Pediatric study demonstrates substantial
reduction in bone disease and improvement in growth
Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE), a biopharmaceutical
company focused on the development of novel products for rare and
ultra-rare diseases, today announced positive interim data from the
ongoing pediatric Phase 2 study of KRN23 for the treatment of
X-linked hypophosphatemia (XLH), demonstrating that serum
phosphorus levels, rickets, growth rates and other functional
outcomes improved with continued KRN23 treatment. The bi-weekly
dose regimen continued to show a better overall response than
patients who were dosed every four weeks, and patients with higher
rickets at baseline showed greater improvements in bone disease and
growth velocity. Data were also presented from the adult Phase 2
study of KRN23 for the treatment of XLH, demonstrating a
significant increase in serum phosphorus levels and evidence of
clinical improvement in walking, mobility, pain and stiffness at 24
weeks of treatment. Adverse events were consistent with what has
been previously observed for KRN23 for the treatment of XLH.
Ultragenyx is conducting the program under a collaboration and
license agreement with Kyowa Hakko Kirin to develop and
commercialize KRN23. Data from the two studies were presented today
at the American Society for Bone and Mineral Research (ASBMR) 2016
Annual Meeting.
“Patients with XLH suffer from substantial bone disease, pain
and stiffness throughout the entire course of their lives,” said
Emil D. Kakkis, M.D., Ph.D., Chief Executive Officer and President
of Ultragenyx. “These data support the potential for KRN23 to treat
XLH in both pediatric and adult patients, who all experience
significant burden of disease and are in need of new treatment
options.”
"The accrued data from the ongoing KRN23 trials in children
affected with XLH provide encouraging expectations for improving
therapeutic outcomes in this condition,” commented Tom Carpenter,
M.D., the lead investigator in this study. “It has become more
evident that the responses to KRN23 therapy observed in patients
have the potential to transform the treatment of XLH.”
Phase 2 Pediatric Study
The randomized, multicenter, open-label, dose finding study
enrolled 52 patients ages five through 12, 49 of whom had been on
currently available therapy (oral phosphate/active Vitamin D
therapy) for an average of approximately seven years prior to
entering the study. The first 36 patients enrolled in the study
have completed the full 64-week dose-titration and treatment
period. A subset of these patients (n=18) were pre-specified as
having higher rickets (greater bone disease), defined by baseline
total RSS scores of > 1.5. An additional 16 patients with
higher rickets have completed 40 weeks of treatment.
Metabolic Measures
Patients demonstrated increases in mean serum phosphorus, renal
phosphate reabsorption (TmP/GFR) and serum 1,25 dihydroxy vitamin D
levels through 64 weeks of treatment. Patients in both dosing
groups had mean serum phosphorus levels in the low normal range
through 64 weeks of treatment, demonstrating that phosphate
wasting, the underlying cause of the disease, improved and patients
were able to maintain increased serum phosphorus levels.
Bone Disease Results
Thacher Rickets Severity Scoring (RSS)
Rickets severity was assessed at 40 weeks (n=52) and 64 weeks
(n=36) using the RSS scoring system. Rickets improved significantly
in all groups, with the greatest improvements in patients with
higher baseline rickets (RSS ≥1.5) who received bi-weekly dosing of
KRN23.
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52 patients/40
weeks |
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Q2W |
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Overall |
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Q2W |
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|
Overall |
RSS, All
Patients |
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RSS, Higher BL
RSS
≥ 1.5 |
|
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|
|
n |
|
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26 |
|
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52 |
|
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|
|
n |
|
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|
17 |
|
|
|
34 |
|
% reduction (p <
0.0001) |
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|
|
61 |
% |
|
|
50 |
% |
|
|
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% reduction (p <
0.0001) |
|
|
|
71 |
% |
|
|
61 |
% |
|
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|
|
|
|
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|
|
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36 patients/64
weeks |
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RSS, All
Patients |
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|
|
|
|
|
RSS, Higher BL
RSS
≥ 1.5 |
|
|
|
|
n |
|
|
|
18 |
|
|
|
36 |
|
|
|
|
n |
|
|
|
9 |
|
|
|
18 |
|
% reduction (p <
0.0001) |
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|
51 |
% |
|
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38 |
% |
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% reduction (p <
0.0001) |
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57 |
% |
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51 |
% |
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Radiographic Global Impression of Change (RGI-C) Scale
The change in the severity of rickets was also assessed at 40
and 64 weeks by the RGI-C score. Data show significant improvement
in rickets in all groups. Substantial healing (RGIC score > 2)
was observed in all but one patient with higher baseline rickets
who received bi-weekly dosing.
