Pharmacological preconditioning for transplantation – Lost in translation?

by Professor Stephen J Wigmore – Ischaemia reperfusion injury is an inevitable consequence of the process of clinical transplantation. Organ injury and delayed function are common events after graft implantation and represent a significant burden of ill health. It is little surprise therefore that ischaemia reperfusion injury has become an important focus for transplantation research. Much of this research is devoted to developing new treatments to reduce organ injury or dysfunction after transplantation. The process of transplantation from either the living donor or deceased heart beating donor lends itself to preconditioning. That is the act of performing an intervention either in the donor or the explanted organ which may improve subsequent function in the transplanted organ. Physical measures such as repeated temporary interruption of the blood supply to an organ – termed ischemic preconditioning are well established. These techniques have allowed an insight into the biology of ischemic injury and organ protection. Molecules such as nitric oxide, glutathione, adenosine, hemeoxygenase-1 and others have been recognised as having mechanistic roles in injury or protection and cellular elements such as platelets, T lymphocytes and macrophages have also been implicated. Preconditioning like ischaemia reperfusion is also now recognised to have an early and a late phase.

Ischemic preconditioning has benefits in that it can be performed immediately before organ removal but detriments in that it may need to be performed to each organ individually. Furthermore, outcomes of clinical trials suggest that although ischaemia reperfusion injury of some cell types may be reduced by preconditioning e.g. hepatocytes, other cell types may be injured e.g. biliary epithelium. A more satisfactory solution would be to use drugs to harness elements of the protective pathways involved in preconditioning.

In my role reviewing and editing for journals I see a great many pre-clinical studies investigating the value of potential new drugs as preconditioning agents. From such a rich and varied pharmacopoeia of drugs with evident pre-clinical benefit it is somewhat surprising and disappointing that these drugs then disappear and never seem to progress to clinical trials. What are the reasons for this apparent loss of agents that are effective in the pre-clinical arena but never make it to man?

Many of the drugs that have demonstrated pre-clinical efficacy in preconditioning have side effects which render them impossible to consider for routine clinical use or the doses at which tissue protection are found in the lab are known to be associated with unacceptable toxicity in vivo.  Laboratory experiments using insoluble agents frequently use dimethylsulphoxide or ethanol as solvents and this restricts their translation to humans or requires further strategies to deal with their limited bioavailability which reduce the commercial interest in the drug.

Most drugs belong to someone and researchers often do not consider the central issue of intellectual property protection and so publication of preclinical data without such protection can render the drug almost valueless and the ownership of the prior art can therefore be lost. Academic research and commercial research have different priorities. Academic research places emphasis on dissemination of knowledge and publication whereas commerce places higher importance on protection of knowledge concepts and information to enable commercial development.  Recognition of the commercial naïveté of many academics combined with a desire by universities to maximise the commercial potential of their research has lead many to incorporate commercial development agencies with the specific role of assisting researchers to interact with commerce.

Drug companies are often happy to enter into collaborative partnerships with academic researchers and this arrangement usually requires the involvement of the legal teams representing the company and university to ensure that the interests of both parties are preserved. The execution of such a materials transfer agreements can allow the development of protected intellectual property and increase the overall commercial value of the research.

Achieving satisfactory levels of evidence to commence human studies can require extensive and costly research involving animals as well as in vitro models. This is however ‘peanuts’ compared with the next step.

Moving a drug pipeline from a preclinical to a clinical setting is a major step. It is essential that the requirements of regulatory authorities are addressed and yet this crucial step is often overlooked. Since the cost of taking a drug from bench to bedside can be astronomical it is astonishing that greater care is not taken in establishing exactly what information or evidence would be required by regulatory authorities to licence the drug. Information from NICE in the UK and PBAC in Australia indicate that failure of recommendation of drugs in general often rested on the use of non-validated surrogate outcome measures leading to uncertainty over clinical effectiveness.¹

Obtaining ethical approval for studies in the deceased donor is a necessary step in the development of preconditioning drugs. The issues of the permissibility of intervention which has no benefit to the deceased and issues of consent in such studies is complex. Clearly the deceased donor cannot give consent and his or her family may not be best placed to understand the need for clinical trials in this setting. Similarly should consent for experimental donor therapies be sought from the recipient? These and other issues require clarification to facilitate future research in preconditioning drugs.²

Many drugs designed for use in preconditioning would be given systemically and could potentially affect any organ. Most heart beating donors are multiorgan donors and the allocation of organs to different subspecialties can raise potential concerns that for example what is good for the kidney may not be so good for the heart or lungs. The reality is however that similar pathways of preconditioning have been demonstrated in all organs commonly transplanted and it is likely that benefit in one organ system is likely to also occur in others.

Clinical trials of preconditioning agents are likely to be difficult to conduct since outcome measures may need to be very different in different organ transplants. In renal transplantation well defined endpoints such as delayed graft function or need for renal support post-transplantation are easily determined. In liver transplantation measurement of transaminase release correlates with injury to the graft but does not correlate with long-term graft function or outcome.

There are many reasons why it may be difficult to translate effective preconditioning drugs from the preclinical to the clinical setting. However, these should be considered challenges rather than barriers. There is a clear potential for such drugs to offer benefit to transplant patients and the transplant community should support clinical trials which do emerge.

 

Professor Stephen J Wigmore

Transplant Unit

Royal Infirmary of Edinburgh

Edinburgh UK.

s.wigmore@ed.ac.uk

 

References:

1. Clement FM, Harris A, Li JJ, Yong K, Lee KM, Manns BJ. Using Effectiveness and Cost-effectiveness to Make Drug Coverage Decisions: A Comparison of Britain, Australia, and Canada. JAMA, 2009; 302(13): 1437-1443

2. McNally SJ, Harrison EM, Wigmore SJ. Ethical considerations in the application of preconditioning to solid organ transplantation. J Med Ethics. 2005; 31(11): 631-4