the first 12 patients enrolled had been on standard of care oral phosphate/Vitamin D therapy for an average of 6 years (3.3-9.4 years) prior to the baseline assessment. The mean rickets score was 1.4 at baseline using the Thacher Rickets Severity Scoring method as evaluated by a blinded expert reader and decreased to 0.6 after 40 weeks of treatment with KRN23, a 58% reduction. Eight out of 11 patients with rickets at baseline demonstrated an improvement in rickets, of which three patients no longer exhibited radiographic evidence of rickets at week 40. One patient in the biweekly dosing group did not present with radiographic evidence of rickets at baseline and was excluded from the analysis. Of the 12 patients, 6 received biweekly dosing and 6 received monthly dosing of KRN23. Of the 5 patients with rickets at baseline in the biweekly dosing group, 100% demonstrated improvement in rickets from a mean baseline rickets score of 1.5 to a mean score of 0.3 at week 40, representing an 80% reduction in rickets score. Of the 6 patients in the monthly dosing group, 50% demonstrated improvement in rickets from a mean baseline score of 1.3 to a mean score of 0.8 at week 40, representing a 38% reduction in rickets score. Two patients in the monthly dosing group did not show a change and one patient in the monthly dosing group worsened by 0.5 points.
• Metabolic Measures: In the biweekly dosing group (n=6), mean serum phosphorus increased by 0.70 mg/dL, from 2.78 mg/dL at baseline to 3.48 mg/dL, which is in the normal range (3.2-6.1 mg/dL). In the monthly dosing group (n=6), mean serum phosphorus at peak increased by 1.06 mg/dL, from 2.42 mg/dL at baseline to 3.48 mg/dL. The monthly dosing patients showed a decrease to the trough level before the next dose, unlike the biweekly regimen which showed stable phosphate levels. Increases in renal phosphate reabsorption (TmP/GFR) and in serum 1,25 dihydroxy vitamin D levels were observed in all 12 patients.
• Safety and Tolerability: No serious adverse events have been reported in the study to date and there have been no discontinuations from the study for any reason. For the 12 patients who had reached 40 weeks at the time of the interim analysis, the most common adverse events considered to be treatment related were injection site reactions. All of the treatment-related adverse events were considered mild in severity. No significant changes were observed in serum calcium, urinary calcium, or serum intact parathyroid hormone (iPTH) in the 12 patients. None of the patients had serum phosphorus levels above the upper limit of normal in either dosing group. Safety data on renal ultrasounds, echocardiograms, or immune response to KRN23 are not yet available.
• All patients in the study continue to receive KRN23. An additional 40-week analysis for 36 patients is planned for the fourth quarter of 2015.
• • On June 2, 2015, Ultragenyx Pharmaceutical announced positive 16-week data from the ongoing pediatric Phase 2 study and provided a regulatory update for KRN23 against fibroblast growth factor 23 (FGF23) for the treatment of X-linked hypophosphatemia (XLH). After 16 weeks of dose-titration, all 36 patients had increases in serum phosphorus levels from baseline. In the monthly dosing group, mean serum phosphorus at peak increased by 1.03 mg/dL, from 2.27 mg/dL at baseline to 3.30 mg/dL, which is in the normal range (3.2-6.1 mg/dL). At the end of the 16-week titration period, 71% of patients receiving monthly dosing reached the normal serum phosphorus range with a mean dose of 0.84 mg/kg per treatment. Of the patients who had reached week 22, 9 out of 12 (75%) reached the normal range after further dose titration. In the biweekly dosing group, mean serum phosphorus increased by 0.59 mg/dL, from 2.48 mg/dL at baseline to 3.07 mg/dL, and was stable throughout the dosing cycle. The proportion of patients reaching the normal serum phosphorus range was 50% at the end of 16 weeks with a mean dose of 0.48 mg/kg per treatment biweekly. Of the patients who had reached week 24, 7 out of 9 (78%) reached the normal range after further dose titration. Mean increases were also observed in renal phosphate reabsorption (TmP/GFR) and in serum 1,25 dihydroxy vitamin D levels. Overall, the dose-response, serum phosphorus, and other metabolite results observed in the pediatric study are consistent with the adult XLH data generated to date.
• Serum phosphorus levels on standard of care: Per protocol, patients discontinued standard of care (SOC: oral phosphate and Vitamin D therapy) after the screening visit, which was 2-4 weeks prior to the baseline visit. Serum phosphorus levels were measured in 16 patients at screening and baseline. While on SOC, the mean serum phosphorus level at screening in these 16 patients was 2.40 mg/dL and after wash-out from SOC at baseline was 2.26 mg/dL, representing a mean change of 0.14 mg/dL. All 16 patients had an increase in serum phosphorus after treatment with KRN23 to a mean of 3.09 mg/dL, representing an improvement of 0.83 mg/dL compared to baseline.
• Safety and tolerability: No serious adverse events have been reported and there have been no discontinuations from the pediatric Phase 2 study for any reason. The most common adverse events considered to be treatment related were injection site reactions in 8 patients (22%), injection site erythema in 4 patients (11%), and injection site rash, injection site swelling, and limb pain in 3 patients (8% each). All of these treatment-related adverse events were considered mild in severity. No significant changes were observed in serum calcium, urinary calcium, or serum intact parathyroid hormone (iPTH). No patients had serum phosphorus levels above the upper limit of normal in either dosing group.
• In recent discussions with the European Medicines Agency (EMA), Ultragenyx received feedback that a Marketing Authorization Application (MAA) filing for conditional approval may be possible for KRN23 in XLH. A conditional MAA filing would be based on data from the 40-week interim analysis of rickets and other endpoints from the pediatric Phase 2 study and from the completed Phase 1/2 and ongoing Phase 2b studies in adults, provided that there is a positive benefit-risk profile, with specific obligations to complete and provide final data from the pediatric and adult studies. If KRN23 is approved, Kyowa Hakko Kirin will commercialize it in Europe, and Ultragenyx will receive a royalty.
• Based on the positive 16-week results and the EMA feedback, Ultragenyx is expanding the pediatric Phase 2 study by up to 16 patients to generate additional safety and efficacy data. The company will determine whether to proceed with an MAA filing for conditional approval after evaluation of the Phase 2 40-week data from the original 36 patients and again, if necessary, data from the fully expanded study. The data analysis at 40 weeks, which will include radiographic evidence of rickets, is expected in late 2015 or early 2016 for the original 36 patients and mid-2016 for all patients.
• Adult Phase 3 Program Expected to Begin in the Second Half of 2015: Based on discussions with the EMA and FDA, the company plans to initiate a Phase 3 randomized, double-blind, placebo-controlled study in approximately 120 adult patients with XLH. The study will include a 24-week blinded period followed by a 24-week open-label cross-over period. The planned primary endpoint will be serum phosphorus levels at 24 weeks. The Brief Pain Inventory (BPI) patient-reported outcome will be a key secondary endpoint. The study will also evaluate biomarkers of bone remodeling, physical function, and other patient-reported outcomes. Ultragenyx also plans to initiate a 48-week open-label bone quality study in approximately ten adult XLH patients evaluating the impact of KRN23 on underlying osteomalacia via bone biopsy.

Is general: Yes