Clin Transplant 2006: 20 (Suppl. 17): 17–24
`
`Copyright ª Blackwell Munksgaard 2006
`
`FTY720 (fingolimod) in renal
`transplantation
`
`Budde K, Schu¨ tz M, Glander P, Peters H, Waiser J, Liefeldt L, Neumayer
`H-H, Bo¨ hler T. FTY720 (fingolimod) in renal transplantation.
`Clin Transplant 2006: 20 (Suppl. 17): 17–24. ª Blackwell Munksgaard, 2006
`
`Abstract: FTY720 (Fingolimod) is a novel immunomodulator with a mode
`of action that is completely different from classical immunosuppressants.
`FTY is a structural and functional analogue of the natural serum lipid,
`sphingosine, and is the first in a new class of drugs called sphingosine
`1-phosphate receptor (S1P-R) modulators. This review discusses the recent
`findings on the mechanism of action, preclinical models and outlines the
`results of the ongoing clinical development program. FTY is highly effective
`in prolonging allograft survival in preclinical models of transplantation and
`in experimental models of autoimmune diseases. In clinical trials, this novel
`compound was investigated in de novo renal transplantation and in multiple
`sclerosis. Pharmacokinetics are characterized by a prolonged absorption
`phase, a large volume of distribution, and a long elimination half-life. FTY
`induces a rapid and transient decrease in lymphocyte counts, which sup-
`ports the modulatory effects of the drug on lymphocyte sequestration. The
`most common adverse event was asymptomatic transient bradycardia, a
`pharmacodynamic effect modulated by atrial S1 P-R. FTY failed to show
`an improvement in efficacy for the prevention of renal allograft rejection in
`two large phase III studies. FTY treatment regimens were associated with
`impaired renal function and the development of macula edema. Conse-
`quently, the further development in renal transplantation was stopped.
`Because initial clinical studies strongly suggest that FTY is highly effective
`in multiple sclerosis FTY is now being explored in phase III studies for the
`treatment of demyelinating diseases, Ongoing studies in multiple sclerosis
`are eagerly awaited because they may provide novel therapeutic options for
`patients with autominnue diseases.
`
`Klemens Buddea, Manuela
`Schu¨ tza, Petra Glandera, Harm
`Petersa, Johannes Waisera, Lutz
`Liefeldta, Hans-H. Neumayera and
`Torsten Bo¨ hlerb
`
`aDepartment of Nephrology, Charite´
`Universitatsmedizin Berlin, Germany and
`bINSERM U466, Institut Louis Bugnard, CHU
`Rangueil, Toulouse, France
`
`Key words: FTY720 – fingolimod – sphingosine 1
`– phosphate receptor – renal transplantation –
`multiple sclerosis
`
`Corresponding author: Klemens Budde MD,
`Department of Nephrology, Charite´, Universi-
`ta¨tsmedizin Berlin, Schumannstr. 20/21, 10098
`Berlin, Germany.
`Tel.: +49 30 450 514 002;
`fax: +49 30 450 514 902;
`e-mail: klemens.budde@charite.de
`
`Current immunosuppressive protocols based on
`calcineurin inhibitors (CNI), anti-metabolites and
`steroids allow one yr renal graft survival rates of
`more than 90% (1). Despite these improvements in
`the prevention of solid organ graft rejection during
`the last decade, there remains a medical need for
`new regimens that minimize the frequent drug-
`related toxicities associated with these agents (2).
`Organ and bone marrow toxicity, severe gastroin-
`testinal side-effects, pharmacokinetic variability
`and chronic allograft dysfunction necessitate the
`development of novel drugs for new immunosup-
`pressive strategies in transplantation medicine. The
`current immunosuppressives have a narrow thera-
`peutic window and are frequently associated with
`clinical signs of overimmunosuppression such as
`malignancies and opportunistic infections (3, 4). In
`
`addition, the transplant community is now seeking
`for better control of cardiovascular risk factors,
`because cardiovascular disease is the main cause of
`death in patients after successful kidney transplan-
`tation (5, 6).
