Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced new
data from the Phase 1/2 study of GTX-102 for the treatment of
Angelman syndrome. Patients in Expansion Cohorts A & B treated
with a set dose and regimen of GTX-102 showed rapid and clinically
meaningful improvement across multiple domains consistent with or
exceeding Dose-escalation Cohorts 4-7 data at Day 170. Treatment of
the Dose-escalation Cohorts 4-7 showed long-term increasing and
sustained clinical benefit far exceeding Natural History data at
Day 758. These data will be discussed in more detail in a corporate
presentation being hosted by the company today at 8:00 a.m. ET and
will also be presented by Kemi Olugemo, M.D., FAAN at the 76th
Annual American Academy of Neurology Meeting (AAN) in Denver on
Tuesday, April 16.
“There is currently no approved disease modifying treatment for
Angelman syndrome, which results in profound impairment in
individuals living with this disease,” said Erick Sell, M.D.,
director of the Angelman clinic at the Children’s Hospital of
Eastern Ontario, and a principal investigator on the Phase 1/2
study. “The multidomain improvement in the Bayley-4 and ASA
measures are significant and in line with the clinically meaningful
change observed by patient families. These kids have continued to
make functional gains over time, which may ultimately lead to more
independence.”
New Expansion Cohorts A & B data include Day 170 results on
24 patients, and long-term Dose-escalation Cohorts 4–7 data include
up to Day 758 results on 15 patients.
Expansion Cohorts at Day 170:
- Cognition assessed by Bayley-4 showed rapid and clinically
significant improvement compared with Natural History data. Day 170
data were consistent with the treatment benefit observed in the
Dose-escalation Cohorts at a similar timepoint.
- Behavior assessed by the Angelman Severity Assessment (ASA)
showed rapid improvement exceeding the treatment benefit observed
in the Dose-escalation Cohorts at Day 170.
- Hyperactivity and noncompliance assessed by the Aberrant
Behavior Checklist-Community (ABC-C) showed rapid and clinically
significant improvement at Day 170 compared with Natural History
data, providing further insight into one of the most commonly
reported behavioral issues.
- Sleep assessed by ASA showed rapid and clinically meaningful
improvement exceeding treatment benefit observed in the
Dose-escalation Cohorts at Day 170.
- Receptive communication assessed by Bayley-4 showed rapid
improvement compared with Natural History data. Day 170 data were
consistent with the treatment benefit observed in the
Dose-escalation Cohorts at a similar timepoint.
- Gross Motor function assessed by ASA showed rapid improvement
exceeding the treatment benefit observed in the Dose-escalation
Cohorts at Day 170. Gross motor assessments as measured by Bayley-4
were not performed at Day 170 in the Expansion Cohorts to reduce
patient testing burden and are not included in this analysis at
this timepoint.
- Multi-domain Responder Index (MDRI) analysis across the four
domains of Cognition, Receptive Communication, Behavior and Sleep
resulted in a total net response of +2.0 (p-value <0.0001). The
majority of patients had already achieved a total net response of
+2 to +4 domains, demonstrating improvement exceeding the minimally
important difference (MID) threshold in several domains even at
this early Day 170 timepoint.
Dose-escalation Cohorts up to Day 758:
- Cognition assessed by Bayley-4 showed continuing long-term
improvement compared with Natural History data and exceeded the
threshold of clinical significance by many-fold in many
patients.
- Behavior assessed by ASA showed continuing clinically
meaningful improvement.
- Sleep assessed by ASA showed sustained clinically meaningful
improvement.
- Receptive communication measured by Bayley-4 showed sustained
and clinically significant improvement compared with Natural
History data.
- Gross motor function assessed by Bayley-4 showed continued and
clinically significant improvement compared with previously
reported Natural History data.
- MDRI analysis across the four domains of Cognition, Receptive
Communication, Behavior and Sleep resulted in a total net response
of +2.0 (p-value = 0.0007) at Day 338. The majority of patients had
a total net response of +2 to +4, as well as a 2- to 5-fold
improvement over the MID threshold in several domains.
“The totality of these interim data demonstrates that treatment
with GTX-102 resulted in rapid, multi-domain improvements that
continued during maintenance dosing. These broad developmental
gains are having a meaningful impact on patients and their
families. For example, we’re hearing about children who are now
able to routinely communicate their needs to family members, which
greatly improves their ability to interact with their caregivers.
We have also heard from families about their children who are
accumulating additional developmental gains such as running,
swimming and independent eating,” said Eric Crombez, M.D., chief
medical officer at Ultragenyx. “Our next step is an end of Phase 2
meeting with the FDA and interactions with other health authorities
to enable timely initiation of a Phase 3 pivotal study.”
