APOTEX ET AL. - EXHIBIT 1055
`Apotex Inc. et al. v. Novartis AG IPR2017-00854
`
`

`

`1554
`
`Wansplantation - Volume 79. Number 11, June 15, 2.005
`
`These findings of great efficacy and synergy in preclin—
`ical models and good tolerability and lack of notable toxicity
`observed in stable renal transplant recipients justify further
`evaluation of FTY720. If these results are confirmed in de
`novo transplantation, FTY720 with its unique immuno-
`modulating mode of action will represent an exciting new
`modality in transplantation therapy.
`The objectives ofthis first phase 2 dose-finding study in
`de novo renal transplantation were (1) to evaluate the efficacy
`of four doses of FT'Y720 in preventing acute rejection com-
`pared with mycophenolate mofetil (MMF), when adminis-
`tered as part of a standard exposure CsA and corticosteroid
`regimen; and {2) to further assess the safety and tolerability of
`FTWZU.
`
`MATERIELS KND METHODS
`
`Study Design
`This multicenter. randomized, open-label, active-con-
`trol, dose-finding, time-staggered, study in de novo renal
`transplant recipients included a 3-month treatment period,
`after which study medication was stopped, followed by a
`3-month follow—up phase to assess drug safety. An open-label
`study design was selected because it would have been difficult
`to maintain the blind while allowing access to pharmacody-
`namic data. such as lymphocyte counts, throughout the study
`period. The study protocol was co nsidered and approved by
`each local research ethics committee, and the study was per-
`formed according to the guidelines of the Declaration of Hel—
`sinki. Patients provided written informed consent before
`study participation.
`
`Patient Population
`Patients aged 18 to 65 years who received a primary
`cadaveric or primary non-identical human leukocyte antigen
`living-donor ltidney transplant from a don or aged 10 years or
`more were included in the study.
`Patients were excluded from the study ifthey were re-
`cipients ofmultiple organs, a kidney from a non—heart-beat-
`trig donor, an ABC incompatible or T-ceil croSsmatch—posi~
`tive organ, or an organ with a cold ischemia time more than
`36 hr. Additional exclusion criteria included the following:
`baseline pulse rate less than 55 beats,l min; panel reactive an—
`tibody greater than 50%: urine output less than 500 mL in the
`first 12 hr after reperfusion ofthe graft; unstable or decreased
`urine output within the 3 hr immediately before randomiza-
`tion; or induction therapy with monoclonal or polyclonal
`antilyrnpliocyte or anti—interleukin-2 receptor antibodies.
`
`Randomization
`Patients were randomized within 12 to 24 hr of trans—
`
`plantation, once allograft function was established. to one of
`four FTY720 dose groups (0.25 mg. 0.5 mg, 1.0 mg, or 2.5 mg
`once daily} or to MMF (CellCept, Roche Laboratories, Inc.
`Nutley, NJ), 2 g per day for 3 months, in combination with
`Carl microemulsion (Neural, Novartis Pharma AG, Basel,
`Switzerland} and corticosteroids. On day 1, patients random~
`ized to FTY720 received the first dose of the study medica-
`tion: 1 mg, 2 mg, 4 mg, or4 mg in the 0.25 mg, 0.5 mg, 1.0 mg,
`and 2.5 mg groups, respectively.
`
`Immunosuppressant Regimen
`FTY720 was administered orally once daily in the
`morning simultaneously with CsA. After an initial dose of
`CsA l[up to 10 mglkgfdayil, the close of CsA was adjusted ac-
`cording to the standard blood concentrations targeted at each
`center. Following the recommendations at the time of the
`study. CsA monitoring was based on the trough concentra-
`tions. Corticosteroids were initiated according to each cen»
`ter’s standard practice, but no later than 24 hr after graft
`reperfusion. The schedule ofcorticosteroid dose tapering was
`20 mglday by the end ofweektl, 15 mg or more per day by the
`end ofweek 12, and 10 mg or more per day for the duration of
`the study (24 weeks). Rejection episodes were treated with
`methylprednisolone according to each center‘s usual prac-
`tice; steroid~resistant or Banff grade ii to 111 rejections were
`treated with antilymphocyte antibodies for 7 to 14 days. dur—
`ing which the study medication was allowed to be inter-
`rupted. The administration of any other maintenance agent
`required that patients be discontinued from the study. Cyto-
`megalovirus (CMV) prophylaxis was required for the trans—
`plantation of confirmed CMV-positive donor organs into
`CMV-negative recipients. Pnenmocysris carinii prophylaxis
`was required for all patients.