`The new therapeutic agent, FTY720 (FTY,
`fingolimod) (7), may address some of the medical
`needs by providing a therapeutic alternative in
`combination therapy. FTY, a structural and
`functional analogue of the natural serum lipid,
`sphingosine, is the first in a new class of drugs
`called sphingosine 1-phosphate receptor (S1P-R)
`modulators (8, 9). FTY is a novel immunomod-
`ulator with a mode of action that appears to be
`completely different from classical
`immunosup-
`pressants: FTY does not impair T- and B-cell
`activation, proliferation and effector function in
`
`17
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2030
`
`

`

`Budde et al.
`
`infection (10). It is
`response to systemic viral
`highly effective in prolonging allograft survival in
`preclinical models of
`transplantation. Further-
`more, FTY acts synergistically with CNIs and
`proliferation inhibitors in these models, suggesting
`that use of FTY in combination with classical
`immunosuppressants may be a promising new
`option for transplant patients. FTY has a unique
`safety profile that may not overlap with currently
`available immunosuppressants. Therefore it offers
`the opportunity to explore synergy in efficacy with
`other agents and avoid their related toxicities.
`FTY is currently being investigated in de novo
`renal transplant population (11, 12) as well as in
`other therapeutic areas, such as multiple sclerosis
`(MS) (13). The aim of this review is to discuss the
`recent findings on the mechanism of action,
`preclinical models and to briefly outline the
`results of the ongoing clinical development pro-
`gram of this drug.
`
`Mechanism of action and preclinical development
`
`Soon after the discovery of the high efficacy of the
`synthetic sphingolipid FTY to prevent allograft
`rejection in animal models it became evident that
`the mechanism of action of FTY differs completely
`from all known conventional immunosuppressive
`drugs (14). FTY does not inhibit proliferation or
`activation of lymphocytes (15). First animal experi-
`ments with FTY showed a reversible reduction of
`lymphocyte counts in the peripheral blood (3) and
`later also in humans (4). The first assumption was
`that peripheral lymphopenia is caused by apoptosis
`of
`lymphocytes
`(16). However, apoptosis of
`lymphocytes could not be detected in FTY720
`treated renal allograft recipients and took place at
`supra-pharmacological
`concentrations of FTY
`in vitro (17). Another hypothesis suggested that
`FTY induced the sequestration of lymphocytes
`from the peripheral blood compartment
`into
`lymphoid tissue, because the FTY induced periph-
`eral
`lymphopenia was associated with increased
`lymphocyte counts in lymph nodes (LN), Peyer’s
`patches and thymus (18, 19). Using adoptive
`transferred lymphocytes it was demonstrated that
`previously labelled lymphocytes return back into
`the circulation after cessation of FTY treatment
`(20). This effect was sensitive to pertussis toxin,
`which indicates a G-protein coupled signal trans-
`duction for FTY. In lymphocyte cultures, FTY
`exerted a differential expression of proteins linked
`to cytoskeleton/cell motility, to cell adhesion and
`vesicle trafficking (21). By synthesis of a chiral
`FTY analogue,
`the modulation of
`lymphocyte
`trafficking could be dissected from the FTY
`
`18
`
`induced lymphocyte apoptosis (22). Pinchewer
`(10) showed that FTY treatment does not affect
`expansion, memory and anti-viral activity of the
`immune response. Therefore FTY can be regarded
`rather as an ÔimmunomodulatorÕ than an Ôimmu-
`nosuppressantÕ.
`The molecular structure of the sphingolipid FTY
`resembles
`the natural occurring sphingosine-1
`molecule. Similar to sphingosine FTY is phos-
`phorylated by sphingosine kinases to FTY-P (23,
`24) and the phosphorylated form is the active
`metabolite binding with higher affinity as its
`natural ligand to the S1P-R (13, 25, 26), formerly
`named endothelial differentiation gene (EDGs).
`Importantly, FTY-P does not solely elicit agonistic
`responses after binding to the S1P-R. After binding
`to S1P-R FTY-P down-regulates the receptor
`expression,
`thus leading to a functional S1P-
`antagonism (27).
`Early in vitro experiments indicated that chem-
`okines and its receptors might be involved in the
`mechanism of action of FTY.
