Chronic kidney disease (CKD) is one of the leading causes of death in the United States, affecting about 37 million people. Of those affected, approximately 786,000 have end-stage kidney disease, and about 228,000 are living with a kidney transplant. By far, the largest unmet need in kidney transplantation is improvement in the long-term survival of the transplant recipient and graft. Current IST regimens have dramatically improved short-term outcomes, with one-year graft survival rates of 97.3% and 93.3% for living and deceased donor transplants, respectively.
Despite these improved short-term outcomes, long-term graft survival remains suboptimal. The 5 and 10-year graft survival rates are 77% and 49% for deceased donor transplants and 86% and 64% for living donor transplants. Consequently, there is a significant need for ISTs that are superior to current therapies and can help improve long-term outcomes.
National Data—OPTN. (n.d.). Retrieved December 12, 2019, from: https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#
In 2017, the American Society of Transplantation (AST) and American Society of Transplant Surgeons (ASTS) partnered with Critical Path Institute (C-Path) and other transplant community members to create the TTC. By facilitating a public-private partnership among scientists from the bio-pharmaceutical industry, diagnostics companies, academic institutions, professional societies, and government and regulatory agencies, TTC fosters consensus and data-driven research to speed the development of new ISTs for transplant recipients.
TTC’s focus has primarily been on gaining regulatory endorsement of an early novel endpoint that is capable of predicting long-term graft survival in pivotal clinical trials designed to support regulatory approval of new ISTs for kidney transplantation.
To develop a novel trial endpoint, it is important to understand the multifactorial causes of late kidney graft failure; predicting failure accurately with a single marker may not be optimal. In 2019, the Paris Transplant Group (PTG), together with 29 key opinion leaders of the transplant community from ten referral centers in Europe and the United States, published a paper on the iBOX risk prediction tool.
iBOX utilizes multiple clinically relevant features that are mechanistically associated with an increased risk of late graft functional decline and failure. iBOX was originally designed to be used at the patient level to inform clinical care and management of kidney transplant patients. While several composite scores have been proposed as surrogates, iBOX is based on the largest dataset and the only specifically designed multivariate model that predicts long-term graft failure.
C-Path, in collaboration with the PTG, is seeking to translate the work from the 2019 Loupy, et al., publication into a regulatory endpoint in hopes of stimulating the introduction of innovative ISTs into transplantation and streamlining drug development by facilitating clinical trials of shorter duration (i.e., one year) that can predict allograft survival.
In 2020, TTC received a Letter of Intent Determination from FDA accepting iBOX into the Biomarker Qualification Program.
In 2022, TTC developed an integrated international kidney transplant database comprised of about 23,000 kidney transplant recipients from 31 total cohorts and clinical trials to support TTC initiatives. Of these, 13,000 kidney transplant recipients from 16 transplant centers and five clinical trials are standardized to the Clinical Data Interchange Standards Consortium (CDISC).
- In December 2022, EMA granted biomarker qualification for iBOX, the first qualified endpoint ever in transplantation. iBox (with or without biopsy) is now available for use in kidney transplant clinical trials, giving sponsors the ability to demonstrate superiority of a novel IST compared to standard of care (SOC) at various time points post-transplant in pivotal or exploratory drug therapeutic studies.
- In Europe, this allows labeling claims and promotion of superiority of the new therapy
- Built a publicly available Sample size calculator using iBOX scores to assist with trial design
- Phase 2/Proof-of-concept studies with iBOX assessments at 6 months post-transplant
- Phase 3 studies where a study duration could be 1 year and up to 2 years post-transplant
- Although conditional marketing authorisation (CMA) is a separate consideration from endpoint Qualification, using the iBOX as a secondary endpoint to demonstrate the superiority of a new therapy as compared to current SOC addresses a key unmet need in kidney transplants, fulfilling one of the key criteria for CMA in the EU