Ultragenyx and Kyowa Kirin Announce Topline Phase 3 Study Results Demonstrating Superiority of Crysvita® (burosumab) Treatment to Oral Phosphate and Active Vitamin D in Children with X-Linked Hypophos

Novato, California, Tokyo and London (ots/PRNewswire) -

Substantial Healing of Rickets Observed in 72% of Patients
Treated with Crysvita Compared to 6% of Patients Receiving
Conventional Therapy at 40 Weeks

Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical
company focused on the development of novel products for rare and
ultra-rare diseases, Kyowa Hakko Kirin Co. Ltd (Kyowa Hakko Kirin),
and Kyowa Kirin International PLC (Kyowa Kirin International) today
announced that the Phase 3 study of Crysvita® (burosumab) met its
primary endpoint demonstrating that Crysvita was superior to oral
phosphate and active vitamin D (conventional therapy) in improving
rickets in children with X-linked hypophosphatemia (XLH) after 40
weeks of treatment (LS Mean treatment difference of +1.14,
p<0.0001). The study also showed improvement in important metabolic
and functional measures with Crysvita treatment, and a safety profile
similar to that observed in other Crysvita pediatric XLH studies.
Crysvita is an antibody that blocks fibroblast growth factor 23
(FGF23), a hormone that causes phosphate urinary excretion and
suppresses active vitamin D production by the kidney.

"This is the first study that directly compares Crysvita to
conventional therapy for XLH, and we have now clearly demonstrated
that Crysvita has a rapid and profound effect on the underlying
disease, an outcome that was not achieved with conventional therapy,"
said Camille L. Bedrosian, M.D. Chief Medical Officer of Ultragenyx.
"These data reinforce the results seen in our earlier Phase 2
studies, and we believe that Crysvita will transform the treatment of
XLH in children."

"The results of this important controlled study demonstrate the
value of directing therapy at the mechanism of renal phosphate
wasting in XLH," said the lead study investigator, Erik Imel, M.D.,
Associate Professor of Medicine and Pediatrics at Indiana University
School of Medicine. "While prior conventional therapy fails to
improve renal phosphate wasting, Crysvita works to improve serum
phosphorus by correcting the renal phosphate wasting. The differences
in mechanism are clearly important to outcomes as demonstrated in
this study. By comparing XLH patients treated with Crysvita to
patients treated with conventional therapy, we are finally able to
demonstrate the magnitude of benefit on parameters of serum
phosphorus, bone metabolism, and improvements in the skeleton."

"I am pleased that the study provides valuable data for pediatric
patients with XLH," said Mitsuo Satoh, Executive Officer, Vice
President Head of Research and Development Division of Kyowa Hakko
Kirin. "I believe Crysvita has the potential to be an effective
treatment option for patients with XLH."

Phase 3 Pediatric XLH Study

The randomized, open-label Phase 3 clinical study enrolled 61
patients ages one through 12 in the US, Europe, Canada, Australia,
Japan, and Korea, and compared the efficacy and safety of Crysvita
(n=29) to conventional therapy (n=32). The study's primary endpoint
was the change in rickets at 40 weeks, assessed by three independent
blinded pediatric radiologists using the radiographic global
impression of change (RGI-C) scale. Secondary endpoints included
additional rickets assessments using the RGI-C scale and the Thacher
Rickets Severity Scoring (RSS) system, pharmacodynamic assessments,
changes in growth velocity and height, walking ability,
patient-reported outcomes assessing pain, fatigue and physical
function, and safety. Prior to study enrollment, all patients
received conventional therapy for an average of approximately four
years. Patients in the Crysvita treatment group received a starting
dose of 0.8 mg/kg administered subcutaneously every two weeks, with
dose increases up to 1.2 mg/kg implemented in five patients. Patients
in the conventional therapy arm received the local standard regimen
based on expert guidelines with ongoing optimization by each
patient's physician.

Bone Disease Results

The study met its primary endpoint demonstrating that Crysvita
significantly improved rickets compared to conventional therapy, as
assessed by three independent blinded pediatric radiologists using
the RGI-C scale. In addition, substantial healing (RGI-C >= +2.0) was
observed in 72% of patients receiving Crysvita compared to 6% of
patients receiving conventional therapy.

Rickets severity was also assessed using the RSS scoring system,
which showed that patients treated with Crysvita showed a 2.8-fold
improvement in rickets compared to patients receiving conventional
therapy.

