Preclinical, PET imaging, and Phase 1 human clinical evidence supporting the ability of Tetra Discovery Partners’ drug candidate, BPN14770, to improve memory formation and provide cognitive benefit was the subject of an oral presentation on Saturday at the 10th Clinical Trials in Alzheimer’s Disease Meeting held November 1‐4, 2017 in Boston, MA. BPN14770 is a highly selective inhibitor of phosphodiesterase‐4D (PDE4D), which regulates brain signaling pathways involved in the early and late stages of memory formation.
“Alzheimer’s disease and other conditions marked by problems of cognition and memory represent a serious and growing problem for U.S. and other aging populations worldwide, and to date, there has been no effective treatment that can stem or help improve such cognitive decline,” said Mark E. Gurney, Ph.D., Chairman and Chief Executive Officer of Tetra Discovery Partners. “Based on the results of our Phase 1 trial of BPN14770, and these supporting preclinical studies, we are cautiously optimistic about the potential of this drug candidate and look forward to conducting its further evaluation in a Phase 2 study in early Alzheimer’s disease patients in the first half of 2018.”
Tetra Discovery and the company’s collaborators at the University of Buffalo and the National Institute of Mental Health demonstrated that single oral doses of BPN14770 at 0.01 or 0.03 mg/kg improved the working and long‐term memory in mice with a humanized PDE4D gene, compared to wild‐type mice. Moreover, after 14 days dosing at the 0.03 mg/kg level, the researchers found elevated levels of biomarkers associated with the cAMP‐PKA‐CREB pathway in the humanized mice. This included elevation of brain‐derived neurotrophic factor (BDNF) in the hippocampus. They also demonstrated by PET imaging that PDE4D distribution was highest in specific regions of the brain in primates that were related to cognition, the hippocampus and prefrontal cortex, which are also targets of Alzheimer’s pathology. The PDE4D PET tracer was displaced from the hippocampus and prefrontal cortex by pretreatment with BPN14770, indicating that the drug enters the brain and engages the desired target.
The researchers also presented data from an initial clinical assessment of BPN14770 cognitive benefit in healthy elderly volunteers that was also consistent with the mechanism of action for the drug. In a Phase 1 dose‐ranging study of BPN14770 in 45 healthy elderly volunteers (age 60 or older), preliminary cognitive assessment suggested that BPN14770 oral doses of 10 and 20 mg bid improved complex attention/ working memory and 24‐hour delayed recall of verbal or sight and space‐related tasks. A pooled, post hoc analysis of the elderly volunteers in the low and mid‐dose groups demonstrated a significant improvement in measures of working memory. There were no adverse events related to gastrointestinal disturbance (nausea, vomiting, or diarrhea).
Working memory is a cognitive system for temporarily storing and managing the information required to carry out complex mental tasks such as learning, reasoning, and comprehension.hippocampus are the parts of the brain responsible for working memory. The prefrontal cortex and hippocampus are the parts of the brain responsible for working memory. These same parts of the brain are impacted by Alzheimer’s disease, and working memory is among the cognitive functions most sensitive to decline.