– Totality of data from these ongoing studies
suggest clinical benefit for patients ages 2 to 18 years old,
including reductions in seizures and improvements in cognition and
behavior that support the potential for disease modification –
– Phase 1/2a ADMIRAL Study Data STK-001 (70mg):
Patients treated with 2 or 3 initial doses experienced substantial
and sustained reductions in convulsive seizure frequency; Median
reductions at 3 months after last dose (n=6) of 80% and 89% (n=3)
at 6 months after last dose, compared to baseline –
– OLE Study Data STK-001 (30mg, 45mg):
Sustained reductions in convulsive seizure frequency and
improvements in cognition and behavior –
– MONARCH & ADMIRAL Study Safety Data:
STK-001 has been generally well-tolerated among 74 patients treated
with single and multiple doses of 10mg to 70mg –
– Additional data anticipated in Q1 2024
following completion of Phase 1/2a studies –
– Management will host a webinar and conference
call for analysts and investors at 8:00 a.m. Eastern Time today
–
Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company
dedicated to addressing the underlying cause of severe diseases by
upregulating protein expression with RNA-based medicines, today
announced positive new safety and efficacy data from patients
treated with STK-001 in the two ongoing Phase 1/2a studies (MONARCH
and ADMIRAL) and the SWALLOWTAIL open-label extension (OLE) study
in children and adolescents with Dravet syndrome. These new data
suggest clinical benefit for patients 2 to 18 years of age treated
with multiple doses of STK-001. The observed reductions in
convulsive seizure frequency as well as substantial improvements in
cognition and behavior support the potential for disease
modification in a highly refractory patient population.
“Together these data support the potential for STK-001 to
address the underlying cause of Dravet syndrome by treating both
seizures and the cognitive and behavioral issues that make this
disease so complex and devastating. Our ongoing studies are
providing a better understanding of a dose and dosing regimen that
may generate substantial and sustained benefits for patients, while
continuing to be generally well tolerated,” said Edward M. Kaye,
M.D., Chief Executive Officer of Stoke Therapeutics. “We are on
track to complete the Phase 1/2a studies by year-end and look
forward to sharing these data, and data from the open-label
extension studies, in the first quarter of 2024.”
“The patients in these studies were already taking the best
available anti-seizure medicines, making the additional observed
reductions in seizures quite meaningful. One of the most exciting
things we are seeing is the early sign that, for the first time, we
may have a therapy that can address the syndrome, in addition to
the seizures,” said Joseph Sullivan, M.D., Professor of Neurology
and Pediatrics and Director of the Pediatric Epilepsy Center of
Excellence at the University of California San Francisco, and a
prominent researcher into Dravet Syndrome. “What we know from the
natural history data is that the profound deficits in cognitive
functioning among patients with Dravet syndrome do not tend to
improve on their own, which makes the improvements indicated in
multiple assessments of cognition and behavior compelling.”
About the Phase 1/2a Studies MONARCH and ADMIRAL are
multi-center, Phase 1/2a studies of children and adolescents who
have an established diagnosis of Dravet syndrome. The primary
objectives for MONARCH in the United States and ADMIRAL in the
United Kingdom are to assess the safety and tolerability of
STK-001, as well as to determine the pharmacokinetics in plasma and
exposure in cerebrospinal fluid. A secondary objective is to assess
the efficacy of STK-001 as an adjunctive antiepileptic treatment
with respect to the percentage change from baseline in convulsive
seizure frequency.
Key Efficacy Findings from a Combined Analysis of Phase 1/2a
Studies MONARCH & ADMIRAL The combined efficacy analysis
reported today was based on clinically evaluable data from 45
patients who were treated with multiple doses (30mg, 45mg, 70mg) in
either of these two ongoing studies. The greatest reduction in
convulsive seizure frequency has been observed among the small
number (n=11) of patients treated with two or three doses of 70mg
in the ADMIRAL study. The analysis of the 70mg multiple dose cohort
from ADMIRAL study consists primarily of patients treated with
three doses of STK-001 (n=5). The Company anticipates that the
remaining ADMIRAL study data will consist primarily of patients
treated with two doses of 70mg (n=6). (See Key Safety Findings
below.)
Based on these new data and an increasing understanding of the
STK-001 mechanism of action and time necessary to produce a
clinical effect, the Company performed multiple analyses, including
a “through” analysis that incorporates data from a period of time
during and after dosing and an “at” analysis that captured data at
a specific timepoint after dosing was completed. The results of
both analyses are reported below. The Company believes that the
“at” analysis more accurately captured the effect of STK-001 and
will be the most relevant for use in future studies, and the
overall development program for STK-001.
