Introduction : Transplantation

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Introduction

Gaston, Robert S.

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Transplantation 80(2S):p S177, October 15, 2005. | DOI: 10.1097/01.tp.0000186384.95916.bf
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The year was 1988. Hans W. Sollinger, a distinguished surgical investigator at the University of Wisconsin, was expectantly monitoring the first observations in humans of an experimental immunosuppressant, mycophenolate mofetil (MMF), with which he had worked previously in preclinical models (1). The novel design of the phase I/II trial (with an escalating dose of MMF in combination with antibody induction, cyclosporine, and corticosteroids) would define the manner in which the new agent would be used for the next decade (2). There was substantial relief in observing the drug to be better tolerated in humans than in dogs, with at least some suggestion of efficacy. At the same time, I was a medical transplant fellow at the University of Alabama at Birmingham (UAB). As noted to the principal investigator at UAB, Mark H. Deierhoi, it seemed to me that azotemia in MMF-treated patients was less frequently due to acute rejection than in those taking azathioprine in our standard quadruple immunosuppressive regimen of that time.

Based on the experience generated from the 48 kidney transplant recipients in this phase I/II trial at both the Universities of Wisconsin and Alabama, three pivotal multicenter trials of 500 subjects each were designed and initiated across the world. Even then, however, the ability of MMF to salvage rejecting kidneys already was becoming recognized, at least in the United States (3). In the early nineties, as the pivotal trials were in progress, Syntex Laboratories offered MMF as “compassionate” therapy on a case-by-case basis. To this day, I continue to encounter individual patients who seemed destined for transplant failure in that era but whose grafts were saved by the administration of MMF. It is noteworthy that ultimately the company was forced to halt compassionate use of MMF after demand far outstripped its ability to manufacture the drug.

The results of the three pivotal trials, the U.S. Renal Transplant Mycophenolate Mofetil Study (4), the Tricontinental Mycophenolate Mofetil Renal Transplantation Study (5), and the European Mycophenolate Mofetil Cooperative Study (6), each documenting 50% reduction in frequency of acute rejection episodes with MMF compared to controls, were widely presented in 1994 and published shortly thereafter. Enthusiasm for clinical utilization of the agent grew, especially at the centers involved in the trials. Indeed, at UAB as early as 1994, selected transplant candidates were advised to consider postponing their operation until the new drug became available for widespread use after approval by the U.S. Food and Drug Administration. That momentous event occurred on May 3, 1995; MMF appeared in clinical pharmacies 2 weeks later. Acceptance of MMF as a key component in kidney transplant immunosuppression occurred quickly. As we (and others) had seen as early as 1988, the drug made a readily perceptible difference in outcomes for our patients. As more studies documented a beneficial impact of MMF in transplantation of other solid organs, usage escalated (7, 8). Since 2002, MMF has been the most widely prescribed immunosuppressive agent for solid organ transplant recipients in the United States (9).

Now we find ourselves 10 years into the MMF experience. It seems fitting to pause and reflect on where we have been with this agent and what new vistas lay ahead, both inside and outside solid organ transplantation. This supplement, with articles from a variety of respected investigators and clinicians, was conceived to do just that. While each article stands alone as an up-to-date review of the topic at hand, we invite the reader to view the supplement as a whole, reflecting on the remarkable changes that have occurred over the past decade. Our goal is that in recognizing the foundation provided by this broad experience, we can facilitate even more remarkable achievements over the next decade.

REFERENCES

1. Platz K-P, Sollinger HW, Hullett DA, et al. RS-61443-a new, potent immunosuppressive agent. Transplantation 1991; 51: 27.
2. Sollinger HW, Deierhoi MH, Belzer FO, et al. RS-61443-a phase I clinical trial and pilot rescue study. Transplantation 1992; 53: 428.
3. Sollinger HW, Belzer FO, Deierhoi MH, et al. RS-61443: rescue therapy in refractory kidney transplant rejection. Transplant Proc 1993; 25: 698.
4. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1995; 60: 225.
5. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029.
6. European Mycophenolate Mofetil Cooperative Study Group. Placebocontrolled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995; 345: 1321.
7. Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998; 66: 507.
8. Stegall MD, Simon M, Wachs ME, et al. Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine. Transplantation 1997; 64: 1695.
9. Helderman JH, Bennett WB, Cibrik DM, et al. Immunosuppression: practice and trends. Am J Transplant 2003; 3(Suppl 4): 41.
© 2005 Lippincott Williams & Wilkins, Inc.