`
`D. Dragun, L. Fritsche, T. Boehler, H. Peters, K. Budde, and H.H. Neumayer
`
`ABSTRACT
`FTY720 is the first in a new class of immunomodulators—sphingosine 1-phosphate
`receptor (S1P-R) agonists. It is highly effective in prolonging allograft survival
`in
`preclinical models of transplantation. Furthermore, FTY720 acts synergistically with
`calcineurin inhibitors and proliferation inhibitors in these models, suggesting that use of
`FTY720 in combination with classical immunosuppressants may be a promising new
`option for transplant patients. Phase I studies conducted in stable renal transplant patients
`maintained on a cyclosporine (CsA)-based regimen have revealed a tolerable profile of
`FTY720 for transplant pharmacotherapy. The pharmacokinetics of FTY720 is character-
`ized by linear dose-proportional exposure over a wide range of doses, only moderate
`interpatient variability, and a prolonged elimination half-life (t1/2 89 to 157 hours). These
`factors suggest that FTY720 can be administered according to a simple once-daily
`schedule, without the need for blood-level monitoring or dose titration. The pharmaco-
`dynamics of FTY720 in humans are characterized by a significant reduction in peripheral
`blood count by up to 85%. In contrast to the nonspecific myelosuppressive effects of other
`immunosuppressants, this effect of FTY720 is specific for lymphocytes, with no effect
`observed on monocytes or granulocytes. In combination with CsA, FTY720 was well
`tolerated following single or multiple dosing, without any evidence of additional toxicities,
`indicating that FTY720 may be useful in the future design of more effective and less toxic
`regimens for prevention of graft rejection.
`
`CYCLOSPORINE (CsA) has made a substantial contri-
`
`bution to the prevention of acute rejection in human
`organ transplantation ever since its introduction into clini-
`cal practice. Development and improvement
`in other
`modes of rejection prophylaxis followed; nevertheless,
`chronic rejection, infection, and immunosuppressant drug
`toxicity remain the most common causes of morbidity and
`mortality in the transplant population.1,2 Consequently,
`research has focused on the development of effective, yet
`less toxic, agents for preventing graft rejection.
`FTY720 is a structural and functional analogue of the
`natural serum lipid sphingosine; hence, it is the first in a
`new class of immunomodulators—sphingosine 1-phosphate
`receptor (S1P-R) agonists. This agent has been shown to be
`effective in prolonging allograft survival in animal models of
`cardiac, renal, and hepatic transplantation.3 Moreover, the
`unique mode of action of FTY720 is synergistic with
`classical immunosuppressive agents. Thus, this completely
`new mode of action with no overlapping toxicity with
`classical agents implies that FTY720 may provide an alter-
`native for the future of transplant rejection prophylaxis.4
`
`MECHANISM OF ACTION OF FTY720
`
`The mode of action of FTY720 is distinct from any other
`drug approved or developed for use in solid-organ trans-
`plantation. After phosphorylation in vivo, FTY720 acts as a
`potent agonist at four S1P-Rs—a novel class of G-protein–
`coupled receptors.5,6 Agonism at S1P-Rs by FTY720 re-
`duces the recirculation of lymphocytes to blood and periph-
`eral tissues,7,8 including inflammatory lesions and graft
`sites.9 FTY720 sequesters naive and activated CD4⫹ and
`CD8⫹ T cells and B cells from the blood into lymph nodes
`and Peyer’s patches, without affecting their functional prop-
`erties.9 –11 This lymphocyte sequestration may be mediated
`by accelerated homing into lymph nodes, or “trapping” of
`
`From University Hospital Charite´ , Department of Nephrology,
`Campus Mitte, Berlin, Germany.
`This work was supported by Novartis Pharmaceutical Corpo-
`ration.
`Address reprint requests to Duska Dragun, MD, Department of
`Nephrology, University Hospital Charite´ , Campus Mitte, Schu-
`mannstr. 20/21, 10117 Berlin, Germany.
`
`0041-1345/04/$–see front matter
`doi:10.1016/j.transproceed.2003.12.048
`
`© 2004 by Elsevier Inc. All rights reserved.
