Transplant Therapeutics Consortium

Overview

The Problem

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 Immunosuppressive Therapy (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. View source

The Solution

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.

The Impact

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.  
  • TTC built a publicly available Sample size calculator using iBOX scores to assist with trial design 
Some key considerations for drug developers are detailed below: FAQ Icon
  • 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.

TTC Mission

The long-term goal of the TTC is to accelerate the medical product development process for transplantation, identifying 1) areas that have hindered product development, 2) potential biomarkers, endpoints, quantitative tools, or process improvements as solutions to address those areas, and 3) appropriate pathways to achieve regulatory endorsement for developed solutions. The consortium is first focusing on kidney transplant and long-term graft survival but may expand to other solid organ transplants in the future.

Current TTC Initiatives

Moving the field forward towards drug development solutions

Innovation Icon

Fostering Innovation

Moving the field forward towards drug development solutions

The TTC enables pre-competitive collaboration with industry, regulatory agencies, academia, and transparent societies to ensure wide-spread consensus-based science with all stakeholders.

Transplant Therapeutics Consortium

Data Collaboration

Providing large-scale data solutions for scientific research

Standardization and integration of key patient-level data from individual clinical trials and real-world datasets to create an aggregated database to support regulatory endorsement submissions

The Critical Path Institute’s experience and track record of success is leveraged to provide a framework to obtain the regulatory agency endorsement of new tools, ensuring regulatory acceptability when implemented in individual product development programs.

C-Path has extensive experience in the aggregation of data from various sources across therapeutic areas. Data sharing with C-Path occurs in a secure manner in keeping with all international regulations. The C-Path Data Collaboration Center (DCC) was founded to provide large-scale data solutions for C-Path’s consortia’s scientific research, with the ability to develop customized data platforms for improved collaboration.

  • The DCC provides safe and secure infrastructure to support the TTC’s global data sharing initiative, which underpins the development of product development solutions.
  • As of January 2021, TTC’s aggregated and standardized database includes data from over 15,000 kidney transplant recipients from seven clinical transplant centers and four clinical trial datasets.
    • The Paris Transplant Group provided data from approximately 8,500 kidney transplant recipients from clinical transplant centers and clinical trial datasets spanning Europe, North America, and South America.

Accelerating the development of Immunosuppressive therapies in kidney transplantation

Seeking regulatory endorsement of the Composite Biomarker Panel used in the first year after transplantation is a reasonably likely surrogate endpoint for the five-year risk of allograft loss in kidney transplant patients for use as a co-primary endpoint in conjunction with efficacy failure in clinical trials to support evaluation of immunosuppressive therapy applications submitted via the Accelerated Approval Program.

U.S. Food and Drug Administration

  • March 2019: Critical Path Innovation Meetings (CPIM) with FDA to discuss goals of the TTC and the iBox Scoring System. FDA encouraged individual drug sponsor conversations regarding the use of iBox to open accelerated approval pathway and recommended seeking qualification as a reasonably likely surrogate endpoint.
  • June 2020: Composite biomarker panel (iBox) formally accepted into Biomarker Qualification Program with a positive Review of Intent Submission.
  • July 2023: Context-of-use modified to include co-primary with efficacy failure; currently under review by the Agency.
    • TTC recognizes that the proposed RLSE cannot be used alone as a sole primary endpoint, and cannot replace efficacy failure. As such, TTC submitted the Qualification Plan, the second stage of the 3-stage process, to FDA with a modified context of use to include coprimary with efficacy failure.
    • This option does not compromise FDA’s current standard, and, in fact, would be held to higher standards than the current efficacy failure endpoint while providing sponsors a pathway to accelerated approval.

European Medicines Agency

Collaborators

Government and Regulatory Agencies

Nonprofit Research Organizations

Pharmaceutical Industry Partners

Academic Institutions

Team

TTC Team

Amanda Klein, PharmD, CDCES
Executive Director, Transplant Therapeutics Consortium

Nicole Spear, MS
Senior Project Manager

Hailey Davenport
Project Manager

Data and Quantitative Team

Luke Kosinski, PhD, Senior Quantitative Medicine Scientist

Eric Frey, Senior Data Manager

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