NOVATO, California,
TOKYO and LONDON, December 4,
2017 /PRNewswire/ --
Further improvement in
disease symptoms and fracture healing observed
through 48 weeks of treatment with burosumab
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) and Kyowa Kirin International PLC
(Kyowa Kirin International) today announced positive 48-week data
from the randomized, double-blind, placebo-controlled Phase 3 study
of burosumab (KRN23) in adults with X-linked hypophosphatemia
(XLH). Treatment with burosumab for 48 weeks showed sustained
maintenance of normal serum phosphorus levels and further
improvement in stiffness, physical function and pain. Patients who
crossed over from placebo to burosumab after 24 weeks showed
normalization of serum phosphorus and improvement in stiffness,
pain and physical functioning. An increased rate of fracture
healing, in favor of burosumab treated patients, was observed
during the first 24 weeks of burosumab treatment and this increased
up to 48 weeks of treatment. Placebo patients who crossed over to
burosumab showed a similar increased rate of fracture healing. The
safety profile was consistent with what has been previously
observed in this study and in other open label studies of burosumab
in adults and children. Ultragenyx is conducting the study under a
collaboration and license agreement with Kyowa Hakko Kirin.
Burosumab is being developed by Ultragenyx, Kyowa Hakko Kirin and
Kyowa Kirin International.
"This longer term data on symptom improvement and fracture
healing support burosumab's potential value in treating serious
disease symptoms and promoting bone healing in adult patients with
XLH," said Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and
President of Ultragenyx. "The continued clinical improvements
in patients and the new data demonstrating a significant decrease
in pain medication use after treatment with burosumab provide
further support for the potential value in the treatment of adults
with XLH."
"This study provides valuable additional long term data for
adult patients with XLH," said Mitsuo
Satoh, Executive Officer, Vice President, Head of Research
and Development Division of Kyowa Hakko Kirin. "I believe burosumab
has the potential to be an effective treatment option for patients
with XLH."
"The longer term data from this adult Phase 3 study demonstrates
the potential of burosumab to positively impact the lives of
patients with XLH and we look forward to progressing our
discussions with the regulatory bodies in Europe and the US," said Dr. Tom Stratford, President and CEO of Kyowa Kirin
International.
48-Week Efficacy Results
The study enrolled 134 patients, randomized 1:1 to burosumab at
a dose of 1 mg/kg or placebo every four weeks for a 24-week double
blind period. After 24 weeks, patients from both treatment arms
continued on to an open-label period, during which they all
received 1mg/kg of burosumab every four weeks.
From 24 to 48 weeks of treatment, 84% of patients who had
received burosumab since the beginning of the study (n=68) achieved
and maintained serum phosphorus levels above the lower limit of
normal (2.5 mg/dL). 89% of patients who crossed over from placebo
to burosumab after 24 weeks (n=66) achieved and maintained serum
phosphorus levels above the lower limit of normal.
Patients treated with burosumab showed continued improvement in
stiffness and physical function as measured by the Western Ontario and McMaster Universities
Osteoarthritis Index (WOMAC®). For patients treated with burosumab,
stiffness further improved from a mean change of 7.42 points at 24
weeks to 16.03 points at 48 weeks. Patients who crossed over from
placebo to burosumab treatment had a mean change of 15.82 points
from 24 to 48 weeks. Physical function also further improved from a
mean change of 2.78 points at 24 weeks to 7.76 points at 48 weeks.
For patients in the crossover group, physical function improved by
a mean change of 8.18 points from 24 to 48 weeks.
Burosumab was associated with a reduction in pain measured by
the Brief Pain Inventory Question 3 (BPI Q3; pain at its worst in
the last 24 hours), as well as a reduction in the use of pain
medication. For patients treated with burosumab, pain scores
further improved from a mean change of 0.81 points at 24 weeks to
1.09 points at 48 weeks. Patients who crossed over from placebo to
burosumab treatment had a mean change of 1.18 points from 24 to 48
weeks. The patient frequency of reported opioid use decreased by
76% from 17 patients (25%) at baseline to four patients (6%) at
week 48 in the burosumab group, and by 70% from 13 patients (20%)
to four patients (6%) in the crossover group. The patient frequency
of reported nonsteroidal anti-inflammatory drugs (NSAIDs) use
decreased by 72% from 47 patients (69%) at baseline to 13 patients
(19%) at week 48 in the burosumab group, and by 74% from 43
patients (65%) to 11 patients (17%) in the crossover group.
