The Cam-Path Forward

Authors


Corresponding author: Allan D. Kirk adkirk@emory.edu

Abstract

The author discusses the drug alemtuzumab as a case study in the benefits and drawbacks of off-label drug use in organ transplantation. See article by van den Hoogen et al on page 192.

Lymphocyte depletion has been a tool in the transplant clinician's armamentarium since the earliest days of the field. Whether it is a “good” tool or not is largely dependent on how and when it is used, with the dominant consideration being the risk-benefit balance between rejection and opportunistic infection or malignancy. In general, lymphocyte depletion has been shown to reduce the rate of acute rejection and to reverse allograft rejection in numerous settings; its long-term benefits are less clearly established. Regardless, lymphocyte depletion is an established part of transplantation.

Over the past 15 years, alemtuzumab (also known as Campath-1H, after its origin from the Cambridge Department of Pathology) has been shown to provide acceptable efficacy when used as a depletional induction agent in combination with modest maintenance immunosuppression, and in particular, to have an attractive consistency of effect (very reproducible and sustained depletion), ease of use (peripheral administration) and cost effectiveness as it relates to the actual product required (single dose). The ideal use of the agent has not yet been codified, but it has been better defined as the field has emerged from the irrational exuberance of early trials that suggested its use allowed for late immunosuppressive drug withdrawal. Remarkably, even in the absence of a corporate champion, a randomized, controlled kidney transplant trial showing alemtuzumab's utility has emerged comparing its merits relative to polyclonal antibody depletion and nondepletional approaches [1]. Indeed, it is now used in approximately 13% of kidney transplants in the United States [2], despite the fact that it has never been indicated, approved or marketed for transplantation. Unfortunately, just as the field of transplantation is starting to understand alemtuzumab, it finds itself constrained by the fact that Sanofi, the current owners of alemtuzumab, have substantially altered the means of acquisition for the drug, making it unavailable through typical commercial methods of drug acquisition, but rather through a Campath Distribution Program (CDP). This move has its unique aspects, but also speaks to a more generalized reality that deserves attention.

Specific to the current state of alemtuzumab, the drug has been withdrawn from general marketing not out of safety or efficacy concerns, but rather to reposition the drug as Lemtrada, for use in multiple sclerosis (MS) [3]. This is an understandable (and presumably at least partially fiscally driven) maneuver by Sanofi based on promising clinical trial results in MS and a substantial population at risk that could benefit from prolonged (e.g. annual) therapy [4, 5]. The business model for alemtuzumab's use in this setting is intuitive and appropriate to pursue. Notably, it is also completely distinct from its use in transplantation, where the drug is not formally indicated and the minute amounts of the drug that are used are difficult to monetize. It is reasonable to note that Sanofi also owns Thymoglobulin, and as such, has essential control over the use of depleting agents for organ transplantation. Thoughts on how this will influence Thymoglobulin remain speculative, but worth following. Regardless, to avoid the impact of the drug's withdrawal on patients who need it (need being somewhat subjective), Sanofi has offered to provide alemtuzumab to transplant patients (and also chronic lymphocytic leukemia and bone marrow transplant patients) free of charge through its world-wide CDP. In general, for nontransplant indications, alemtuzumab is available upon request for specific patients. For centers that treat solid-organ transplant recipients, a process is available to maintain immediate inventory for use in these patients only. Establishing a readily available inventory for solid-organ transplant programs requires, among other things, an established induction protocol. The use of alemtuzumab to treat ongoing rejection is not currently addressed in the documents outlining the CDP, but acquisition on an individual basis is considered. Engagement with the CDP involves a rapid medical review process that appears to be direct, guided by members of the transplant community with experience in alemtuzumab's use, and designed more to provide consistency of distribution than limit access.

On the surface, the CDP would appear to be a reasonable solution for transplant clinicians and patients. However, this access is granted with no promise of sustainability, and as such, already there is anxiety regarding continued development of the drug in transplantation. Significant concern from funding agencies, being averse to fund studies that could end in a regimen for which there is no drug available, is already influencing major multicenter transplant collaboratives. In general, while alemtuzumab is available for use at present, the lack of control and uncertainty about its future threatens to curtail its potential addition as a well-established tool of the trade. It is unclear whether this will perceptibly alter clinical transplantation; but it is hard to perceive what could have been.

Viewed generally, transplant's gradual metamorphosis from a dynamic cutting-edge discipline with results that have marked room for improvement, into a standard practice with good acute results based on maintenance drugs whose patents have expired, makes the field a less attractive testing ground for novel therapeutic approaches. Increasingly, the field has adopted a compensatory use of off-label drugs, like alemtuzumab, in a continued search for better ways to prevent rejection and minimize immunosuppressive comorbidities. However, this increased dependence on off-label drug use strips investigators of any real control of a drug's development in transplantation. With most immune-directed agents now seeking indication in nontransplant-related diseases, the pipeline for transplantation is becoming constrained not by the lack of novel agents with likely relevant biological actions against alloimmunity, but by a critical uncertainty about agent availability even if the trials show that the drug clearly works in transplantation. Another example is the withdrawal from the market of efalizumab, an LFA-1-specific monoclonal antibody, just as strikingly good results were emerging in islet transplantation [6, 7]. In this case Genentech based its decision on an adverse risk-benefit balance for its approved indication, psoriasis, citing 4 cases of progressive multifocal leukoencephalopathy (PML) detected in over 40 000 patients exposed, and transplantation was left unable to counter despite its substantially different risk-benefit assessment (the PML rate in transplant under the standard of care is higher than that reported for efalizumab in psoriasis) as the drug was not indicated for transplantation. Transplantation's appropriate drive to use less medication does not help the matter, as it lessens the potential for an economically viable path for transplant-specific drug development. Treating an illness is profitable, but curing an illness is less so, and preventing an illness perhaps buys more liability that profit.

The path forward for clinical drug development in transplantation is not clearly mapped. Use of orphan drug development principles for transplant indications is one potential step to incentivize continued interest in transplantation. Off-label use also seems reasonable to gather attention for a drug's potential outside its original indication. Importantly, funding agencies should be willing to let early stage trials proceed even while in an off-label realm, as it is reasonable to anticipate that promising results will help influence a drug's future. Indeed, a fundamental role of research is to guide clinical medicine down new paths rather than follow those well trodden. We must, however, commit to convert promising results into meaningful use with transplantation as a destination indication. The financial challenges of that are daunting. However, failure to do so will leave clinicians to either be content with the existing approved agents, or be forever beholden to the mercurial existence of drugs borrowed but never owned.

Disclosure

The author has no conflicts of interest to disclose as described by the American Journal of Transplantation.

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