`360 Park Avenue South, New York, NY 10010-1710
`
`544S
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`Transplantation Proceedings, 36 (Suppl 2S), 544S⫺548S (2004)
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`FTY720: EARLY CLINICAL EXPERIENCE
`
`545S
`
`Table 1. Mean Values for Pharmacokinetic Parameters Following 28-Day Treatment With Multiple Doses of FTY720 in Stable Renal
`Transplant Patients
`
`Dose
`(mg)
`
`0.125
`0.25
`0.5
`1.0
`2.5
`5.0
`Placebo
`
`n
`
`9
`9
`10
`9
`9
`5
`
`Mean Values (%CV)
`
`Cmax (ng/mL)
`
`tmax* (h)
`
`0.74 (79)
`1.4 (42)
`3.1 (39)
`5.7 (50)
`11.2 (49)
`24.9 (54)
`NA
`
`11.9 (0.6 –22.2)
`18.8 (11.4 –24.5)
`21.3 (0.3–24.2)
`11.9 (1.3–22.7)
`11.8 (10.0 –24.0)
`11.5 (11.3–12.1)
`NA
`
`AUC0 –24 h
`(ng*h/mL)
`
`16.9 (21)
`28.2 (52)
`72.7 (29)
`129.5 (48)
`236.8 (45)
`575.9 (31)
`NA
`
`CL (L/h)
`
`7.7 (20)
`23.7 (190)
`7.4 (28)
`9.5 (47)
`13.4 (65)
`9.4 (33)
`NA
`
`Mean Values (SD)
`
`† (h)
`t1⁄2
`
`168 (136 –281)
`184 (141–252)
`205 (145–528)
`199 (133–399)
`220 (134 –526)
`212 (157–338)
`NA
`
`Mg2⫹
`
`1.93 (0.2)
`1.94 (0.3)
`1.81 (0.3)
`1.93 (0.2)
`1.95 (0.2)
`1.94 (0.3)
`1.96 (0.3)
`
`SCr
`
`1.13 (0.5)
`1.45 (0.5)
`1.51 (0.4)
`1.33 (0.5)
`1.33 (0.4)
`1.39 (0.3)
`1.53 (0.5)
`
`Abbreviations: %CV, percent coefficient of variation; CL, clearance; NA, not applicable; SCr, serum creatinine.
`t1⁄2 was assessed during the terminal elimination phase (days 28 to 56).
`*Median value (range).
`†Harmonic value (range).
`Reproduced with permission by Kahan et al (Ref. 21).
`
`lymphocytes in lymphatic tissues.3 Importantly, FTY720
`does not impair cellular or humoral immunity to systemic
`viral
`infection, and it does not affect T-cell activation,
`expansion/proliferation, or immunological memory in pre-
`clinical models.8
`
`EFFICACY AND SAFETY OF FTY720 IN ANIMAL
`MODELS OF TRANSPLANTATION
`
`When used alone, FTY720 has been shown to prolong
`allograft survival with remarkable potency in animal models
`of transplantation.10 –12 FTY720 has no antiproliferative
`activity at therapeutically relevant concentrations10,13 and
`synergizes effectively with inhibitors of T-cell activation and
`proliferation to prevent acute rejection.3 In combination
`with subtherapeutic concentrations of CsA, FTY720 has
`been shown to protect skin, heart, small bowel, liver, and
`kidney allografts in rats, dogs, and nonhuman primates.14
`Similar results have been observed when FTY720 has been
`used in combination with rapamycin,15 RAD,16 and tacroli-
`mus.17 In combination with CsA, FTY720 has also been
`shown, in a murine cardiac transplantation model, to pre-
`vent perivascular inflammation and allograft arteriosclero-
`sis, which are markers of chronic rejection.18
`In addition, FTY720 has shown no nephrotoxic or muta-
`genic activity in any of the in vitro or in vivo studies
`performed to date.13 Furthermore, there was no evidence
`of infection in cynomolgus monkeys administered with
`extremely high doses of FTY720 of up to 10 mg/kg per day
`for a 52-week period.13 FTY720 is extensively metabolized
`in the liver via cytochrome enzymes that are not involved in
`the metabolism of CsA, rapamycins, or tacrolimus, and thus
`drug-drug interactions between these agents when co-
`administered with FTY720 are unlikely.13
`
`CLINICAL EXPERIENCE WITH FTY720 IN PHASE 1
`TRIALS
`
`The pharmacokinetics, pharmacodynamics, and safety of
`FTY720 have been investigated in two randomized, double-
`blind, placebo-controlled, phase I studies involving stable
`renal transplant patients (at least one-year posttransplanta-
`
`tion) maintained on a CsA-based regimen.19 –21 The first
`study involving 20 patients was designed to evaluate ascend-
`ing (0.25–3.5 mg), single oral doses of FTY720,19,20 while
`the second examined the effects of multiple, once-daily
`doses (0.125–5.0 mg), given over a 28-day period (FTY720,
`n ⫽ 61; placebo, n ⫽ 15).21
`
`Pharmacokinetics
`
`The pharmacokinetics after single-dose administration of
`FTY720 to patients have been characterized by a prolonged
`absorption phase, with an elimination half-life (t1⁄2) ranging
`from 89 to 157 hours, which was independent of dose.19
`Furthermore, the absorption phase was very long and wide,
`with a time to maximum plasma concentration (tmax) of 8 to
`36 hours across subjects. Maximum plasma concentration
`(Cmax) and area under the curve (AUC) were proportional
`to dose up to 3.5 mg, with low intersubject variability.
