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Development of EP2 Receptor Antagonist to Treat Alzheimer's Disease

Award Number: U01AG088113
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Development of EP2 Receptor Antagonist to Treat Alzheimer's Disease - Lay Summary Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Currently, about 6.5 million Americans are living with AD. Alzheimer’s and other dementias are estimated to cost the US $321 billion per year and this number is expected to 1 trillion by 2050, yet no small molecule therapeutic agent on the horizon that clearly alters the disease progression and inevitable cognitive decline. The small molecule drugs and anti-bodies that have been developed based on the amyloid cascade hypothesis showed a limited (if any) disease modifying benefit so far. Thus, it would be very important to validate novel drug targets and small molecules that work through a novel mechanism of action for future AD therapy. Neuroinflammation is recognized as a key phenotype in the AD brain that is associated with the development of dementia. Prostaglandin-E2 receptor EP2, which acts downstream of complex signaling by cyclooxygenase-2 (COX-2) appears as a key driver of neuroinflammation. Activation of this receptor further induces COX-2 creating a vicious reactive cycle in the brain. We have recently developed a suite of small-molecule antagonists for this receptor and derived a proof-of-concept in 5xFAD mouse models demonstrating antagonism of EP2 attenuates neuroinflammation and the amyloid load in the brain. Moreover, we have validated that EP2 receptor antagonism is associated with cognition sparing benefits in acute brain injury models of status epilepticus and a peripheral inflammatory sepsis model. We have identified several preclinical lead candidates for development into a clinical lead and candidate drug to mitigate neuroinflammation and cognitive deficits in Alzheimer’s patients. We now propose to define PK/PD relations of the lead EP2 antagonists on Alzheimer’s pathology markers in the brain and determine PK/PD relation on the AD relevant biomarkers in the blood (plasma), CSF and the brain tissue in two different mouse (5xFAD and APPSAA) models that that display features of early-onset of AD (EOAD) and late-onset of AD (LOAD) in human. Furthermore, we proposed to conduct drug development studies to determine therapeutic index and NOAEL for the lead EP2 antagonist and complete all other IND-enabling studies required by the FDA. Our overall goal is to achieve a disease modifying efficacy by the EP2 drug that delays the progression of Alzheimer’s dementia at least by 5 years. We envision that targeting EP2, a specific prostanoid receptor downstream of COX-2, rather than a generic block of the entire COX-2 signaling is a superior therapeutic strategy for AD that will bypass the adverse cardiovascular events found with chronic dosing of COX-2 drugs.


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: 2026 ( Subtotal = $0 )
2026	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	2	11/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,392,306 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	001	2	7/17/2025	NON-COMPETING CONTINUATION	$1,392,306
2025	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	1	10/24/2024	NEW	$0
														Subtotal = $1,392,306

Issue Date FY: 2024 ( Subtotal = $1,737,244 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Aging Research	000	1	9/18/2024	NEW	$1,737,244
														Subtotal = $1,737,244

Grand Total All Awards = $3,129,550

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Development of EP2 Receptor Antagonist to Treat Alzheimer's Disease

Award Number: U01AG088113

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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