Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief
Executive Officer: Isao Teshirogi, Ph.D.; hereafter "Shionogi")
today announced progress on the development program for zatolmilast
(BPN14770), an investigational drug for Fragile X syndrome (FXS),
the leading cause of inherited intellectual disabilities, like
autism spectrum disorder.1 Zatolmilast was discovered by Tetra
Therapeutics Inc., (hereafter “Tetra”), which was acquired by
Shionogi in 2020.
Zatolmilast is the first and only selective PDE4D inhibitor
being investigated for FXS.2 There are currently no pharmacological
agents approved by the U.S. Food and Drug Administration (FDA) to
treat FXS.3
The FDA recently granted Fast Track designation to zatolmilast,
reflecting the significant unmet medical need for FXS. The FDA
previously granted zatolmilast Rare Pediatric Disease Designation
and Orphan Drug Designation. The European Commission granted Orphan
Medicinal Product designation for zatolmilast in FXS earlier this
year. These designations are designed to facilitate the development
and expedite the review of potential new therapies that treat
serious conditions and fulfill an unmet medical need.
“My husband and I have spent the past 30 years raising and
directing funds to support early-stage research in Fragile X
syndrome. This is a full circle moment for us as our organization
funded the early development of zatolmilast,” said Katie Clapp,
President and Co-Founder of the FRAXA Research Foundation, a
non-profit organization dedicated to funding research for FXS.
“It’s important to realize that this progress is possible because
of the families that participate in clinical trials. I hope more
families will consider participating in clinical research to help
our loved ones, not only today, but also for future
generations.”
Making Zatolmilast Clinical Trials More Accessible for
Families
Tetra is currently enrolling participants in zatolmilast
clinical studies at 15 sites across the U.S., with additional sites
anticipated this year.4-6 The studies are evaluating the safety and
efficacy of zatolmilast in males aged 9 to 45 years with FXS. 4-6
Tetra recently completed several protocol amendments to make the
clinical trials more accessible for people living with FXS and
their families,7-9 including:
- Lowering eligibility age: The
adolescent study age minimum is now 9 years old, reduced from 12
years old, and the weight minimum was lowered to 55 pounds from 95
pounds.
- Adding remote visits: All studies
now incorporate remote visits, reducing the number of on-site
visits from six to four over the 13-week trials.
- Extending the open-label extension
period: The open-label extension study, in which all
participants will receive zatolmilast, is now up to two years long
(previously one year).
- Covering travel services: Travel
to and from sites for a study participant and his caregiver may be
covered by Tetra and may include transportation and lodging
arrangements and reimbursement for meals (limitations may
apply).
“I’ve been working on Fragile X syndrome and with the community
for more than 30 years. Enrolling participants in late-stage (Phase
2b/3) clinical studies of zatolmilast is a significant step in our
efforts to bring a potential treatment option to families,” said
Elizabeth Berry-Kravis, MD, PhD, clinical trial investigator and
professor of pediatrics, neurological sciences and biochemistry at
Rush University Medical Center in Chicago. “If the positive Phase 2
trial data can be replicated, this investigational drug has the
potential to improve cognition and could offer people living with
Fragile X syndrome and their families the first cognitive treatment
developed specifically for this rare genetic disorder.”
Commitment to Patient Advocacy
In addition to supporting FRAXA, Tetra has supported the
National Fragile X Foundation since 2017. This year, Tetra and
Shionogi are sponsors of the National Fragile X Foundation
International Fragile X Conference taking place July 25-28 in
Orlando, Florida. The conference brings together people living with
FXS and their families, caregivers, friends and professionals to
learn from one another during the FXS journey.
About the Zatolmilast Clinical Program
In a Phase 2 randomized, double-blind, placebo-controlled,
two-way crossover trial that included 30 adult males with FXS, the
primary endpoint of safety was demonstrated. An exploratory
analysis of the efficacy of zatolmilast showed improvement in
cognition, specifically in language domains including picture
vocabulary and oral reading recognition.2 Clinically meaningful
improvements in daily functioning were also observed.2 The most
commonly reported adverse events were vomiting and upper
respiratory tract infections. However, rates were similar between
the active and placebo arms.2 No participants discontinued the
study due to adverse events.2
Zatolmilast is being evaluated in a pivotal Phase 2b/3 program
in the U.S., with two randomized, double-blind, placebo-controlled
studies of 150 participants each.4-6 The first, Study 204
(NCT05163808), includes adolescent males ages 9-17.4 The second,
Study 301 (NCT05358886), includes adult males ages 18-45.5 The
zatolmilast clinical program also includes Study 302 (NCT05367960),
an open-label extension study, that may last for up to two years,
available to participants after completing Study 204 or Study
301.6
Primary endpoints for the studies include cognitive assessment
of the efficacy of zatolmilast, as measured by the cognition
crystallized composite score of the National Institutes of Health
Toolbox Cognitive Battery (NIH-TCB), a calculated score from a
series of tests to assess the patients’ change from baseline of the
Picture Vocabulary and Oral Reading domains of the NIH-TCB.
Secondary endpoints include assessments of language, daily
function, caregiver and clinician improvement scales and other
domains from the NIH-TCB, as well as further determination of the
investigational drug’s safety and tolerability.4-6
Learn about the zatolmilast clinical program at
https://tetratherapeutics.com/clinical-trials/.
Zatolmilast is an investigational drug. Safety and efficacy have
not been established. There is no guarantee that zatolmilast will
be approved by any health authority.