`Furthermore, FTY720 had an unusually high apparent
`volume of distribution (median 1407 L) and a relatively low
`apparent oral clearance (median, 158 mL/min). The long
`absorption phase of FTY720 in humans is consistent with
`the results of experiments with FTY720 in animal models;
`the absolute bioavailability of FTY720 in different animal
`species is high (60%–90%), with maximum blood concen-
`trations achieved in 2 to 24 hours.22,23
`The findings of the single-dose study have been con-
`firmed by those of an analysis of the pharmacokinetics of
`FTY720 following multiple dosing.21 In this latter study,
`steady-state pharmacokinetic parameters were determined
`for the blood concentration versus time values from the
`time of the last FTY720 dose (day 28) until the end of the
`follow-up period (day 56) (Table 1). Consistent with the
`long t1⁄2 of FTY720, almost all subjects took about 4 weeks
`of daily dosing to reach steady-state concentrations (mean t
`1⁄2 200 hours). At steady state, the median tmax was about 8
`hours and was similar for all doses. Again, Cmax and AUC
`displayed linear kinetics over a wide range. Importantly,
`there was no evidence of a drug-drug interaction between
`FTY720 and CsA in this study, and CsA exposure appeared
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`DRAGUN, FRITSCHE, BOEHLER ET AL
`
`unaffected by coadministration of FTY720 at any dose
`measured.21
`The prolonged t1⁄2 of FTY720 implicates that the agent
`can be given once daily, with little fluctuation over the
`dosing interval at steady state. Furthermore, the low inter-
`subject variability observed following administration of
`FTY720 indicates consistent absorption and disposition of
`the drug, which should allow for a simple, standardized
`dosing regimen for all subjects, without the need for
`blood-level monitoring or individualized dose titration.19
`The use of a pharmacodynamic loading dose of FTY720 is
`currently under evaluation for certain situations where
`rapid attainment of decreased lymphocyte count is required
`(eg, in the de novo transplant setting).21
`
`Pharmacodynamics
`
`Animal transplantation models have consistently shown
`that FTY720, administered at pharmacological doses, in-
`duces a decrease in lymphocyte count; this has been a
`prerequisite for efficacy in preclinical trials.7,9,14,16,22 This
`pharmacodynamic effect of FTY720 has also been observed
`in studies in humans following single and multiple dosing.
