Sirolimus and FTY720: New Approaches to
`Transplant Immunosuppression
`
`B.D. Kahan
`
`DUE TO THE PLEIOTROPIC toxicities of presently
`
`available immunosuppressive agents (nucleoside syn-
`thesis blockers, calcineurin antagonists, and steroids), two
`new approaches to the transplant enterprise are being
`evaluated in clinical trials. These strategies are based
`upon the development of synergistic drug combinations
`that not only achieve greater efficacy but also permit
`marked reduction in the dose of each component drug.
`The new agents are primarily being developed to poten-
`tiate the actions of the calcineurin antagonists (cyclo-
`sporine [CsA] or tacrolimus) and thereby to minimize
`their nephrotoxicity, neurotoxicity, and other less com-
`mon adverse events.1
`
`SIROLIMUS
`
`Sirolimus (and its structural analog everolimus) acts as a
`proliferation signal inhibitor of a multifunctional kinase,
`mammalian target of rapamycin (mTOR). The enzyme
`catalyzes the activation of signal 2, CD28-induced transcrip-
`
`From the Division of Immunology and Organ Transplantation,
`University of Texas–Houston, Houston, Texas, USA.
`This work was supported by a grant from the National Institute
`of Diabetes and Digestive and Kidney Diseases (NIDDK 38016-14).
`Address reprint requests to Barry D. Kahan, PhD, MD, Division
`of Immunology and Organ Transplantation, University of Texas–
`Houston, 6431 Fannin, Suite 60240, Houston TX.
`
`Fig 1. Actions of mTOR. (a) Transduction of DC28-mediated signal 2, leading to NF-␬B. (b) Phosphorylation of P70S6 kinase, leading
`to S6 ribosomal protein. (c) Release of elongation factors for protein translation. (d) Dissociation of P27 Kipl, leading to activation of
`cyclin and cyclin-dependent kinase activities.
`
`0041-1345/02/$–see front matter
`PII S0041-1345(02)03472-3
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`2520
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`© 2002 by Elsevier Science Inc.
`360 Park Avenue South, New York, NY 10010-1710
`
`Transplantation Proceedings, 34, 2520 –2522 (2002)
`ARGENTUM EX1030
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`SIROLIMUS AND FTY720
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`2521
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`Fig 2. Schematic diagram of the effect of FTY720 to block emigration of lymphocytes into a graft with sequestration in secondary
`lymphoid structures (SLS). Up-regulation of chemokine receptor 7 binding to lymph node chemokines SLC and ELC may represent
`one component of drug action.
`
`including nuclear factor-␬B (NF-␬B);
`the
`tion factors,
`dissociation of elongation factors for microsomal proteins
`translation; the synthesis of the S6 ribosomal protein; and
`the activation of cyclins and cyclin-dependent kinases (Fig
`1). Based upon the exciting results of preclinical studies,
`sirolimus, a macrolide product of the actinomycete Strepto-
`myces hygroscopicus, was evaluated in clinical trials.
`Following a Phase I study of toxicity and a Phase I/II trial
`documenting efficacy, a multicenter Phase II trial revealed
`that treatment with sirolimus in combination with full or
`reduced exposures to CsA equally decreased the occur-
`rence and severity of acute allograft rejection episodes
`among non-African American recipients. A median effect
`analysis of the large Phase III multicenter trials docu-
`mented a synergistic interaction between sirolimus and
`CsA.2 Subsequent experience in human renal transplanta-
`tion has shown that compared to patients treated with
`full-dose CsA, recipients treated with a 60% reduced
`exposure to CsA with an almost 80% decrease in sirolimus
`display reductions in acute and chronic rejection as well as
`improvements in renal function. Despite the enhanced
`efficacy, patients in the sirolimus/CsA arms did not display
`an increased incidence of infectious or malignant compli-
`cations. However, they did experience a range of nonim-
`mune toxicities, including exacerbation of the hypercholes-
`terolemia associated with CsA, as well as myelosuppression,
`hypertriglyceridemia, and diarrhea due to sirolimus.
`There are at least three circumstances in which the
`unique properties of sirolimus have been exploited in
`clinical renal transplantation. First, addition of sirolimus to
`a calcineurin antagonist-steroid regimen has been shown to
`reverse rejection episodes refractory to antilymphocyte
`
`preparations. Second, because of the enhanced potency of
`the sirolimus-CsA combination, it has proved possible to
`withdraw steroids with little penalty and with possible
`benefits on the toxicities of hyperlipidemia, hypertension,
`and bone pain. Third, due to its lack of intrinsic nephro-
`toxicity in salt-depleted rats or in psoriatic patients, siroli-
`mus offers unique advantages for maintenance immunosup-
`pression, particularly in recipients bearing acutely or
`chronically injured renal allografts. In the setting of delayed
`graft function, induction therapy with sirolimus provides a
`window for freedom from calcineurin antagonists de novo.3
`In the maintenance phase, the renal function of patients
`who display nephrotoxic effects of calcineurin antagonists
`may be improved by withdrawal of CsA or tacrolimus to a
`maintenance regimen of sirolimus/steroid treatment.
