Fragile X drug zatolmilast misses main goal in Phase 3 trials
Developer Shionogi notes caregiver-reported improvements in functioning
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Zatolmilast, Shionogi’s experimental oral therapy, was not superior to a placebo in improving key measures of cognition, including verbal knowledge and language skills, in boys and men with fragile X syndrome (FXS) in two late-stage clinical trials.
The results come from two U.S.-based Phase 3 studies, EXPERIENCE-204 (NCT05163808), which enrolled boys aged 9 to 17, and EXPERIENCE-301 (NCT05358886), which involved men aged 18 to 45.
While the main goal was not met, zatolmilast was generally safe and well tolerated and associated with significant improvements in a caregiver-reported measure of communication and daily functioning in adult patients, Shionogi said.
“We continue to work diligently to gain a comprehensive understanding of the clinical trial data so we can fully characterize the safety and efficacy of zatolmilast in individuals with FXS, particularly in the context of zatolmilast’s well-established mechanism of action and the promising results of the earlier Phase 2 study,” Juan Carlos Gomez, MD, Shionogi’s chief medical officer, wrote in a letter to the FXS community announcing the results.
The company plans to conduct additional exploratory analyses of data from the EXPERIENCE-204 and -301 studies, as well as data analyses of the ongoing open-label extension study, EXPERIENCE-302 (NCT05367960), in which participants completing either of the Phase 3 trials are receiving the therapy for up to four years.
Company plans to continue talks with FDA
“We are pleased to hear that Shionogi plans to continue the open-label extension and to continue analyzing the data in hopes of conducting further trials,” the FRAXA Research Foundation said in a press release. “But this definitely sets the program back considerably.”
Shionogi, which discussed the clinical program update in a webinar, plans to continue discussions with the U.S. Food and Drug Administration before providing further updates later this year.
Originally developed by Tetra Discovery and later acquired by Shionogi, zatolmilast (formerly BPN14770) works by reducing the activity of PDE4D, an enzyme active in brain regions involved in learning and memory.
PDE4D fine-tunes levels of cAMP, a signaling molecule involved in nerve cell communication that is low in people with FRX, by breaking it down.
By reducing PDE4D activity, zatolmilast is expected to increase cAMP levels and improve nerve cell communication, easing FXS symptoms by rebuilding the brain networks affected by the condition.
An earlier Phase 2 clinical trial (NCT03569631) enrolled 30 men with FXS who were randomly assigned to receive either zatolmilast (25 mg) or a placebo, twice daily for 12 weeks (about three months).
The main goal was to test the safety of zatolmilast compared with the placebo for up to 24 weeks (about six months), with secondary goals looking at changes in cognitive function and daily functioning. Data showed that zatolmilast was generally safe and superior to the placebo at improving language and daily functioning.
The larger Phase 3 trials tested zatolmilast against a placebo in a total of 334 adolescent boys and men with FXS. The therapy was given at 15 mg or 25 mg in EXPERIENCE-204 and at 25 mg in EXPERIENCE-301.
The studies’ main goal was to determine whether 13 weeks of treatment with zatolmilast could improve cognitive function compared with the placebo, using a battery of tests developed by the U.S. National Institutes of Health (NIH).
Neither trial met the main goal of showing that zatolmilast significantly improves the NIH Cognition Crystallized Composite score, which is calculated using tests involving picture-word matching and reading aloud.
However, EXPERIENCE-301 showed significant improvements with zatolmilast relative to the placebo in caregiver-reported FXS-Numerical Rating Scale scores for language and daily function.
Patients who completed either Phase 3 trial were given the choice to enter the open-label extension study, EXPERIENCE-302, which is assessing the therapy’s effects over four years.
“We continue to receive positive feedback from families participating in the trial; there is a general sense that this medication is effective, yet we continue to struggle to find the best clinical trial methods to demonstrate this,” said the FRAXA Research Foundation. “We are determined to learn as much as possible from this experience and to use those lessons to guide the next steps toward effective treatments and ultimately a cure for Fragile X syndrome.”