Reductions in Convulsive Seizure Frequency Were Observed
Across Dose Cohorts*
Median % Reduction from Baseline
in Convulsive Seizure Frequency
30mg MAD
(3 doses, n=18)
45mg MAD
(3 doses, n=16)
70mg MAD**
(3 doses, n=5)
(2 doses, n=6)
At 3 Months After Last Dose
27% (n=16)
19% (n=14)
80% (n=6†)
At 6 Months After Last Dose
4% (n=13)
45% (n=8)
89% (n=3†)
Day 29 Through 3 Months After Last
Dose
28% (n=17)
18% (n=16)
42% (n=8†)
Day 29 Through 6 Months After Last
Dose
24% (n=16)
26% (n=14)
42% (n=6†)
* Patient numbers were primarily variable due to the fact that
patients with ≥50% of the data points
in each time period were included in the applicable “through”
cohort (bottom two data rows), even if the patient had not yet
reached the last timepoint in the time period.
** ADMIRAL patients only. The MONARCH study is evaluating single
doses of 70mg and data from this cohort are not yet available.
†5/6 patients (at 3 months), 3/3 patients (at 6 months), 5/8
patients (day 29 through 3 months) and 5/6 patients (day 29 through
6 months) after last dose were treated with 3 doses of 70mg
Key Efficacy Findings From the SWALLOWTAIL Open-Label
Extension Study Following treatment in the Phase 1/2a MONARCH
study, patients who meet study entry criteria are eligible to
continue treatment with STK-001 in SWALLOWTAIL. An analysis of a
subset of these patients was performed to assess the potential
impact of ongoing treatment with STK-001. This analysis was based
only on the group of patients who received a cumulative total dose
of at least 30mg of STK-001 in MONARCH and then continued treatment
in SWALLOWTAIL with 30mg or 45mg doses every four months.
Twenty-six patients met these criteria when they began treatment in
SWALLOWTAIL.
Data from this analysis provide evidence of the potential for
disease modification with ongoing treatment with STK-001. Durable
reductions in convulsive seizure frequency were observed throughout
the course of treatment. Data from a mixed model repeated measures
(MMRM) analysis indicated substantial improvements from baseline
through 12 months in multiple assessments of cognition and
behavior, including:
- Expressive and receptive communication as measured by the
Vineland Adaptive Behavior Scale (VABS-III)
- Gross motor skills as measured by VABS-III
- Executive function as measured by the Behavior Rating Inventory
of Executive Function-Preschool Version (BRIEF-P)
- Global Impression of Change scores as reported by caregivers
and by clinicians
Data from the Company’s BUTTERFLY natural history study showed
little to no change in these assessments among patients treated
with currently available anti-seizure medicines.
Key Safety Findings from an Analysis of the Phase 1/2a
MONARCH and ADMIRAL Studies: The safety analysis for the Phase
1/2a studies reported today was based on data from 74 patients who
were treated with single or multiple doses of STK-001 (10mg, 20mg,
30mg, 45mg, 70mg) and followed for up to six months after their
last dose.
- STK-001 was generally well-tolerated among 74 patients treated
with single and multiple doses of 10mg to 70mg in the Phase 1/2a
studies and there were no discontinuations related to study
drug.
- 32% (24/74) of patients experienced a treatment-emergent
adverse event (TEAE) that was related to study drug. The most
common TEAEs related to study drug were CSF protein elevations,
vomiting, and irritability.
- 20% (15/74) of patients had a treatment-emergent serious
adverse event (TESAE). The TESAEs experienced by 14 of the 15 were
not considered related to study drug.
- One patient who received multiple doses of 70mg STK-001 in the
ADMIRAL study experienced Suspected Unexpected Serious Adverse
Reactions (SUSARs) that were attributed by the investigator to
STK-001. The patient went on to complete the study.
- Subsequently, the study protocol for ADMIRAL was amended to
allow investigators to decide whether to administer two or three
doses of STK-001 (70mg) in the ADMIRAL study before patients would
be eligible to enroll in the LONGWING OLE.
Safety findings from patients who continued treatment in
SWALLOWTAIL OLE (n=44) were consistent with the findings from
MONARCH and ADMIRAL with the exception of a greater incidence of
CSF protein elevation. In SWALLOWTAIL, 64% (28/44) of patients had
at least 1 CSF protein value >50 mg/dL. No clinical
manifestations have been observed in these patients, although one
patient discontinued treatment in SWALLOWTAIL due to elevated CSF
protein.
Key PK and CSF Exposure Findings:
- A dose-dependent increase in study drug exposure was observed
in plasma. The plasma PK profile was consistent across MONARCH and
ADMIRAL patients who were treated at the same dose level.
- STK-001 drug levels increased in CSF following 3 doses of 30mg
and 45mg, suggesting STK-001 accumulation in CNS tissues. CSF
exposure was measurable up to six months following multiple
intrathecal doses of STK-001, indicating sustained exposure of
STK-001 in the brain. CSF exposure data from the 70mg cohort will
be included in the end of study analysis.
