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

DESCRIPTION provided by applicant PTI is a novel compound with a novel target designed to treat and slow the progression of Alzheimerandapos s disease AD PTI works by binding extremely tightly to a particular site on filamin A FLNA a protein we recently demonstrated to be critical to beta amyloidandapos s toxicity Beta amyloid A exerts its toxic effects by binding and hijacking the a nicotinic acetylcholine receptor a nAChR 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 A requires the help of FLNA which is recruited to interact with a nAChR when A binds this receptor A andapos s toxic signaling via a nAChR 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 a nAChR association PTI prevents A andapos s toxic effects and restores normal function of these three receptors PTI also disrupts a similar association of FLNA with toll like receptor TLR a receptor responsible for releasing inflammatory cytokines hence PTI has a second function of blocking the inflammation noted in AD brain PTI 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 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 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 week and chronic GLP toxicology studies that would support a first in human study as well as clinical trials in AD and an NDA PUBLIC HEALTH RELEVANCE There is currently no approved therapeutic for Alzheimerandapos s disease AD that can slow or halt the course of the disease PTI is a novel compound has been shown to alleviate multiple pathological features of AD in a mouse model of the disease as well as in postmortem brain tissue from AD patients including receptor dysfunctions inflammation and the hallmark plaques and tangles In this proposal we will complete the week and chronic GLP toxicology studies to ensure safety for a first in human clinical trial of PTI and to support clinical trials in AD and an eventual new drug application NDA