The pioneering trial that could transform organ transplantation

A pioneering trial taking place within King’s Health Partners could one day transform organ transplantations and reduce the burden on the NHS.

The EMPIRIKAL-2 study, which was awarded a £4.8m grant from the Medical Research Council (MRC) Developmental Pathway Funding Scheme, is currently in the phase IIa dose-finding stage.

Central to the trial is the application of a compound directly to the donor kidney before it’s transplanted into the patient, to reduce the chance of delayed graft function. Patients with delayed graft function face a higher chance of acute rejection and reduced graft survival, and longer hospitalisation. It is hoped that the technique might also benefit liver, heart, and pancreas transplants.

Below, Dr Theodoros Kasimatis [pictured], a consultant nephrologist at King’s College Hospital NHS FT, explains the technicalities of the trial, and how working within the KHP Liver, Renal, Urology, Transplant, Gastro/Gastro Intestinal Surgery Clinical Academic Group (CAG) has helped develop the study.

Please can you tell us about your career to date and what motivates you?

I am a clinician-scientist. I am a Consultant Nephrologist at King’s College Hospital NHS FT. I have a MPhil in Pharmacokinetics and a PhD in Anatomy where I studied the molecular mechanisms of renal fibrosis in human glomerulonephritis.

In 2015, I joined Prof Sacks’ team at the MRC Centre for Transplantation as a Research Fellow. I played a critical role in all operational aspects of the original EMPIRIKAL trial. I also co-led the interim dose-finding study of Mirococept in a pig kidney model.

This study was conducted in collaboration with the Nuffield department of Surgery in Oxford and led to the grant application for the EMPIRIKAL-2 study. This was a £4.8m grant awarded by the MRC Developmental Pathway Funding Scheme.

I also co-led another grant application to the NIHR EME Programme for the validation of a home-discovered peripheral blood mRNA biomarker signature in kidney transplantation. This signature is able to predict acute rejection up to six weeks before its clinical presentation and may enable early treatment of rejection before significant damage has occurred.

My motivation has always been to translate research findings into clinical practice, aiming to improve patient management and the quality of care. Innovation and clinical excellence have been my main drive.

Can you introduce us to the EMPIRIKAL-2 trial?

Let me give you some scientific background to the study.

Ischaemia reperfusion injury is inherent in kidney transplantation as the organs are devoid of blood until their implantation. The clinical consequence of ischaemia reperfusion injury is delayed graft function. This is a failure of the organ to function straight away and means that the patient might have to receive dialysis treatment for some days after transplantation.

Delayed graft function has been associated with higher rates of acute rejection, reduced graft survival and prolonged hospitalisation, so strategies to prevent IRI and consequent delayed graft function are therefore a priority. 

Previous work in our lab has shown that the complement system, and especially the locally synthesised complement components, play a critical role in ischaemia reperfusion injury.

We have constructed a membrane-targeted analogue of human complement receptor 1, which is an endogenous regulator of complement activation. This compound, called Mirococept, consists of the functional part of complement receptor 1 attached to a membrane-binding tail. This enables tethering of the therapeutic agent to cell membranes.

The beauty of this unique membrane-targeting approach is that it permits treatment of the organ rather than the patient. Therefore it has greater efficacy and fewer off-target effects than systemically given inhibitors.

We developed a strategy to administer Mirococept to the donor kidney ex vivo via the renal artery prior to transplantation, in order to prevent delayed graft function.

The EMPIRIKAL-2 is a phase IIa dose-finding RCT investigating the safety and efficacy of Mirococept in reducing delayed graft function in Kidney transplantation. The primary objective of this study is to identify the optimal dose of Mirococept to reduce delayed graft function so that this can be taken forward to a pivotal Phase III study.

At the moment there is no established treatment for delayed graft function. There are ongoing trials with devices or pharmaceutical agents but ours is the only strategy that delivers an agent at the site of complement-mediated injury.

The tailing technique is generic and has been applied for localised delivery of several therapeutic agents, for example to block complement and coagulation pathways.

How will this benefit patients?

As I already mentioned, delayed graft function has been associated with higher rates of acute rejection, reduced graft and patient survival, and prolonged hospitalisation. It is also associated with higher NHS costs.

The incidence of delayed graft function has risen substantially over the last decade due to a marked increase in the use of donation after circulatory death and expanded criteria donor kidneys. The EMPIRIKAL-2 trial addresses the unmet need to prevent delayed graft function which is now affecting about 50% of kidney transplants. 

Patients with a failed kidney have to return to maintenance dialysis, which is associated with higher mortality, inferior quality of life but also has an extra cost of around £26,000/patient per year for each failed transplant.

Mirococept might also benefit patients with other organ transplants such as liver, heart and pancreas transplants, as well as diseases involving complement activation. Wider application to other organs and diseases mediated by the complement system would follow proof-of-concept.

How does being part of a Clinical Academic Group help your work?  

Our work has benefited enormously from the Liver, Renal, Urology, Transplant, Gastroenterology and Gastrointestinal Surgery Clinical Academic Group.

The King’s Health Partnership has enabled a successful working relationship with its clinical trials and support teams. As the main study site, we benefited greatly from one of the largest transplant units in the UK, facilitating patient recruitment as well as biopsy collection and complement analysis.

The statistical support from the Clinical Trials Unit has been particularly valuable in allowing the study to evolve a more efficient statistical design.

KHP and our Clinical Academic Group has enabled the formation of multidisciplinary teams that played a crucial role in the preclinical and clinical development of Mirococept. The basic science underpinning this trial belongs to King’s College London (KCL).

Bringing in eminent researchers from biotechnology has also made this trial possible. This trial could not have happened without the establishment of the Protein Therapeutics laboratory which is a KCL product. At the moment, there is a pipeline of molecules being developed at the Protein Therapeutics Laboratory for various indications.

What would your advice be to someone starting out in research? 

Speaking as a physician I would very much encourage junior doctors to get involved in research even if they do not aim to pursue an academic career. It will help them to review critically original studies and to build valuable skills such as resilience and thoroughness.

They can get involved early on in their training by performing audits or by taking part in research projects of their departments. They can also pursue an academic clinical fellowship or a research fellowship, targeting a higher degree. In any case, they should aim to discuss their interests with their educational supervisor and liaise accordingly with academic members of their departments.

They should aim to have a clear sense of direction. Their research subject needs to be original; I would advise them to get a taste of both basic and clinical research to help shape their preference.

They should make consistent efforts to be persistent and adaptable, as research results can be very unpredictable, and so can be funding sources. I believe they should also be prepared to lean on a variety of management and interpersonal skills; research requires providing direction, guiding and motivating a team and making and keeping to budgets and other practical matters.

To learn more about the Liver, Renal, Urology, Transplant, Gastro/Gastro Intestinal Surgery Clinical Academic Group, visit its webpage here.