`
`Study Schedule
`During the 3-month treatment period, patients were
`evaluated on days 1,2, 3, 5, and 7. then twice weekly until the
`end of week 4, and then weekly until week 12. During the
`3-month follow-up phase (after the protocol-mandated ces-
`sation of study medication), patients were maintained on
`each center’s standard CsA-based immunosuppressive regi-
`men. Patients were evaluated weekly until the end of week 16
`and then at weeks 20 and 24.
`
`Primary efficacy assessments included a biopsy—con-
`firmed acute rejection episode (BCAR) and a composite end-
`point of incidence of BOAR, graft loss, or death at months 3
`and 6. Biopsies were reported locally, and BCARs were graded
`according to the Banff1997 criteria {20}. Secondary efficacy
`assessments included the incidence of death, graft loss, clini-
`cally confirmed rejection. BCAR, BCAR treated with anti—
`body therapy. recurrence of rejection, and histologic severity
`of rejection episodes. Safety assessments included laboratory
`evaluations, electrocardiograms, chest xvray films, and mon-
`itoring of adverse events. including infections.
`
`Pharmacokinetics
`
`FTY720 and CsA whole—blood trough concentrations
`were monitored on day 2 and weekly throughout the treat—
`ment period. During follow-up, CsA levels were evaluated
`every 4 weeks, with analysis of whole-blood trough concen-
`trations measured by radioirnmunoassay at a central labora—
`tory. In addition, CsA levels were determined locally for dos-
`age
`adjustments
`according
`to
`each
`center’s
`local
`methodology. Whole-blood trough levels were collected 5
`min before the first dose of FTY720, 5 min before the first
`FTY720 maintenance dose. and weekly thereafter during the
`treatment period. Additional blood sampling was per-
`formed during the follow-up period for patients who
`maintained a stable dose of FTY720 for at least the last 4
`
`weeks of the treatment period. FTY720 concentrations
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`© 2005 Lippincott Willimns d Wilkins
`
`Tedesco-Silva et al.
`
`1555
`
`Pollen": enrolled in z 209:
`
`Patients elem-“loci
`lrtirn (study In : '2]
`
`
`
`
`
`
`
`
`
`Patients who completed the. ti-monlua IGIfIJlN-IID [n = 2m}:
`
`
`
`
`
`
`
`
`
`
`
`erzo
`I125 mg
`than
`
`mm:
`0.5 mg
`in :42]
`
`Frvrao
`1.0 mg
`tn=sn
`
`more
`2.5 mg
`[n no]
`
`”MP
`“=39?
`
`were measured in the Novartis Bioanalytics Laboratory.
`Whole-blood concentrations were measured using high-
`performance liquid chromatography coupled to mass
`spectrometry. Noncompartmental pharmacokinetic pa-
`rameters for FTY720 were determined using Microsoft Ex—
`cel (Redmond, WA) and WinNonlin Pro version 3.]
`fPharsight. Mountain View CA}. The parameters derived
`were trough steady-state blood concentrations (CH),
`steady-state exposure (AUCH), population clearance [CU
`f}. and terminal half-life (tm). Dose proportionality was
`assessed using observed blood trough C5,.
`
`Statistical Analyses
`This dOse-finding study was primarily exploratory, and
`all statistical hypothesis tests were performed for exploratory
`and descriptive purposes. The primary focus of the efficacy
`analysis was the Kaplan-Meier estimate of the probability of
`being free ofeach primary efficacy variable within 12 weeks of
`the initial dose of study medication. The difference in
`Kaplan-Meier estimates between the FTY720 treatment
`groups and the MMF group, and the two-sided confidence
`interval for die difference in Kaplan-Meier estimates were
`calculated. As a further analysis, the Kaplan-Meier estimates
`were compared using the a test and the log—rank test. For the
`efficacy analyses. the intent-to—treat (ITT) population in-
`cluded all randomized patients who received at least one dose
`of study medication. Patients fitting these criteria with at least
`one safety measurement were included in safety analyses The
`safety population included all randomized patients who re—
`ceived at least one dose of study medication and one safety
`measurement.
`
`Because of the limited size ofthe study, all statistical
`analyses and P values were considered to be descriptive only.
`The sample size was deemed adequate to detect whether
`FTY720 therapy was ineffective based on a sample rate of
`BCAR, graft loss, or death in an IT? population with a two—
`sided significance level of 0.05% and a power of 90% to detect
`a significant difference from the null hypothesis based on a
`theoretic rejection rate onO‘l/o with steroids, CSA, and MMF,
`and 40% for the alternate hypothesis oftio efficacy (the the-
`oretic rejection rate with steroids and CsA alone). Because a
`sample size of36 patients per treatment group was predicted.
`a sample size ofilil patients per treatment group was planned.
