TTS Consensus Conference
In September this year, The Transplantation Society held a Consensus Conference in Arlington, Virginia, with the aim of stimulating renewed interest in clinical trials of immunosuppression. The Society brought together 28 experts from around the globe to identify the current roadblocks to approval of new immunosuppressive agents in transplantation and to identify a path forward.
Currently, trials of immunosuppression in transplantation are in the decline because the objectives of current clinical trials are focused on improving acute rejection rates and graft survival in the first 12 months. With a 1-year renal graft survival rates of >90% for standard care patients, the best that can be hoped for is non-inferiority compared to current standard of care. This is financially unviable for companies trying to bring new agents into the field. Moreover, trials for difficult clinical care issues or high-risk patients are not being undertaken. Furthermore, current trial design is not leading to improvements in long-term outcomes and safety, and hence important needs in transplantation are not being met.
Whilst current immunosuppressive protocols are providing good outcomes for many patients and the costs of immunosuppression are falling, there are many patients who have unmet clinical needs and who develop intolerable and life threatening side effects as the result of the current treatment protocols. Clearly, there are many situations where therapy could be improved in order to achieve better outcomes for our patients. At this time where there are many opportunities to use sophisticated patient profiling technologies, and with the advent of new, more specific and more effective immunosuppressive agents, there is the tantilising prospect of tailoring personalized immunosuppression for our patients. In this respect, there is much we can lean from our colleagues in infectious disease and oncology.
With this in mind, a working group consisting of Randall Morris, Rosalyn Mannon, Dirk Kuypers and myself developed a program with the aim of producing a consensus document to substantially realign the priorities of clinical trials of transplant immunosuppression with the current clinical problems and priorities. To achieve this, it was agreed that we need to redesign clinical trials of transplant immunosuppression in order to provide data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve regulatory approval for transplantation.
The meeting was held in conjunction with an FDA workshop on surrogate endpoints in clinical trials in transplantation where several TTS members who are experts in the field spoke. The FDA workshop was an excellent backdrop to the TTS Consensus Conference as it allowed us to understand what was required to achieve regulatory approval under the recently introduced Food and Drug Administration Safety and Innovation Act of 2012 where there is an opportunity for enhanced expedited pathways for drug approval, including breakthrough therapy designation, based on surrogate end-points that have been shown to be predictive of hard end points such as patient death and graft loss.
Realising that there is a new opportunity to rethink how we approach trials of immunosuppression, the members of the TTS consensus group set to the task of defining patient subgroups, such as those at high risk of immunological graft loss, proposing biomarkers that may define patient groups, and identifying surrogate end points predictive of graft loss 5 to 7 years after transplant. Whilst the detailed outcomes of the conference will be summarized in an opinion piece that will be submitted for publication in the near future, it can be said that much progress was made identifying gaps in our knowledge and proposing new trials for specific subgroups of patients. In terms of maintenance immunosuppression, whilst a number of agents are currently available, there remain significant shortfalls in efficacy and safety for calcineurin inhibitors (due to nephrotoxicity, side effects and rejection risk), antiproliferative agents (azathioprine, mycophenolate preparations), and mTOR inhibitors due to incomplete efficacy and side effects.
Antibody mediated rejection (AMR) was identified as an area of unmet medical need, as no approved drugs exist for either prevention or therapy. Considerable discussion was held regarding clinical phenotypes induced by donor-specific antibodies, including clinically silent AMR. Similarly, no approved drugs or regimens exist for desensitization (defined as reduction or elimination of preformed HLA antibodies) at present. The role of antibody in chronic renal allograft injury was identified as an area where currently applied therapies remain poorly studied, and the clinical condition is poorly defined. It was also felt that the pathogenesis of chronic graft loss in renal transplantation was not well understood and should be a focus area of further research if we are to develop new therapies to treat this difficult condition.
Clearly, there are many situations where therapy could be improved in order to achieve better outcomes for our patients
The conference did propose new ways to design clinical trials that will be able to identify superior treatments using realistic numbers of participants. Issues that the group felt needed to be addressed included but were not limited to:
- Better 5- and 10-year graft outcomes
- Better treatments for highly sensitized patients
- Better treatments for patients with immunological high risk
- immunosuppressive combinations that are better tolerated by patients with less side effects
- less morbidity and mortality as a result of long term immunosuppression especially cancer risk
What was clear was that, as a community, we need to be more proactive in developing collaborative clinical trial groups. It is our responsibility to be a voice for our patients and identify the unmet clinical needs that should be addressed. We also need to develop clinical trials in areas where patient outcomes are poor such as in highly sensitized patients. This cannot be left to someone else. It is important that we identify the priorities for new treatments and communicate these to both regulators and industry. This has to be done with a more unified voice if we are to achieve real change. All who attended the Consensus Conference were encouraged by the spirit of co-operation, which we hope will be communicated to the broader community.
The outcomes of this meeting will be submitted for publication soon and will be discussed at a special session at the annual scientific meeting in Hong Kong in 2016. I look forward to seeing you there as we move this initiative forward.
Philip J. O’Connell