Shionogi Provides Updates on Zatolmilast, an Investigational Drug for Fragile X Syndrome, Including Recent Changes to Study Protocol to Increase Access for Participants and Families

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:

1. Fragile X Syndrome (FXS). Cleveland Clinic. Accessed June 11, 2024. Available at: https://my.clevelandclinic.org/health/diseases/5476-fragile-x-syndrome.
2. 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.
3. 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.
4. ClinicalTrials.gov. A Randomized Study of BPN14770 in Male Adolescents (Aged 9 to <18 Years) With Fragile X Syndrome. Identifier: NCT05163808.
5. ClinicalTrials.gov. Safety and Efficacy Study of BPN14770 in Subjects With Fragile X Syndrome. Identifier: NCT05358886.
6. ClinicalTrials.gov. An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome. Identifier: NCT05367960.
7. BPN14770-CNS-204. Tetra Therapeutics. Accessed June 24, 2024. Available at: https://tetratherapeutics.com/clinical-trials/bpn14770-cns-204/
8. BPN14770-CNS-301. Tetra Therapeutics. Accessed June 24, 2024. Available at: https://tetratherapeutics.com/clinical-trials/bpn14770-cns-301/
9. BPN14770-CNS-302. Tetra Therapeutics. Accessed June 24, 2024. Available at: https://tetratherapeutics.com/clinical-trials/bpn14770-cns-302/
10. 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/.
11. 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
12. 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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