Announcement of Results from Long-Term Phase 1/2 Study of KRN23 in X-linked Hypophosphatemia in Adults

September 16, 2014

Tokyo, Japan, September 16, 2014 --- Kyowa Hakko Kirin Co., Ltd. (Tokyo; 4151, President and CEO: Nobuo Hanai, "Kyowa Hakko Kirin") announced the presentation of results from a long-term Phase 1/2 study of the investigational anti-FGF23 monoclonal antibody KRN23 in adult patients with X-linked hypophosphatemia (XLH). XLH is an inherited metabolic bone disease characterized by an excess of FGF23 which causes hypophosphatemia, leading to rickets and osteomalacia associated with short stature, skeletal deformities, bone pain, fractures, and muscle weakness. The data were presented at the American Society of Bone and Mineral Research (ASBMR) Annual Meeting in Houston, TX.

The Phase 1/2 extension study (KRN23-INT-002) was designed to evaluate long-term safety and efficacy following an initial 4-month dose escalation study (KRN23-INT-001) that was conducted in the US and Canada. During the extension study (KRN23-INT-002), 22 adult patients with XLH were evaluated for an additional 12-months. Patients received subcutaneous injections of KRN23 every 28 days at a dose range of 0.1 to 1 mg/kg.

Data from the KRN23 INT-002 study demonstrated that the increases in serum phosphorus levels, urinary phosphorous reabsorption, and 1,25 dihydroxy vitamin D₃ levels observed in the initial KRN23 INT-001 study were generally sustained during the 12-month extension. All of the patients continued to demonstrate improvement in serum phosphorus levels. The majority of patients had serum phosphorus levels in the normal range (2.5 to 4.5 mg/dL) at peak time by Day 7 or Day 14 for each dosing interval over the 12-month period. Additionally, the mean increases in markers of bone remodeling (procollagen type I N propeptide (P1NP) and osteocalcin) observed in KRN23 INT-001 were generally sustained in the extension study.

KRN23 was well tolerated over the long-term treatment period. The most common treatment-related adverse events were injection site reaction, diarrhea, arthralgia, injection site erythema, restless legs syndrome, injection site pain, upper abdominal pain, headache, and decreased neutrophil count.

Serious adverse events were reported in three subjects but were unrelated to KRN23. One patient discontinued treatment due to nephrolithiasis and one patient discontinued due to restless legs syndrome. There were no significant changes in parathyroid hormone or renal ultrasound. Serum calcium levels did not change significantly, and mild hypercalcemia was observed intermittently in two subjects. Three subjects had transient hypercalciuria and urinary calcium was not increased. No anti-KRN23 antibodies were observed.

In the US and EU, Kyowa Hakko Kirin and Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) initiated a Phase 2 study of KRN23 in pediatric patients in June 2014 and expect to continue the clinical development of KRN23 in adults with XLH.

About X-linked Hypophosphatemia (XLH): XLH is a disorder of phosphate metabolism caused by phosphate wasting in the urine leading to severe hypophosphatemia. XLH is the most common heritable form of rickets that is inherited as an X-linked dominant trait affecting both males and females, though some reports indicate that the disease may be more severe in males. Studies suggest there are approximately 12,000 XLH patients in the United States. XLH is a distinctive bone disease characterized by inadequate mineralization of bone that leads to a spectrum of abnormalities, including rickets, progressive bowing of the leg, osteomalacia, bone pain, waddling gait, short stature, gross motor impairment, muscle weakness, osteopenia, frequent/poorly healing microfractures, spinal stenosis, enthesopathy, and osteoarthritis.
Most patients are managed using oral phosphate replacement and vitamin D (calcitriol) therapy, which requires frequent divided doses and careful medical monitoring. It is partially effective at reducing rickets, but it does not improve growth and can be challenging to optimize the dose without increasing the risk of depositing phosphate-calcium precipitates in the kidneys (nephrocalcinosis).
About KRN23 and FGF23: KRN23 is an investigational recombinant fully human monoclonal IgG1 antibody discovered by KHK against the phosphaturic hormone fibroblast growth factor 23 (FGF23) being developed to treat XLH, 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 KHK entered into a collaboration and license agreement in August 2013 to develop and commercialize KRN23.
About Ultragenyx: Ultragenyx is a clinical-stage biotechnology company committed to bringing to market novel products for the treatment of rare and ultra-rare diseases, with a focus on serious, debilitating genetic diseases. Founded in 2010, the company has rapidly built a diverse portfolio of product candidates with the potential to address diseases for which the unmet medical need is high, the biology for treatment is clear, and for which there are no approved therapies.
The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx's strategy is predicated upon time and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency.
For more information on Ultragenyx, please visit the company's website at www.ultragenyx.com.

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