Clinical Progress Updates and Next Steps
- These data are planned for presentation at the 35th
International Epilepsy Congress September 2-6, 2023 in Dublin,
Ireland, and also at the American Epilepsy Society (AES) December
1-5, 2023 in Orlando, Fla.
- The Company anticipates additional data, including the end of
study data from MONARCH (including patients treated with a single
dose of 70mg) and ADMIRAL, as well as additional data from the
SWALLOWTAIL and LONGWING OLEs, in the first quarter of 2024.
- The Company plans to share an update on Phase 3 planning in the
first half of 2024, pending the results from the completed Phase
1/2a studies and ongoing OLEs.
Stoke Webinar and Conference Call for Analysts and
Investors Stoke will host a webinar and conference call for
analysts and investors at 8:00 a.m. Eastern Time on Tuesday, July
25, 2023, to present positive new data from the two ongoing Phase
1/2a studies (MONARCH and ADMIRAL) and the SWALLOWTAIL open-label
extension study in children and adolescents with Dravet syndrome.
The webinar will be broadcast live on the Investors & News
section of Stoke’s website at
https://investor.stoketherapeutics.com/. An archived replay of the
webinar will be available for at least 90 days following the event.
Participants who want to join the call and ask a question may
register here to receive the dial-in numbers and unique PIN to
seamlessly access the call. Otherwise please access the listen-only
webinar by clicking here.
About Dravet Syndrome Dravet syndrome is a severe and
progressive genetic epilepsy characterized by frequent, prolonged
and refractory seizures, beginning within the first year of life.
Dravet syndrome is difficult to treat and has a poor long-term
prognosis. Complications of the disease often contribute to a poor
quality of life for patients and their caregivers. The effects of
the disease go beyond seizures and often include intellectual
disability, developmental delays, movement and balance issues,
language and speech disturbances, growth defects, sleep
abnormalities, disruptions of the autonomic nervous system and mood
disorders. The disease is classified as developmental and epileptic
encephalopathy due to the developmental delays and cognitive
impairment associated with the disease. Compared with the general
epilepsy population, people living with Dravet syndrome have a
higher risk of sudden unexpected death in epilepsy, or SUDEP. There
are no approved disease-modifying therapies for people living with
Dravet syndrome. One out of 16,000 babies are born with Dravet
syndrome, which is not concentrated in a particular geographic area
or ethnic group.
About STK-001 STK-001 is an investigational new medicine
for the treatment of Dravet syndrome currently being evaluated in
ongoing clinical trials. Stoke believes that STK-001, a proprietary
antisense oligonucleotide (ASO), has the potential to be the first
disease-modifying therapy to address the genetic cause of Dravet
syndrome. STK-001 is designed to upregulate NaV1.1 protein
expression by leveraging the non-mutant (wild-type) copy of the
SCN1A gene to restore physiological NaV1.1 levels, thereby reducing
both occurrence of seizures and significant non-seizure
comorbidities. STK-001 has been granted orphan drug designation by
the FDA and the EMA, and rare pediatric disease designation by the
FDA as a potential new treatment for Dravet syndrome.
About the Phase 1/2a MONARCH Study (United States) The
MONARCH study is a Phase 1/2a open-label study of children and
adolescents ages 2 to 18 who have an established diagnosis of
Dravet syndrome and have evidence of a genetic mutation in the
SCN1A gene. The primary objectives for the study are to assess the
safety and tolerability of STK-001, as well as to determine the
pharmacokinetics in plasma and exposure in cerebrospinal fluid. A
secondary objective is to assess the efficacy as an adjunctive
antiepileptic treatment with respect to the percentage change from
baseline in convulsive seizure frequency. Stoke also intends to
measure non-seizure aspects of the disease, such as quality of
life, as secondary endpoints. Additional information about the
MONARCH study can be found at https://www.monarchstudy.com/.
Patients who participated in the MONARCH study and meet study
entry criteria are eligible to continue treatment in SWALLOWTAIL,
an open-label extension (OLE) study designed to evaluate the
long-term safety and tolerability of repeat doses of STK-001. We
expect that SWALLOWTAIL will also provide valuable information on
the preliminary effects of STK-001 on seizures along with
non-seizure aspects of the disease, such as quality of life and
cognition.
Enrollment and dosing in SWALLOWTAIL are ongoing.