`Indeed, FTY
`modulates the migratory response toward chem-
`okines in lymphocyte culture experiments (28).
`Foerster observed a delayed lymphopenia after
`administration of FTY to CCR7 knock-out mice
`suggesting chemokine receptor CCR7 dependent
`and independent mechanisms
`(29). FTY may
`render lymphocytes more susceptible to the chem-
`okine-driven migration into LN. Naive lympho-
`cytes entering the LN through high endothelial
`venules (HEV) down-regulate their S1P-R in order
`to stay and interact with antigen presenting cells in
`the LN (30). In order to migrate from LN back
`into the circulation lymphocytes need to up-regu-
`late their S1P-R. High S1P-concentrations in the
`blood create a concentration gradient between
`blood and LN, and S1P serves as one of the most
`powerful chemoattractants for S1P-R expressing
`lymphocytes in LN. The group of Cyster (31)
`showed that down-regulation of S1P-R on lympho-
`cytes reduced the egress of lymphocytes from LNs
`into the blood stream, thus causing peripheral
`lymphopenia. By permanent down-regulation of
`the S1P-R FTY interferes with the egress of
`activated lymphocytes,
`resulting in peripheral
`lymphopenia and a profound decrease of periph-
`eral effector lymphocytes. Because only naive
`CD62L-expressing lymphocytes
`encounter LN
`through HEV, FTY does not interfere with already
`activated effector cells or memory T-cells from the
`peripheral blood by this mechanism.
`In line with the proposed mechanism of action of
`FTY, experiments performed in non-human pri-
`mates (32) and humans (11) revealed that the
`severity of FTY-induced lymphopenia varies
`
`

`

`between different lymphocyte subsets. T cells were
`more reduced than B-cells, CD4 more than CD8
`T-cells, however, granulocytes and monocytes were
`not affected by FTY. Patients treated with FTY
`had a predominant reduction of CD62L-positive
`cells, while CCR5-positive T-cells were affected to
`a lesser degree (33). It is conceivable that the
`remaining T-cells in the periphery can infiltrate the
`graft and mediate graft rejection (34). Interestingly,
`FTY concentrations needed to induce lymphope-
`nia are lower than those to yield optimal rejection
`prophylaxis in transplant models. This observation
`suggests, that the anti-rejection properties of FTY
`are mediated at least in part by other mechanisms
`besides the effects on lymphocyte homing. S1P-R
`are also expressed on other cell types like dendritic
`cells, heart muscle, and endothelial cells, however
`these cells express a different pattern of S1P-R
`subtypes (35). Recently, it has been shown that
`FTY interferes with effector functions of human
`monocyte-derived DC (36, 37), providing new
`insights into the immunomodulatory mechanism
`of FTY.
`The S1P-R expression on atrial myocytes ex-
`plains the FTY effect on heart rate (38). Recent
`data indicated that direct agonism of FTY-P on
`S1P-R expressed in atrial myocytes of the heart is
`responsible for the negative chronotropic effects of
`FTY. FTY has been shown to activate cardiac
`G-protein-gated potassium channels IKACh (39).
`The reduction in heart rate observed following
`FTY is thought to be mediated by activation of
`these channels and the transient nature of the effect
`may be due to agonist-induced homologous desen-
`sitization involving S1P-R internalization (38).
`Furthermore, FTY exerts profound effects on
`endothelial cell function and permeability (40, 41),
`as evidenced by the fact that the S1P-Rs were first
`identified as receptors involved in endothelial
`differentiation. Endothelial cell
`layers serve as
`selective barriers regulating the transmigration
`from macromolecules and lymphocytes. It has
`been demonstrated that FTY affects lymphocyte
`transmigration explaining reduced lymphocyte
`infiltrates in grafted organs. The effects of FTY
`on endothelial cells could also account for the
`observed protective effects of FTY in models of
`chronic graft rejection. On the other hand one
`might speculate that the effects of FTY on endo-
`thelial cell permeability are related to some of the
`observed side-effects in FTY treated patients.
`The research on the biology of S1P-R is just in
`the beginning and new derivatives of FTY-P with
`better S1P-R subtype specificity may help to better
`elucidate these mechanism and eventually help to
`avoid some of the observed side-effects.
