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 safety and
efficacy data from the first dose cohort of the Phase 1/2 study of
DTX301, an adeno-associated virus (AAV) gene therapy for the
treatment of ornithine transcarbamylase (OTC) deficiency.
“We are encouraged by these initial data showing activity with
our AAV8 vector in patients in the first, lowest-dose cohort.
Patient 1 showed a normalization of ureagenesis that was maintained
through 12 weeks, and we view this initial efficacy data as
clinically meaningful and a promising indication of the potential
of DTX301,” said Emil D. Kakkis, M.D., Ph.D., Chief Executive
Officer and President of Ultragenyx. “Based on the data to date, we
expect to be able to move to the higher-dose second cohort pending
the data monitoring committee’s review of the 12-week safety data
for all three patients in this cohort, and data from this second
cohort should be available in the second half of 2018.”
DTX301 Interim Data SummaryThe study is
designed to enroll patients with late-onset disease who are
clinically stable and on a stable dose of alternate pathway
medication. All three patients in the first, lowest -dose cohort
received a single DTX301 dose of 2.0 × 10^12 GC/kg. As of the
December 22, 2017 data cutoff date, two of the three patients have
been followed for at least 12 weeks, the pre-defined endpoint for
efficacy evaluation, and the third patient has been followed for 6
weeks.
Safety Summary
As of December 22, 2017 there have been no infusion-related
adverse events and no serious adverse events reported. All adverse
events have been Grade 1 or 2 and have resolved. The only
treatment-related adverse events were mild, clinically asymptomatic
and manageable elevations in alanine aminotransferase (ALT) in two
patients, peaking at 45 (Patient 1) and 118 IU/L (Patient 2). These
ALT elevations were mild and similar to what has been observed in
other programs using AAV gene therapy. Both patients completed a
standard tapering course of corticosteroids to treat the ALT
elevations, and as of the data cutoff date, their ALT levels were
in the normal range (below 40 U/L). The third patient had ALTs that
remained in the normal range through six weeks.
Efficacy Summary
The first patient’s rate of ureagenesis was normalized and
maintained over 12 weeks. Their rate of ureagenesis at baseline was
200 umol/kg/hr (67% of normal, defined as 300 umol/kg/hr). At 6
weeks, their rate of ureagenesis increased to 335 umol/kg/hr (67%
increase from baseline, 112% of normal). At 12 weeks, their rate of
ureagenesis was 261 umol/kg/hr (30% increase from baseline, 87% of
normal). The second patient did not show a clinically meaningful
change in rate of ureagenesis over the 12-week period. The third
patient showed a modest increase in ureagenesis from baseline over
the first six weeks of treatment. This patient has not yet reached
the 12-week post-dosing point. This cohort dose is at the low
end of the expected range and showed some signs of efficacy with an
acceptable safety profile. The second cohort dose planned is
6.0 x 10^12 GC/kg and will be initiated after the third patient
reaches 12 weeks and a DMC review is completed.
About the OTC Phase 1/2 Study (DTX301)
To evaluate therapeutic response of DTX301, the study measures
the change in the rate of ureagenesis, the pathway for the
metabolism of ammonia which is deficient in OTC patients. This is
determined using a well-established stable 13C-acetate labeling
approach. Ammonia levels, neurocognitive assessment,
biomarkers, and safety will also be evaluated. There are three
potential dose cohorts in the study. Patients in the first cohort
received a dose of 2.0 × 10^12 GC/kg; patients in cohort 2 would
receive a dose of 6.0 × 10^12 GC/kg; patients in cohort 3 would
receive a dose of 1.0 × 10^13 GC/kg. The decision to proceed to the
next, higher dose cohort will be made after the data monitoring
committee (DMC) evaluates the efficacy and safety data for all
patients in the previous dosing cohort.
About OTC Deficiency
OTC deficiency, the most common urea cycle disorder, is caused
by a genetic defect in a liver enzyme responsible for
detoxification of ammonia. Individuals with OTC deficiency can
build up excessive levels of ammonia in their blood, potentially
resulting in acute and chronic neurological deficits and other
toxicities. It is estimated that more than 10,000 patients are
affected by OTC deficiency worldwide, of which approximately 80%
are classified as late-onset. In the late-onset form of the
disease, elevated ammonia can lead to significant medical issues
for patients who are in need of new disease-modifying therapies.
The greatest percentage of patients, including males and females,
experience late-onset disease, representing a clinical spectrum of
disease severity. Neonatal onset disease occurs in males, presents
as severe disease, and can be fatal at an early age. Approved
therapies, which must be taken multiple times a day for the
patient's entire life, do not eliminate the risk of future
metabolic crises. Currently, the only curative approach is liver
transplantation.
About DTX301
DTX301 is an investigational AAV type 8 gene therapy designed to
deliver stable expression and activity of OTC following a single
intravenous infusion and has been shown in preclinical studies to
normalize levels of urinary orotic acid, a marker of ammonia
metabolism. DTX301 was granted Orphan Drug Designation in both the
United States and Europe.
About Ultragenyx Pharmaceutical Inc.
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.
The Company has rapidly built and advanced 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.
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 the timing of
release of additional data for its product candidates, and plans
for its clinical programs and its 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.
Contact Ultragenyx Pharmaceutical Inc.Investors &
MediaDanielle Keatley415-475-6876
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