`
`RESULTS
`
`Study Population
`Twenty-five centers in Europe [13 centers). the United
`States {9). Brazil (2), and Canada (1) enrolled 209 patients, of
`whom 207 were randomized and eligible for [TT analyses
`(n=208; 167 received FTY720 and 41 received MMF; one
`patient was not randomized but received the study drug and
`was therefore included in the ITT population.) (Fig. l). The
`demographics and donor characteristics of the FTY720
`groups were generally similar to those of the MMF group
`(Table 1). However, there was an imbalance in livin g- related
`and living-unrelated donors, which was probably because of
`the different centers’ policies.
`The study drug was discontinued in 27 of 167 patients
`(16.2%) in the entire FTY720 cohort and in 4 oféll patients
`{9.8%} in the MMF group; however. the difference was not
`
`'One Dallenl not randomized but treated with F‘I‘YTED was Included In the tT‘l'anrt
`satiety simulations.
`“include: all patterns receiving treatment at a months.
`cIncludes patients who were discontlnued [rem treatment during nit-trims [3—3 but
`followed up for the entire 6-month study period.
`
`FIGURE 1. Disposition of patients throughout the study.
`
`statistically significant. The most common reason for discon-
`tinuation of the study medication was related to adverse
`events. At the end ofthe 3—month treatment period, almost all
`patients receiving the study medication were receiving the
`initial prescribed dose. After the protocol-mandated cessa-
`tion of FTY72O at 3 months posttransplant, 13% and 56% of
`the patients received azathioprine or MMF, respectively, ac—
`cording to local standard immunosuppressive practice. The
`mean doses oszA were similar in the entire FTY720 cohort
`and the MMF cohort at month 6 (3.6 and 3.7 mglkgfday.
`respectively), as were doses of corticOsteroids (0.14 and 0.15
`mgi'ltg/day, respectively). The mean CsA blood trough con—
`centrations were within the target range and did not differ
`between die FTY720 and MMF groups during the 3-month
`treatment period or the follow-up.
`
`Efficacy Outcomes
`
`At 3 months posttransplant. FTY720 at the two highest
`doses investigated (1.0 and 2.5 mg) was as effective as MMF
`with respect to the incidence of BCAR [Table 2). A similar
`trend was observed for the composite endpoint and the inci-
`dence of clinically confirmed rejection. From these results,
`the efficacy of FTY720 seemed to be dose-dependent with a
`trend toward lower incidences of BCAR and the composite
`endpoint in the FTY720 2.5 mg group. Statistical analysis re—
`vealed no significant differences in the incidence of either
`primary endpoints between any of the FTY720 treatment
`
`Copyright © Lippincott Williams 81 Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`1556
`
`Transplantation - Volume 79. Number 11,}une 15, 2005
`
`—-———-—-—-—-_—__._—___—_
`
`TABLE 1.
`
`Demographics and baseline characteristica“
`
`FTY'FZO (mg)
`
`0.25
`(INT-=43)
`
`0.5
`(N=43)
`
`1.0
`(N=4[}1
`
`2.5
`(N=41)
`
`MMF
`(N=41)
`
`Demography (%)
`Gender, 11
`
`Male
`Female
`Mean age. yr {SD}
`Ethnic origin, :1 {9th}
`
`‘Nhite
`Black
`OLhcl‘S
`Donor source. 11 [%1
`
`(65.1)
`23
`(34.9)
`15
`43.3 (11.0)
`
`30
`7
`6
`
`{69.8)
`(16.3]
`(13.9]
`
`(46.5)
`20
`(53.5)
`23
`43.01130}
`
`35
`3
`5
`
`(31.4)
`(7.0}
`(11.6)
`
`(52.5}
`21
`(47.5)
`19
`46.8(115)
`
`26
`S
`9
`
`(65.01
`{12.5)
`{22.5)
`
`(61.0)
`25
`(39.0]
`16
`463112.11
`
`32
`3
`IS
`
`{73.0}
`{7.3)
`(14.7)
`
`(56.1]
`23
`{43.9)
`13
`43.4 (12.2)
`
`31.1
`3
`3
`
`(73.2}
`(7.3)
`(19.51
`
`(53.5}
`24
`(53.7)
`22
`[55.0)
`22
`(53.5}
`23
`(60.5}
`26
`Cadaver
`{39.0)
`16
`(43.91
`18
`(35.0)
`14
`(34.9)
`15
`(20.9)
`9
`Living related
`{2.4)
`1
`{2.4)
`1
`(10.0)
`4
`(11.6}
`S
`(18.6)
`8
`Living unrelated
`——_—_——__—___
`" None of the differences are statistically significant.
`MMF. mycophenolate mofetil; SD. standard deviation.