`
`FTY720 (fingolimod) in renal transplantation
`
`FTY was preclinically investigated in several
`animal species and in numerous transplantation
`models (42). The most prominent pharmacody-
`namic effect in all animal models tested was the
`induction of reversible lymphopenia. FTY was
`shown to prevent skin, kidney, liver and heart in
`models of allograft rejection (7, 9, 42). FTY exerts
`synergism with all other tested immunosuppres-
`sants including CNIs, proliferation inhibitors and
`mycophenolate to prevent acute and chronic
`allograft rejection. An overlap and therefore a
`synergistic increase of the incidence and severity of
`side-effects of FTY with the conventional drugs
`has not been observed. Furthermore, FTY may
`attenuate ischaemia-reperfusion injury in hepatic
`and renal transplantation (43, 44). The potential of
`FTY to treat autoimmune disease was also con-
`firmed in several experimental models for MS,
`auto-immune diabetes,
`lupus nephritis and Thy
`1-induced mesangial
`proliferative
`glomerulo-
`nephritis (45).
`
`First clinical experience with FTY in phase I and II
`trials
`
`Early phase I and phase II studies (4, 11, 46) have
`shown that FTY is well tolerated in renal trans-
`plant recipients and provides effective rejection
`prophylaxis (12) with minimal addition to the
`side-effect burden. The pharmacokinetics, phar-
`macodynamics and safety of FTY have been
`investigated in two randomized, double-blind,
`placebo-controlled, phase I studies involving stable
`renal transplant patients (at least one-yr post-
`transplantation) maintained on a cyclosporin A
`(CsA)-based regimen.
`
`Pharmacokinetics
`
`These studies revealed unique pharmacokinetics
`characterized by a prolonged absorption phase,
`with an elimination half-life >100 h, independent
`of dose. Consistent with the long half-life of FTY
`(47), almost all subjects took around four wk of
`daily dosing to reach steady-state concentrations.
`Maximum plasma concentration (Cmax) and area
`under the curve (AUC) were dose-proportional,
`with low inter-subject variability. Furthermore,
`FTY had an unusually high apparent volume of
`distribution (>1400 L) and a relatively low appar-
`ent oral clearance (median 158 mL/min). Addi-
`tional pharmacokinetic data were obtained from a
`phase II study, confirming the pharmacokinetic
`results from phase I studies. Again, FTY exhibited
`a long terminal half-life of around 200 h, a high
`volume of distribution (>3000 L) and a low
`
`19
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`

`

`Budde et al.
`
`clearance (10.8 L/h) in de novo renal allograft
`recipients. The high volume of distribution is
`consistent with the lipophilic character of the drug
`and suggests widespread tissue distribution, e.g., in
`cellular membranes throughout
`the body. The
`prolonged half-life of FTY suggests 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 FTY indicates consistent absorp-
`tion 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.
`
`Pharmacodynamics
`
`Animal transplantation models have consistently
`shown that FTY, administered at pharmacological
`doses, induces a decrease in lymphocyte count (3,
`48, 49). This pharmacodynamic effect of FTY has
`also been observed in all human studies. Admin-
`istration of a single dose of FTY to stable renal
`transplant patients resulted in a transient decrease
`in lymphocyte count within four h of administra-
`tion in all subjects (4, 11). This pharmacodynamic
`effect of FTY exhibited non-linear dose-depend-
`ence, with the most prolonged and intensive
`reduction in lymphocyte count being observed in
`the highest dose group. The reduction in lympho-
`cyte counts is much faster than the pharmacoki-
`netics of the drug with a long terminal half-life
`might predict. Furthermore, the effect of FTY on
`lymphocyte count was pan-lymphocytic, affecting
`all principal lymphocyte subsets, with the greatest
`effects being observed on CD4+ and naı¨ ve T cells,
`while monocyte and granulocyte counts remain
`unaffected (11). A marked decline in peripheral
`lymphocytes (of around 85% of baseline) has also
`been demonstrated following multiple doses of
`FTY in stable renal transplant patients (11, 46) and
`in de novo allograft recipients following transplan-
`tation (12). After cessation of treatment, recovery
`was evident within three d after the last dose, with
`a trend toward complete recovery to baseline
`values in all dose groups four wk after last dose
`(47). All doses of FTY appeared to affect all
`lymphocyte subsets tested to a similar degree. In
`contrast to other immunosuppressive agents, mul-
`tiple doses of FTY had no effect on blood
`granulocytes, monocytes or eosinophils, and also
`had no effect on the number of erythrocytes or
`platelets (11). The predominant effect of FTY on
`CD4+ and naı¨ ve T cells observed in these phar-
`macodynamic studies supports the potential mod-
`ulatory effect of the drug on sequestration of these
`
`20
`
`cells into lymph nodes and Peyer’s patches (50).
