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Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT

Award Number: R44HL123126
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT - We have discovered the first-ever inhibitors of PF4, a platelet protein central to the pathophysiology of heparin induced thrombocytopenia (HIT). Heparin is a naturally-occurring anticoagulant that prevents the formation of clots and extension of existing clots within the vasculature, and major medical applications of heparin include dialysis, cardiac catheterization, and cardiopulmonary bypass surgery. Heparin therapy is usually safe and effective; however, some patients (10,000-20,000 per year in the US) develop HIT as a serious complication caused by an immunological reaction that targets platelets leading to a low platelet count (thrombocytopenia). HIT increases the risk of blood clots forming within blood vessels and blocking the flow of blood (thrombosis), referred to as HITT when thrombosis occurs. HITT develops in approximately 1-3% of patients treated with heparin for 5-10 days. Affected individuals have a 20-50% risk of developing new thromboembolic events, a mortality rate ~20%, and an additional ~10% of patients require amputations or suffer other major pathological events. Current treatment for HIT relies on elimination of heparin exposure from patients with suspected HIT and administration of direct thrombin inhibitors, which carry a significant risk of bleeding. Despite the removal of heparin from these patients, they remain at significant risk for thrombosis and death. We have previously discovered a novel approach to the treatment of HIT via the destabilization of the functionally-active PF4 tetramers yielding inactive monomers and dimers. The tetrameric form of PF4 binds to heparin to form Ultralarge Complexes (ULC). Using the combined expertise of Fox Chase Chemical Diversity Center, Inc. in medicinal chemistry and drug discovery, the Sachais Laboratory at the New York Blood Center in HIT-based drug discovery approaches, and the McKenzie laboratory at Thomas Jefferson University in HIT mouse models, we have identified and characterized novel PF4 tetramerization inhibitors (PF4TIs) that disrupt PF4 tetramerization, ULC formation, and ameliorate HIT in an in vivo mouse model. In this grant proposal we plan to take our current lead FC-7259 or a related compound(s) as required into IND-enabling studies to support an IND application and eventual human clinical trials. During our first three aims in Yr 1 we will find alternative preclinical candidates, and backup compounds that could replace the current lead candidate if unforeseen liabilities are identified, via iterative synthesis and in vitro testing (lead optimization). The best compounds from lead optimization will undergo drug disposition evaluation (ADMET and PK), and the best among these will be evaluated in the HIT mouse model. Using this paradigm, we will choose the absolute best candidate for IND-enabling pre-clinical development activities in Yrs 2 and 3, including preparation of GMP drug substance and a 14 day repeat dose toxicity in rat and dog. By the end of this period of study, we expect to have PF4 tetramerization inhibitor preclinical drug candidates with suitable efficacy and safety properties to advance to an IND, ultimately leading to clinical development and commercialization as treatments for HITT.


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 = -$205,249 )
2024	2021	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Blood Diseases and Resources Research	000	6	1/26/2024	NON-COMPETING CONTINUATION	-$205,249
														Subtotal = -$205,249

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2019	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Blood Diseases and Resources Research	000	4	11/21/2022	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $999,965 )
2021	2021	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Blood Diseases and Resources Research	000	6	6/2/2021	NON-COMPETING CONTINUATION	$999,965
														Subtotal = $999,965

Issue Date FY: 2020 ( Subtotal = $996,228 )
2020	2020	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Blood Diseases and Resources Research	001	5	6/3/2020	NON-COMPETING CONTINUATION	$996,228
2020	2019	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Blood Diseases and Resources Research	000	4	11/11/2019	COMPETING CONTINUATION	$0
														Subtotal = $996,228

Issue Date FY: 2019 ( Subtotal = $999,945 )
2019	2019	FOX CHASE CHEMICAL DIVERSITY CENTER INC.	3805 OLD EASTON RD	DOYLESTOWN	PA	18902	BUCKS	USA	Blood Diseases and Resources Research	000	4	9/11/2019	COMPETING CONTINUATION	$999,945
														Subtotal = $999,945

Grand Total All Awards = $2,790,889

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Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT

Award Number: R44HL123126

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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