Kyowa Shares KRN23 Data From a First-in-Human, Single Dose Phase 1 Study

Kyowa Shares KRN23 Data

Announcement of Results from a Single Dose Phase 1 Study of a Human Monoclonal Anti-FGF23 Antibody (KRN23) in X-linked Hypophosphatemia in Adults

Tokyo, Japan, October 7, 2013 -- Kyowa Hakko Kirin Co., Ltd. (Tokyo; 4151, President and CEO: Nobuo Hanai, "Kyowa Hakko Kirin") announced that results from a first-in-human, single dose Phase 1 study of a human monoclonal anti-FGF23 antibody (KRN23) in X-linked hypophosphatemia (XLH) in adults were presented at the American Society of Bone Mineralization Research (ASBMR) 2013 Annual Meeting on October 6, 2013. A randomized, double-blind, placebo-controlled, Phase I study (US-02) was conducted to assess its safety, tolerability, pharmacokinetics and pharmacodynamics in adult patients with XLH. Thirty-eight adults with XLH were randomized to receive single doses of KRN23 or placebo via intravenous (IV) (0.003 to 0.3 mg/kg) or subcutaneous (SC) (0.1 to 1.0 mg/kg) routes.

Data were presented by Thomas Carpenter, MD, Yale University at the ASBMR 2013 Annual Meeting. The study showed single doses of either IV or SC KRN23 increased serum phosphate level compared to placebo for higher doses (p<0.01). Peak serum phosphate effects occurred later with SC (8-15 days) than with IV dosing (0.5-4 days). Duration of effect on phosphate was dose-related, greater with SC than IV, and persisted beyond 29 days with SC. Increases in renal reabsorption of phosphate and 1,25 dihydroxyvitamin D were observed. No meaningful changes in serum calcium, serum parathyroid hormone, and urinary calcium excretion occurred. The majority of adverse events were mild, and there were no serious adverse events, and no changes in safety biochemistries, electrocardiograms, or renal sonograms. No patient developed anti-KRN23 antibodies. Single dose administration of KRN23 was safe and well-tolerated.

Kyowa Hakko Kirin has a collaboration and license agreement with Ultragenyx Pharmaceutical Inc. ("Ultragenyx") to jointly develop and commercialize KRN23. Kyowa Hakko Kirin and Ultragenyx plan to continue the development of KRN23 in adult XLH patients while initiating a pediatric XLH program in 2014.

About KRN23 and FGF23
KRN23 is a recombinant fully human monoclonal IgG1 antibody discovered by KHK and being developed to treat X-linked hypophosphatemia (XLH). KRN23 is designed to bind to and thereby reduce the biologic activity of fibroblast growth factor 23 (FGF23). FGF23 is a hormone that promotes phosphate excretion by the kidney and suppresses vitamin D production. FGF23 also reduces the expression of the enzyme that is required to synthesize a hormone that normally increases renal tubular absorption of both phosphate and calcium. Therefore, FGF23 induces profound reductions in serum phosphate levels. Phosphate wasting in XLH is caused by excessive levels and activity of FGF23.

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 the disease in males by some reports may be more severe. XLH is a distinctive bone disease characterized by inadequate mineralization of bone that leads to a spectrum of abnormalities, including progressive bowing of the leg, osteomalacia, bone pain, waddling gait, short stature, gross motor impairment, muscle weakness, osteopenia, frequent/poorly healing microfractures, spinal stenosis and osteoarthritis.

Most patients are managed using oral phosphate replacement and vitamin D (calcitriol) therapy, which is poorly tolerated and only partially effective at restoring bone physiology and growth. Current treatment with oral phosphate requires extremely close monitoring and can result in complications such as secondary hyperparathyroidism, hypercalciuria, hypercalcemia and nephrocalcinosis. XLH was originally called vitamin D-resistant rickets, because doses of vitamin D effective for the treatment of vitamin D-deficient nutritional rickets did not have an impact on phosphate levels in these patients.

About Ultragenyx Pharmaceutical Inc.
Ultragenyx is a privately held, clinical-stage biotechnology company committed to bringing to market life-transforming therapeutics for patients with rare and ultra-rare metabolic genetic diseases. Founded in 2010, the company is rapidly building 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 effective treatments.

