Rapamycin on trial

Steven H. Sacks

Guy's, King's College and St Thomas' Hospitals' Medical School, Renal Medicine and Transplantation, Guy's Hospital, London, UK

Correspondence and offprint requests to: Steven H. Sacks, Guy's, King's College and St Thomas' Hospitals' Medical School, Renal Medicine and Transplantation, 5th Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK. E-mail: steven.sacks{at}kcl.ac.uk.

The need for additional immunosuppressive agents

Do we need another T-cell suppressive agent, when calcineurin inhibitors (cyclosporin and tacrolimus) seem to work so well? The arrival of rapamycin, structurally similar to tacrolimus and binding the same intracellular protein, but with a more downstream mode of action in the T-cell activation cascade, is likely to challenge this view. The Seventeenth World Congress of the Transplant Society heard the results of early phase III trials [1,2].

At present, cyclosporin and tacrolimus are the drugs of choice in clinical transplantation. However, both are toxic to kidneys and other organs. Furthermore, they are not completely effective. Most patients need additional immunosuppression to prevent acute rejection. Even when calcineurin inhibitors are given in combination with prednisolone and azathioprine, as many as 15–45% of renal allograft recipients need further treatment. Moreover, despite the benefits of calcineurin inhibitors in the first year of treatment, they appear to have had little impact on chronic graft loss, which has remained virtually unchanged at about 4% per annum. Thus there is considerable room for improvement on these drugs.

Discovery and mode of action of rapamycin

Rapamycin is a macrolide antibiotic produced by a species of the fungus Streptomyces, found in Easter Island (Rapa Nui). The Ayerst Company in Canada first investigated rapamycin as an anti-fungal and anti-tumour agent. It caused severe lymphocyte depletion in experimental animals and therefore was shelved. Some 20 years later, when the similarity of its molecular structure to tacrolimus (FK506) struck, it was investigated as an immunosuppressive agent. Although it binds to the FK506-binding protein it does not inhibit calcineurin-dependent signal transduction in T cells, and therefore does not affect interleukin (IL)-2 generation [3]. It dampens the response of T cells to cytokines such as IL-2, and also acts on B cells and non-immune cells, by inhibiting the phosphorylation of protein kinases [4,5]. As a consequence, rapamycin interferes with T-cell activation at a later stage of the cell cycle than tacrolimus or cyclosporin. Rapamycin and tacrolimus cannot be used together since they compete with each other, but the combination of rapamycin and cyclosporin is very effective.

The ongoing trials

Rapamycin in addition to cyclosporin
A present focus is on the development of rapamycin for combination therapy with cyclosporin, with a view to reducing cyclosporin toxicity and improving graft outcome. Two large multicentre trials, the US study [1] and the Global study [2], are in progress. The protocols in both studies involve first cadaveric grafts and unmatched living donor grafts. The US study is comparing rapamycin with azathioprine, in combination with Neoral and steroid. It randomized patients 24 h after transplantation, putting the results in a slightly better light, as it will exclude any early graft failures. Analysis at 6 months showed a remarkably low rejection rate (10–12%), with less use of antibody to treat rejection (Table 1Go). Graft survival improved in the lower dose rapamycin group (2 mg/day). The Global study (Australia, Canada, USA and Europe) compared rapamycin with placebo, in combination with Neoral and steroid. It randomized patients before transplantation. At 6 months, the incidence of acute rejection was also markedly reduced compared with placebo, although there was no clear difference in graft survival (Table 1Go).


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Table 1. Phase III rapamycin studies: interim 6-month analysis
 
Rapamycin instead of cyclosporine
Less remarkable was the performance of rapamycin as a replacement for cyclosporin in triple therapy. In a phase II European trial (83 patients, 11 centres) comparing rapamycin-based therapy and cyclosporine-based therapy [6], analysis at 12 months found similar results in both treatment groups, in terms of acute rejection episodes (41.5% vs 38.1%) and graft survival (97.6% vs 92.5%). Plasma creatinine was lower in the rapamycin group than in the cyclosporine group at 4 months (124 µmol/l vs 153 µmol/l) but there was no statistically significant difference at later time points.

