Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced data
demonstrating treatment with UX111 (ABO-102) AAV gene therapy
resulted in rapid and sustained decreased levels of heparan sulfate
(HS) in cerebrospinal fluid (CSF) in patients with Sanfilippo
syndrome type A (MPS IIIA), and that sustained reduction in CSF HS
exposure over time was correlated with improved long-term cognitive
development. These data are from the modified intention to treat
group (mITT) in the pivotal Transpher A study (N=17). The results
of this study along with the additional data from the long-term
follow-up study for these subjects will be presented at the
WORLDSymposium™ 2024 20th annual research meeting taking place
February 4-9 in San Diego.
“It's impressive to see how our study patients
treated with UX111 have maintained their communication skills
despite being the age in which regression begins to occur,” stated
Mireia del Toro, M.D., coordinator of the Metabolic Unit, Pediatric
Neurology Department, Hospital Universitari Vall d´Hebron,
Barcelona. “Sustaining the ability to communicate also has a very
relevant impact on improving behavioral problems and thus family
daily life.”
Following treatment with UX111 (3x1013 vg/kg), levels of CSF-HS
decreased within the first month post treatment in all patients. 8
of 17 patients in the mITT group who reached 24 months
post-treatment achieved an overall mean percent reduction from
baseline of 51% (p <0.0001). An alternative way to assess CSF-HS
is to look at the reduction in CSF HS exposure over time
post-administration of UX111 using time-normalized area under curve
(AUC). The 17 patients in the mITT group had a mean follow-up
duration of 29 months (range = 11.3-60 months). There was a mean
reduction in CSF HS exposure of 63% (p<0.0001) using
time-normalized AUC. This type of analysis incorporates all
post-baseline reductions in CSF-HS available at the time of data
cut-off (August 2023) and allows for a robust quantification of the
treatment effect of UX111 on reduction of toxic CSF HS exposure
over time.
Cognitive function was measured using Bayley-III (BSITD-IIID)
cognitive raw scores and an estimated yearly rate of change (EYC)
was calculated to reflect a patient-specific rate of change in
BSITD-III cognitive raw scores after UX111 treatment. At the time
of the data cut-off, the individual EYC in cognitive raw scores
showed a positive rate of change indicating either stability or
gains from baseline in 16 of the 17 patients during the expected
window of plateau into decline, defined as >30 months of age.
There was a statistically significant correlation between the CSF
HS exposure and the EYC in cognitive raw score, which was
maintained with and without adjustment for age, resulting in a
Spearman’s Rank Order Correlation Coefficient of -0.64 (p=0.0076)
and -0.72 (p=0.0011), respectively. Specifically, 15 of 17 patients
had both a reduction in toxic CSF HS exposure and an improvement in
cognitive function.
“It’s important to look at the impact of CSF-HS as the brain’s
length of exposure to a toxic substrate rather than just one moment
in time and if you correct the underlying biochemical disease at a
molecular level, you provide the ability for neurons to survive and
the brain to maintain and gain function over time,” said Emil D.
Kakkis, M.D., Ph.D., chief executive officer and president of
Ultragenyx. “This recovery from exposure takes time, and while
we’ll see rapid reduction in exposure, we then need to follow up
over the course of several years to see the developmental gains in
these children.”
The most frequently reported treatment-related adverse events to
date were elevations in liver enzymes and the majority
of these events were mild (Grade 1) or moderate (Grade 2)
in severity. The only treatment-related adverse event ≥ Grade
3 reported to date was one event of increased alanine
aminotransferase (ALT) that resolved, which is a known effect of
AAV gene therapy.
The Transpher A study has enrolled and treated 28 patients
across 3 dose Cohorts at 5 sites in 3 countries. The high dose
Cohort 3 (3x1013 vg/kg) consists of 22 patients, and 17 are in the
mITT group. The mITT group is defined as patients who were either
age 0-2 years old, or patients older than 2 years with a cognitive
developmental quotient of 60 or above at time of enrollment. These
patients received the highest dose of UX111. Subjects who completed
the Transpher A study were invited to enroll into a long term
follow study. As of the data cut-off, 15 of the 17 patients were at
least 2.5 years of age and 6 of 17 were over five years of age.
Mean duration of follow-up post-treatment was 29 months. Both
trials are ongoing, and patients will continue to be followed for a
minimum of 5 years following treatment with UX111.