`
`—-—-—-———.—_.._—_—_
`
`TABLE 2.
`
`Efficacy endpoints at 3 and 8 months
`
`M720 (mg)
`MMF
`2.5
`0.5
`1.0
`0.25
`(N=41)
`(N=41)
`(N=43)
`(N=43)
`(N=40}
`—.—._—._—____—_—__
`
`Primary endpoints at 3 mo, :1 (9’0)
`
`First biopsy—confirmed rejection, death, or grafiloss
`First biopsy-confirmed rejection
`Banffgrading
`1A
`IB
`2A
`213
`3
`Missing
`Number of patients with )1 biopsy—confirmed rejection episodes
`Secondary endpoints at 3 mo, n (%J
`
`Death
`Graft loss
`Death or graft loss
`First ciirticaliy confirmed rejection
`First biopsy—confirmed rejection treated with antilymphocyte
`antibody therapy
`Primary endpoints at 6 mo. n 0%)
`
`11 (25.6)
`10 (23.3)
`
`15 (34.9)
`15 (34.9)
`
`7 (17.5}
`7 (17.5)
`
`6 (14.6]
`4 (9.81
`
`8 (19.5}
`7 (17.1)
`
`4
`1
`3
`l
`l
`0
`[1
`
`0
`214.7)
`214.7)
`11 (25.6}
`3 (7.0)
`
`5
`2
`7
`l
`O
`l]
`1 (2.31
`
`0
`(J
`1)
`15 (34.9)
`419.31
`
`2
`0
`2
`1
`1
`l
`i (2.5)
`
`0
`0
`0
`9 (22.5}
`3 {7.5)
`
`l
`0
`l
`2
`0
`0
`1)
`
`3
`0
`3
`1
`0
`0
`0
`
`l (2.4)
`l (2.4)
`2 (4.9)
`5 [12.2)
`2 (4.9)
`
`0
`2 (4.91
`2 (4.9)
`7 {17.1)
`1 (2.4}
`
`10 (24.4)
`7 {17.1)
`9122.5)
`17 (39.51
`12 (27.9)
`First biopsy—confirmed rejection, death, or graft loss
`
`
`
`
`
`11 (25.6] 17 (39.5) 9 (22.5) 5 {12.2)First biopsy-confirmed rejection 8 (19.5)
`
`groups and the MMF group during the 3-month treatment
`period.
`The majority offirst BCAR episodes were mild to mod-
`Erate in severity in all treatment groups, and most episodes
`resolved after corticosteroids bolus (Table 2}. Few patients
`experienced more than one BCAR during the 3-month treat—
`ment period (2l167 FTY720—treated patients and 0l4l MMF-
`
`treated patients) (Table 3). Moreover, few additional acute
`rejection episodes were reported in any treatment group dur—
`ing the 3-month follow-up period {three and zero episodes in
`patients who received FTY720 and MM F, respectively).
`Death or graft loss occurred in 4 of 167 FTY720-treated
`patients (2.4%) and 2 of 41 MMF-treated patients (4.9%).
`Three deaths occurred during the entire study period. One
`
`Copyright © Lippincott Williams a Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`o 2005 Lippincotr Wiliimns t} Wilkins
`
`Tedesco-Silva et a1.
`
`1557
`
`———.._._———___
`
`TABLE 3. Frequency of clinically notable adverse events and notable laboratory abnormalities during the 3-month
`treatment period
`
` ana (mg)
`Pooled FTY'ZZO arms
`
`0.25 (N=43}
`
`0.5 (N=43)
`
`1.0 (N=4fl)
`
`2.5 (N=4l)
`
`{N=167)
`
`MMF
`
`{N=41)
`
`W S
`
`[5 (34.9)
`6 (14.0)
`3 [7.0)
`10123.3)
`
`20 [46.5)
`5 (11.61
`2 (4.7}
`17 (39.5)
`
`15 (37.51
`71117.5}
`7 (17.5)
`18 (45.0}
`
`17 {41.5}
`9 (22.0)
`a (14.6)
`18 (43.9}
`
`67 (40.1)
`27 {16.2)
`18 (10.3}
`63 (37.7]
`
`[5 {36.6)
`4 (9.8)
`2 (4.9)
`l5 (36.6)
`
`erious adverse evenl
`Discontinued treatment
`Disoontinuation due to AB
`Any drug-related adverse event
`Notable adverse events. n (9%]
`
`Lymphopenia
`Bradycardia
`Diarrhea
`Abdominal pain
`Hypercholesterolemia
`Hypertryglyceridemia
`Infections, n {We}
`
`All infections
`Serious infections
`CMV infection
`Notable laboratory abnormalities. :3 (96]
`
`Leukopenia (£2.8X 10921.)