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.

Contact:
Kyowa Hakko Kirin
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+81-3-3282-1903


Posted: October 2013

XLH Network's Scientific Advisory Board presenting papers at ASBMR

XLH Network's Scientific Advisory Board members are presenting papers at this year’s American Society of Bone and Mineral Research (ASBMR) held in Baltimore Maryland, USA, October 4-7. Scientific advisors Carolyn Macica, Ph.D, Thomas Carpenter, M.D., Michael Econs, M.D., Suzanne Jan de Beur, M.D., and Peter S. N. Rowe, Ph.D., along with distinguished colleagues, are presenting papers on the following topics.

INTRACORTICAL REMODELING TO MEET MINERAL DEMANDS IN X-LINKED HYPOPHOSPHATEMIA (XLH)

Carolyn Macica*1, Richard Feinn2, Steven Tommasini3. 1Frank H. Netter School of Medicine Quinnipiac University, USA, 2Frank H. Netter, M.D., School of Medicine at Quinnipiac University, USA, 3Yale School of Medicine, USA Disclosures: Carolyn Macica, None

METABOLIC BONE DISEASE AND DISORDERS OF MINERAL

METABOLISM: IDIOPATHIC HYPERCALCIURIA, NEPHROLITHIASIS

Increased Frequency of Renal Stones and Nephrocalcinosis in Heterozygous and Homozygous Carriers of Sequence Variations in SLC34A3/NPT2c

Clemens Bergwitz*1, Monica Reyes2, Amita Sharma2, Thomas Carpenter3, Marco Janner4, Andrew Biggin5, Shamir Tuchman6, H. Jorge Baluarte7, Shoji Ichikawa8, Craig Munns5, Harald Jueppner2. 1Massachusetts General Hospital & Harvard Medical School, USA,2Massachusetts General Hospital, USA, 3Yale University School of Medicine, USA, 4University Children’s Hospital, Switzerland, 5The Children’s Hospital at Westmead, Australia, 6Children’s National Medical Center, USA, 7The Children’s Hospital of

Philadelphia, USA, 8Indiana University School of Medicine, USA

Disclosures: Clemens Bergwitz, None

PHARMACOKINETICS AND PHARMACODYNAMICS OF A HUMAN MONOCLONAL ANTI-FGF23 ANTIBODY (KRN23) AFTER SINGLE-DOSE ADMINISTRATION TO PATIENTS WITH X-LINKED HYPOPHOSPHATEMIA

Xiaoping Zhang*1, Thomas Carpenter 2, Erik Imel3, Mary Ruppe4, Thomas Weber5, Mark Klausner1, Tetsuyoshi Kawakami1, Takahiro Ito1, Jeffery Humphrey1, Karl Insogna2, Munro Peacock6. 1Kyowa Hakko Kirin Pharma Inc, USA, 2Yale University School of

Medicine, USA, 3Indiana University School of Medicine, USA, 4The Methodist Hospital, USA, 5Duke University Medical Center, USA, 6Indiana University Medical Center, USA

Disclosures: Xiaoping Zhang, Kyowa Hakko Kirin Pharma Inc, 3

2013 ASBMR MOST OUTSTANDING CLINICAL ABSTRACT AWARD

Thomas O. Carpenter, M.D.

2013 ASBMR Most Outstanding Clinical Abstract Award

A FIRST-IN-HUMAN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE-DOSE STUDY OF A HUMAN MONOCLONAL ANTI-FGF23 ANTIBODY (KRN23) IN X-LINKED HYPOPHOSPHATEMIA

Thomas Carpenter*1, Erik Imel2, Mary Ruppe3, Thomas Weber4, Mark Klausner5, Margaret Wooddell6, Tetsuyoshi Kawakami6, Takahiro Ito6, Xiaoping Zhang6, Jeffrey Humphrey6, Karl Insogna1, Munro Peacock7. 1Yale University School of Medicine, USA,

2Indiana University School of Medicine, USA, 3The Methodist Hospital, USA, 4Duke University Medical Center, USA, 5Kyowa Hakko Kirin, USA, 6Kyowa Hakko Kirin Pharma Inc, USA, 7Indiana University Medical Center, USA

Disclosures: Thomas Carpenter, Kyowa Hakko Kirin Inc., 2; Kyowa Hakko Kirin Inc., 5

GENETIC RESCUE OF GLYCOSYLATION-DEFICIENT FGF23 IN THE GALNT3-NULL MOUSE

Shoji Ichikawa*1, Amie Gray1, Erica Clinkenbeard2, Kenneth White1, Michael Econs 1.

