Ultragenyx Reports Positive 16-Week Interim Data from Pediatric Phase 2 Study of KRN23: No Serious Adverse Events Reported, Sees Potential Conditional Approval Pathway in Europe

Ultragenyx Pharmaceutical Inc. RARE, a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, today announced positive 16-week data from the ongoing pediatric Phase 2 study and provided a regulatory update for its recombinant human monoclonal antibody KRN23 against fibroblast growth factor 23 (FGF23) for the treatment of X-linked hypophosphatemia (XLH). XLH is an inherited metabolic bone disease characterized by short stature, skeletal deformities, bone pain, fractures, and muscle weakness. Ultragenyx and Kyowa Hakko Kirin entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23. Positive Interim Safety and Efficacy Data from Phase 2 Study in Pediatric XLH Patients 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. "The 16-week data from the Phase 2 study in pediatric XLH patients corroborates the Phase 1/2 data in adults demonstrating increases in serum phosphorus in all patients and a favorable safety and tolerability profile," commented Sunil Agarwal, M.D., Chief Medical Officer of Ultragenyx. "Based on the positive data and productive discussions with the U.S. and European regulatory agencies we are expanding our Phase 2 pediatric study and moving ahead with a Phase 3 program in adults." 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. Potential Conditional Approval Pathway in Europe 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 U.S. Food and Drug Administration (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. Both studies are expected to start in the second half of 2015.