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Development of a novel therapeutic for the treatment of diabetic nephropathy and renal fibrosis

Award Number: R44DK092005
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Development of a novel therapeutic for the treatment of diabetic nephropathy and renal fibrosis - Summary The ultimate goal of our project is to develop novel therapeutics effective in chronic kidney diseases, such as diabetic nephropathy (DN), that normally develop fibrosis, lead to end stage renal disease and require renal replacement therapy. DN is a complication of diabetes and is characterized by thickening of the glomerular basement membrane and mesangial expansion, with progression into glomerulosclerosis, tubular necrosis, and interstitial fibrosis that ultimately results in renal failure. Around 177 million people have diabetes mellitus worldwide, and it has been estimated that this number will increase to 360 million by 2030. Of these people, about 20-30% are expected to develop DN. This SBIR phase 2B application builds on the results obtained in phase 2 where novel and selective small molecule antagonists of the lysophosphatidic acid receptor subtype 1 (LPA1R) were optimized for in vitro potency, ADME, drug-like properties and pharmacokinetics. EPGN696 emerged as an optimized lead compound which is effective in preserving proximal tubule structure and function, reducing both tubule interstitial fibrosis and macrophage infiltration in a mouse model of renal fibrosis (ureteral unilateral obstruction - UUO). LPA1R antagonism in this model led to marked reductions in pro-fibrotic and pro-inflammatory markers, including TNF- α, TGF-β, CTGF, PDGF, α-SMA, Col-IV. In a mouse model of type 1 diabetic kidney disease (F1Akita), EPGN696 provided organ protection by preventing and reversing mesangial matrix expansion. However, measures of urinary albumin excretion and albumin to creatinine ratio (ACR) values, which are important functional read outs in clinical practice, are not consistent in mouse models of DN. In addition, preliminary safety assessment in a non-GLP 14-day study in rats indicated EPGN696 was well tolerated up to 300 mg/kg dose. In this application, we propose to evaluate EPGN696 in rat models of type 1 (STZ) and type 2 (ZDF) diabetic kidney disease, which reflect the typical changes in urinary albumin excretion and ACR observed in humans. Moreover, the time course of robust ACR increases and plasma creatinine decreases in these rat models have been documented by our collaborative team. Prevention and reversal studies, either alone or in combination with a standard of care agent, Losartan are planned. EPGN696 will be evaluated in rat DN models, ZDF and STZ, following determination of systemic exposure to select a suitable therapeutic dose, in collaboration with Professors Kumar Sharma and Nigel Calcutt. Urinary metabolomic analysis will be performed to identify pathways that are elevated in the pathological state and can be modulated by EPGN696. Existing human metabolomic data will be compared with the rat data to establish common pathways and metabolites that could be useful clinically in stratifying patients for drug therapy. Additionally, IND-enabling studies will be conducted according to guidance received by the FDA. These studies will support opening an IND and initiation of phase 1 clinical trials in humans.


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: 2024 ( Subtotal = $0 )
2024	2020	EPIGEN BIOSCIENCES INC	6725 MESA RIDGE RD STE 260	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	1/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	6/24/2022	NON-COMPETING CONTINUATION	$0
2022	2020	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	11/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $999,838 )
2020	2020	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/2/2020	NON-COMPETING CONTINUATION	$999,838
														Subtotal = $999,838

Issue Date FY: 2019 ( Subtotal = $999,274 )
2019	2019	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/25/2019	NON-COMPETING CONTINUATION	$999,274
														Subtotal = $999,274

Issue Date FY: 2018 ( Subtotal = $999,500 )
2018	2018	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/18/2018	COMPETING CONTINUATION	$999,500
2018	2015	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/11/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $999,500

Issue Date FY: 2016 ( Subtotal = $2,000 )
2016	2016	EPIGEN BIOSCIENCES INC	10225 BARNES CANYON ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/1/2016	SUPPLEMENT FOR EXPANSION	$2,000
														Subtotal = $2,000

Issue Date FY: 2015 ( Subtotal = $835,306 )
2015	2015	EPIGEN BIOSCIENCES INC	10225 BARNES CANYON ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/26/2015	NON-COMPETING CONTINUATION	$835,306
														Subtotal = $835,306

Issue Date FY: 2014 ( Subtotal = $616,326 )
2014	2014	EPIGEN BIOSCIENCES INC	10225 BARNES CANYON ROAD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/27/2014	COMPETING CONTINUATION	$616,326
														Subtotal = $616,326

Grand Total All Awards = $4,452,244

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Development of a novel therapeutic for the treatment of diabetic nephropathy and renal fibrosis

Award Number: R44DK092005

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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