Endpoint Treatment Effect
Treatment difference

(95% CI)
Crysvita Conventional
Crysvita vs. conventional
n=29 therapy
therapy
n=32
RGI-C Score (Primary Endpoint)
LS Mean* +1.92 +0.77
1.14

(0.83, 1.45)

P<0.0001

Substantial healing, % patients Odds
ratio: 39.139
(RGI-Cgreater than or equal
(7.238, 211.656)
to +2.0) 72% 6%
P<0.0001
RSS Total Score
-1.34
(-1.74, -0.94)
LS Mean Change from Baseline -2.04 -0.71
P<0.0001

*LS Mean: Least Squares Mean

Metabolic Measures and Other Secondary Endpoints

At baseline, patients in both the Crysvita and conventional
therapy arms had mean serum phosphorus levels and mean renal
phosphate reabsorption levels below the lower limits of normal. In
the Crysvita arm, mean serum phosphorus and renal phosphate
reabsorption levels post-baseline through Week 40 were in the normal
range. In the conventional therapy arm, mean serum phosphorus and
renal phosphate reabsorption levels remained below the lower limits
of normal over the 40-week period.

Endpoint Treatment Effect
Treatment

difference

Crysvita Conventional
Crysvita vs.
therapy
conventional
n=29 n=32
therapy
Serum Phosphorus (mg/dL)*
Mean baseline 2.42 2.30
Mean post-baseline 3.38 2.55
LS Mean Change from Baseline 1.00 0.23
0.77

p<0.0001

*Serum phosphorus lower limit of normal: 3.2mg/dL

Patients in both the Crysvita and conventional therapy arms
demonstrated increases in serum 1,25-dihidroxy vitamin D, and
maintained levels within the normal range through 40 weeks.

Treatment with Crysvita showed a significant improvement in mean
alkaline phosphatase levels into the normal range after 40 weeks of
treatment, compared to conventional therapy. Patients treated with
Crysvita also demonstrated a greater numeric but not statistically
significant improvement in growth (height z-score and growth
velocity) and in the six-minute walk test, compared to conventional
therapy.

Safety and Tolerability

The Crysvita safety profile observed in this study was generally
consistent with that seen in other Crysvita pediatric XLH studies.
There were no treatment discontinuations and no deaths reported in
the study. There were three serious adverse events in the Crysvita
arm and one serious adverse event in the conventional therapy arm,
none of which were considered treatment-related. In the Crysvita arm,
45% of patients had injection site reactions, all but one were mild
and none were considered serious. No clinically meaningful changes
were observed in mean serum calcium and serum intact parathyroid
hormone in either treatment arm. No clinically significant changes
were observed in renal ultrasounds pre-and post-treatment in either
treatment arm.

Full results will be presented at an upcoming medical meeting.

About X-linked hypophosphatemia (XLH)

XLH is a rare, hereditary, progressive and lifelong skeletal
disorder characterized by renal phosphate wasting caused by excess
FGF23 production. It affects both children and adults. In children,
XLH causes rickets that leads to lower-extremity deformity, delayed
growth and decreased height. Adults with XLH have an increased risk
of fractures.

About Crysvita

Crysvita is a recombinant fully human monoclonal IgG1 antibody,
discovered by Kyowa Hakko Kirin, against the phosphaturic hormone
fibroblast growth factor 23 (FGF23). FGF23 is a hormone that reduces
serum levels of phosphorus and active vitamin D by regulating
phosphate excretion and active vitamin D production by the kidney.
Phosphate wasting in XLH is caused by excessive levels and activity
of FGF23. Crysvita is designed to bind to and thereby inhibit the
biological activity of FGF23. By blocking excess FGF23 in patients,
Crysvita is intended to increase phosphate reabsorption from the
kidney and increase the production of active vitamin D, which
enhances intestinal absorption of phosphate and calcium.

On April 17, 2018 the U.S. Food and Drug Administration (FDA)
approved Crysvita for the treatment of XLH in adult and pediatric
patients 1 year of age and older. On February 23, 2018 Crysvita
received a positive European Commission decision granting conditional
marketing authorization Crysvita for the treatment of XLH with
radiographic evidence of bone disease in children 1 year of age and
older and adolescents with growing skeletons. This Phase 3 pediatric
study will serve as a confirmatory study in Europe; it was not
required for the regulatory application in the U.S.

Kyowa Hakko Kirin, Kyowa Kirin International, a wholly owned
subsidiary of Kyowa Hakko Kirin, and Ultragenyx have been
collaborating in the development and commercialization of Crysvita
globally, based on the collaboration and license agreement between
Kyowa Hakko Kirin and Ultragenyx.

INDICATION (IN THE U.S.)

Crysvita is indicated for the treatment of X-linked
hypophosphatemia (XLH) in adult and pediatric patients one year of
age and older.

IMPORTANT SAFETY INFORMATION

Crysvita should not be taken if:

- An oral phosphate supplement and a specific form of vitamin D
supplement are taken
- Phosphorus levels from a blood sample are within or above the
normal range for age
- Kidney problems are present

What is the most important information to know about Crysvita?

- Some patients developed allergic reactions (rash and hives) while
taking Crysvita. Doctors will monitor for symptoms of an allergic
reaction while Crysvita is taken.
- High levels of phosphorus in the blood have been reported in some
patients taking Crysvita. This may be related to a risk of high
calcium levels in the kidneys. Doctors will collect samples to
monitor levels.
- Administration of Crysvita may result in reactions at the injection
site, such as hives, reddening of the skin, rash, swelling,
bruising, pain, severe itching of the skin, and collection of blood
outside of a blood vessel (hematoma).

