Zatolmilast earns FDA’s rare pediatric disease designation

Trial data has shown the investigational fragile X therapy improved cognitive function

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

Share this article:

Share article via email
A person wearing a baseball cap is shown speaking through a megaphone.

The U.S. Food and Drug Administration (FDA) has granted rare pediatric disease (RPD) designation to zatolmilast, Tetra Therapeutics’ investigational oral therapy for fragile X syndrome.

The designation is given to experimental therapies with the potential to provide clinically meaningful benefits to patients, primarily those younger than age 18, with serious rare diseases.

It is intended to encourage pharmaceutical companies to develop treatments for rare pediatric diseases that might not be profitable otherwise. Should the FDA approve zatolmilast, Tetra may qualify for a voucher redeemable for  priority review of a subsequent application for a different product. Priority review status shortens the agency’s review from a standard 10 months to about six months.

Recommended Reading
Clipboard with a checklist of the words

Screening underway for microdose psilocybin trial in Canada

“We are committed to advancing a potential medicine for people with Fragile X syndrome, a rare genetic disorder which affects all aspects of life for individuals and families,” Chad Coberly, CEO of Tetra, said in a press release from Shionogi, which acquired Tetra in 2020.

Zatolmilast previously was granted orphan drug status, another FDA designation intended to expedite the development of therapies for rare diseases by offering financial incentives and regulatory support.

Previous Phase 2 clinical trial data showed the experimental therapy improved cognitive function significantly in fragile X patients.

“While symptoms vary among individuals, intellectual disability is one of the most prevalent neuropsychiatric hallmarks of the disorder,” Coberly said.

“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.” Coberly added.

Normal cognitive function relies on creating and maintaining synapses, the points of near contact between nerve cells where they release signals for communicating with each other. In fragile X, synapses don’t mature properly, leading to intellectual disability and significant cognitive impairments, among other symptoms.

Importance of the cAMP signaling molecule

A signaling molecule called cyclic AMP (cAMP) is important for controlling synaptic activity and the way nerve cells communicate. Too much or too little cAMP activity can have negative consequences on cognitive function and the molecule has been found to be deficient in the brains of fragile X patients.

Previously known as BPN14770, zatolmilast is thought to help promote the maturation and stabilization of synapses by specifically binding to and partially blocking the activity of the phosphodiesterase 4D (PDE4D) enzyme, which limits cAMP spread.

Notably, the experimental therapy exerts its effects only when certain cellular activities are happening.

The overall goal is to prolong cAMP signaling, thereby improving cognition, but without the side effects that might come with complete and constant PDE4D suppression.

In a previous Phase 2 clinical trial (NCT03569631) involving 30 men with fragile X, zatolmilast was found safe, and to lead to significant cognitive improvements and clinically meaningful gains in daily functioning relative to a placebo.

The most common side effects were vomiting and upper respiratory tract infections, which were observed at similar rates between the zatolmilast and placebo groups.

Phase 2 studies ongoing at US sites

Zatolmilast is now being tested against a placebo in two trials involving a total of up to 300 fragile X male patients, recruited at sites across the U.S.

The Phase 2/3 Study 204 (NCT05163808) may still be recruiting up to 150 boys, ages 12-17, while the Phase 3 Study 301 (NCT05358886) may still be enrolling up to 150 men, ages 18-45.

The main goal of these trials is to evaluate whether zatolmilast is superior to a placebo at improving cognitive function after 13 weeks of treatment (about three months). This will be assessed through changes in the cognition crystallized composite score of the National Institutes of Health Toolbox Cognitive Battery (NIH-TCB), which accounts for performance on the picture vocabulary and oral reading domains of the measure.

Secondary goals include assessments of daily living, caregiver and clinician improvement scales, and other cognitive domains of the NIH-TCB. Safety and tolerability also will be assessed. Both studies are expected to finish in 2024.

After completing the main trial, participants in either study are eligible to enter the open-label extension Study 302 (NCT05367960), in which all will receive zatolmilast for one year to assess the therapy’s long-term safety and efficacy.