About the Phase 1/2a ADMIRAL Study (United Kingdom) The
ADMIRAL study is a Phase 1/2a open-label study of children and
adolescents ages 2 to <18 who have an established diagnosis of
Dravet syndrome and have evidence of a genetic mutation in the
SCN1A gene. The primary objectives for the study are to assess the
safety and tolerability of multiple doses of STK-001, as well as to
determine the pharmacokinetics in plasma and exposure in
cerebrospinal fluid. A secondary objective is to assess the effect
of multiple doses of STK-001 as an adjunctive antiepileptic
treatment with respect to the percentage change from baseline in
convulsive seizure frequency. Stoke also intends to measure
non-seizure aspects of the disease, such as overall clinical status
and quality of life, as secondary endpoints.
Patients who participated in the ADMIRAL study and meet study
entry criteria are eligible to continue treatment in LONGWING, an
open-label extension (OLE) study designed to evaluate the long-term
safety and tolerability of repeat doses of STK-001. We expect that
LONGWING will also provide valuable information on the preliminary
effects of STK-001 on seizures along with non-seizure aspects of
the disease, such as quality of life and cognition.
Enrollment and dosing in LONGWING are ongoing.
About TANGO TANGO (Targeted Augmentation of Nuclear Gene
Output) is Stoke’s proprietary research platform. Stoke’s initial
application for this technology are diseases in which one copy of a
gene functions normally and the other is mutated, also called
haploinsufficiencies. In these cases, the mutated gene does not
produce its share of protein, resulting in disease. Using the TANGO
approach and a deep understanding of RNA science, Stoke researchers
design antisense oligonucleotides (ASOs) that bind to pre-mRNA and
help the functional (or wild-type) genes produce more protein.
TANGO aims to restore missing proteins by increasing – or stoking –
protein output from healthy genes, thus compensating for the mutant
copy of the gene.
About Stoke Therapeutics Stoke Therapeutics (Nasdaq:
STOK), is a biotechnology company dedicated to addressing the
underlying cause of severe diseases by upregulating protein
expression with RNA-based medicines. Using Stoke’s proprietary
TANGO (Targeted Augmentation of Nuclear Gene Output) approach,
Stoke is developing antisense oligonucleotides (ASOs) to
selectively restore protein levels. Stoke’s first compound,
STK-001, is in clinical testing for the treatment of Dravet
syndrome, a severe and progressive genetic epilepsy. Dravet
syndrome is one of many diseases caused by a haploinsufficiency, in
which a loss of ~50% of normal protein levels leads to disease.
Stoke is pursuing the development of STK-002 for the treatment of
autosomal dominant optic atrophy (ADOA), the most common inherited
optic nerve disorder. Stoke’s initial focus is haploinsufficiencies
and diseases of the central nervous system and the eye, although
proof of concept has been demonstrated in other organs, tissues,
and systems, supporting its belief in the broad potential for its
proprietary approach. Stoke is headquartered in Bedford,
Massachusetts with offices in Cambridge, Massachusetts. For more
information, visit https://www.stoketherapeutics.com/ or follow
Stoke on Twitter at @StokeTx.
Cautionary Note Regarding Forward-Looking Statements This
press release contains forward-looking statements within the
meaning of the “safe harbor” provisions of the Private Securities
Litigation Reform Act of 1995, including, but not limited to the
ability of STK-001 to treat the underlying causes of Dravet
syndrome and reduce seizures or show improvements in non-seizure
comorbidities at the indicated dosing levels or at all, and the
timing and expected progress of clinical trials, data readouts and
presentations. Statements including words such as “plan,” “will,”
“continue,” “expect,” or “ongoing” and statements in the future
tense are forward-looking statements. These forward-looking
statements involve risks and uncertainties, as well as assumptions,
which, if they prove incorrect or do not fully materialize, could
cause our results to differ materially from those expressed or
implied by such forward-looking statements, including, but not
limited to, risks and uncertainties related to: the Company’s
ability to advance, obtain regulatory approval of and ultimately
commercialize its product candidates; the timing and results of
preclinical and clinical trials; the risk that positive results in
a clinical trial may not be replicated in subsequent trials or
successes in early stage clinical trials may not be predictive of
results in later stage trials and preliminary interim data readouts
of ongoing trials may show results that change when such trials are
completed; the Company’s ability to fund development activities and
achieve development goals; the Company’s ability to protect its
intellectual property; and other risks and uncertainties described
under the heading “Risk Factors” in the Company’s Annual Report on
Form 10-K for the year ended December 31, 2022, its quarterly
reports on Form 10-Q, and the other documents the Company files
from time to time with the Securities and Exchange Commission.
These forward-looking statements speak only as of the date of this
press release, and the Company undertakes no obligation to revise
or update any forward-looking statements to reflect events or
circumstances after the date hereof.
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version on businesswire.com: https://www.businesswire.com/news/home/20230725401422/en/
Stoke Media & Investor Contacts: Dawn Kalmar Chief
Communications Officer dkalmar@stoketherapeutics.com
781-303-8302
Eric Rojas Vice President, Investor Relations
IR@stoketherapeutics.com 617-312-2754
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