Shionogi and Jordan’s Guardian Angels Announce First-Ever Human Drug Study for Jordan’s Syndrome, an Ultra-Rare Genetic Neurodevelopmental Disorder

OSAKA, Japan & SACRAMENTO, Calif.--( BUSINESS WIRE )-- Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President and CEO: Isao Teshirogi, PhD.; hereinafter “Shionogi”) and Jordan’s Guardian Angels announced a research collaboration between their organizations and the first-ever clinical trial evaluating an investigational drug for PPP2 syndrome type R5D (Houge-Janssens syndrome 1, HJS1), commonly referred to as Jordan's Syndrome.

The Phase 2 randomized, double-blind, placebo-controlled study will evaluate the safety and tolerability of zatolmilast ( BPN14770 ), an investigational selective PDE4D inhibitor, in people with Jordan’s Syndrome.¹ The study will also explore preliminary assessments of efficacy and obtain pharmacokinetic and biomarker data.²

Zatolmilast was discovered by Tetra Therapeutics, which was acquired by Shionogi in 2020. The drug is also being evaluated for Fragile X syndrome (FXS), the leading cause of inherited intellectual disabilities, ³ in a pivotal Phase 2b/3 program in the U.S.

Jordan’s Guardian Angels, the only patient advocacy group for Jordan’s Syndrome, an ultra-rare genetic disorder, ⁴ has dedicated the past eight years to raising awareness and securing funding for research. This clinical program is the result of an innovative, groundbreaking collaboration with 10 research and academic institutions: Columbia University, Seattle Children’s Hospital, Boston Children’s Hospital, UC Davis, University of South Alabama, Vanderbilt University, the University of Wisconsin Madison, Katholieke Universiteit Leuven, the University of Iowa and the University of Rochester, and was supported by funding from the state of California.

“When my daughter, Jordan, was finally diagnosed after years of testing, it became my family’s mission to cultivate and grow a supportive community with the shared goal of advancing the understanding of this disorder and progressing towards potential treatment options,” said Joe Lang, a co-founder of Jordan’s Guardian Angels and father of Jordan, one of the first patients to be diagnosed with the condition. “While we know this is just the beginning, this is a profound moment for our community, and we are hopeful for our children’s futures and the future of rare disease drug development.”

The Phase 2 study of zatolmilast in Jordan’s Syndrome will enroll 30 participants in early 2025 aged 9-45 years with a confirmed/documented history of PPP2R5D neurodevelopmental disorder.^1,2 Participants will receive a weight-adjusted dose of the study drug or placebo twice daily during the 24-week double-blind period.² Participants will have the opportunity to continue in a 24-week open-label extension period.² The study is expected to conclude in late 2026.¹ See ClinicalTrials.gov ID: NCT06717438 for additional study details and locations.

Jordan’s Syndrome is characterized by global developmental delays, seizures, physical abnormalities, vision problems, muscle weakness, attention disorder, social and sensory challenges commonly associated with autism, disordered sleep and feeding difficulties. Symptoms and severity vary depending on the individual.⁵

There are currently no specific medications or curative treatments available for people with Jordan's Syndrome.⁶ While only about 350 people have been diagnosed with Jordan’s Syndrome globally,⁷ it is estimated that many more go undiagnosed.⁵ Jordan's Syndrome is difficult to diagnose because symptoms can vary widely, and the condition can co-exist with other developmental disorders like autism spectrum disorder.⁵ In addition, whole-exome sequencing or diagnostic testing for a panel of genes associated is needed to identify the specific mutation in the PPP2R5D gene to confirm a Jordan's Syndrome diagnosis, a test that may be difficult to access.⁵

“We are excited to embark on the next step in our journey to develop a treatment for Jordan’s Syndrome,” said Wendy Chung MD, PhD, Chief of the Department of Pediatrics at Boston Children’s Hospital, Professor of Pediatrics at Harvard Medical School and lead principal investigator of the study. “This milestone would not be possible without the collaboration of our research teams, the dedication of our families, and this new partnership with Shionogi, an organization with a history of delivering scientific breakthroughs for patients around the world.”

Stefan Strack, PhD, Vice Chair of Neuroscience and Pharmacology at the University of Iowa, led preclinical research involving zatolmilast to assess cognitive function and underlying disease processes in animal models for Jordan’s Syndrome, paving the way for this Phase 2 study.

“Shionogi is honored to partner with Jordan’s Guardian Angels on this historic study as we work together to advance our shared commitment to helping patients and families affected by Jordan's Syndrome,” said Juan Carlos Gomez, MD, MBA, Chief Medical Officer, Shionogi & Co. Ltd. “Through this expansion of our zatolmilast clinical program, we hope to bring meaningful advances to the Jordan's Syndrome community.”