`Neutropenia (51.5): 10911..)
`Lymphopenia l<0.2>< [WED
`Anemia (Hb<7 33:111..)
`Thrombotytopmia (575x 1092'1.)
`New laboratory abnormalities, :1 (9%)
`
`2(41}
`4 {9.3}
`6 (14.01
`9 (20.9]
`3 (7.0)
`l [2.3)
`
`20 {46.5)
`5 {11.6)
`4 {9.3}
`
`4 (9.31
`2 (4.7)
`19 (44.2)
`4 (9.3)
`0
`
`5 (14.0}
`3 (7.0)
`7 (1.6.3)
`5 (11.6)
`4 (9.3}
`2 (4.7)
`
`32 (74.4)
`4 {9.3)
`4 {9.3}
`
`3 (18.6)
`4 (9.3)
`27 (62.81
`3 {7.01
`l (2.5)
`
`4 (10.0)
`8 (20.0]
`3 (30.0)
`3(75)
`3 (7.5}
`2 (5.0)
`
`27 (67.5)
`4 (10.0)
`3 (7.5)
`
`2 (5311]
`D
`31 (77.5)
`1 {2.5)
`2 [5.0)
`
`7 (17.1)
`5 (12.2)
`6l14.61
`5 [12.2)
`3 {7.3)
`l (2.4)
`
`25 (63.3}
`3 (7.3}
`2 {4.9)
`
`B (19.5)
`2 (4.9)
`36 (37.8)
`l {214]
`3 {7.3)
`
`19 (11.4)
`20 (12.0}
`27 {16.2)
`.13 {13.2}
`13 (7.3)
`6(16)
`
`107 (64.1}
`16 (9.6)
`13 [7.3)
`
`1 (2.4)
`2 (4.9)
`6 (14.6]
`9 [22.Dl
`3 (7.3}
`1 [3.41
`
`22 (53.?)
`7 (l7.l}
`4 (9.8)
`
`6 (14.6}
`5 (12.2}
`5 {12.2)
`2 (4.9}
`l (2.4)
`
`3 {7.31
`l [2.4)
`l {2.5)
`3 {7.0)
`3 (711)
`Hypercholesterolemia (2350 mgldL}
`
`
`
`
`
`0 1 {2.3) D l (2.4)Hypertriglyceridemia (2750 mgidLl 0
`
`patient in the FTY720 2.5 mg group died of myocardial in-
`farction on day 5, one patient receiving FTY720 1.0 mg died
`of thrombotic thrombocytopenic purpura on day 102, and
`one patient treated with MMF died of cardiopulmonary ar-
`rest on day 198. No death was considered to be drug-related
`by the investigator.
`
`Safety Profile
`As anticipated. all patients experienced at least one ad-
`verse event during the treatment period. The majority of ad-
`
`verse events were mild or moderate in severity. During
`months 0 to 3. the incidence of serious adverse events was
`comparable (40.1% vs. 36.6%, respectively) (Table 3), and
`the rate of adverse events suspected by the investigator to be
`drug-related was similar in patients receiving FTY720 and
`MM F. The frequency of adverse events commonly expected
`in the renal transplant population did not differ notably
`among treatment groups (Table 3). The adverse events re-
`ported with the highest rates in the FTY720 cohort were con—
`stipation (32.9%) and postoperative pain (31.1%] compared
`
`
`
`TABLE 4. Mean (CV96) steady-state FI'Y'Z 20 pharmacokinetic parameters after 3 months of dosing
`
`
`
`
`
`
`
` F'I'Y72t) dose, mg C“ (1'thr mL)“ AUGfl lngr'hrimL) CLif (Uhrlb tI ,2 (hr)"
`
`
`
`201 (85—1434]
`10.3
`30 {37}
`1.0 (0.3—6.7)
`025 [11:40)
`187 (31—810)
`11.3
`521591
`1.9 {0.3—5.8}
`0.5 ([1:40)
`221 (75-87le
`13.2
`102 {fill}
`4.0 (4.9—107)
`1.0
`(n=38}
`
`
`
`
`S.8(0.1-24.3) 225 (56] 14.32.5 (n=37l 227 (97—7071
`
`C“. steady-state concentration; AUG“. area under lhe curve at steady state; CLif, population clearance; tm. terminal half‘life.
`" Median trangel.
`" Geometric mean.
`‘ Harmonic mean (range).
`
`Copyright © Lippincott Williams 8r Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`1558
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`Transplantation - Volume 19, Number 11. June 15. 2005
`
`with insomnia (39.0%) and postoperative pain (3 1.7%} in the
`MMF group (data not shown). There was no evidence of ex-
`acerbation of GSA-related toxic effects (lipid disorders, hy-
`pertension, tremor, hyperkalemia, or hyperglycemia).
