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Safety and efficacy of Belatacept in heart transplantation

Award Number: U01AI174997
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/06/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Safety and efficacy of Belatacept in heart transplantation - Project Summary: Although calcineurin inhibitors (CNIs), including tacrolimus have led to excellent 1-year outcomes in heart transplantation, long-term survival remains limited by cardiac allograft vasculopathy, driven by donor-specific-antibodies (DSA), and by CNI-associated morbidity, dominated by chronic kidney disease. Belatacept, a selective costimulation blocker, is FDA approved for use in kidney transplantation as a CNI- alternative. By inhibiting CD28/CD80/CD86 interactions belatacept prevents activation of both naïve T cell and T follicular helper cells associated with the development of DSA, but less effectively inhibits memory T cells. In kidney transplant recipients, this has translated to sustained improvement in kidney function, suppression of DSA, and improved graft/patient survival, albeit at the cost of more early rejection which has since been markedly reduced by using a delayed CNI substitution strategy. Building on these findings, we propose a randomized controlled trial of belatacept in first-time heart transplant recipients, in conjunction with gradual tacrolimus withdrawal over 9-months to achieve a CNI-free immunosuppressive regimen (with mycophenolate mofetil and prednisone). We hypothesize that the gradual approach to CNI withdrawal will promote quiescence in graft-reactive T cells, thereby preventing rejection, inhibiting the development of DSA, and eliminating CNI- related morbidity, together increasing survival after heart transplantation. The specific aims are: Aim 1. Clinical trial to determine safety of belatacept in heart transplantation. We will perform a multicenter clinical trial in EBV seropositive heart transplant recipients randomized 2:1 to receive belatacept with gradual tacrolimus withdrawal (9-months) post-heart transplant or standard-of-care tacrolimus (control). The objectives are to a) establish safety of the protocol based on stopping criteria defined by the composite of historical control event rates and b) test efficacy for kidney sparing and DSA. Aim 2. Impact of CNI withdrawal under costimulation blockade on graft-reactive immune responses. We will serially analyze donor reactive, and autoantigen reactive T cell and B cell subsets using state-of-the-art phenotypic and functional assays and will quantify DSA and autoantibodies. Results will be compared between study arms and the kinetics of responses will be evaluated in individual subjects over time. Aim 3. Other mechanistic/biomarker studies relevant to primary and secondary endpoints in the trial. We will use molecular approaches to define differences in the intragraft response, explore markers of kidney injury and fibrosis, and test donor derived cell-free DNA as a potential biomarker of impeding rejection during CNI withdrawal. If successful, belatacept has the potential to transform the heart transplant field, removing CNI-morbidities and preventing DSA as major barriers to improving long-term survival. The comprehensive mechanistic studies will provide novel information, regardless of outcomes of the trial.


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 = $2,042,672 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	4/21/2026	NON-COMPETING CONTINUATION	$2,042,672
														Subtotal = $2,042,672

Issue Date FY: 2025 ( Subtotal = $1,710,716 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	4/30/2025	NON-COMPETING CONTINUATION	$1,710,716
														Subtotal = $1,710,716

Issue Date FY: 2024 ( Subtotal = $1,672,806 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	3/20/2024	NON-COMPETING CONTINUATION	$1,672,806
														Subtotal = $1,672,806

Issue Date FY: 2023 ( Subtotal = $1,775,433 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	6/6/2023	NEW	$1,775,433
														Subtotal = $1,775,433

Grand Total All Awards = $7,201,627

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Safety and efficacy of Belatacept in heart transplantation

Award Number: U01AI174997

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 06/06/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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