`The decrease in PBL occurs immediately after the
`first dose, persists throughout the entire period of
`treatment and recovers slowly and completely after
`treatment discontinuation. Furthermore, the find-
`ings of these studies suggest that pharmacokinetics
`only partially explain the pharmacodynamic re-
`sponse to FTY. Consequently, pharmacodynamic
`monitoring, by measuring lymphocyte number,
`may be a useful predictor of the response to FTY
`in future trials (47).
`
`Safety
`
`FTY has been found to have an excellent tolerab-
`ility profile in these early phase I and II trials:
`overall, FTY was well tolerated following single-
`dose and multiple dose administration (4, 12, 46).
`The most common adverse event was bradycardia.
`Already in the first in human study, an increased
`frequency of bradycardia was observed in patients
`receiving higher doses of FTY and in patients with
`mild bradycardia at baseline (4). Similar to lymp-
`hopenia, heart rates reached a nadir around four to
`eight h after FTY administration and lasted for up
`to 24 h. The transient reduction in heart rate was
`asymptomatic and required no clinical interven-
`tion; all patients recovered without sequelae. In
`subsequent studies in de novo transplant patients
`about 25% of patients, this negative chronotropic
`effect
`led to reports of
`transitory bradycardia
`events that were mild or moderate in severity
`(12). The vast majority of bradycardia adverse
`events (70%) as reported by the investigators were
`reported within 24 h after the first dose and 85%
`within the first 48 h after the first drug adminis-
`tration. These events were asymptomatic in most
`of the patients, with no changes of blood pressure
`and no other cardiac abnormality, and none
`resulted in clinical
`sequelae. Bradycardia was
`reversible spontaneously (in about 60% of the
`cases) or following administration of atropine
`or b2-adrenergic agents. Only 1.6% of treated
`patients discontinued FTY because of bradycardia.
`FTY has not been associated with any other
`cardiac events in clinical trials to date, and the
`incidences of cardiac failure and myocardial
`infarction observed in a phase II trial with the
`agent were similar to those reported in the litera-
`ture (5, 6). FTY did not appear to cause any other
`specific adverse events, electrocardiogram or phys-
`ical examination changes or laboratory abnormal-
`ities. No additional organ toxicity was observed in
`these phase I and II studies. Despite some preclin-
`ical data suggesting lung toxicity, in these early
`clinical trials, there has been no evidence of an
`
`

`

`increased rate of pulmonary adverse events and no
`abnormalities in the pulmonary tests performed in
`renal transplant patients treated with FTY (4). In
`conclusion, from the clinical trials in phase I and
`II, it appeared that there were no safety concerns,
`and the transient effect of FTY on heart rate with
`treatment initiation is asymptomatic, self limiting
`and manageable and is not associated with any
`measurable increase in mortality or cardiac mor-
`bidity.
`
`Ecacy and safety in recent clinical trials
`
`To date, more than 1000 subjects have received
`FTY (2.5 or 5.0 mg/d)
`in combination with
`cyclosporine and corticosteroids in the context of
`de novo renal transplantation with a mean follow-
`up of >12 months after transplantation. FTY has
`not been examined in maintenance patients. Over-
`all, FTY was well tolerated and has demonstrated
`efficacy in the prevention of acute graft rejection in
`human kidney transplantation.