`Adverse events that occurred more frequently in
`FTY720-treated patients compared with MMF+treated pa-
`tients were lymphopenia and bradycardia. As expected, lym-
`phopenia was reported as an adverse event by investigators
`more frequently in patients receiving FTY720 (11.4%} than
`MMF (2.4%) during the 3-month study period. However, the
`mean Lymphocyte counts remained at or greater
`than
`0,2x 10 (L during the treatmentperiod, even among patients
`treated with the FTY720 2.5 mg dose. Moreover, this effect
`was not clinically significant because FTY720 was only dis-
`continued because of a lymphopenia adverse event in one
`patient (in the FTY720 0.5 mg group}. The administration of
`FTY720 was typically associated with a mild and transient
`reduction in heart rate. The decrease in heart rate from base—
`
`line was 12 to 15 beatsfmin on average in all FTY720 treat-
`ment groups after treatment initiation. The nadir occurred
`approximately 6 hr post-close. and then the heart rate re—
`turned to baseline, with no evidence of rebound on with-
`drawal of study medication (data not shown). The proper
`tion ofpatients with a heart rate below 30 beatsr’min after the
`first dose was 11.6%, 4.6%, 15.0%, 17.0%, and 4.9% in the
`FTY720 0.25, 0.5, 1.0, 2.5 mg and MMF groups, respectively.
`The incidence of bradycardia reported as an adverse event by
`the investigators was greater in patients receiving FTY720
`than in patients receiving MMF (Table 3}. However, defini-
`tions of bradycardia and minimal heart rate had not been
`given to investigators, thus, bradycardia incidence was based
`on events defined and reported as bradycardia by each inves-
`tigator at his or her discretion. Most episodes were reported as
`mild or moderate and related to the administration ofthe first
`
`dose of FTY720. All patients recovered, either spontaneously
`or after atropine administration. Notably, only one patient
`was discontinued from the study because of bradycardia.
`Other cardiac events were similar between the FTY720 group
`and MMF group; atrial fibrillation was reported in 6 of 167
`patients (3.6%) and l of4l patients (2.4%), respectively.
`The groups did not differ significantly in hematologic and
`biochemistry parameters (data not shown}. Except for the de~
`crease in peripheral blood lymphocytes, no other signifith ef-
`fect on hematologic parameters was observed with W720. 111
`the first 3 months, more patients had peripheral blood lympho—
`cyte concentrations lower than 200 X 1091‘Lin the FTY720 group,
`and more patients had blood neutrophils concentrations lower
`than 1.5X109JL in the MMF group (Table 3). The frequency of
`new abnormal cholesterol and triglyceride concentrations was
`low in all groups.
`The mean creatinine clearance estimated using the
`Cockroft-Gault
`formula was similar
`in all
`treatment
`
`groups (55.2 er’min, 56.8 le’min, 59.4 lemin. 57.6
`mlJmin, and 60.7 lemin in the FTY720 0.25 mg, 0.5 mg.
`1.0 mg, 2.5 mg, and MMF groups, respectively) at 3
`months posttransplantation.
`
`Malignancies and Infections
`No malignancies were reported in the PTY720 group dur-
`ing the 6-month study period, and one case of breast cancer was
`reported in the MMF group. During months 0 to 3, the inci-
`
`dence ofinfections in the entire FTY720 group was similar and
`not statistically diiferent than that in the MMF group (64.1% vs.
`53.7%; Table 3). Among those receiving FTY720, the incidence
`was lowest in the patients receiving the 0.25 mg dose. The distri—
`bution of infectious cause (bacterial, viral, and fungal) in pa-
`tients receiving FTY720 and MMF was similar (data not shown).
`CMV infection was reported in 7.8% of all patients in the
`FTY720 group and in 9.8% of patients in the MMF group. There
`was a trend toward a lower incidence of serious infections in the
`
`entire PTY720 cohort compared with the MMF cohort during
`both the treatment period (9.6% and 17.1%, respectively) and
`the overall study period (_ 13.8% and 19.5%. respectively).
`
`Pharmacodynanuo Effects
`After administration of the first dose of medication,
`absolute peripheral blood lymphocyte counts were reduced
`relative to baseline in patients receiving FTY720 or MMF
`(Fig. 2). Thereafter. lymphocyte counts recovered rapidly in
`patients receiving MMF, whereas reductions from baseline in
`lymphocyte counts were sustained in patients receiving
`FTY720 throughout
`the treatment period. However,
`the
`mean lymphocyte counts remained at or above 200 CEllemm3
`during the treatment period, even among patients treated
`with the FTY720 2.5 mg dose. After the protocol-mandated
`cessation ofFTY720 after 3 months oftreatment, recovery to
`baseline lymphocyte levels was observed in all FTY720
`groups. The mean lymphocyte count was at or above baseline
`at month 6. Furthermore, absolute lymphocyte counts did
`not differ in FTY720~treated patients with and without BCAR
`and with or without serious infections (data not shown).
