IND- and NDA-enabling toxicology studies for PTI-125, a novel small molecule for Alzheimer's disease



 DESCRIPTION (provided by applicant): PTI-125 is a novel compound with a novel target, designed to treat and slow the progression of Alzheimer's disease (AD). PTI-125 works by binding extremely tightly to a particular site on filamin A (FLNA), a protein we recently demonstrated to be critical to beta amyloid's toxicity. Beta amyloid1-42 (Aß42) exerts its toxic effects by binding and hijacking the a7-nicotinic acetylcholine receptor (a7nAChR), disrupting its normal function and causing the signature tangles and plaques found in brains of AD patients. We recently showed that this toxic signaling by Aß42 requires the help of FLNA, which is recruited to interact with a7nAChR when Aß42 binds this receptor. Aß42's toxic signaling via a7nAChR also impairs the function of two other receptors key to cognition, memory and neuronal survival, the NMDA receptor and the insulin receptor. By disrupting the FLNA - a7nAChR association, PTI-125 prevents Aß42's toxic effects and restores normal function of these three receptors. PTI-125 also disrupts a similar association of FLNA with toll-like receptor-4 (TLR-4), a receptor responsible for releasing inflammatory cytokines; hence, PTI-125 has a second function of blocking the inflammation noted in AD brain. PTI-125 has passed the Ames and hERG tests (non-GLP) for mutagenicity and cardiac toxicity, respectively. It easily passes the blood brain barrier, has an estimated 75% oral bioavailability and has a reasonable half-life for a drug candidate. It was safe given orally for two months in mice. We know the effective concentrations in brain from brain slice culture experiments. PTI- 125 is ready to start the proposed IND-enabling studies to ensure safety prior to a clinical trial. In this proposal, our Phase I work will include the non-GLP dose selection studies, more formal PK/ADME work, genotoxicity studies and the GLP validation of previously developed analytical and bioanalytical methods. Barring unexpected toxicity in a dose range close to the anticipated therapeutic dose, we will proceed to the Phase II scope of work: GLP safety pharmacology and both 4-week and chronic GLP toxicology studies that would support a first-in-human study as well as clinical trials in AD and an NDA.