The drug is now in Phase 2 clinical trials in patients with Alzheimer’s and Fragile X syndrome

New drug may protect against memory loss in Alzheimer’s disease

A new drug discovered through a research collaboration between the University of Buffalo and Tetra Therapeutics could protect against memory loss, nerve damage and other symptoms of Alzheimer's disease.

Preclinical research has shown that the drug - called BPN14770 - discourages the effects of beta-amyloid protein, a protein characteristic of Alzheimer's disease that is toxic to nerve cells.

Recent studies indicate that Alzheimer's disease can develop without dementia in nearly 25% of healthy 80-year-old patients, suggesting that the body may turn to compensatory mechanisms to maintain the nervous system.

BPN14770, under development by Tetra Therapeutics, may help activate these mechanisms that support nerve health and prevent dementia, even with the progression of Alzheimer's disease.

Its benefits could also include Fragile X syndrome, developmental disorders and schizophrenia, according to the researchers.

"Such observations imply that the pathology of Alzheimer's disease can be tolerated by the brain to some extent because of compensatory mechanisms operating at the cellular and synaptic levels," said Ying Xu, MD, PhD, co-principal investigator and associate professor of research at the School of Pharmacy and Pharmaceutical Sciences at the University of New Brunswick.

"Our new research suggests that BPN14770 may be able to activate multiple biological mechanisms that protect the brain from memory deficits, neural damage and biochemical alterations."

The study, published on September 5 in The Journal of Pharmacology and Experimental Therapeutics, was also led by James M. O'Donnell, PhD, Dean and Professor in the School of Pharmacy and Pharmaceutical Sciences at the University of New Brunswick. Mark E. Gurney, PhD, Chairman and Chief Executive Officer of Tetra Therapeutics, located in Grand Rapids, Michigan, was involved in the research.

Protecting memory from toxic proteins

Research in mice has found that BPN14770 inhibits the activity of phosphodiesterase-4D (PDE4D), an enzyme that plays a key role in memory formation, learning, neuroinflammation and traumatic brain injury.

PDE4D lowers cyclic adenosine monophosphate (cAMP) - a messenger molecule that signals physiological changes such as cell division, change, migration and death - in the body, causing physical changes in the brain.

AMPc has many beneficial functions, including memory enhancement. By inhibiting PDE4D, BPN14770 increases cAMP signalling in the brain, ultimately protecting against the toxic effects of beta-amyloid.

"The role of PDE4D in modulating the brain pathways involved in memory and cognition formation, and the ability of our PDE4D inhibitor to selectively improve this process, has been well studied," said Gurney. "We are very excited by our colleagues' findings, which now suggest a second protective mechanism of action for BPN14770 against progressive neurological damage associated with Alzheimer's disease.

"The development of effective drugs for memory disorders associated with Alzheimer's disease has proven difficult," said Mr. O'Donnell. "BPN14770 works through a new mechanism to increase the cyclic signalling of AMP in the brain, which has been shown to improve memory. The collaborative project has led to clinical trials that will begin to test its effectiveness."

Tetra Therapeutics is currently conducting Phase 2 clinical trials with BPN14770 in patients with early Alzheimer's disease and in adults with Fragile X syndrome, a genetic disorder that causes intellectual and developmental disabilities.

Results from previous Phase 1 studies in healthy elderly volunteers suggest that the benefits of the drug are effective, i.e., memory is immediate. Animal studies have shown that BPN14770 has the potential to promote the maturation of connections between neurons, which are altered in patients with Fragile X syndrome, as well as to protect these connections, which are lost in patients with Alzheimer's disease.

"Our ongoing Phase 2 study of BPN14770 has generated significant interest in 255 patients with early-stage Alzheimer's disease, and we hope that this study will show an impact of PDE4D modulation in this disease. The best results are expected in mid-2020," said Mr. Gurney.

The research was supported by the National Institutes of Health Blueprint Neurotherapeutics Network through the National Institute of Neurological Disorders and Stroke, the National Institute on Aging and the National Institute of Mental Health.

About Tetra Therapeutics

Tetra Therapeutics is a clinical-stage biotechnology company developing therapeutic products for Alzheimer's disease, Fragile X syndrome, head injuries and other brain diseases.