`
`Pharmacokinetics
`
`The pharmacokinetic profile of FTY720 was dose pro-
`portional and characterized by a one-compartment model
`with first-order absorption and elimination. The pharmaco-
`kinetics of FTY720 were characterized by a long half-life of
`approximately 200 hr across all four maintenance doses of
`FTY720 (Table 4}. Terminal elimination phase. tm, was as—
`sessed during the washout period (days 84~1 12}. On the basis
`of the observed time course of trough FTY720 blood concen-
`trations during the 12-week dosing period, the FTY720 blood
`concentrations seem to plateau by day 42 (weekel). giving rise
`to sustained blood levels for the remainder ofthe dosing pe—
`riod. The population clearance was 10.3 Llhr, and the volume
`ofdistribution was high at 3,280 L. The intersubiect variation
`of clearance rate was 55%, whereas the intrasubject variation
`of FTYFZO concentrations was 23%. FTY720 is excreted re-
`nally. Simultaneous administration of FTY720 and CsA did
`not influence the pharmacokinetics of CsA when compared
`with those oszA administered with MMF (data not shown).
`A full pharmacokinetic report will be published separately.
`
`DISCUSSION
`
`This phase 2a studyshows for the first time that FTY720
`in combination with CsA and steroids provides equivalent
`efficacy to the standard therapy, MMF, for the prevention of
`acute rejection in de nova renal transplant recipients.
`The incidence ofBCAR observed with FTY720 at a dose of
`2.5 mg (9.8%) waslower than that observed with MMF (17.10.41),
`although not statistically different. The trend for a lower inci-
`
`Copyriqht © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`© 2005 Lippincott William a Wilkins
`
`Tedesco-Silva et al.
`
`1559
`
`Treatment group
`O FTYD.25mg
`0 FTYO.5mg
`A F‘I'Y1rng
`E1 I’D/25mg
`# MMFZQ
`
`
` Changeinabsolute
`
`lymphocytes[1059/Ll
`
`FIGURE 2. Mean change from
`baseline in absolute lymphocyte
`count by visit: 0 to 6 months.
`D=day, W=week. Vr-viait.
`
`W2V1
`
`WW2
`
`Endofstudy
`
`dence of both primary and secondary efficacy parameters with
`FTY720 at a dose of 1.0 and 2.5 mg compared with 0.25 and 0.5
`mg suggests that its efficacy is dose-dependent. The incidences of
`BCAR at 3 and 6 months reported with MMF in the present
`study are consistent with rates reported in previous randomized
`multicenter trials that used a similar regimen without induction
`therapy (21—23). Therefore, the diliferences in efficacy parame-
`ters observed between the FTY720 and MMF groups are unlikely
`to be related to a bias in these results with the MMF-based regi—
`men. ln addition, the clinical and histologic severiw of acute
`rejection were not higher with FTY720 compared with MMF.
`The incidence of BCAR in any FTY720 treatment groups did not
`increase during the 3-month follow-up period, indicating that
`the cessation of FTY720 therapy is not associated with risk of
`rebound in allograft rejection.
`trials in stable renal patients,
`As observed in phase 1
`FTY720 was as safe as MMF in combination with CsA in this
`
`population of de novo renal transplant recipients. Up to the
`highest dose of FTY720, 2.5 mg, the tolerability of FTY720
`was found to be similar to MMF. The incidence of drug—
`related adverse events was comparable between FTY720- and
`MMF-treated patients, and few patients receiving FTY72U
`had to discontinue therapy because ofadverse events. FTY720
`was not associated with exacerbation qusA toxicity or gas—
`trointestinal or hematologic (except
`for its pharmacody-
`namic eifect on peripheral lymphocytes) side effects. Al-
`though a transient reduction in heart rate was observed with
`treatment initiation of FTY720, there was no evidence of a
`
`close relationship in the range ofdoses tested in this study. No
`other cardiac effect was detected, and no long-term effect on
`conduction was reported. The characteristics and the mech-
`anism underlying this effect oftreatment initiation deserves
`further investigation. In addition to the excellent efficacy of
`
`FTY720 at a dose of2.5 mg, no evidence ofthe typical effects
`of over-immunosuppression with currently used transplan-
`tation therapies, such as increased incidence of infections,
`have been observed with FTY720. However, a safety evalua-
`tion with a longer follow-up will be needed for further con-
`firmation. These short—term safety results are encouraging
`considering that it was the first study to assess the safety of
`FTY720 in de novo renal transplantation and that the trial was
`open label and used the renowned immunomppressive agent
`MMF as the comparison agent. Moreover, the lack of com-
`mon toxicities observed with calcineurin inhibitors or mam-
`
`malian target of rapamycin inhibitors and its potential syn~
`ergy with these agents, if confirmed, could be a real clinical
`advantage ofthis new immunomodulator.
