Fragile X Clinical Trial

Conditions & Diseases: Fragile X syndrome
By Carlo Paribello
Posted on October 05,2018


FRAXA Research Foundation has just funded a Fragile X clinical trial of an investigational new drug, led by Dr. Elizabeth Berry-Kravis at the Rush Fragile X Clinic and Research Program in Chicago. This trial will treat 30 adult males with Fragile X syndrome with a new PDE4D allosteric inhibitor from Tetra Discovery Partners using in a crossover design so that everyone gets active drug for part of the time and placebo for part of the time.

This study is a major advance in clinical research for a number of reasons.PDE4 - Potential Fragile X Treatment Target

First of all, the enzyme phosphodiesterase 4 (PDE4), which breaks down the signaling molecule cyclic AMP, has been singled out as a promising treatment target for a long time. In fact, it was first proposed before FRAXA Research Foundation existed when Dr. Berry-Kravis found low levels of cAMP in Fragile X patients. She notes, “this trial will bring my earliest work on Fragile X syndrome, showing abnormal cyclic AMP signaling in FXS, to fruition, with a treatment trial directed at correcting the mechanism I discovered in 1990 when in my Child Neurology fellowship.”

Indeed, many researchers have shown that PDE4 inhibitors can fix Fragile X-related problems in animal models. Most recently, FRAXA researchers (including FRAXA Medical Director, Dr. Michael Tranfaglia, and FRAXA-DVI Director, Dr. Patricia Cogram) in collaboration with Dr. Mark Gurney of Tetra Discovery Partners showed that this new compound exhibited powerful rescue effects in the knockout mouse, which persisted long after the drug was discontinued (

Tetra Discovery Partners
Until now, no PDE4 inhibitors were available for us to use in Fragile X clinical trials. In part, this is because most drug companies have been interested in other much larger indications for these drugs, like Alzheimer Disease. There is still a great deal of interest in these blockbuster indications, but FRAXA has forged a close collaboration with Tetra Discovery Partners, a small biotech company based in Michigan. Tetra has developed an advanced PDE4D allosteric inhibitor which is highly selective, non-toxic, and easy to take (it doesn’t have the side effect of GI upset that most other drugs in this class have). While Tetra is also developing this drug for Alzheimer’s and is currently conducting clinical trials in this population, they have willing to branch out into Fragile X.

As Dr. Gurney notes, “Dr. Berry-Kravis’ research gives us hope that BPN14770 may address a core biochemical change in Fragile X patients. The results of our collaborative preclinical studies with the FRAXA Research Foundation in the Fragile X mice are very promising. We look forward to initiating the Phase 2 clinical trial that will be conducted by Dr. Berry-Kravis with support from the FRAXA Research Foundation. Tetra Discovery Partners has a patient-focused culture that meshes perfectly with the passion of FRAXA Research Foundation and the dedication of Dr. Berry-Kravis to the care of her patients.”

Tetra has just announced that the FDA has granted Orphan Drug Designation to BPN14770 for treatment of Fragile X syndrome.

Advanced Clinical Trial Design
One interesting aspect of this study is that the crossover design, with every participant taking active drug for half of the trial period, will allow us to look for the same kind of “carry-over effects” in the Fragile X patients that were observed in the Fragile X mice. Trial subjects will also receive a full therapeutic dose of the drug, so clinically meaningful responses are possible. Most importantly, this trial will use state-of-the-art objective cognitive and physiologic outcome measures, including eye-tracking and measuring brain-wave responses to sounds, a major step forward from previous studies of investigational compounds.

We are excited about this new clinical trial, and we look forward to developing a new therapeutic option for Fragile X! We are grateful to the Pierce Family Fragile X Foundation for contributing funds toward this project.

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