The U.S. Food and Drug Administration (FDA) recently granted zatolmilast Rare Pediatric Disease Designation (RPD) for the treatment of Jordan’s Syndrome, a designation granted for serious and life-threatening diseases that primarily affect children ages 18 years or younger with fewer than 200,000 people in the United States.⁸

About the Zatolmilast Clinical Program in FXS

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.⁹ Clinically meaningful improvements in daily functioning were also observed.⁹ The most commonly reported adverse events were vomiting and upper respiratory tract infections.⁹ However, rates were similar between the active and placebo arms.⁹ No participants discontinued the study due to adverse events.⁹

Shionogi is currently conducting multicenter, late-stage (Phase 2b/3) clinical studies to further evaluate the safety and efficacy of zatolmilast on cognition and other aspects of FXS.^10-12 The zatolmilast FXS clinical program, which has also been referred to as BPN14770-CNS-204,¹⁰ BPN14770-CNS-301,¹¹ BBPN14770-CNS-302¹² and the Tetra studies, is now known as the EXPERIENCE (Evaluation of Fragile X Experience in Cognition Expression) clinical trials, which include EXPERIENCE-204 (adolescent)¹⁰, EXPERIENCE-301 (adult)¹¹ and EXPERIENCE-302 (open-label extension).¹²

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 Jordan’s Guardian Angels

Jordan’s Guardian Angels is a Sacramento-based non-profit foundation working to unlock some of the world’s greatest medical mysteries.¹³ Jordan’s Guardian Angels is leading groundbreaking international research into a mutation on the genes PPP2R5D (Jordan’s Syndrome), PPP2R5C, and PPP2R1A.¹³ It causes global developmental delays among other symptoms and is linked to autism, epilepsy, Alzheimer’s, cancer and Parkinson’s.¹³ Jordan’s Guardian Angels has united families around the world. In partnership with major research institutions, Jordan’s Guardian Angels is on a mission to make a better future for our children, and potentially millions more, through research that world-renowned medical experts believe will change the world.¹³

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 the daily lives of individuals and families around the world. In the U.S., Shionogi is advancing clinical programs for rare diseases and disorders including Fragile X syndrome, Jordan’s 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. Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome [JS]). National Library of Medicine. Accessed December 24, 2024. Available at https://clinicaltrials.gov/study/NCT06717438?cond=Jordan%27s%20Syndrome&rank=1 .
2. Clinical Trial Protocol. Protocol Title: A Phase 2 Randomized, Double-blind, Placebo-controlled, Study of Zatolmilast (BPN14770) in Subjects with PPP2R5D Neurodevelopmental Disorder (Jordan’s Syndrome).
3. Fragile X Syndrome (FXS). Cleveland Clinic. Accessed January 21, 2025. Available at: https://my.clevelandclinic.org/health/diseases/5476-fragile-x-syndrome .
4. Smith CIE, et al. Estimating the number of diseases - the concept of rare, ultra-rare, and hyper-rare. iScience. 2022 Jul 1;25(8):104698. doi: 10.1016/j.isci.2022.104698. PMID: 35856030; PMCID: PMC9287598.
5. Levine AD, et al. Clinical features of PPP2 syndrome type R5D (Jordan's syndrome) to support standardization of care. Cold Spring Harb Mol Case Stud. 2023 Jul 11;9(3):a006285. doi: 10.1101/mcs.a006285. PMID: 37339871; PMCID: PMC10393186.
6. GENE GUIDE: PPP2R5D-Related Syndrome. Simon’s Searchlight. Accessed January 14, 2025. Available at: https://www.simonssearchlight.org/gene-guide/ppp2r5d/ .
7. Data on file at Jordan’s Guardian Angels.
8. Rare Pediatric Disease Designation and Priority Review Voucher Programs. The U.S. Food and Drug Administration. Accessed January 21, 2025. Available at: https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/rare-pediatric-disease-designation-and-priority-review-voucher-programs
9. 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 .
10. ClinicalTrials.gov. A Randomized Study of BPN14770 in Male Adolescents (Aged 9 to <18 Years) With Fragile X Syndrome. Identifier: NCT05163808.
11. ClinicalTrials.gov. A Randomized, Double-blind, Placebo-controlled, Parallel Group Study of BPN14770 in Male Adults (Aged 18 to 45) With Fragile X Syndrome. Identifier: NCT05358886.
12. ClinicalTrials.gov. An Open-Label Extension Study of BPN14770 in Subjects With Fragile X Syndrome. Identifier: NCT05367960.
13. Jordan’s Guardian Angels.org. Accessed January 14, 2025. Available at: https://jordansguardianangels.org/

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