`The efficacy of FTY in preventing acute rejection
`in de novo renal transplant recipients has been
`evaluated in two phase II studies (12, 51). These
`studies have demonstrated that FTY 2.5 mg plus
`full dose CsA microemulsion (NeoralÒ; FDN
`Novartis Pharma, Basel, Switzerland) and 5 mg
`plus reduced dose Neoral (RDN) provides equiv-
`alent efficacy to mycophenolate mofetil (MMF)
`with conventional Neoral dose – currently consid-
`ered the standard of care in de novo renal trans-
`plantation. Doses of FTY below 1 mg in
`combination with CsA were associated with a
`slightly higher incidence of rejection compared to
`standard therapy with MMF (12). Furthermore,
`FTY was well tolerated and did not appear to be
`associated with nephrotoxicity, bone marrow tox-
`icity or other side-effects commonly observed with
`immunosuppressant therapies (4, 12). As men-
`tioned above, bradycardia was the most prominent
`side-effect in these studies. Because of the favour-
`able safety profile and the good efficacy two large
`phase III studies were initiated in order to thor-
`oughly evaluate the safety and efficacy of this
`compound in comparison to mycophenolate in a
`large cohort of de novo renal allograft recipients
`with low to medium immunological risk.
`Two large phase III clinical trials compared the
`efficacy and safety of two doses of FTY (2.5 and
`5 mg) plus either RDN or FDN with MMF plus
`FDN in adult de novo renal transplant recipients
`(56, 57). Both 12-month phase III studies have
`shown that FTY 2.5 mg plus FDN provides com-
`parable efficacy for the prevention of acute rejection
`in de novo renal transplant recipients compared
`
`FTY720 (fingolimod) in renal transplantation
`
`with MMF plus FDN. The higher incidence of
`rejection observed with the FTY 5 mg plus RDN
`regimen suggests that FTY combined with CsA
`minimization (reduction ‡50%) may not provide
`sufficient prophylaxis from acute rejection.
`Surprisingly, renal allograft function was lower
`for the two FTY treatment arms compared with the
`MMF arm. Although the mean creatinine clearance
`increased over time in both FTY treatment groups,
`the rate and absolute increase was significantly lower
`in the FTY arm compared with MMF. Preliminary
`analysis suggests that renal function remains relat-
`ively stable with no evidence of progressive deteri-
`oration. The reason for this impairment is unknown
`and is currently under investigation, and could result
`from both sub-clinical
`immune injury and non-
`immunologic drug effects. Initial post hoc analysis of
`a population at low immunological risk without
`clinical evidence for rejection revealed also lower
`renal function in this subpopulation of patients
`suggesting direct or indirect non-immunological
`effects of FTY on renal function.
`Additional side-effects observed more frequently
`with FTY in these large phase III studies were a
`mild increase in airway resistance without evidence
`of progressive changes in lung volumes over time.
`Moderate elevations in ALT and bilirubin levels
`were noted with FTY compared with MMF; these
`differences are not
`thought
`to be of clinical
`significance. The two FTY regimens were also
`associated with twofold higher incidence of macu-
`lar oedema compared to the control group with
`MMF. The clinical significance of this effect is
`currently unclear and further detailed characteri-
`zation is ongoing.
`Given the fact that FTY offers no improvement
`in efficacy, however, may pose the patients at risk
`for these previously unknown side-effects of this
`novel class of drugs, it became clear that more
`analyses are needed to fully investigate this inter-
`esting drug and the causes of renal dysfunction in
`de novo renal transplant recipients. Especially the
`impaired renal function and the development of
`macula oedema are new unexpected and unex-
`plained side-effects, observed in the phase III trials,
`which need further thorough investigation, and
`have led to the temporary discontinuation of all
`ongoing trials in renal transplantation.
`
`Multiple sclerosis
`
`The remarkable effects of the drug in all animal
`models for autoimmune diseases tested so far
`provide a strong rationale for testing this com-
`pound in the clinical
`setting of autoimmune
`diseases. Especially the impressive results obtained
`
`21
`
`

`

`Budde et al.
