Shionogi Initiates First-Ever Human Study Testing Therapy for Ultra-Rare Jordan’s Syndrome

Wendy Chung, MD, PhD

Shionogi and Jordan’s Guardian Angels have announced a collaborative research study (NCT06717438) testing the effects of zatolmilast (BPN14770), an investigational selective PDE4D inhibitor, in patients with Jordan’s syndrome, an ultra-rare neurodevelopmental disorder.

Also known as PPP2R5D-related intellectual disability, Jordan’s syndrome is caused by de novo mutations in the PPR2R5D gene. Individuals with the condition often experience global developmental delays, intellectual disability, macrocephaly, hypotonia, seizures, and may exhibit features associated with autism spectrum disorder (ASD). As of 2019, approximately 23 individuals had been diagnosed with Jordan’s syndrome, but more recent estimates suggest around 350 people globally have ben identified, with many more potentially undiagnosed due to symptom variability and diagnostic challenges.

The newly initiated study, a phase 2 trial, is expected to include 30 individuals with the disease, aged 9-45 years, who will receive a weight-adjusted dose of the study drug or placebo twice daily for a 24-week double-blind period. Expected to conclude in late 2026, the trial also includes a 24-week open-label extension period for patients who decide to continue treatment following the double-blind portion.

"We are excited to embark on the next step in our journey to develop a treatment for Jordan’s Syndrome,” lead investigator Wendy Chung, MD, PhD, chief of the department of pediatrics at Boston Children’s Hospital, and professor of pediatrics at Harvard Medical School, said in a statement.¹ "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."

To be eligible for the study, patients must have a confirmed or documented history of PPP2R5D Neurodevelopmental Disorder and are currently receiving no more than 3 prescribed psychotropic medications. Patients are excluded if they weigh less than 25 kg or exhibit clinically significant abnormalities in safety laboratory tests, vital signs, or electrocardiogram results, as determined by the investigator during screening. Additionally, those with concurrent major psychiatric conditions, such as major depressive disorder, schizophrenia, or bipolar disorder, are not eligible, though participants with ASD or anxiety disorder may still qualify.

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"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," Joe Lang, co-founder of Jordan’s Guardian Angels and father of Jordan, one of the first patients to be diagnosed with the condition, said in a statement. "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."

Zatolmilast is currently being tested in patients with Fragile X syndrome (FXS) in a multi-study program called EXPERIENCE. It includes 3 major phase 2/3 studies, EXPERIENCE-204 (NCT05163808), which includes adolescent males ages 9-17, EXPERIENCE-301 (NCT05358886), which comprises adult males ages 18-45, and EXPERIENCE-302 (NCT05367960), which is an open-label extension available to participants after completing Study 204 or Study 301. To date, the therapy has gained FDA fast track, rare pediatric disease, and orphan drug designations for the treatment of FXS.

In a previous phase 2 trial (NCT03569631) involving 30 men with FXS, zatolmilast was found safe, and to lead to significant cognitive improvements and clinically meaningful gains in daily functioning relative to placebo. Published in Nature, the 24-week, randomized, two-way crossover study featured 30 adult males with FXS who received zatolmilast 25 mg twice daily or placebo. All told, the trial met its primary end point, as the treatment was well tolerated and had no safety differences when compared with placebo.

The study also achieved key secondary efficacy outcomes in cognition and daily function. Cognitive improvements were observed through the NIH Toolbox Cognition Battery assessments, with significant gains in Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342), and Cognition Crystallized Composite score (+5.31, P = 0.0018). Additionally, clinically meaningful benefits were reported on caregiver-rated visual analog scales for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017).

REFERENCES
1. Shionogi and Jordan’s Guardian Angels Announce First-Ever Human Drug Study for Jordan’s Syndrome, an Ultra-Rare Genetic Neurodevelopmental Disorder. News release. Shionogi & Jordan’s Guardian Angels. February 4, 2025. Accessed February 11, 2025. https://www.businesswire.com/news/home/20250204784467/en/Shionogi-and-Jordan%E2%80%99s-Guardian-Angels-Announce-First-Ever-Human-Drug-Study-for-Jordan%E2%80%99s-Syndrome-an-Ultra-Rare-Genetic-Neurodevelopmental-Disorder
2. Study of Zatolmilast (BPN14770) in Participants With PPP2R5D Neurodevelopmental Disorder (Jordan's Syndrome [JS]). Clinicaltrials.gov. Updated January 8, 2025. Accessed February 11, 2025. https://clinicaltrials.gov/study/NCT06717438
3. 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. Nature. 2021;27:862-870. doi:10.1038/s41591-021-01321-w