Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical
company focused on the development and commercialization of novel
therapies for rare and ultra-rare diseases, today announced
positive longer-term data from the Glycogen Storage Disease Type Ia
(GSDIa) and Ornithine Transcarbamylase (OTC) Deficiency Phase 1/2
studies demonstrating ongoing durability of response, as well as
data highlighting further advancements to the company’s proprietary
HeLa producer cell line (PCL) manufacturing platform. Data were
presented this week at the American Society of Gene & Cell
Therapy (ASGCT) 24th Annual Meeting.
“In the GSDIa and OTC programs, the durable responses coupled
with the successful implementation of prophylactic steroids are
encouraging as we move into our pivotal Phase 3 studies for these
programs this year,” said Emil D. Kakkis, M.D., Ph.D., Chief
Executive Officer and President of Ultragenyx. “We have also made
significant progress with the latest 3.0 generation of our
proprietary HeLa PCL manufacturing platform that will allow even
greater product yield at the 2000 liter scale while maintaining or
even improving product quality. This enables us to study larger
disease indications and expand into central nervous system and
muscle disorders that may require higher doses, all while
continuing to drive down AAV production costs.”
DTX401 (GSDIa) ProgramLonger-term Phase 1/2
data demonstrate durability of response, with sustained responses
lasting more than 2.5 years since treatment All nine patients
continue to demonstrate improved glucose control while tapering or
discontinuing oral glucose replacement with cornstarch and
improvements in energy metabolism pathways over the long term, with
patients in the first cohort sustaining responses more than 2.5
years since treatment. Patients continue to taper the amount and
frequency of cornstarch dosing reaching an overall mean reduction
of cornstarch intake of 79% (p-value<0.001) by their latest
visit (ranging from 60 weeks to 131 weeks). In Cohort 3 continuous
glucose monitoring was implemented, and data indicate that these
patients achieved significant cornstarch reductions while
increasing the time spent in euglycemia, defined by blood glucose
levels in the normal range of 60 to 120 mg/dL.
All three patients in the prophylactic steroid cohort are doing
well and have demonstrated early reduction in daily cornstarch
intakeAll patients in the prophylactic cohort in the Phase 1/2
study have demonstrated early, clinically meaningful cornstarch
reductions ranging from 64% to 83%. One of the patients has
recently completed the prophylactic course of steroids, and the
other two continue to taper steroids.
Across the Phase 1/2 study, there have been no infusion-related
adverse events and no treatment-related serious adverse events
(SAEs) reported.
Phase 3 study of DTX401 in GSDIa expected to initiate early in
the second half of 2021The Phase 3 study has a 48-week primary
efficacy analysis period and will enroll approximately 50 patients,
randomized 1:1 to DTX401 (1.0 x 10^13 GC/kg dose) or placebo. The
primary endpoint is expected to be the reduction in oral glucose
replacement with cornstarch while maintaining or improving glucose
control assessed by continuous glucose monitoring. The study design
has been submitted and endpoints are being finalized with
regulators.
DTX301 (OTC) ProgramLonger-term Phase 1/2 data
show durable metabolic control and sustained responses lasting more
than three years since treatmentThe six patients who previously
demonstrated a response remain clinically and metabolically stable,
including all three treated at the highest dose (1.7 x 10^13 GC/kg
dose), which is the dose that will be used in the Phase 3 study.
Some patients have now demonstrated a durable response three years
after treatment, and more than two years after discontinuing
ammonia-scavenger medications and liberalizing protein-restricted
diets. All responders remain in excellent clinical condition with
no significant adverse events, hospitalizations, or other events
related to OTC deficiency.
Prophylactic steroid cohort: Both patients dosed; first patient
has demonstrated a response, second patient responder status will
be evaluated after patient finishes steroid regimen Both patients
in the prophylactic steroid cohort are doing well clinically with
good metabolic control and without any safety issues. The first
patient has maintained normal ammonia levels and has reduced their
ammonia-scavenger drug by 45% so far, following completion of the
prophylactic course of steroids. This patient is continuing to
taper medications. The second patient continues to taper their
course of steroids, and changes in ammonia-scavenging drugs or diet
will only be attempted after the prophylactic steroid taper is
complete. This patient has maintained normal ammonia levels since
treatment.
Across all cohorts of the Phase 1/2 study, there have been no
infusion-related adverse events and no treatment-related serious
adverse events reported. All treatment-related adverse events have
been Grade 1 or 2.