1Indiana University School of Medicine, USA, 2Indiana University-Purdue University

Indianapolis, USA

Disclosures: Shoji Ichikawa, None

DOSAGE EFFECT OF A PHEX MUTATION IN A MURINE MODEL OF X-LINKED HYPOPHOSPHATEMIA

Shoji Ichikawa*, Amie Gray, Emmanuel Bikorimana, Michael Econs. Indiana University School of Medicine, USA

Disclosures: Shoji Ichikawa, None

SIBLING FAMILY GENES AND BONE MINERAL DENSITY: ASSOCIATION AND ALLELE-SPECIFIC EXPRESSION IN HUMAN

Imranul Alam*1, Leah Padgett2, Shoji Ichikawa1, Mohammed Alkhouli2, Daniel Koller1, Dongbing Lai3, Munro Peacock4, Xiaoling Xuei5, Tatiana Foroud3, Howard Edenberg6, Michael Econs1. 1Indiana University School of Medicine, USA, 2Medicine, IUPUI, USA, 3Medical & Molecular Genetics, IUPUI, USA, 4Indiana University Medical Center, USA, 5Biochemistry & Molecular Biology, USA, 6Biochemistry & Molecular Biology, Medicine,

IUPUI, USA

Disclosures: Imranul Alam, None

IRON STATUS REGULATES SERUM C-TERMINAL FGF23 IN HEALTHY ADULT WOMEN.

Erik Imel*1, Siu Lui Hui1, Amie Gray1, Dena Acton1, Anthony Acton1, Leah Padgett1, Munro Peacock2, Michael Econs 1. 1Indiana University School of Medicine, USA, 2Indiana University Medical Center, USA

Disclosures: Erik Imel, Kyowa Hakko Kirin Pharma, Inc., 2; Kyowa Hakko Kirin Pharma, Inc., 5

OSTEOSARCOMA CELLS MODULATE BONE MICROENVIRONMENT VIA EXTRACELLULAR MEMBRANE VESICLE

Biogenesis and Calcium Signaling Pathways

Rama Garimella*1, Laurie Washington2, Janalee Isaacson3, Ossama Tawfik4, Raymond

Perez5, Peter Rowe 1, Julian Vallejo6, Madoka Spence7, Marco Brotto8. 1University of Kansas Medical Center, USA, 2Division of Medical Clinical Oncology, Department of Internal Medicine, The University of Kansas Medical Center, USA, 3Muscle Biology Research Group, School of Nursing & Health Studies, University of Missouri-Kansas City, USA, 4Department of Pathology, The University of Kansas Medical Center, USA, 5Division of Medical Clinical Oncology, Department of Internal Medicine, The University

of Kansas Cancer Center, The University of Kansas, USA, 6Muscle Biology Research Group, School of Nursing & Health Sciences, The University of Missouri-Kansas City, USA, 7Muscle Biology Research Group, School of Nursing & Health Studies, The University of Missouri-Kansas City, USA, 8University of Missouri - Kansas City, USA

Disclosures: Rama Garimella, None

Suzanne Jan de Beur is chairing a session:

DISTINGUISHED ORALS - NEW PERSPECTIVES IN METABOLIC BONE DISEASE

8:00 am - 10:00 am Baltimore Convention Center

Hall A

Moderators:

Suzanne Jan De Beur, M.D.

Johns Hopkins University, USA

Disclosures: Suzanne Jan De Beur, None

Roland Chapurlat, M.D., Ph.D.

E. Herriot Hospital, France

Disclosures: Roland Chapurlat, None