Burosumab treatment resulted in increased healing of fractures
(active fractures and pseudofractures) compared to placebo at week
24, and this improvement continued through 48 weeks. When
evaluating follow-up X-rays in the 52% of patients with identified
fractures or pseudofractures at baseline, the 43% rate of fracture
healing observed at 24 weeks on burosumab increased to 63% at 48
weeks. In the crossover group which had an 8% rate of
fracture healing at 24 weeks, the rate increased to 35% at week 48.
The crossover patient group fracture healing result was consistent
with the effect observed in the first 24 weeks of the burosumab
group treatment.
Safety Results
There was no difference in the overall frequency of treatment
emergent serious and non-serious adverse events, treatment related
adverse events and serious adverse events between the group who
received burosumab for the 48-week period compared to the group who
received placebo for the 24-week double-blind period and then
crossed over to burosumab. The safety profile at 48 weeks was
generally similar to that observed at 24 weeks. The most common
adverse events in patients during treatment with burosumab
(>10%) were arthralgia (24%), nasopharyngitis (22%), headache
(20%), back pain (16%), tooth abscess (13%), fatigue (13%),
restless leg syndrome (11%), pain in extremity (11%), pain (11%),
toothache (11%), vitamin D deficiency (10%), and musculoskeletal
pain (10%). Eleven % of patients who received burosumab experienced
clinical symptoms compatible with hypersensitivity. There were 15
patients who experienced serious adverse events (SAEs) during
treatment with burosumab, but none of these SAEs were considered
treatment-related. No meaningful changes were observed in serum
intact parathyroid hormone levels or ectopic mineralization as
assessed by renal ultrasounds or echocardiograms.
Of the 134 patients enrolled in the study, one patient in the
burosumab arm discontinued treatment during the 24-week
double-blind treatment period, as previously reported. During the
open-label period, seven patients discontinued treatment. No
discontinuations were related to adverse events or tolerability.
There has been one non-treatment related death due to a car
accident that was reported after the Week 48 data cutoff date.
About the Phase 3 Adult XLH
Program
This Phase 3 study is a randomized, double-blind,
placebo-controlled clinical study designed to assess the efficacy
and safety of burosumab administered every four weeks in 134 adult
XLH patients in the US, EU, Canada, Japan, and South
Korea. The primary endpoint of the study is the percentage
of patients who achieved average serum phosphorus levels in the
normal range over 24 weeks. Secondary and other endpoints include
pain measured by BPI Q3, stiffness and physical function, both
measured by WOMAC®, radiographic healing of active
fractures/pseudofractures, and safety. After 24 weeks, all patients
receive burosumab through the 72-week open-label extension period
of the study.
Ultragenyx is conducting a second open-label bone quality Phase
3 study in 14 adult XLH patients evaluating the improvement in
osteomalacia, the underlying bone pathology of XLH, via bone
biopsy. The bone quality study complements the phosphate and
patient symptom data from the larger Phase 3 XLH study by
evaluating the effect of burosumab more directly on the bone.
About Burosumab (KRN23)
Burosumab is an investigational 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. Burosumab is being developed to treat XLH
and tumor-induced osteomalacia (TIO), diseases characterized by
excess levels of FGF23. Phosphate wasting in XLH and TIO is caused
by excessive levels and activity of FGF23. Burosumab is designed to
bind to and thereby inhibit the biological activity of FGF23. By
blocking excess FGF23 in patients with XLH and TIO, burosumab is
intended to increase phosphate reabsorption from the kidney and
increase the production of vitamin D, which enhances intestinal
absorption of phosphate and calcium.
A clinical program studying burosumab in adults and pediatric
patients with XLH is ongoing. Burosumab is also being developed for
TIO, a disease characterized by typically benign tumors that
produce excess levels of FGF23, which can lead to severe
osteomalacia, fractures, bone and muscle pain, and muscle
weakness.
About Ultragenyx
Ultragenyx is a biopharmaceutical 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.
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 centered
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 realize 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 commercialization 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: 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 expectations regarding plans for its
clinical programs and clinical studies, 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 November 3, 2017, and its subsequent periodic
reports filed with the Securities and Exchange
Commission.