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52 patients/40
weeks |
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|
Q2W |
|
|
Overall |
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Q2W |
|
|
Overall |
RGI-C, All
Patients |
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RGI-C, Higher
BL RSS
≥ 1.5 |
|
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n |
|
|
26 |
|
|
52 |
|
|
|
n |
|
|
17 |
|
|
34 |
Score change (p <
0.0001) |
|
|
1.72 |
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|
1.56 |
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Score change (p <
0.0001) |
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2.04 |
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|
1.91 |
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36 patients/64
weeks |
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RCI-C, All
Patients |
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RGI-C, Higher
BL RSS
≥ 1.5 |
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n |
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18 |
|
|
36 |
|
|
|
n |
|
|
9 |
|
|
18 |
Score change (p <
0.0001) |
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|
1.35 |
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|
1.35 |
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Score change (p <
0.0001) |
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1.96 |
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1.91 |
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Growth Velocity
Patients with higher baseline RSS scores > 1.5 showed more
growth impairment (baseline height percentile for 40-week group =
5.8%; baseline height percentile for 64-week group = 3.9%), and
these patients demonstrated greater improvement in growth velocity
and height z-score.
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52 patients/40
weeks |
|
|
Q2W |
|
|
Overall |
|
|
|
|
|
|
Q2W |
|
|
Overall |
Growth, All
Patients |
|
|
|
|
Growth, Higher
BL RSS
≥ 1.5 |
|
|
|
n |
|
|
26 |
|
|
52 |
|
|
|
n |
|
|
17 |
|
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34 |
Growth velocity change
(cm/yr) |
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|
+0.96 |
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+0.68 |
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Change in growth
velocity (cm/yr) |
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+1.69 |
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+1.23 |
p value |
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0.0088 |
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|
0.0321 |
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p value |
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|
<0.0001 |
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|
0.0046 |
Change in height
z-score |
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0.17 |
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0.13 |
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Change in height
z-score |
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|
0.22 |
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|
0.18 |
p value |
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|
<0.0001 |
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|
<0.0001 |
|
|
|
p value |
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|
<0.0001 |
|
|
0.0003 |
|
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36 patients/64
weeks |
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|
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Growth, All
Patients |
|
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|
|
|
|
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|
Growth, Higher
BL RSS
≥ 1.5 |
|
|
|
|
|
|
n |
|
|
18 |
|
|
36 |
|
|
|
n |
|
|
9 |
|
|
18 |
Growth velocity change
(cm/yr) |
|
|
+0.35 |
|
|
+0.27 |
|
|
|
Change in growth
velocity (cm/yr) |
|
|
+0.74 |
|
|
+0.58 |
p value |
|
|
N.S. |
|
|
N.S. |
|
|
|
p value |
|
|
0.0173 |
|
|
0.023 |
Change in height
z-score |
|
|
0.21 |
|
|
0.16 |
|
|
|
Change in height
z-score |
|
|
0.21 |
|
|
0.19 |
p value |
|
|
<0.0001 |
|
|
<0.0001 |
|
|
|
p
value |
|
|
0.0056 |
|
|
0.0002 |
|
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|
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|
Functional Measurements: 6 Minute Walk Test (6MWT) and
Patient Reported Outcomes (PROs)
Patients with walking impairment at baseline (defined by <
80% predicted normal walk distance in 6MWT) in the bi-weekly dosing
group achieved a mean increase of 84 meters (p<0.001) at 40
weeks (n=14), and 97 meters (p<0.001) at 64 weeks (n=7).
Functional disability scores were measured with the Pediatric
Orthopedic Society North America/Pediatric Outcome Data Collection
Instrument (POSNA/PODCI). When evaluating the Global score of
all five domains in those patients with substantial impairment at
baseline (n=28, defined as baseline scores < 40 or one standard
deviation below the normalized score of 50), a mean improvement of
+17.5 (p< 0.0001) was observed at 40 weeks. Though the magnitude
of these changes in functional measurements are substantial, any
conclusions must be tempered by the fact that these data are from
an uncontrolled, open-label study.
Safety and Tolerability
The most common treatment-related adverse events reported by
preferred term was injection site reaction in 33% of patients. All
of these reactions were considered mild. All other
treatment-related adverse events were also considered mild. There
was one serious adverse event considered possibly
treatment-related. This was a previously reported patient with
fever and muscle pain who improved without complication and is
still in the trial. There have been no deaths or discontinuations
from the study for any reason. No clinically meaningful changes
were observed in mean serum calcium, urinary calcium and in serum
intact parathyroid hormone. None of the patients had serum
phosphorus levels above the upper limit of normal at any time
point. No clinically significant changes were observed in renal
ultrasounds pre- and post-treatment.
Phase 2 Adult Extension Study
The open-label, long-term extension study enrolled 20 adult
patients with XLH who had previously participated in the phase 1
INT-001 or INT-002 studies of KRN23. All patients had at least a
12-month KRN23 treatment break before enrolling in the extension
study. Patients who had resumed oral phosphate and active vitamin D
therapy between studies (65%) completed a 21-day washout period.