`The pharmacokinetics of FTY720 are characterized by a
`linear relation between dose and exposure with less inter-patient
`variability than other immunosuppressive agents, suggesting
`that therapeutic drug monitoring may not be needed. These
`findings and the lack of drug—drug interactions reported so far
`for FTY720 could represent a notable advantage compared with
`current immunosuppressive drugs or regimens that require
`close monitoring for adequate patient management.
`FTY720 has been shown to induce a dose-dependent
`and reversible reduction in lymphocyte count in animals {2,
`15—17} and stable renal transplant recipients {12—14, £8). The
`finding that FTY720 produces a dose—dependent and sus-
`tained decrease in peripheral lymphocyte count during the
`treatment period of this study is therefore in line with these
`earlier results. During the 3-month treatment period, the
`mean lymphocyte counts remained at or above 200 cellslmm3
`during the treatment period, even among patients treated
`with FTY720 2.5 mg. This pharmacodynamic effect seems not
`to be ofclinical concern and only required discontinuation in
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`

`1560
`
`Transplantation - Volume '1'9. Number 11.june 15, 2005
`
`l of 167 FTY720-treated patients. This reduction in periph-
`eral lymphocyte count was not associated with an increase or
`change in the rate, nature, or severity ofinfections. This find
`ing is consistent with observations in animal models. The
`peripheral blood lymphocyte count was also not different in
`patients with or without acute rejections. On the basis ofthese
`findings. monitoring oflymphocyte counts is not likely to be
`a clinically relevant tool to evaluate the immunomodulating
`effect ofthe drug or to adjust the daily dose.
`The immunosuppressive efficacy of antilymphocyte-do
`pleting agents is well loiow; however the mode of action of
`W720 differs in many aspects: (1) The apparent decrease in
`peripheral lymphocytes with FI’YVEU is not related to the death
`oflymphocytes but to an increased sequestration in the homing
`to the lymph nodes and Peyer's patches where cells are fully ac-
`tive and responsive to immune stimuli. (2) After FTY720 cessa-
`tion, the speed in recovery of a normal lymphocyte count reflects
`the pharmacology of the drug. and the recovery of all lympho-
`cyte subsets is also complete. (3) The apparent lymphocyte de-
`pletion in FTY720-treated patients is not associated with in~
`creased infections. for example, the incidence of CMV infection
`was not increased as described. These important characteristics
`differentiate FTY720 from fire induction therapies, and these
`findings should enable its use as a maintenance therapy.
`Treatment with FTY720 results in a decrease ofthe pe-
`ripheral lymphocyte count; however, absolute lymphocyte
`counts in patients with or without acute rejection did not
`differ. Moreover, cellular infiltration of interstitium and tu-
`bules was found to be present in the allograft biopsies of an—
`imals and patients who had experienced rejection. Despite the
`fact that depletion of peripheral lymphocytes seems to be a
`necessary requirement for the efficacy of FTY720, these ob
`servations suggest that its immunomodulating effect is not
`solely mediated through its pharmacodynamic effect on cir-
`culating lymphocytes.
`
`CONCLUSION
`
`FTY720 is the first SIP-R agonist to modulate lympho-
`cyte homing and prevent allograft rejection in preclinical
`models. In de novo renal transplant recipients, this study con-
`firms that this novel drug, at a dose of 1.0 or 2.5 mglday in
`combination with a standard dose of CsA. provides efficacy
`equivalent to an MMF-based therapy for the prevention of
`acute rejection. During the 3-month treatment period, the
`safety and tolerability ofthe drug were also comparable to the
`MMF regimen. The trend toward impmved rejection pro-
`phylaxis in patients treated with FTY720 at 2.5 mg/day. with
`no incremental risk of infection or adverse events, indicates
`that, of the doses investigated in this study. FTY720 at 2.5 mg
`daily offers the best safety to efficacy ratio. These promising
`findings require further confirmation in larger studies with
`longer follow-up. FTY720 is a first—class agent with an excel-
`lent efficacy and safety profile and exhibits no overlapping
`toxicity with t