There were no unexpected serious adverse events. Three patients
had serious adverse events (mild to moderate) of lower extremity
weakness assessed as related to study treatment; one in Cohort 7,
two in Cohorts A & B; none reported in Cohorts C–E to
date. All resolved rapidly without sequelae and remain in the study
without ongoing safety concerns. The five original patients
affected by lower extremity weakness from Cohorts 1–3 have been
re-dosed safely multiple times and are receiving maintenance
treatment without recurrence. The Cohort 7 patient has also been
re-dosed safely multiple times and is receiving maintenance
treatment without recurrence. The two patients in Cohorts A & B
remain in study and are expected to continue dosing. The FDA and
other regulatory agencies were notified of all safety events and
raised no issues nor required additional actions. The foregoing
safety information is current as of April 5, 2024.
Conference Call and Webcast
Information
Ultragenyx will host a conference call at 8:00 a.m. ET today to
discuss the new efficacy and safety data from the GTX-102 Phase 1/2
clinical study. The live and replayed webcast of the call will be
available through the company’s website at
https://ir.ultragenyx.com/events-presentations.
About GTX-102
GTX-102 is an investigational antisense oligonucleotide
delivered via intrathecal administration and designed to target and
inhibit expression of UBE3A-AS. Nonclinical studies have shown that
GTX-102 reduces levels of UBE3A-AS and reactivates expression of
the paternal UBE3A allele in neurons of the CNS. Reactivation of
paternal UBE3A expression in animal models of Angelman syndrome has
been associated with improvements in some of the neurological
symptoms associated with the condition. GTX-102 has been granted
Orphan Drug Designation, Rare Pediatric Disease Designation, and
Fast Track Designation from the FDA, and Orphan Designation and
PRIME designation from the EMA.
About the Phase 1/2 study
The Phase 1/2, open-label, multiple-dose, dose-escalating study
is evaluating the safety and tolerability of GTX-102 administered
by intrathecal (IT) injection to pediatric patients with Angelman
syndrome with a genetically confirmed diagnosis of full maternal
UBE3A gene deletion. The study is also assessing clinical response
as measured by a panel of efficacy assessments for the functional
domains impacted in Angelman syndrome. The study has enrolled and
treated 74 patients in both dose-escalation and expansion cohorts.
Patients in Cohorts 4-7 (dose-escalation) are receiving long-term
maintenance dosing. Data from the expansion cohorts will be used to
verify the GTX-102 dose and treatment regimen for the pivotal Phase
3 study.
About the Angelman Syndrome Natural History
Study
The Angelman Syndrome Natural History Study (NCT00296764) is a
multisite, prospective, observational study. The study data are
combined with clinic and registry data and stored in the Linking
Angelman and Dup15q Data for Expanded Research (LADDER) database
platform, which is managed by Boston Children’s Hospital and spans
different Angelman syndrome cohorts. The Natural History study
populations analyzed for comparative purposes to GTX-102 are a
subset of the larger populations, and only include 4- to
17-year-old gene deletion patients. These data are illustrative
only; differences exist between study designs, subject
characteristics and geographical regions and caution should be
exercised when comparing data across studies. Natural history data
are not available for the ASA assessments.
About Angelman Syndrome
Angelman syndrome is a rare, neurogenetic disorder caused by
loss-of-function of the maternally inherited allele of the UBE3A
gene. The maternal-specific inheritance pattern of Angelman
syndrome is due to genomic imprinting of UBE3A in neurons of the
central nervous system (CNS), a naturally occurring phenomenon in
which the maternal UBE3A allele is expressed and the paternal UBE3A
is not. Silencing of the paternal UBE3A allele is regulated by the
UBE3A antisense transcript (UBE3A-AS), the intended target of
GTX-102. In almost all cases of Angelman syndrome, the maternal
UBE3A allele is either missing or mutated, resulting in limited to
no protein expression. This condition is generally not inherited
but instead occurs spontaneously. It is estimated to affect ~60,000
people in commercially accessible geographies.
Individuals with Angelman syndrome have a lifelong
neurodevelopmental disorder including cognitive impairment, motor
impairment, balance issues, and debilitating seizures. Some
individuals with Angelman syndrome are unable to walk and most do
not speak. Anxiety and disturbed sleep can be serious challenges in
individuals with Angelman syndrome. Although individuals with
Angelman syndrome have a normal lifespan, they require continuous
care and are unable to live independently. Angelman syndrome is not
a degenerative disorder, but the loss of the UBE3A protein
expression in neurons results in abnormal communications between
neurons. Angelman syndrome is often misdiagnosed as autism or
cerebral palsy. There are no currently approved therapies for
Angelman syndrome; however, several symptoms of this disorder can
be reversed in adult animal models of Angelman syndrome suggesting
that improvement of symptoms can potentially be achieved at any
age.
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 the
clinical benefit, tolerability and safety of GTX-102 and the
corresponding impact on patients, the anticipated dosing of the
Phase 2 study for GTX-102 and the timing for initiation of a Phase
3 study for GTX-102 and associated regulatory meetings 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 GTX-102, the Company’s ability to achieve its
projected development goals in its expected timeframes, the risk
that results from earlier studies may not be predictive of future
study results, 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 product 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 Annual Report
on Form 10-K filed with the Securities and Exchange Commission
(SEC) on February 21, 2024, 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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