What are the possible side effects of Crysvita?

- The most common adverse reactions that were seen in children with
XLH are: - Headache
- Injection site reaction
- Vomiting
- Fever
- Pain in arms and legs
- Decreased vitamin D levels
- Rash
- Toothache
- Muscle pain
- Tooth infection
- Dizziness
- The most common adverse reactions that were seen in adults with XLH
are: - Back pain
- Headache
- Tooth infection
- Restless leg syndrome
- Decreased vitamin D levels
- Dizziness
- Constipation
- Phosphorus levels increased in the blood
- Narrowing of the spaces within the spine is common in adults with
XLH and pressure on the spinal cord has been reported in adults
taking Crysvita. It is not known if taking Crysvita worsens the
narrowing of the spaces within the spine or the pressure on the
spinal cord.

Before taking Crysvita, doctors should be informed about all
medical conditions, including if:

- One is pregnant, thinks she may be pregnant, or plans to become
pregnant. There is not enough experience to know if Crysvita may
harm an unborn baby. Report pregnancies to the Ultragenyx Adverse
Event reporting line at 1-888-756-8657.
- One is breastfeeding or plans to breastfeed. There is not enough
experience to know if Crysvita passes into breast milk. Women
should talk with their doctors about the best way to feed their
babies while taking Crysvita.

While taking Crysvita, doctors should be informed if one
experiences:

- An allergic reaction such as rash or hives
- A rash, swelling, bruising or other reaction at the injection site
- New or worsening restless leg syndrome

These are not all the possible side effects of Crysvita. Doctors
should be contacted for medical advice about side effects.

Side effects may be reported to the FDA at (800) FDA-1088 or
http://www.fda.gov/medwatch. Side effects may also be reported to
Ultragenyx at 1-888-756-8657.

Please see full Prescribing Information (http://www.ultragenyx.com
/file.cfm/29/docs/Crysvita_Full_Prescribing_Information.pdf) for
additional Important Safety Information.

About Ultragenyx

Ultragenyx is a biopharmaceutical company committed to bringing to
patients novel therapies 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
approved and investigational therapies 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 http://www.ultragenyx.com.

About Kyowa Kirin

Kyowa Hakko Kirin Co., Ltd. is a research-based life sciences
company, with special strengths in biotechnologies. In the core
therapeutic areas of oncology, nephrology and immunology/allergy,
Kyowa Hakko Kirin leverages leading-edge biotechnologies centred on
antibody technologies, to continually discover innovative new drugs
and to develop and market those drugs world-wide. In this way, the
company is working to realise its vision of becoming a Japan-based
global specialty pharmaceutical company that contributes to the
health and wellbeing of people around the world.

Kyowa Kirin International PLC is a wholly owned subsidiary of
Kyowa Hakko Kirin and is a rapidly growing specialty pharmaceutical
company engaged in the development and commercialisation of
prescription medicines for the treatment of unmet therapeutic needs
in Europe and the United States. Kyowa Kirin International is
headquartered in Scotland.

You can learn more about the business at:
http://www.kyowa-kirin.com .

Forward-Looking Statements

Except for the historical information contained herein, the
matters set forth in this press release, including statements
relating to Ultragenyx's plans or expectations regarding the
availability of Crysvita, and the potential effectiveness of
Crysvita as a treatment option, are forward-looking statements
within the meaning of the "safe harbor" provisions of the Private
Securities Litigation Reform Act of 1995. Such forward-looking
statements involve substantial risks and uncertainties that could
cause our clinical development programs, future results, performance
or achievements to differ significantly from those expressed or
implied by the forward-looking statements. Such risks and
uncertainties include, among others, the uncertainties inherent in
the clinical drug development process, such as the regulatory
approval process, the timing of regulatory filings, and other matters
that could affect sufficiency of existing cash, cash equivalents and
short-term investments to fund operations and the availability or
commercial potential of our drug candidates. Ultragenyx undertakes no
obligation to update or revise any forward-looking statements. For a
further description of the risks and uncertainties that could cause
actual results to differ from those expressed in these
forward-looking statements, as well as risks relating to the business
of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form
10-Q filed with the Securities and Exchange Commission on May 8,
2018, and its subsequent periodic reports filed with the Securities
and Exchange Commission.

ots Originaltext: Ultragenyx Pharmaceutical Inc. and Kyowa Kirin
Im Internet recherchierbar: http://www.presseportal.de

Contact:
media@kyowa-kirin.co.jp. Contact Kyowa Kirin International PLC
Media
Callum Spreng
Spreng Thomson Ltd. (For Kyowa Kirin International PLC)
+44(0)141-548-5191
Mobile: +44(0)7803-970103

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