Phosphodiesterase 4D Inhibition Shows Promise for Treatment of Cognitive Disorders, Fragile X and Alzheimer’s Disease 

The investigational molecule BPN14770 (Tetra Discovery Partners, Grand Rapids, MI) is being studied as potential treatment for multiple cognitive disorders, including Fragile X syndrome, Alzheimer’s disease, and traumatic brain injury. A potentially neuroprotective molecule, BPN14770 is the first allosteric inhibitor of PDE4D and inhibits the active form of PDE4D preferentially. 

A role for PDE4D in learning, memory, and cognition is established across multiple species, from the dunce mutant fruit fly that is unable to learn conditioned behavior, to children with a rare cause of intellectual disability, acrodysostosis type 2, caused by missense mutations in PDE4D. In both nonhuman primates and humans, PET tracer studies show PDE4D expression in the frontal cortex, entorhinal and temporal cortex, and hippocampus—all areas where pathology of Fragile X and Alzheimer’s disease occur and where learning and memory are localized. Development of a PDE4D selective inhibitor provides an opportunity to address disorders of learning and memory in a new way. 

In Fragile X syndrome, the most common genetic cause of autism, cAMP levels that are typically modulated by PDE4D are lower than normal and do not respond as much as in healthy controls to stimulation of adenylate cyclase. Morphologically, excitatory synapses form but do not mature or become fully functional. In a mouse model of Fragile X syndrome, dendritic synapse morphology was improved by treatment with BPN14770, hyperarousal was reduced, and social/natural behaviors were increased. A phase 2 clinical trial of BPN14770 for treatment of Fragile X syndrome is underway (NCT03569631) and approximately two-thirds of the target enrollment has been reached. The initial phase 2 study is examining safety and tolerability as well as any preliminary signals for benefits on behavior, cognition, and biomarkers. 

For Alzheimer’s disease, it is hoped that treatment with BPN14770 could be neuroprotective and delay or slow the course of AD. The thought is that the role of BPN14770 in stabilizing synapses may prevent or reduce damage to the synapse caused by AD pathology. A phase 2 trial (NCT03817684) is enrolling 255 participants (age 55 to 85) with a clinical diagnosis of early AD who will be randomly assigned to treatment with 1 of 2 doses of BPN14770 or placebo for 3 months. The primary outcome being studied is changes in cognition as measured with the Repeatable Battery for the Assessment of Neuropsychological Status (R-BANDs) Delayed Memory Index.  

Mark Gurney, PhD, chairman and chief executive officer of Tetra Discovery Partners said, “There is a need to study new and different therapies for Alzheimer’s disease and other dementias as well as neurodevelopmental disorders. We are hopeful that BPN14770 will provide a new tool with a novel mechanism for addressing the cognitive and memory deficits of AD, and potentially delay onset and/or slow the course of the disease.”

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