IND FIH study and month tox for PTI a novel therapeutic for Alzheimer s disease

PTI is a novel compound with a novel target designed to treat and slow the progression of Alzheimer s disease AD PTI binds with femtomolar affinity to a particular site on filamin A FLNA a scaffolding protein we recently demonstrated is critical to beta amyloid s toxicity Beta amyloid A exerts its toxic effects by hijacking the nicotinic acetylcholine receptor nAChR and signaling via this receptor to hyperphosphorylate tau In addition to disrupting normal function of nAChR and tau this toxic signaling leads to the signature tangles and plaques found in brains of AD patients We have shown that this toxic signaling of A requires FLNA recruitment to nAChR The recruited FLNA stabilizes A nAChR complexes promoting a femtomolar interaction to enable further A piling and the toxic signaling that leads to eventual neurodegeneration PTI binding to FLNA prevents or reverses the FLNA nAChR association and A s tight binding and subsequent toxic effects A also impairs the function of two other receptors that are pivotal to neuronal survival cognition and memory the NMDA receptor and the insulin receptor By binding to FLNA PTI restores normal function of all 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 Preclinical efficacy was demonstrated in an acute ICV A infusion mouse model in normal aged mice and most importantly in human postmortem AD brain tissue The effective concentration in postmortem human brain is as low as pM PTI has completed and cleared all IND enabling studies and the GMP manufacture and Phase I clinical drug supply is underway The day toxicity studies demonstrated a fold safety margin between the NOAEL no observable adverse event level in rat and a fold safety margin in dog compared to the efficacious doses in both mouse efficacy studies PTI is rapidly absorbed and eliminated with nearly oral bioavailability dose proportional PK and no accumulation Metabolic profiling showed minimal metabolism across species In Phase I of this Fast track proposal we will file an IND With a successful IND submission we will initiate Phase II a single ascending dose SAD study in healthy volunteers followed by month toxicity studies in two species Further work outside this proposal included a SAD clinical study in AD patients which will determine the dosing frequency for a multi dose PK and safety study in AD patients The month toxicity studies will support clinical trials of month duration but are also needed to determine doses for the chronic toxicity studies needed to support clinical trials of any duration as well as an NDA There is currently no approved therapeutic for Alzheimer 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 mouse models and in postmortem brain tissue from AD patients including receptor dysfunctions inflammation a marker for synaptic plasticity and the hallmark plaques and tangles IND enabling studies are complete and the GMP manufacture of the clinical lot ongoing With a successful IND submission that is Phase I of this proposal we will advance to Phase II conduct a single ascending dose Phase I clinical trial followed by month toxicity studies in two species