`
`FTY720
`
`Despite reductions in the exposures of CsA and sirolimus,
`the comorbidities of the regimen are substantial, a limita-
`tion that may be addressed through the introduction of a
`third synergistic agent that permits further decreases in the
`two baseline immunosuppressants. Preclinical studies have
`documented that administration of FTY720, a structural
`analog of myriocin, which is a biologic product of Isaria
`sinclarii, prolongs allograft survival in preclinical models.
`Experimental studies demonstrated that FTY720 produces
`synergistic interactions with CsA and/or sirolimus (SRL) in
`rats4 and in nonhuman primates.5
`Upon oral administration, the drug acts to divert lympho-
`cytes from the circulation and therefore from the inflamed
`graft. The cells are sequestered in secondary lymphoid
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`2522
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`KAHAN
`
`structures (SLS) (Fig 2). Studies in gene knockout animals
`bearing deletions or reductions in the expression of chemo-
`kine receptor 7 (CCR7) or the SLC and ELC chemokines
`suggest that this network may play a role, albeit not
`exclusive, in the drug’s action. Chemokine receptor signals
`are transduced by G-proteins, some of which are also
`receptors for sphingosine-1-phosphate (S1P). By cross-
`reacting with S1P receptors, FTY-720-phosphate, which is
`generated by intracellular phosphorylation of the drug by
`sphingosine kinase, up-regulates actin polymerization and
`the cytoskeleton, thereby promoting cell mobility. FTY720
`seems to enhance lymphocyte responsiveness to a variety of
`chemokines, not merely the SLC-ELC/CCR7 axis but also
`inflammatory mediators that would promote cell infiltration
`into the graft. Therefore our understanding of the molec-
`ular mechanism of drug action is incomplete.
`Of great import to the use of FTY720, in addition to its
`unique mechanism of action, is the observation that the
`drug undergoes metabolism by the cytochrome P450 (CYP)
`4F rather than CYP 3A4 system, rendering it free of
`pharmokinetic interactions with calcineurin antagonists,
`sirolimus/everolimus, and a variety of other drugs used in
`the polypharmacy practice of transplantation. Furthermore,
`because FTY720 showed only modest interindividual vari-
`ability, therapeutic drug monitoring is not likely to be
`useful.
`A Phase I multiple-dose clinical study confirmed the
`findings in animal models: FTY720 produces a reversible,
`dose-dependent depletion of peripheral blood lymphocytes,
`but neither polymorphonuclear leukocytes nor monocytes,
`from the circulation.6 A multicenter, randomized, open-
`label early Phase II study showed that 2.5 mg/d doses of
`FTY720, when used in combination with CsA and steroids,
`was more effective for the prevention of acute rejection
`episodes than 2 g/d of mycophenolate mofetil. Another
`clinical study combined FTY720 (2.5 mg/d) and everolimus
`(doses targeted to achieve trough levels between 6 and 8
`ng/mL) in a calcineurin antagonist-free regimen for patients
`at increased risk for delayed graft function (DGF). The
`regimen showed good tolerability, but in the absence of a
`control group, it was impossible to assess efficacy.
`
`The primary side effect of FTY720 is bradycardia, which
`is at least partially dose-dependent, and is observed most
`commonly after administration of the loading dose. Based
`on the hypothesis of an interaction between FTY720–
`phosphate with S1P receptors including those mediating
`M2-muscarinic effects on atrial myocytes, bradycardia may
`ensue if FTY720 is administered concomitant with para-
`sympathetic stimulation or with sympathetic beta-blockade.
`
`CONCLUSION
`
`Although the role of sirolimus has evolved from that of an
`adjunctive agent to the foundation of renal transplant
`immunosuppression, the side effect profile of the drug
`combination with CsA, particularly the hyperlipidemia and
`compromised renal function, produce appreciable comor-
`bidity. FTY720, a sphingosine analog, the mechanism of
`action of which is uncertain, produces a reversible, dose-
`dependent depletion of the peripheral blood lymphocytes
`(but neither granulocytes nor monocytes). Addition of
`FTY720 to the regimen may permit further reduction in the
`doses of cyclosporine and of sirolimus/everolimus, an excit-
`ing new avenue for immunosuppressive development. Just
`as the action of sirolomus on signal 3, the cytokine-driven
`stimulus, profferred an attractive new mechanism of action
`10 years ago, chemokines certainly represent a hot target
`for further drug development. In the interim, encouraging
`preclinical results with the use of FTY720 in combination
`with calcineurin antagonists and/or proliferation signal in-
`hibitors (sirolimus or everolimus) suggest that regimens
`with low comorbidity may be within our grasp.
`
`REFERENCES
`
`1. Kahan BD, Camardo JS: Transplantation 72:1181, 2001
`2. Kahan BD, Kramer WG: Clin Pharmacol Ther 70:74, 2001
`3. Hong JC, Kahan BD: Transplantation 71:1320, 2001
`4. Wang ME, Tejpal N, Qu X, et al: Transplantation 65:899,
`1998
`5. Troncoso P, Stepkowski SM, Wang ME, et al: Transplanta-
`tion 67:145, 1999
`6. Kahan BD, Chodoff L, Leichtman J, et al: Transplantation
`69(Suppl 1):S132, 2000
`7. Tedesco H, Kahan BD, Mouad G, et al: Am J Transplantation
`1(Suppl 1):243, 2001
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