Sunday, May 12, 2024 5/12/2024

TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS

Award Number: R21AR069189
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Project Summary/Abstract Antiphospholipid syndrome (APS) is an autoimmune disorder that occurs most commonly in women of reproductive-age and is associated with thrombosis and adverse pregnancy outcomes (APOs), such as fetal loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). The diagnosis of APS requires the presence of antiphospholipid antibodies (aPL), including the lupus anticoagulant (LAC). Therapy for APS focuses on preventing thrombosis, but thromboprophylaxis has not effectively prevented poor pregnancy outcomes. In PROMISSE, a prospective multicenter observational study of 724 patients, 44% of pregnancies in women with APS and LAC resulted in APOs despite treatment with heparin and low dose aspirin. Angiogenic dysregulation early in pregnancy predicted APOs, most of which were due to failure of adequate vascularization of the developing placenta and underperfusion of the fetus. Mouse models show that poor placental vascularization in APS is due to inflammation: aPL target placental tissue, and activate complement, leading to recruitment of neutrophils and release of inflammatory mediators and anti-angiogenic factors. We found that TNF-a was a critical downstream effector of abnormal placental development and fetal damage, and that TNF-a blockade restored angiogenic balance, normalized placentation and spiral artery remodeling, and rescued pregnancies. Based on our observations in PROMISSE and the favorable results of TNF-a blockade in our mouse models, we hypothesize that TNF-a blockade will significantly decrease the rate of preterm delivery due to PE and PI in women with APS and LAC. With the infrastructure created for PROMISSE, we are poised to conduct the first trial of a biologic therapy to prevent APOs in high-risk APS pregnancies. Our specific aims are to determine whether TNF-a blockade during pregnancy, added to a regimen of heparin and low dose aspirin, (1) reduces the rate of APOs in women with clinical APS and LAC, and (2) alters angiogenic markers of poor placental vascularization. We will conduct an open label single stage Phase II trial of certolizumab (a TNF-a inhibitor that does not cross the placenta). The potential public health impact of this trial extends beyond the population of women with APS. A reduction of severe APOs in certolizumab-treated patients would provide a rationale for trials of TNF-a blockade in pregnant women without APS, but at risk for severe PE or PI, and extend the benefits of measuring angiogenic factor biomarkers in early pregnancy to many more patients.


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 = -$10,594 )
2024	2022	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/14/2024	SUPPLEMENT FOR EXPANSION	-$10,594
														Subtotal = -$10,594

Issue Date FY: 2022 ( Subtotal = $174,810 )
2022	2022	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	9/20/2022	SUPPLEMENT FOR EXPANSION	$174,810
2022	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $174,810

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $196,279 )
2020	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	7/28/2020	SUPPLEMENT FOR EXPANSION	$196,279
2020	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $196,279

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/21/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $143,980 )
2018	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/31/2018	NON-COMPETING CONTINUATION	$143,980
														Subtotal = $143,980

Issue Date FY: 2017 ( Subtotal = $224,372 )
2017	2017	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/14/2017	NON-COMPETING CONTINUATION	$224,372
														Subtotal = $224,372

Issue Date FY: 2016 ( Subtotal = $251,908 )
2016	2016	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/12/2016	NEW	$251,908
														Subtotal = $251,908

Grand Total All Awards = $980,755

Top

All Categories

About

Search

Reports

Data Submission

Award Information

TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS

Award Number: R21AR069189

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer