Fragile X Treatment Shows Promise in Phase II Trial

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X and Y chromosomes. Genetics concept. 3D rendered illustration.

Results from a Phase II study, run by Rush University Medical Center and U.S. biotech Tetra Therapeutics, show promising results for an experimental drug designed to treat cognitive symptoms in patients with Fragile X syndrome.

Fragile X is the most common genetic cause of autism and intellectual disability. Individuals with the condition inherit a dominant repeat mutation carried on the X chromosome meaning the condition is less common—1 in 6000-8000 girls vs 1 in 4000 boys—and often less severe in girls than boys.

There is no cure for the condition and treatments have mostly involved management of symptoms with therapy, educational assistance and medications such as selective serotonin reuptake inhibitors to treat variable moods and stimulants to treat ADHD-type symptoms.

The drug candidate, BPN14770, is the first in a new drug class of phosphodiesterase‐4D (PDE4D) allosteric inhibitors developed to treat individuals with neurological conditions such as fragile X. The PDE4D enzyme is thought to play a role in cognition and memory formation and Tetra’s drug candidate acts to inhibit it and increase levels of the chemical cAMP, which also helps regulate brain function. This in turn is thought to promote the maturation and stabilization of neurological connections in the brain.

Notably, the drug is also being tested at Phase II for treatment of cognition problems in patients with Alzheimer’s disease by the company.

In this study, led by Elizabeth Berry-Kravis, M.D., P.D., a physician and researcher at Rush University and Mark Gurney, Ph.D., Founder and CEO of Tetra, 30 adult (aged 18-41 years), male, fragile X patients received two doses of BPN14770 a day or placebo for 12 weeks.

The results, published in the journal Nature Medicine, showed that the drug was well tolerated with no major side effects, meeting the primary endpoint of the study.

Cognition was also improved in those given the drug. The National Institutes of Health (NIH) Toolbox Cognition Battery assessments of Oral Reading Recognition, Picture Vocabulary, and Cognition Crystallized Composite score all improved by an average of 2.81, 5.81, and 5.31, respectively, in this group.

Language and daily functioning of men given the drug were also significantly improved, according to caregivers, by an average of 14 and 14.5 points, respectively, using visual analog caregiver rating scales.

To allow all the participants to benefit, the groups switched at 12 weeks to the other treatment group and the study continued. Those initially in the treatment group continued to see cognitive benefits after 12 weeks on placebo, showing a sustained benefit of the treatment.

“It’s exciting that we have a drug that potentially addresses a core biochemical deficit in FXS, a deficiency of cAMP, that has been documented in patients, and which I discovered during my pediatric neurology fellowship 30 years ago,” Berry-Kravis said.

“In just three months, we saw improvement specifically in the verbal subtests of the NIH Toolbox, coupled with parent rating of improvements, particularly in language.”

Tetra plans to continue development of the drug in larger and more advanced studies with a view to taking it to market and achieving FDA approval.

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