- SKYLINE Study in Dravet Syndrome Narrowly Missed its Primary
Endpoint of Reduction in Convulsive Seizure Frequency and Showed
Clinically Meaningful and Nominally Significant Effects in Multiple
Key Secondary Efficacy Endpoints
- SKYWAY Study in Lennox-Gastaut Syndrome Missed its Primary
Endpoint of Reduction in Major Motor Drop Seizures
- Soticlestat Showed a Consistent and Favorable Safety and
Tolerability Profile in Both Studies
- Takeda Will Move Forward to Discuss the Totality of the Data
with Regulatory Authorities
Takeda (TSE:4502/NYSE:TAK) today announced topline data from its
SKYLINE and SKYWAY studies.
SKYLINE (TAK-935-3001) was a multicenter, randomized,
double-blind Phase 3 study that evaluated soticlestat (TAK-935)
plus standard of care versus placebo plus standard of care in
patients with refractory Dravet syndrome (DS).1 Soticlestat
narrowly missed the primary endpoint of reduction from baseline in
convulsive seizure frequency as compared to placebo (p-value =
0.06). Among the six key secondary endpoints, soticlestat showed
clinically meaningful and nominally significant results in the
responder rate, measures of caregiver and clinician global
impression of improvement, and seizure intensity and duration
scales over the 16-week treatment period (all p-values ≤
0.008).
SKYWAY (TAK-935-3002) was a multicenter, randomized,
double-blind Phase 3 study that evaluated soticlestat plus standard
of care versus placebo plus standard of care in patients with
refractory Lennox-Gastaut syndrome (LGS).2 Soticlestat missed the
novel primary endpoint of reduction from baseline in Major Motor
Drop (MMD) seizure frequency as compared to placebo.
In SKYLINE and SKYWAY, some pre-specified subgroups of patients
also showed nominally significant treatment effects on the primary
and secondary efficacy endpoints of caregiver and clinician global
impression of improvement, and seizure intensity and duration
scales over the 16-week treatment period. Further analyses are
being conducted.
Soticlestat was generally well tolerated in both SKYLINE and
SKYWAY studies and demonstrated a safety profile consistent with
the findings of previous studies.
“We are grateful to all the participants and their families, as
well as investigators and clinical staff for their participation in
these important studies,” said Sarah Sheikh, M.Sc., B.M., B.Ch.,
MRCP, Head, Neuroscience Therapeutic Area Unit and Head, Global
Development at Takeda. “Even with currently available therapies, we
know that many patients with developmental encephalopathies like DS
and LGS still experience persistent unmet need across multiple
dimensions, such as seizure burden and treatment tolerability.
While we would have wished for more declarative results on the
primary endpoints, we are encouraged by positive outcomes seen in
the totality of the data and are looking forward to engaging health
authorities to determine the best path forward.”
In the Phase 2 study, ELEKTRA, soticlestat demonstrated a
statistically significant reduction of seizures from baseline
compared to placebo (p-value = 0.002) in the combined DS and LGS
study population during the full treatment period.3 In the DS
cohort, statistically significant reduction in convulsive seizure
frequency from baseline compared to placebo (p-value = 0.0007) was
also achieved.3 In a pooled analysis of SKYLINE and the DS cohort
of the Phase 2 ELEKTRA study, soticlestat also showed a reduction
from baseline in convulsive seizure frequency compared to placebo
(p-value = 0.001).
Takeda will engage with regulatory authorities to discuss the
totality of the data generated by these studies to determine next
steps. Takeda will also plan to present results of both Phase 3
studies at an upcoming scientific congress.
Takeda is continuing to assess the financial impacts of the
study results, including impairment loss for intangible assets, on
the first quarter ending June 30, 2024 and will communicate as
necessary in due course.