All patients began KRN23 treatment at the last dose received in the
INT-001 or 002 study with an option to titrate during the first 12
weeks. An analysis of 24-week data is being presented.
Metabolic Measures
Patients treated with KRN23 demonstrated increased serum
phosphorus at 24 weeks of treatment, and maintained levels in the
low normal range. Renal phosphate reabsorption (TmP/GFR) and serum
1,25 dihydroxy vitamin D levels also increased from baseline to 24
weeks.
Patient-Reported Outcomes and Physical
Function
At baseline, 19 of 20 patients had worst pain scores measured by
the Brief Pain Inventory Question 3 (BPI-Q3) of > 4, classified
as moderate to severe pain. The mean BPI-Q3 score was significantly
reduced from baseline (p=0.0268; 1.1 point reduction from 6.6 at
baseline to 5.5 at 24 weeks). These patients also demonstrated
significant improvements in BPI pain interference (p=0.0009) and
pain severity (p=0.0141) scores.
WOMAC pain, stiffness and physical function domain scores were
significantly reduced at 24 weeks in these patients. Patients
demonstrating the greatest improvements in stiffness (WOMAC
stiffness responders) and pain (BPI-SF worst pain responders) had
greater improvements in mobility tests, including the Timed Up and
Go (TUG test for balance and agility) and the 6MWT. Mean patient
TUG scores improved by 2 seconds (p=0.04) at week 24. At
baseline, nearly all patients (19/20) were impaired in walking
(defined by < 80% predicted normal walk distance in 6MWT). The
mean increase in distance walked was 25 meters (p=0.05) from
baseline.
Safety and Tolerability
The most common adverse events were arthralgia (30%),
nasopharyngitis (25%), back pain (20%), injection site reaction
(20%), and pain in extremity (20%). Treatment-related adverse
events occurred in 40% of patients, and were all considered mild.
None of the four serious adverse events were considered
treatment-related. There have been no deaths or discontinuations
from the study.
Conference Call Details
Ultragenyx will host a conference call on Monday, September 19
at 11am ET during which Dr. Kakkis will discuss results of the
KRN23 studies being presented at the ASBMR Annual Meeting. The live
and replayed webcast of the call will be available through the
company's website at http://ir.ultragenyx.com/events.cfm. To
participate in the live call by phone, dial 855-797-6910 (USA) or
262-912-6260 (international) and enter the passcode 83882106. The
replay of the call will be available for one year.
About 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 (the softening and weakening
of bones), that is inherited as an X-linked dominant trait
affecting both males and females. XLH is a distinctive 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, frequent/poorly healing
pseudofractures, spinal stenosis, enthesopathy, and osteoarthritis.
Most pediatric patients and some adult patients are managed using
oral phosphate replacement and active vitamin D (calcitriol)
therapy, which requires multiple divided doses each day and
monitoring for potential risks such as nephrocalcinosis,
hypercalciuria, and hyperparathyroidism.
About KRN23
KRN23 is an investigational recombinant fully human monoclonal
IgG1 antibody, discovered by Kyowa Hakko Kirin, against the
phosphaturic hormone fibroblast growth factor 23 (FGF23). It is
being developed by Ultragenyx and Kyowa Hakko Kirin to treat XLH
and TIO, diseases characterized by excess activity of 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 and TIO 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 and TIO, KRN23
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 Phase 3 program studying KRN23 in adults and a Phase 2 study
in pediatric patients with XLH are ongoing. KRN23 is also being
developed for tumor-induced osteomalacia (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 clinical-stage 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 Hakko Kirin
Kyowa Hakko Kirin is a leading biopharmaceutical company in
Japan focusing on its core business area of oncology, nephrology,
and immunology/allergy. Kyowa Hakko Kirin leverages
antibody-related leading-edge technologies to discover and develop
innovative new drugs aiming to become a global specialty
pharmaceutical company which contributes to the health and
well-being of people around the world.
For more information, please visit www.kyowa-kirin.com.
Forward-Looking Statements
Except for the historical information contained herein, the
matters set forth in this press release, including statements
regarding Ultragenyx's expectations regarding the timing of release
of additional data for its product candidates, plans to initiate
additional studies for its product candidates and timing regarding
these studies, plans regarding ongoing studies for existing
programs and its intent to file for conditional approval, 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,
including the regulatory approval process, the timing of our
regulatory filings, and other matters that could affect the success
of our drug development programs, including KRN23. 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 the Company in general, see
Ultragenyx's Quarterly Report on Form 10-Q filed with the
Securities and Exchange Commission on August 9, 2016, and its
subsequent periodic reports filed with the Securities and Exchange
Commission.
Contact Ultragenyx Pharmaceutical Inc.
Investors & Media
Ryan Martins
844-758-7273
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