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Solid oral dosage form and chronic tox for PTI-125

Award Number: R44AG056166
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2020

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Solid oral dosage form and chronic tox for PTI-125 - Project Summary/Abstract PTI-125 is a novel small molecule AD therapeutic candidate with a novel target and mechanism of action. PTI-125 binds and reverses an altered conformation of the scaffolding protein filamin A (FLNA) to prevent Aß42's tight binding to and toxic signaling via the a7-nicotinic acetylcholine receptor (a7nAChR) as well as Aß42's aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNA's native shape and blocking these two toxic cascades, PTI-125 reduces both tau hyperphosphorylation and neuroinflammation. Downstream effects include reduced neurofibrillary lesions and amyloid deposits, suggesting disease modification, and improved synaptic plasticity and function of a7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. We will initially pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification and will therefore conduct clinical studies in mild-to-moderate AD. Conducted under a US IND, the first-in-human clinical trial showed no drug-related adverse effects (AEs) and dose proportional pharmacokinetics (PK) of the oral solution. In this renewal proposal, we will select a solid oral dosage form based on an accelerated 3-month stability study (under stress conditions) of three candidate formulations currently being developed. With the successful selection of a stable formulation, we will manufacture clinical trial supplies for multi-dose clinical trials (clinical trials not included in this proposal). We will concurrently optimize the crystallization process for Drug Substance to minimize methanol content, a study needed prior to further GMP manufacturing of Drug Substance. We will also conduct a transporter study to examine whether PTI-125 is a substrate or inhibitor of P- glycoprotein (Pgp) and other efflux and uptake transporters, as requested by FDA in pre- IND guidance. Finally, we will conduct chronic repeat dose oral toxicity studies of PTI-125 in rat and dog. Chronic tox studies will support clinical trials for efficacy as well as an eventual NDA. Along with a multi-dose Phase I clinical trial that we plan to conduct separately, the work proposed here will progress the clinical development of PTI-125 and make PTI-125 more attractive to potential commercialization partners.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	CASSAVA SCIENCES, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	000	3	1/27/2021	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	CASSAVA SCIENCES, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	001	3	9/7/2019	COMPETING CONTINUATION	$0
2019	2017	CASSAVA SCIENCES, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	000	2	3/15/2019	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $3,246,320 )
2018	2018	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	002	3	9/20/2018	SUPPLEMENT FOR EXPANSION	$350,000
2018	2018	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	001	3	9/12/2018	COMPETING CONTINUATION	$2,896,320
2018	2017	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	000	1	12/15/2017	NEW	$0
														Subtotal = $3,246,320

Issue Date FY: 2017 ( Subtotal = $1,866,748 )
2017	2017	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	001	1	8/1/2017	NEW	$0
2017	2017	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	000	1	5/31/2017	NEW	$225,000
2017	2017	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	003	2	9/13/2017	SUPPLEMENT FOR EXPANSION	$141,748
2017	2017	PAIN THERAPEUTICS, INC.	7801 N CAPITAL OF TEXAS HWY STE 260	AUSTIN	TX	78731	TRAVIS	USA	Aging Research	002	2	9/11/2017	EXTENSION WITH OR WITHOUT FUNDS	$1,500,000
														Subtotal = $1,866,748

Grand Total All Awards = $5,113,068

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Solid oral dosage form and chronic tox for PTI-125

Award Number: R44AG056166

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2020

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