Rapamycin and chronic graft nephropathy

There is much interest in whether rapamycin will reduce chronic allograft nephropathy. Here, rapamycin has two possible advantages. First, unlike cyclosporine and tacrolimus, it is non-nephrotoxic in humans, although work in experimental animals suggests that it might enhance cyclosporin nephrotoxicity [7]. Secondly, rapamycin inhibits growth-factor-triggered proliferation of smooth muscle cells, endothelial cells and fibroblasts [4]. Consequently, it might lessen vascular and interstitial cell proliferation, and so reduce the severity of chronic injury. Several protocols are looking into this, including the discontinuation of cyclosporin from combination therapy with rapamycin, and the substitution of cyclosporin with rapamycin for patients who have progressive graft dysfunction.

Side-effects of rapamycin

The major side-effects of rapamycin are thrombocyopenia and hyperlipidaemia. Both are dose dependant [1,2]. At the higher dose of rapamycin (5 mg) thrombocytopenia occurred in about 23% compared with 3% in the placebo group, and 11% at the lower dose of rapamycin (3 mg). Hypercholesterolaemia and hypertriglyceridaemia occurred in about half the patients on the higher dose of rapamycin, compared with about one-fifth in the placebo group (on cyclosporine and steroids). Herpetic lesions were more common only in the rapamycin 5 mg/day group; otherwise there was no apparent difference in infection between the treatment and control groups. The risk of late malignancy with rapamycin therapy is unknown, although caution is needed with any combination of two potent immunosuppressive drugs.

Conclusion

Rapamycin is thus a powerful immunosuppressive drug, relatively free from nephrotoxicity although with a toxicity profile of its own. Its future use in primary therapy will depend on its ability to deliver better mid-term graft survival, without over-immunosuppression or excessive cardiovascular risk. It is also seen as a potential rescue therapy for chronic rejection, subject to validation by clinical trial. In addition, as pilot studies have shown, it may be effective in liver [8] and heart recipients, avoiding the renal toxicity associated with cyclosporin.

References

  1. Kahan BD, for the Rapamune US Study Group, University of Texas School of Medicine, Houston Texas. A Phase III comparative efficacy trial of rapamune in renal allograft recipients. Oral Abstract 198, The Transplantation Society XVII World Congress, Montreal 1998
  2. MacDonald AS, The Rapamune Global Study Group, QE11 Health Sciences Centers, Halifax, Nova Scotia. A randomised, placebo-controlled trial of rapamune in primary renal allograft recipients. Oral Abstract 426, The Transplantation Society XVII World Congress, Montreal, 1998; 116
  3. Morris RE. Mechanisms of action of new immunosuppressive drugs. Ther Drug Monit 1995; 17: 564–569[ISI][Medline]
  4. Chung J, Kuo CJ, Crabtree GR, Blenis J. Rapamycin-FKBP specifically blocks growth dependent activation of and signalling by the 70kd S6 protein kinases. Cell 1992; 60: 1227–1236
  5. Brunn GR, Hudson CC, Sekulic A et al. Phosphorylation of the translational repressor PHAS-1 by the mammalian target of rapamycin. Science 1997; 277: 99–101[Abstract/Free Full Text]
  6. Backman L, Groth CG, Morales JM et al. Rapamune (Rapamycin) versus cyclosporine in a triple-drug regimen for the prevention of acute renal allograft rejection: 1 year results of a randomized phase II trial. Oral Abstract 427, The Transplantation Society XVII World Congress, Montreal 1998, 116
  7. Andoh TF, Lindsley J, Franceschini N, Bennett WM. Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 1996; 62: 311–316[ISI][Medline]
  8. Watson CJE, Friend PJ, Jamieson NV, Frick TW, Alexander G, Gimson AE, Calne R. Sirolimus: A potent new immunosuppressant for liver transplantation: Transplantation 1999; 67: 505–509[ISI][Medline]