About Soticlestat (TAK-935) Soticlestat (TAK-935) is an
investigational, first-in-class potent and selective inhibitor of
cholesterol 24-hydroxylase (CH24H), an enzyme primarily expressed
in the brain that catabolizes cholesterol to 24-S
hydroxycholesterol (24HC) resulting in a reduction in glutamatergic
hyperexcitability.4,5
About Dravet Syndrome and Lennox-Gastaut Syndrome Dravet
syndrome and Lennox-Gastaut syndrome are types of developmental and
epileptic encephalopathies (DEEs), a group of rare epilepsy
syndromes that typically become apparent during infancy or early
childhood and are highly drug-resistant to many antiseizure
medications.6,7 Individuals with DS and LGS also suffer from common
non-seizure symptoms such as problems with alertness, communication
and disruptive behavior.7,8
Dravet syndrome is most commonly caused by a genetic mutation in
the SCN1A gene and affects approximately 1 in 15,000 to 1 in 21,000
people in the United States.7,9 Dravet syndrome is characterized by
prolonged focal seizures that can evolve to convulsive tonic-clonic
seizures.7 Children with Dravet syndrome experience developmental
disabilities as seizures increase.7 Other common symptoms include
changes in appetite, difficulty balancing and a crouched gait when
walking.7
Lennox-Gastaut syndrome is estimated to affect fewer than 1 in
1,000 people in the United States.10 Lennox-Gastaut syndrome is a
heterogeneous condition and characterized by several different
types of seizures, most commonly atonic (drop), tonic and atypical
absence seizures.6 Children with Lennox-Gastaut syndrome may also
develop cognitive dysfunction, delays in reaching developmental
milestones and behavioral problems.6,8 Lennox-Gastaut syndrome can
be caused by a variety of underlying conditions but in some cases
no cause can be identified.8
About Takeda’s SKYLINE Trial The Phase 3 SKYLINE is a
global, multicenter, 1:1 randomized, double-blind,
placebo-controlled, parallel group study to evaluate the efficacy,
safety, and tolerability of soticlestat as adjunctive therapy in
pediatric and young adult subjects with Dravet syndrome. The
primary endpoint was percent change from baseline in convulsive
seizure frequency per 28 days in subjects receiving soticlestat as
compared with placebo during the full treatment period. Key
secondary endpoints included evaluation of effects on treatment
response, Care GI-I (Caregiver Global Impression of Improvement),
CGI-I, CGI-I Non-Seizure Symptoms, QI-Disability, CGI-I seizure
intensity and duration.1
A total of 144 subjects aged 2 – 21 years were enrolled in the
study. The diagnosis of Dravet syndrome was adjudicated
independently by the Epilepsy Study Consortium. The study treatment
period was 16 weeks including a 4-week titration period and 12
weeks maintenance period. Patients were randomized 1:1 to receive
either soticlestat or matching placebo twice daily (BID) added to
current antiseizure therapy administered orally or via enteral tube
feeding. Soticlestat was started at 100 mg BID or weight equivalent
dose for 7 days and titrated up weekly, based on tolerability, up
to 300 mg BID or weight equivalent dose. Upon completion of the
study, willing subjects had the option to enroll in an ongoing
open-label extension study (ENDYMION 2).1,11,12
About Takeda’s SKYWAY Trial The Phase 3 SKYWAY is a
global, multicenter, 1:1 randomized, double-blind,
placebo-controlled, parallel group study to evaluate the efficacy,
safety, and tolerability of soticlestat as adjunctive therapy in
pediatric and adult subjects with Lennox-Gastaut syndrome. The
primary endpoint was percent change from baseline in Major Motor
Drop (MMD) seizure frequency per 28 days in subjects receiving
soticlestat as compared with placebo during the full treatment
period. Key secondary endpoints included evaluation of effects on
treatment response, Care GI-I, CGI-I, CGI-I Non-Seizure Symptoms,
QI-Disability, CGI-I seizure intensity and duration.2
A total of 270 subjects aged 2 – 55 years were enrolled in the
study. The diagnosis of Lennox-Gastaut syndrome was adjudicated
independently by the Epilepsy Study Consortium. The study treatment
period was 16 weeks including a 4-week titration period and 12
weeks maintenance period. Patients were randomized 1:1 to receive
either soticlestat or matching placebo twice daily (BID) added to
current antiseizure therapy administered orally or via enteral tube
feeding. Soticlestat was started at 100 mg BID or weight equivalent
dose for 7 days and titrated up weekly, based on tolerability, up
to 300 mg BID or weight equivalent dose. Upon completion of the
study, willing subjects had the option to enroll in an open-label
extension study (ENDYMION 2).2,11,12
About Takeda Takeda is focused on creating better health
for people and a brighter future for the world. We aim to discover
and deliver life-transforming treatments in our core therapeutic
and business areas, including gastrointestinal and inflammation,
rare diseases, plasma-derived therapies, oncology, neuroscience and
vaccines. Together with our partners, we aim to improve the patient
experience and advance a new frontier of treatment options through
our dynamic and diverse pipeline. As a leading values-based,
R&D-driven biopharmaceutical company headquartered in Japan, we
are guided by our commitment to patients, our people and the
planet. Our employees in approximately 80 countries and regions are
driven by our purpose and are grounded in the values that have
defined us for more than two centuries. For more information, visit
www.takeda.com.