About Fragile X Syndrome (FXS)
Fragile X syndrome is the leading cause of inherited
intellectual disabilities, like autism spectrum disorder.1 FXS is
known to have a greater effect on males than females because the
mutation of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene
is carried on the X chromosome.1 The most important clinical
abnormality associated with FXS is global developmental delay and
intellectual disability.10 Other common symptoms of FXS include
behavioral problems, attention deficits and anxiety.1 FXS can cause
challenges across many aspects of daily life, such as impacting
individuals’ ability to care for themselves and communicate with
others.11
About Tetra Therapeutics
Tetra Therapeutics, a Shionogi Group Company, is a clinical
stage biotechnology company focused on developing a portfolio of
therapeutic products to address unmet needs in central nervous
system diseases and disorders. In addition to advancing the
zatolmilast clinical program, Tetra also has a PDE4B inhibitor in
pre-clinical development. Tetra Therapeutics is headquartered in
Kalamazoo, Michigan. For more information, visit
tetratherapeutics.com/clinical-trials/.
About Shionogi in Rare Disease
Shionogi is committed to the research and development of
innovative medicines that address unmet medical needs for people
worldwide. Rare diseases often have limited treatment options and
affect daily lives of individuals and families around the world.12
In the U.S., Shionogi is advancing clinical programs for rare
diseases and disorders including Fragile X syndrome and Pompe
disease. For more information, see our pipeline here:
https://www.shionogi.com/us/en/innovation/pipeline.html.
About Shionogi & Co., Ltd.
Shionogi & Co., Ltd. is a leading global research-driven
pharmaceutical company dedicated to bringing benefits to patients
based on its corporate philosophy of "supplying the best possible
medicine to protect the health and well-being of the patients we
serve." Shionogi has discovered and developed novel antibiotics,
medicines for HIV and influenza, and currently markets medicines
for infectious diseases and central nervous system disorders.
Shionogi’s global pipeline includes research programs in infectious
disease, pain/CNS, metabolic disorders, rare disease, oncology and
stroke. For more information, visit
https://www.shionogi.com/global/en.
Forward-Looking Statements
This announcement contains forward-looking statements. These
statements are based on expectations in light of the information
currently available, assumptions that are subject to risks and
uncertainties which could cause actual results to differ materially
from these statements. Risks and uncertainties include general
domestic and international economic conditions such as general
industry and market conditions, and changes of interest rate and
currency exchange rate. These risks and uncertainties particularly
apply with respect to product-related forward-looking statements.
Product risks and uncertainties include, but are not limited to,
completion and discontinuation of clinical trials; obtaining
regulatory approvals; claims and concerns about product safety and
efficacy; technological advances; adverse outcome of important
litigation; domestic and foreign healthcare reforms and changes of
laws and regulations. Also, for existing products, there are
manufacturing and marketing risks, which include, but are not
limited to, inability to build production capacity to meet demand,
lack of availability of raw materials and entry of competitive
products. The company disclaims any intention or obligation to
update or revise any forward-looking statements whether as a result
of new information, future events or otherwise.
References:
- Fragile X Syndrome (FXS). Cleveland Clinic. Accessed June 11,
2024. Available at:
https://my.clevelandclinic.org/health/diseases/5476-fragile-x-syndrome.
- Berry-Kravis EM, Harnett MD, Reines SA, et al. Inhibition of
phosphodiesterase-4D in adults with fragile X syndrome: a
randomized, placebo-controlled, phase 2 clinical trial. Nat Med 27,
862–870 (2021). https://doi.org/10.1038/s41591-021-01321-w.
- Alusi G, Berry-Kravis E, Nelson D, Orefice LL, Booker SA.
Emerging Therapeutic Strategies for Fragile X Syndrome: Q&A.
ACS Chem Neurosci. 2022 Dec 21;13(24):3544-3546. doi:
10.1021/acschemneuro.2c00674. Epub 2022 Dec 7. PMID: 36475635;
PMCID: PMC9782331.
- ClinicalTrials.gov. A Randomized Study of BPN14770 in Male
Adolescents (Aged 9 to <18 Years) With Fragile X Syndrome.
Identifier: NCT05163808.
- ClinicalTrials.gov. Safety and Efficacy Study of BPN14770 in
Subjects With Fragile X Syndrome. Identifier: NCT05358886.
- ClinicalTrials.gov. An Open-Label Extension Study of BPN14770
in Subjects With Fragile X Syndrome. Identifier: NCT05367960.
- BPN14770-CNS-204. Tetra Therapeutics. Accessed June 24, 2024.
Available at:
https://tetratherapeutics.com/clinical-trials/bpn14770-cns-204/
- BPN14770-CNS-301. Tetra Therapeutics. Accessed June 24, 2024.
Available at:
https://tetratherapeutics.com/clinical-trials/bpn14770-cns-301/
- BPN14770-CNS-302. Tetra Therapeutics. Accessed June 24, 2024.
Available at:
https://tetratherapeutics.com/clinical-trials/bpn14770-cns-302/
- Ciaccio C, Fontana L, Milani D, et al. Fragile X syndrome: A
review of clinical and molecular diagnoses. Ital J Pediatr. 19,
43(1): 39 (2017).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5395755/.
- Fragile X Syndrome: Learning What Families Need. The Centers
for Disease Control and Prevention. Accessed June 11, 2024.
Available at:
https://www.cdc.gov/fragile-x-syndrome/articles/learning-what-families-need.html
- Han Q, Fu H, Chu X, Wen R, Zhang M, You T, Fu P, Qin J, Cui T.
Research advances in treatment methods and drug development for
rare diseases. Front Pharmacol. 2022 Oct 12;13:971541. doi:
10.3389/fphar.2022.971541. PMID: 36313320; PMCID: PMC9597619.
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