`Administration of a single dose of FTY720 (0.25–3.5 mg)
`to 20 stable renal transplant patients resulted in a transient
`decrease in lymphocyte count within 4 hours of administra-
`tion in all subjects.20 This pharmacodynamic effect of
`FTY720 exhibited nonlinear dose-dependence, with the
`most prolonged and intensive reduction in lymphocyte
`count being observed in the 3.5-mg group; the effect on
`lymphocyte count had returned to baseline within 24 to 72
`hours in patients receiving 0.25 to 1.0 mg FTY720, but
`lasted more than 96 hours in those receiving 3.5 mg
`FTY720.20 Administration of FTY720 affected both B and
`T cells, with the greatest effects being observed on CD4⫹
`and CD45RA⫹ naı¨ve T cells, while NK cells, monocyte,
`and granulocyte counts were unaffected.20
`A marked decline in peripheral lymphocytes has also
`been demonstrated following multiple doses of FTY720
`(0.125–5.0 mg) in stable renal transplant patients.21 Twenty-
`eight-day treatment with FTY720 at doses greater than 1.0
`mg produced a sustained reduction of blood lymphocyte
`count of approximately 85% of baseline (Fig 1). After
`cessation of treatment, recovery was evident within 3 days
`after the last dose, with a trend toward complete recovery to
`baseline values in all dose groups at the end of the
`follow-up period (day 56). All doses of FTY720 appeared to
`affect to a similar degree all lymphocyte subsets tested:
`CD3⫹ (pan-T cell), CD4⫹ (T helper), CD8⫹ (T suppres-
`sor), CD45RA⫹ (T naı¨ve), CD45RO⫹ (T memory), CD20⫹
`(B cell), CD16⫹ (natural killer). In contrast to that ob-
`served with immunosuppressive agents that display nonspe-
`cific myelosuppressive effects (eg, azathioprine, mycophe-
`nolate mofetil, sirolimus), multiple doses of FTY720 had no
`effect on blood granulocytes, monocytes, or eosinophils,
`and also had no effect on the number of erythrocytes or
`platelets.21
`The predominant effect of FTY720 on CD4⫹ and naı¨ve T
`
`Fig 1.
`Impact of dose on the kinetics of percent change from
`baseline of the absolute lymphocyte count by study day during
`FTY720 treatment (28 days) and posttreatment (days 29 –56)
`periods. Reproduced with permission by Kahan et al (Ref 21)
`
`cells observed in these pharmacodynamic studies supports
`the potential enhancing effect of the drug on sequestration
`of these cells into lymph nodes and Peyer’s patches.9,14
`Furthermore, the findings of these studies suggest that
`pharmacokinetics may not completely account for the phar-
`macodynamic response to FTY720. Consequently, pharma-
`codynamic monitoring, by measuring lymphocyte number,
`may also be a useful predictor of the response to FTY720 in
`future trials.20
`
`SAFETY AND TOLERABILITY
`
`It has been found that FTY720 has a good tolerability
`profile in phase I trials, which may be related to the novel
`mode of action of the agent.19 –21 Use of FTY720 (0.25–3.5
`mg) was well tolerated following single-dose administration,
`with no serious adverse events reported.19 In the study by
`Budde et al,19 91% of FTY720-treated patients and 75% of
`placebo-treated patients experienced an adverse event. The
`most common adverse event reported was asymptomatic
`bradycardia, occurring in 10 FTY720-treated patients and
`none receiving placebo (Fig 2A). An increased frequency of
`reported bradycardia was observed in patients receiving
`higher doses of FTY720 (9 of 12 patients receiving ⱖ0.75
`mg FTY720 vs 1 of 12 patients receiving ⱕ0.5 mg FTY720),
`mainly in patients with mild bradycardia (ⱕ60 beats per
`minute [bpm]) at baseline. Heart rates reached a nadir
`about 4 to 8 hours after FTY720 dosing and lasted for up to
`24 hours (Fig 2B). This transient reduction in heart rate on
`
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`Table 2. Adverse Events Occurring in More Than 10% of
`Stable Renal Transplant Patients Following Multiple Doses of
`FTY720 (0.125–5 mg q.d.) or placebo for 28 days
`
`Adverse Event, n (%)
`
`Any adverse event
`Any serious adverse event
`Any severe adverse event
`Lymphocytopenia
`Coughing
`Rhinitis
`Urinary tract infection
`Headache
`Gastroenteritis
`Increased BUN
`
`FTY720
`(n ⫽ 61)
`
`54 (88.5)
`6 (9.8)
`4 (6.60)
`18 (29.5)
`9 (14.5)
`9 (14.8)
`7 (11.5)
`6 (9.8)
`1 (1.6)
`1 (1.6)
`
`Placebo
`(n ⫽ 15)
`
`11 (73.3)
`3 (20.0)
`3 (20.0)
`1 (6.7)
`1 (6.7)
`1 (6.7)
`1 (6.7)
`4 (26.7)
`2 (13.3)
`2 (13.3)
`
`BUN, blood urea nitrogen.
`Reproduced with permission by Kahan et al (Ref. 21).