`
`with FTY in EAE, the animal model of human
`MS, shows the potential of FTY for the treatment
`of demyelinating diseases (52, 53). The exact
`pathophysiology of MS remains unclear but an
`autoimmune response directed against central
`neuronal system antigens is suspected (54). Current
`treatment options consist of interferon, which may
`reduce relapse rates, and also may reduce disease
`progression (54). However to date, no effective
`treatment is available to prevent or cure MS. The
`convincing results from the animal models provi-
`ded the rationale for developing FTY in the clinical
`indication of MS. As recently reported (55), a
`phase II trial using 1.25 and 5 mg FTY showed a
`highly significant reduction (55%) in relapse rates.
`In addition, time to first relapse was significantly
`prolonged and 86% remained relapse free over six
`month compared with 70% in the placebo group.
`Inflammatory disease activity was reduced dramat-
`ically by 80% over six month treatment as evalu-
`ated by MRI lesions. Furthermore, new disease
`activity was reduced by more than two thirds
`compared with placebo (55). The oral application
`form and a less toxic profile makes FTY a
`promising candidate for the treatment of MS.
`Importantly, safety data from this trial did not
`reveal any nephrotoxicity and no cases of macula
`oedema have been reported in this setting so far,
`suggesting that especially the combination therapy
`with cyclosporine in the setting of renal transplan-
`tation might be responsible for the observed
`adverse events like nephrotoxicity and macula
`oedema. Thus, in conclusion phase II clinical data
`suggest that FTY will be a safe and effective
`treatment option for MS, and large prospective
`phase III trials are ongoing to confirm the exciting
`phase II results in relapsing MS.
`
`Conclusions
`
`The availability of agents with different mecha-
`nisms of action for preventing graft rejection that
`can be combined safely will be essential for the
`future of organ transplantation if further improve-
`ments in outcomes post-transplant are to be
`achieved. In contrast to classical immunosuppres-
`sants, FTY has no anti-proliferative activity at
`therapeutic dosing and rather acts as a Ôimmuno-
`modulatorÕ, suggesting that this agent may be
`useful to augment the immunosuppressive actions
`of other drugs. After phosphorylation FTY-P
`exerts its effects via binding to S1P-R on various
`cell types including lymphocytes, dendritic cells,
`endothelial cells and atrial myocytes. FTY leads to
`down-regulation of S1P-R, which causes lympho-
`cyte trapping within LN. Preclinical studies with
`
`22
`
`FTY have demonstrated that the agent is highly
`effective in a wide range of animal models of
`transplantation. Initial clinical studies with FTY
`suggested that this novel immunomodulator is also
`effective in human transplant recipients, producing
`a marked reduction in blood lymphocyte count
`following single and multiple dosing. Furthermore,
`FTY in combination with CsA was well tolerated
`in phase I and II studies in renal transplantation,
`with no significant safety issues except transient
`and asymptomatic bradycardia. Because phase II
`studies demonstrated in combination therapy with
`cyclosporine similar efficacy of FTY compared to
`standard therapy with mycophenolate, a large
`phase III program was initiated exploring the
`ability of FTY to provide equivalent efficacy to
`classical immunosuppressive regimens in the pre-
`vention of acute rejection. Although these studies
`demonstrated similar efficacy with respect
`to
`rejection prophylaxis of FTY in combination with
`regular cyclosporine doses, no clear benefit over
`conventional therapy with mycophenolate could be
`established. Furthermore,
`it was discovered in
`these pivotal studies that FTY therapy was asso-
`ciated with renal impairment and macula oedema
`and consequently, the clinical programme for the
`development of FTY in renal transplantation was
`paused.
`The FTY is also being investigated in patients
`with MS. However, the MS population differs
`considerably from the renal transplant population
`and the agent will be used at lower doses than in the
`renal
`transplant setting, and as monotherapy.
`Thus, the findings of the current study conducted
`in renal transplant recipients cannot be extrapola-
`ted to the use of FTY in MS patients. Furthermore,
`the drug represents a new modality that might lead
`to a quantum improvement in the treatment of
`autoimmune disorders. In conclusion,
`the full
`analysis of the ongoing studies is eagerly awaited,
`which might provide new insights on its novel
`mechanism of action and will allow to better define
`its role in the treatment of renal allograft recipients
`and patients with autoimmune diseases like MS.
`
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