FDA Grants Shionogi’s Tetra Rare Pediatric Disease Designation for Experimental Fragile X Therapy

Rare Daily Staff

The U.S. Food and Drug Administration granted Shionogi’s Tetra Therapeutics Rare Pediatric Disease designation for zatolmilast, its experimental therapy for Fragile X syndrome, a leading cause of inherited intellectual disability and autism.

Fragile X syndrome (FXS) is known to have a greater effect on males than females because the mutation of the FMR1 gene is carried on the X chromosome. The most important clinical abnormality associated with FXS is global developmental delay and intellectual disability. Other common symptoms of FXS include aggressiveness, attention problems, and anxiety. FXS can cause challenges across many aspects of daily life, such as impacting individuals’ ability to care for themselves and communicate with others.

Zatolmilast is an experimental drug that is believed to work by modulating a signaling molecule called cyclic AMP (cAMP), which may promote the maturation of connections between neurons that are impaired in individuals with FXS.

The FDA grants Rare Pediatric Disease designation for serious and life-threatening diseases that primarily affect children ages 18 years or younger and fewer than 200,000 people in the United States. The RPD designation allows Tetra to request a priority review voucher from FDA that, if granted, may be used for a subsequent human drug application. Zatolmilast was also awarded Orphan Drug designation by the FDA in 2018.

In a randomized, double-blind, placebo-controlled two-way crossover phase 2 trial that included 30 adult males with FXS, the primary endpoint of this study was safety. An exploratory analysis of the efficacy of zatolmilast showed improvement in cognition, specifically in language domains including picture vocabulary and oral reading recognition. Clinically meaningful improvements in daily functioning were also observed. The most commonly reported adverse events were vomiting and upper respiratory tract infections, however rates were similar between the active and placebo arms. No participants discontinued the study due to adverse events.

Zatolmilast is currently being evaluated in a pivotal phase 2b/3 program, which includes two randomized, double-blind, placebo-controlled studies of 150 participants each. The first, Study 204, includes adolescent males ages 9-17. The second, Study 301, includes adult males ages 18-45. The zatolmilast clinical program also includes Study 302, an open-label extension study available to participants after completing Study 204 or Study 301.

Primary endpoints for the studies include a 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 subjects’ change from baseline of the Picture Vocabulary and Oral Reading domains of the NIH-TCB, as well as determinations of the drug’s safety and tolerability. Secondary endpoints include assessments of daily living, caregiver and clinician improvement scales and other domains from the NIH-TCB.

“While symptoms vary among individuals, intellectual disability is one of the most prevalent neuropsychiatric hallmarks of the disorder,” said Chad Coberly, CEO of Tetra Therapeutics. “A treatment that has the potential to improve cognition could lead to enhanced memory formation as well as improved vocabulary and reading skills. Overall gains in these domains may help people with Fragile X syndrome, their families and caregivers.”