Ultragenyx and Kyowa Hakko Kirin Announce Additional Burosumab Data in X-Linked Hypophosphatemia (XLH) and Tumor-Induced Osteomalacia (TIO) at ASBMRPositive data in bone disease in pediatric XLH patients under 5 years old and in TIO patients

Novato, CA and Tokyo, Japan— September 11 and 12, 2017 — Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development of novel products for rare and ultra-rare diseases, and Kyowa Hakko Kirin Co., Ltd. (Kyowa Hakko Kirin) today announced positive data from two ongoing Phase 2 studies - 40 week data from the study in children less than five years old with X-linked hypophosphatemia (XLH) and 24 week data from the study in adult tumor-induced osteomalacia (TIO) patients. Data presented at the American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting also included a late-breaker presentation of 24-week data from the Phase 3 study in adult XLH patients, a presentation of 64-week data from another Phase 2 study in pediatric XLH patients (5 to 12 years old), and a poster on functional outcomes in the patients enrolled in this pediatric Phase 2 study. Ultragenyx is conducting the studies under a collaboration and license agreement with Kyowa Hakko Kirin to develop and commercialize burosumab.

"The results from the under five year old study support the value of early treatment initiation with burosumab in XLH patients in treating bone disease," said Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President of Ultragenyx. "The early improvements in bowing observed in these younger patients is a particularly important result for the treatment of XLH bone disease."

"These data are a product of our efforts to develop this antibody in order to make a positive contribution to the lives of patients with XLH and TIO worldwide, "said Mitsuo Satoh, Ph.D., Executive Officer, Vice President, Head of R&D Division of Kyowa Hakko Kirin. "We will continue to conduct studies that strengthen the clinical evidence base for burosumab to contribute to patients with XLH and TIO worldwide."

The open-label Phase 2 study enrolled 13 children between the ages of one and four years old (mean age 2.9 years), 12 of whom had previously been on oral phosphate/active vitamin D therapy. This 64-week study is assessing the safety, pharmacodynamics, and efficacy of burosumab administered subcutaneously every 2 weeks. All patients received 0.8mg/kg starting dose and have completed 40 weeks of treatment.

Burosumab increased mean serum phosphorus levels by 1.2 mg/dL into the low normal range after one week of treatment and these levels were maintained through week 40 with 77% of children achieving normal serum phosphorus levels at week 40. Serum 1,25 dihydroxy vitamin D levels were also increased from baseline to week 40 of treatment.

All patients had rickets at baseline and 12/13 patients had RSS ≥ 1.5. Rickets severity was assessed at 40 weeks using the RSS scoring system. The mean total RSS score improved significantly (59% reduction) at week 40 (p<0.0001). The change in rickets severity was also assessed at week 40 by the RGI-C score which showed substantial healing (RGIC score > 2) in all patients (p<0.0001). Burosumab treatment also resulted in significantly improved bowing as determined by RGI-C lower limb deformity (p<0.0001). Additionally, mean levels of alkaline phosphatase were significantly reduced (-39%, p<0.0001) in these patients at week 40.

All patients experienced one or more adverse events. There was one serious adverse event of a tooth abscess that was considered unrelated to burosumab treatment. All other events were assessed as mild or moderate in severity except for a Grade 3 food allergy that was considered unrelated to burosumab treatment. Three patients had injection site reactions and four patients experienced hypersensitivity events that were all mild and considered unrelated to burosumab treatment. No clinically meaningful changes were observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone. There have been no events of hyperphosphatemia and there have been no deaths or discontinuations from the study.

The open label dose-finding Phase 2 study is evaluating the safety and efficacy of burosumab in 17 adult patients with TIO. The co-primary endpoints in this 48 week study are change in serum phosphorus and key biopsy parameters of osteomalacia. In 16 patients with baseline and week 24 data, mean serum phosphorus, renal phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D levels increased after the first dose and over 24 weeks of treatment. The baseline mean serum phosphorus level of 1.6 mg/dL was well below the lower limit of normal of 2.5 mg/dL. The mean serum phosphorus level entered the normal range within two weeks of treatment, and was maintained in the low normal range through week 24 of treatment. At week 24 there was a statistically significant increase in mean percent change from baseline levels (51% and 38% respectively) of the bone turnover markers, Procollagen type 1 N-terminal propeptide (P1NP) and collagen type 1 cross-linked C-telopeptide of type I collagen (CTx).

All patients had moderate to severe osteomalacia at baseline as assessed by histomorphometric indices of osteomalacia. Four patients who completed 48 weeks of treatment had bone biopsy data. In three of these patients burosumab treatment was associated with improvements in histomorphometric indices of osteomalacia. One patient did not receive burosumab consistently. Burosumab demonstrated a clinically meaningful improvement in patient reported outcomes. At 24 weeks, patients experienced a statistically significant reduction in all four fatigue parameters as assessed by the Brief Fatigue Inventory (BFI). Burosumab also demonstrated a statistically significant increase in lower limb strength as seen with the increase in repetitions at 24 weeks in the Sit-to-Stand test (p<0.01). These results are particularly relevant to the TIO population since weakness and fatigue are key clinical problems that these patients experience

Adverse events occurred in all patients (n=16). Treatment-related adverse events were observed in seven patients (44%), and included, as previously disclosed, Vitamin D deficiency and rash, and dysgeusia, all mild in grade. Three patients had a serious adverse event(previously disclosed tumor progression, thoracic epidural tumor compression, and a mesenchymal tumor progression). None of the serious adverse events were considered treatment related and all of these patients had a history of tumor progression at baseline and one patient discontinued to treat their tumor progression. Most adverse events were grade 1 or 2 and included two patients with injection site reactions and two patients with restless leg syndrome that were previously disclosed. No clinically meaningful changes were observed in mean serum calcium, urinary calcium and in serum intact parathyroid hormone.