GRAND RAPIDS—The Grand Rapids-based pharmaceutical startup Tetra Therapeutics announced that new preclinical research suggests the ability of its investigational drug, BPN14770, to protect against memory loss and neuronal atrophy induced by amyloid beta1-42, a hallmark protein of Alzheimer’s disease.
In a humanized mouse model of amyloid beta1-42 neurotoxicity, BPN14770, a selective inhibitor of phosphodiesterase-4D (PDE4D), was shown to trigger multiple compensatory mechanisms in the brain that reduced memory impairment, damage to nerve morphology, deficits in synaptic proteins, and impaired neurological signaling.
Tetra is currently conducting Phase 2 clinical trials of BPN14770 in patients with early Alzheimer’s disease and adults with Fragile X Syndrome.
The new research, entitled “Protection from amyloid beta peptide-induced memory, biochemical and morphological deficits by a phosphodiesterase-4D (PDE4D) allosteric inhibitor,” has been published online in the Journal of Pharmacology & Experimental Therapeutics (JPET) by Su-Ying Cui and colleagues at the School of Pharmacy and Pharmaceutical Sciences at the University at Buffalo, and other Tetra Therapeutics collaborators at West Virginia University and Peking University.
Human brain imaging studies with amyloid and tau, as well as multiple post mortem studies, reveal that Alzheimer’s pathology may develop without clinical dementia in 25 to 30 percent of healthy 80-year-olds. “Such observations imply that Alzheimer’s pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels,” said Ying Xu, M.D., research associate professor at Buffalo, a corresponding author of the research. “Our new research suggests that BPN14770 may be capable of activating multiple biological mechanisms that protect the brain from memory deficits, neuronal damage, and biochemical impairments, even with the onset of the amyloid pathology associated with Alzheimer’s disease.”
Added Mark E. Gurney, Tetra chairman and CEO: “The role of PDE4D in modulating brain pathways involved in memory formation and cognition, and the ability of our PDE4D inhibitor to selectively enhance this process has been well studied. We are very excited by our colleagues’ findings which now suggest a second, protective mechanism of action for BPN14770 against the progressive neurological damage associated with Alzheimer’s disease. There has been enormous interest in our ongoing Phase 2 trial of BPN14770 in 255 patients with early Alzheimer’s disease, and we are hopeful this study will show an impact of PDE4D modulation in this disease. Topline results are expected mid-2020.”
And James O’Donnell, dean of the School of Pharmacy and Pharmaceutical Science at Buffalo: “Developing effective drugs for memory deficits associated with Alzheimer’s disease has been challenging. BPN14770 works by a novel mechanism to increase cyclic AMP signaling in the brain, which has been shown to improve memory. The collaborative project has led to clinical trials that are beginning to test its effectiveness.”
Results of previous Phase 1 studies with BPN14770 in healthy elderly volunteers suggested a cognitive benefit for this investigational drug, as observed in two different tests of working (immediate) memory. Working memory is a system for temporarily storing and managing the information required to carry out complex cognitive tasks such as learning, reasoning, and comprehension. The part of the brain responsible for working memory is also responsible for focus and concentration. Working memory is a domain of cognition that is impacted by Alzheimer’s disease.
For further information about the Phase 2 trial of BPN14770 in early stage Alzheimer’s disease and patient enrollment criteria please visit https://clinicaltrials.gov/ct2/show/NCT03817684.
The newly published research was supported by research grants from the National Institutes of Health Blueprint Neurotherapeutics Program through the National Institute of Neurological Disorders and Stroke and the National Institute on Aging (grant number NS078034) and the National Institute of Mental Health (grant number MH091791).
Tetra Therapeutics is a clinical stage biotechnology company developing a portfolio of therapeutic products that will bring clarity of thought to people suffering from Alzheimer’s disease, Fragile X Syndrome, traumatic brain injury, and other brain disorders. Tetra uses structure-guided drug design to discover mechanistically novel, allosteric inhibitors of phosphodiesterase 4 (PDE4), an enzyme family that plays key roles in memory formation, learning, neuroinflammation, and traumatic brain injury. BPN14770 was developed through a cooperative research agreement with the Blueprint Neurotherapeutics Program of the National Institutes of Health with funding from the National Institute on Aging, National Institute on Neurological Disorders and Stroke, the National Institute of Mental Health, the FRAXA Research Foundation and the Alzheimer’s Drug Discovery Foundation. More at www.tetratherapeutics.com.