Protocols for US trials of zatolmilast amended to increase accessibility
Studies recruiting at 15 sites countrywide, more expected to open this year
Tetra Therapeutics has amended the protocols of two ongoing late-stage clinical trials testing zatolmilast, its experimental oral therapy for fragile X syndrome, to improve access for patients and their families.
The similarly designed studies are recruiting up to 300 male fragile X patients at 15 sites across the U.S., with additional sites expected to open this year, Shionogi, which acquired Tetra in 2020, announced in a company press release.
To increase accessibility, Tetra lowered the age of eligibility from 12 to 9 years and the weight minimum from 95 to 55 pounds in the Phase 2/3 clinical trial called Study 204 (NCT05163808), which aims to recruit up to 150 adolescent boys. The Phase 3 trial, dubbed Study 301 (NCT05358886), is enrolling up to 150 men, ages 18 to 45.
For both studies, the number of on-site visits over the three-month treatment period was reduced from six to four. Tetra also may cover expenses related to study participation, including travel, lodging, and meal reimbursement (limitations may apply).
“I hope more families will consider participating in clinical research to help our loved ones, not only today, but also for future generations,” said Katie Clapp, president and co-founder of the FRAXA Research Foundation.
Fragile X is a genetic condition marked by cognitive and learning difficulties, but also leading to motor and behavioral problems and specific physical features. In people with the disease, connections between nerve cells, called synapses, don’t mature as they should, impairing nerve cell communication and brain development.
Zatolmilast may promote better nerve cell communication, improve cognitive function
Formerly known as BPN14770, zatolmilast is designed to partially suppress the activity of phosphodiesterase 4D (PDE4D), an enzyme that’s naturally most active in brain regions important for intellect and that are affected by fragile X. PDE4D helps regulate cyclic adenosine monophosphate (cAMP), a brain-signaling molecule involved in how nerve cells communicate.
By boosting cAMP levels, which are low in fragile X patients, zatolmilast may promote better nerve cell communication, strengthen nerve cell connections that otherwise fail to develop in fragile X patients, and improve cognitive function.
In a previous Phase 2 trial (NCT03569631), which enrolled 30 men with fragile X, zatolmilast was shown to safely improve cognition and daily functioning compared with a placebo.
Building on these findings, Tetra launched the two late-stage clinical trials in 2022 to test zatolmilast in a larger number of patients and with a broader age range.
“Enrolling participants in late-stage (Phase 2b/3) clinical studies of zatolmilast is a significant step in our efforts to bring a potential treatment option to families,” said Elizabeth Berry-Kravis, MD, PhD, clinical trial investigator and professor of pediatrics, neurological sciences, and biochemistry at Rush University Medical Center in Chicago. “If the positive Phase 2 trial data can be replicated, this investigational drug has the potential to improve cognition and could offer people living with Fragile X syndrome and their families the first cognitive treatment developed specifically for this rare genetic disorder.”
The main goal of the late-stage trials is to determine whether zatolmilast treatment outperforms a placebo at improving cognitive function, particularly language-vocabulary comprehension and language-reading decoding, after 13 weeks, as assessed by a set of cognitive tests developed at the National Institutes of Health (NHI).
Secondary measures include safety and tolerability, as well as changes in daily living assessments, caregiver and clinician scales, and other cognitive domains of the NIH assessment.
Patients completing either study may choose to enroll in the open-label extension Study 302 (NCT05367960), in which all will be given zatolmilast over long term. The original protocol had a duration of one year, but Tetra has now extended it to two years.
“My husband and I have spent the past 30 years raising and directing funds to support early-stage research in Fragile X syndrome,” Clapp said. “This is a full circle moment for us as our organization funded the early development of zatolmilast. It’s important to realize that this progress is possible because of the families that participate in clinical trials.”
Zatolmilast received orphan drug status in both the U.S. and Europe, as well as rare pediatric disease designation in the U.S., for the treatment of fragile X. These designations facilitate the clinical development and accelerate the review of potential new treatments for serious conditions that address unmet medical needs.
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