Phase 3 study to initiate in second half 2021The Phase 3 study
will include a 64-week primary efficacy analysis period and enroll
approximately 50 patients 12 years of age and older, randomized 1:1
to DTX301 (1.7 x 10^13 GC/kg dose) or placebo. The co-primary
endpoints are the percentage of patients who achieve a response as
measured by discontinuation or reduction in baseline disease
management and the 24-hour plasma ammonia levels.
HeLa 3.0 Producer Cell Line (PCL) advancements
significantly increase productivity of the platformData on
the HeLa 3.0 platform demonstrated that genetic engineering of the
HeLa cell significantly improved AAV production. This increased
productivity was achieved while maintaining or improving product
quality. Permanent knockout of target genes identified by RNA
sequencing (HeLa 3.0) was shown to increase titer in established
PCLs (HeLa 2.0), and the single knockout HeLa 3.0 PCLs displayed
similar phenotype to parental PCLs (HeLa 2.0) during production.
These cell line engineering improvements result in a 2- to 5-fold
yield improvement over the HeLa 2.0 platform, and a 50-fold yield
improvement over HeLa 1.0. Additional improvements in yield are
expected with future combinatorial knockdowns, with early studies
suggesting a further 5-to 10-fold improvement.
These improvements in the HeLa platform allow for increased
productivity and reproducibility with higher full-to-empty AAV
ratios while continuing to drive down AAV production costs, all
important attributes in the manufacturing of gene therapies for
diseases where high product yield is required.
About GSDIa and DTX401
GSDIa is the most severe genetically inherited glycogen storage
disease. It is caused by a defective gene coding for the enzyme
G6Pase-α, resulting in the inability to regulate blood sugar
(glucose). Hypoglycemia in patients with GSDIa can be
life-threatening, while the accumulation of the complex sugar
glycogen in certain organs and tissues can impair the ability of
these tissues to function normally. If chronically untreated,
patients can develop severe lactic acidosis, progress to renal
failure, and potentially die in infancy or childhood. There are no
approved pharmacologic therapies. An estimated 6,000 patients
worldwide are affected by GSDIa.
DTX401 is an investigational AAV8 gene therapy designed to
deliver stable expression and activity of G6Pase-α under control of
the native promoter. DTX401 is administered as a single intravenous
infusion and has been shown in preclinical studies to improve
G6Pase-α activity and reduce hepatic glycogen levels, a
well-described biomarker of disease progression. DTX401 has been
granted Orphan Drug Designation in both the United States and
Europe, and Regenerative Medicine Advanced Therapy (RMAT)
designation and Fast Track designation in the United States.
About OTC Deficiency and DTX301
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 people are
affected by OTC deficiency worldwide, of whom approximately 80
percent are classified as late-onset and represent a clinical
spectrum of disease severity. In the late-onset form of the
disease, elevated ammonia can lead to significant medical issues
for patients. Neonatal onset disease occurs only 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.
DTX301 is an investigational AAV type 8 gene therapy designed to
deliver stable expression and activity of OTC following a single
intravenous infusion. It 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 novel
therapies to patients for the treatment of serious rare and
ultra-rare genetic diseases. The company has built a diverse
portfolio of approved medicines and treatment candidates aimed at
addressing diseases with high unmet medical need and clear biology,
for which there are typically no approved therapies treating the
underlying disease.
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
related to Ultragenyx's expectations and projections regarding its
future operating results and financial performance, anticipated
cost or expense reductions, the timing, progress and plans for its
clinical programs and clinical studies, future regulatory
interactions, and the components and timing of regulatory
submissions 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, collaboration with third parties, 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 effects from the
COVID-19 pandemic on the company’s clinical activities, business
and operating results, risks related to reliance on third party
partners to conduct certain activities on the company’s behalf,
uncertainty and potential delays related to clinical drug
development, smaller than anticipated market opportunities for the
company’s products and product candidates, manufacturing risks,
competition from other therapies or products, and other matters
that could affect sufficiency of existing cash, cash equivalents
and short-term investments to fund operations, the company’s future
operating results and financial performance, the timing of clinical
trial activities and reporting results from same, and the
availability or commercial potential of Ultragenyx’s products and
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 10Q filed with the
Securities and Exchange Commission on May 5, 2021, and its
subsequent periodic reports filed with the Securities and Exchange
Commission.
Contact Ultragenyx Investors & MediaJoshua Higa(415)
475-6370
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