About UX111
UX111 is a novel gene therapy in Phase 1/2 development for
Sanfilippo syndrome type A (MPS IIIA), a rare fatal lysosomal
storage disease with no approved treatment that primarily affects
the central nervous system (CNS). UX111 is dosed in a one-time
intravenous infusion using a self-complementary AAV9 vector to
deliver a functional copy of the SGSH gene to cells of the CNS and
peripheral organs. The therapy is designed to address the
underlying SGSH enzyme deficiency responsible for abnormal
accumulation of heparan sulfate, a glycosaminoglycan, in the brain
and throughout the body that results in progressive cell damage and
neurodevelopmental and physical decline. The UX111 program has
received Regenerative Medicine Advanced Therapy, Fast Track, Rare
Pediatric Disease, and Orphan Drug designations in the U.S., and
PRIME and Orphan medicinal product designations in the EU.
About the Transpher A
and Long-term Follow-up Studies
The Transpher A Study is an ongoing, two-year, open-label,
dose-escalation, Phase 1/2/3 global clinical trial assessing UX111
for the treatment of patients with Sanfilippo syndrome type A (MPS
IIIA). The current eligibility criteria focused on a modified
target population and enrolled patients from birth to 2 years of
age, or patients older than 2 years with a cognitive developmental
quotient of 60 or above based on BSITD-III. These patients received
the highest dose of 3 x 1013 vg/kg UX111 gene therapy delivered
using AAV9 technology via a single-dose intravenous infusion. The
study endpoints include heparan sulfate levels in CSF,
neurodevelopmental outcomes, ganglioside levels in CSF, brain
volumes as measured by MRI and safety. Upon completion of the
Transpher A study, subjects treated with UX111 were invited to
enroll in a long-term follow-up study for continued monitoring of
safety and efficacy. Further details can be referenced here:
https://clinicaltrials.gov/ct2/show/NCT02716246
About Sanfilippo Syndrome Type A (MPS IIIA)
Sanfilippo syndrome type A (MPS IIIA) is a rare, fatal lysosomal
storage disease with no approved treatment that primarily affects
the CNS and is characterized by rapid neurodevelopmental and
physical decline, with onset in early childhood. MPS IIIA has a
global incidence of one in 100,000 with a median life expectancy of
15 years.
Children with MPS IIIA present with global developmental delay
which eventually leads to progressive language and cognitive
decline and behavioral abnormalities and early death. Other
symptoms include sleep problems, frequent ear infections and
liver/spleen enlargement. MPS IIIA is caused by biallelic
pathogenic variants in the SGSH gene that lead to a deficiency in
the sulfamidase (SGSH) enzyme responsible for breaking down heparan
sulfate, a glycosaminoglycans, which accumulate in cells throughout
the body resulting in rapid health decline associated with the
disorder.
About Ultragenyx Pharmaceutical Inc.
Ultragenyx is a biopharmaceutical company committed to bringing
novel products to patients for the treatment of serious rare and
ultrarare genetic diseases. The company has built a diverse
portfolio of approved therapies and product candidates aimed at
addressing diseases with high unmet medical need and clear biology
for treatment, 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.
Ultragenyx Forward-Looking Statements and Use of Digital
Media
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, business plans
and objectives for UX111, expectations regarding the tolerability
and safety of UX111, and future clinical and regulatory
developments for UX111 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 uncertainty
of clinical drug development and unpredictability and lengthy
process for obtaining regulatory approvals, the ability of the
company to successfully develop UX111, the company’s ability to
achieve its projected development goals in its expected timeframes,
risks related to adverse side effects, risks related to reliance on
third party partners to conduct certain activities on the company’s
behalf, 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 10-Q filed with the Securities and Exchange
Commission (SEC) on November 3, 2023, and its subsequent periodic
reports filed with the SEC.
In addition to its SEC filings, press releases and public
conference calls, Ultragenyx uses its investor relations website
and social media outlets to publish important information about the
company, including information that may be deemed material to
investors, and to comply with its disclosure obligations under
Regulation FD. Financial and other information about Ultragenyx is
routinely posted and is accessible on Ultragenyx’s Investor
Relations website (https://ir.ultragenyx.com/) and LinkedIn website
(https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/).
ContactsUltragenyx Pharmaceutical
Inc.InvestorsJoshua
Higa+1-415-475-6370ir@ultragenyx.com
MediaCarolyn Wang+1-415-225-5050media@ultragenyx.com
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