`
`viral and fungal) were similar in patients receiving multiple-
`dose FTY720 and in those receiving placebo, consistent
`with a lack of alteration of primary or memory responses to
`bacterial or viral infectious challenges, in accord with the
`findings of preclinical studies.8,13 In addition, no deaths or
`episodes of rejection or emergence of malignancy were
`observed in this study, in either group, during the treatment
`or follow-up phases. Importantly, in contrast to the cal-
`cineurin inhibitors,24,25 there is no evidence to date that
`FTY720 is associated with increased neurotoxicity or dia-
`betogenic side effects,21 suggesting that the agent may have
`an improved tolerability profile over classical immunosup-
`pressants.
`In contrast to the effects observed with FTY720 in the
`single-dose study, reduction in heart rate occurred infre-
`quently in the multiple-dose study: in only 3.27% (2/61) of
`FTY720 patients and 6.6% (1/15) of placebo-treated pa-
`tients.21 This lower incidence may have been due to the
`exclusion of patients with resting pulses of less than 60 bpm
`and those receiving beta-adrenergic antagonists or calcium
`channel blockers at baseline.
`Although the mechanism for this effect of FTY720 on
`heart rate is undergoing further investigations, it is reported
`that direct agonism of FTY720-P at S1P-R expressed in
`atrial myocytes of the heart is responsible.3,26,27 Further-
`more, the observation of a reduction on heart rate in the
`single-dose FTY720 study has led to the design of all
`subsequent trials with the drug to include close monitoring
`of heart rate in all patients. However, from trials completed
`to date, it appears that the transient effect of FTY720 on
`heart rate with treatment initiation is asymptomatic, self-
`limiting, and manageable and is not associated with any
`measurable increase in mortality or cardiac morbidity.
`
`CONCLUSIONS
`
`The availability of agents with different mechanisms of
`action for preventing graft rejection that can be combined
`safely will be essential for the future of organ transplanta-
`tion if further improvements in outcomes posttransplant are
`
`(A) Heart rate for 10 stable renal transplant patients with
`Fig 2.
`bradycardia receiving a single oral dose of FTY720 (0.25–3.5
`mg). (B) Mean heart rate in placebo-treated subjects (n ⫽ 8) and
`in those receiving a low (0.25– 0.5 mg; n ⫽ 12) or a high (0.75–3.5
`mg; n ⫽ 12) dose of FTY720. Reproduced with permission by
`Budde et al.19
`
`treatment initiation was asymptomatic, had normal blood
`pressure (BP) recordings at the time of nadir rate and
`required no clinical intervention in all cases; all patients
`recovered without sequelae. No additional organ toxicity
`was observed in this single-dose study, and no clinical signs
`or symptoms of pulmonary dysfunction were identified in
`any subject.
`Following multiple dosing, FTY720 was equally well
`tolerated, with no significant difference noted between the
`incidences of adverse events in FTY720-treated patients
`compared with that seen in patients receiving placebo
`(88.5% vs 73.3%, respectively; Table 2).21 Furthermore,
`serious and severe adverse events were reported more
`frequently in placebo-treated patients than in FTY720-
`treated patients (20.0% vs 9.8%, respectively, and 20.0% vs
`6.6%). The incidences and patterns of infections (bacterial,
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`to be achieved. In contrast to classical immunosuppressants,
`FTY720 has no antiproliferative activity at therapeutic
`dosing and rather acts as a “stimulant immunomodulator,”
`suggesting that this agent may be useful to augment the
`immunosuppressive actions of other drugs. Preclinical stud-
`ies with FTY720 have demonstrated that the agent is highly
`effective in a wide range of animal models of transplanta-
`tion.13 Initial clinical studies with FTY720 suggest that this
`novel immunomodulator is also effective in human trans-
`plant recipients, producing a marked reduction in blood
`lymphocyte count following single and multiple dosing.19 –21
`Furthermore, FTY720 in combination with CsA was well
`tolerated, with no significant safety issues. The novel mech-
`anism of action of FTY720, its unique pharmacodynamic
`profile, and absence of additional toxicities when combined
`with CsA suggest that this agent may offer important
`benefits for the transplant setting. The results of ongoing
`studies investigating the ability of FTY720 to provide
`equivalent efficacy to classical immunosuppressive regimens
`in the prevention of acute rejection, without additional
`toxicity, are eagerly awaited.
`
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