Forward-Looking Statements This press release and any
materials distributed in connection with this press release may
contain forward-looking statements, beliefs or opinions regarding
Takeda’s future business, future position and results of
operations, including estimates, forecasts, targets and plans for
Takeda. Without limitation, forward-looking statements often
include words such as “targets”, “plans”, “believes”, “hopes”,
“continues”, “expects”, “aims”, “intends”, “ensures”, “will”,
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“projects” or similar expressions or the negative thereof. These
forward-looking statements are based on assumptions about many
important factors, including the following, which could cause
actual results to differ materially from those expressed or implied
by the forward-looking statements: the economic circumstances
surrounding Takeda’s global business, including general economic
conditions in Japan and the United States; competitive pressures
and developments; changes to applicable laws and regulations,
including global health care reforms; challenges inherent in new
product development, including uncertainty of clinical success and
decisions of regulatory authorities and the timing thereof;
uncertainty of commercial success for new and existing products;
manufacturing difficulties or delays; fluctuations in interest and
currency exchange rates; claims or concerns regarding the safety or
efficacy of marketed products or product candidates; the impact of
health crises, like the novel coronavirus pandemic, on Takeda and
its customers and suppliers, including foreign governments in
countries in which Takeda operates, or on other facets of its
business; the timing and impact of post-merger integration efforts
with acquired companies; the ability to divest assets that are not
core to Takeda’s operations and the timing of any such
divestment(s); and other factors identified in Takeda’s most recent
Annual Report on Form 20-F and Takeda’s other reports filed with
the U.S. Securities and Exchange Commission, available on Takeda’s
website at:
https://www.takeda.com/investors/sec-filings-and-security-reports/
or at www.sec.gov. Takeda does not undertake to update any of the
forward-looking statements contained in this press release or any
other forward-looking statements it may make, except as required by
law or stock exchange rule. Past performance is not an indicator of
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Medical information This press release contains
information about products that may not be available in all
countries, or may be available under different trademarks, for
different indications, in different dosages, or in different
strengths. Nothing contained herein should be considered a
solicitation, promotion or advertisement for any prescription drugs
including the ones under development.
References
- Soticlestat as an Add-on Therapy in Children and Young Adults
With Dravet Syndrome. ClinicalTrials.gov. Published June 25, 2021.
Last accessed June 14, 2024.
https://classic.clinicaltrials.gov/ct2/show/NCT04940624.
- A Study of Soticlestat as an Add-on Therapy in Children,
Teenagers, and Adults With Lennox-Gastaut Syndrome. Published June
24, 2021. Last accessed June 14, 2024.
https://clinicaltrials.gov/study/NCT04938427?term=TAK-935-3002&rank=1
- Hahn CD, Jiang Y, Villanueva V, et al. A phase 2, randomized,
double‐blind, placebo‐controlled study to evaluate the efficacy and
safety of SOTICLESTAT as adjunctive therapy in pediatric patients
with Dravet Syndrome or Lennox–Gastaut syndrome (elektra).
Epilepsia. 2022;63(10):2671-2683. doi:10.1111/epi.17367
- Nishi T, Kondo S, Miyamoto M, et al. Soticlestat, a novel
cholesterol 24-hydroxylase inhibitor shows a therapeutic potential
for neural hyperexcitation in mice. Scientific Reports. 2020;10(1).
doi:10.1038/s41598-020-74036-6
- Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW.
Knockout of the cholesterol 24-hydroxylase gene in mice reveals a
brain-specific mechanism of cholesterol turnover. Journal of
Biological Chemistry. 2003;278(25):22980-22988.
doi:10.1074/jbc.m303415200
- Arzimanoglou A, French J, Blume WT, et al. Lennox-Gastaut
syndrome: a consensus approach on diagnosis, assessment,
management, and trial methodology. The Lancet Neurology.
2009;8(1):82-93. doi:10.1016/s1474-4422(08)70292-8
- Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet
Syndrome: An Overview. Cureus. 2019;11(6).
doi:10.7759/cureus.5006
- Jahngir MU, Ahmad MQ, Jahangir M. Lennox-Gastaut Syndrome: In a
Nutshell. Cureus. 2018;10(8). doi:10.7759/cureus.3134
- Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet
Syndrome in a US Population. Pediatrics. 2015;136(5):e1310-e1315.
doi:10.1542/peds.2015-1807
- Trevathan E, Murphy CC, Yeargin‐Allsopp M. Prevalence and
descriptive epidemiology of Lennox‐Gastaut Syndrome among Atlanta
Children. Epilepsia.1997;38(12):1283-1288.
doi:10.1111/j.1528-1157.1997.tb00065.x
- A Study of Soticlestat in Adults and Children With Rare
Epilepsies (Endymion 1). Published August 18, 2017. Last accessed
June 14, 2024. https://clinicaltrials.gov/study/NCT03635073
- Ovid Therapeutics Announces Positive Initial Data from Ongoing
ENDYMION Open-Label Extension Trial. Published September 23, 2019.
Accessed June 14, 2024.
https://investors.ovidrx.com/news/news-details/2019/Ovid-Therapeutics-Announces-Positive-Initial-Data-from-Ongoing-ENDYMION-Open-Label-Extension-Trial-of-Soticlestat-in-People-with-Rare-Epilepsies-09-23-2019/default.aspx
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Japanese Media Jun Saito jun.saito@takeda.com
U.S. and International Media Rand Walton
rand.walton@takeda.com
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