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Strategies to Improve Novel Drug Development in Kidney Transplantation Through the Clinical Trials Process
Stanley C Jordan1, Jua Choi1, Ashley Vo1
1Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA.
Abstract:
Kidney transplantation has emerged as the preferred treatment for end-stage renal disease. Despite excellent short-term outcomes with standard T-cell centric immunosuppression, long-term outcomes have not improved. Indeed, approximately 5,000 renal allografts fail in the United States each year. Until recently, the focus on causes for late graft failures was on calcineurin inhibitor toxicity and the effects of primary co-morbid conditions (i.e., diabetes and hypertension) or recurrent glomerular diseases. However, several recent studies have identified donor-specific antibodies and chronic antibody-mediated rejection as the primary causes of late allograft failures. This finding has resulted in a renaissance of interest in the development of new agents focused on modifying B cells and alloantibody responses. In 2015, the Food and Drug Administration (FDA) held a conference of experts focused on delineating a path forward for developing a more streamlined clinical trials process to obtain labeling for novel agents in transplantation. The particular focus was on developing new drugs to deal with desensitization and prevention and treatment of antibody-mediated rejection since there are currently no approved drugs in this area. In this manuscript, we will discuss each of these important issues in depth, with particular focus on how to improve the clinical trials process to obtain FDA approval for new drugs that would be of benefit to our patients. It is also encouraging that since the FDA meeting, two new labeling trials have gone forward and one has already begun patient entry.
Insights
Kidney transplant graft failures are often caused by antibody-mediated rejection. New clinical trials are improving the development of targeted therapies to prevent and treat this rejection, improving long-term transplant success.
Area of Science:
- Nephrology
- Transplantation Immunology
- Clinical Trials
Background:
- Kidney transplantation is the leading treatment for end-stage renal disease, but long-term graft survival remains a challenge.
- Standard immunosuppression has not improved long-term outcomes, with approximately 5,000 renal allografts failing annually in the US.
- Donor-specific antibodies and chronic antibody-mediated rejection are now recognized as primary causes of late graft failure.
Purpose of the Study:
- To review the challenges and advancements in developing novel immunosuppressive agents targeting B cells and alloantibody responses.
- To discuss strategies for streamlining the clinical trials process for new transplantation drugs.
- To address the need for FDA-approved therapies for desensitization and treatment of antibody-mediated rejection.
Main Methods:
- Review of recent studies identifying causes of late kidney allograft failure.
- Analysis of the 2015 FDA expert conference recommendations for clinical trial design.
- Discussion of pathways for obtaining FDA labeling for novel immunosuppressive agents.
Main Results:
- Identification of donor-specific antibodies and chronic antibody-mediated rejection as key factors in late graft loss.
- Initiation of new FDA labeling trials for novel transplantation agents since the 2015 conference.
- One new trial has already commenced patient enrollment.
Conclusions:
- A shift in focus towards antibody-mediated rejection necessitates new therapeutic strategies.
- Improving the clinical trials process is crucial for accelerating the approval of novel immunosuppressive drugs.
- Recent progress indicates a promising future for developing effective treatments for antibody-mediated rejection in kidney transplantation.
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