The new england
`journal of medicine
`
`established in 1812
`
`february 4, 2010
`
`vol. 362 no. 5
`
`A Placebo-Controlled Trial of Oral Fingolimod
`in Relapsing Multiple Sclerosis
`Ludwig Kappos, M.D., Ernst-Wilhelm Radue, M.D., Paul O’Connor, M.D., Chris Polman, M.D.,
`Reinhard Hohlfeld, M.D., Peter Calabresi, M.D., Krzysztof Selmaj, M.D., Catherine Agoropoulou, Ph.D.,
`Malgorzata Leyk, Ph.D., Lixin Zhang-Auberson, M.D., Ph.D., and Pascale Burtin, M.D., Ph.D.,
`for the FREEDOMS Study Group*
`
`Abs tr act
`
`Background
`Oral fingolimod, a sphingosine-1-phosphate–receptor modulator that prevents the
`egress of lymphocytes from lymph nodes, significantly improved relapse rates and end
`points measured on magnetic resonance imaging (MRI), as compared with either pla-
`cebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.
`
`Methods
`In our 24-month, double-blind, randomized study, we enrolled patients who had re-
`lapsing–remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to
`5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher
`scores indicating greater disability), and had had one or more relapses in the previ-
`ous year or two or more in the previous 2 years. Patients received oral fingolimod at
`a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized
`relapse rate (the primary end point) and the time to disability progression (a second-
`ary end point).
`
`Results
`A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse
`rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40
`with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and
`1.25 mg significantly reduced the risk of disability progression over the 24-month pe-
`riod (hazard ratio, 0.70 and 0.68, respectively; P = 0.02 vs. placebo, for both compari-
`sons). The cumulative probability of disability progression (confirmed after 3 months)
`was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1%
`with placebo. Both fingolimod doses were superior to placebo with regard to MRI-
`related measures (number of new or enlarged lesions on T2 -weighted images, gadolin-
`ium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months).
`Causes of study discontinuation and adverse events related to fingolimod included bra-
`dycardia and atrioventricular conduction block at the time of fingolimod initiation,
`macular edema, elevated liver-enzyme levels, and mild hypertension.
`
`Conclusions
`As compared with placebo, both doses of oral fingolimod improved the relapse rate, the
`risk of disability progression, and end points on MRI. These benefits will need to be
`weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.)
`
`From the Departments of Neurology and
`Biomedicine (L.K.) and the Medical Im-
`age Analysis Center (E.-W.R.), University
`Hospital, University of Basel; and Novar-
`tis Pharma (C.A., M.L., L.Z.-A., P.B.) —
`both in Basel, Switzerland; St. Michael’s
`Hospital, Toronto (P.O.); Free University
`Medical Center, Amsterdam (C.P.); Insti-
`tut für Klinische Neuroimmunologie, Mu-
`nich, Germany (R.H.); Johns Hopkins Hos-
`pital, Baltimore (P.C.); and the Medical
`University of Lodz, Lodz, Poland (K.S.).
`Address reprint requests to Dr. Kappos at
`the Departments of Neurology and Bio-
`medicine, University Hospital, Petersgra-
`ben 4, CH 4031, Basel, Switzerland, or at
`lkappos@uhbs.ch.
`
`*Members of the FTY720 Research Eval-
`uating Effects of Daily Oral Therapy in
`Multiple Sclerosis (FREEDOMS) study
`group are listed in the Supplementary
`Appendix, available with the full text of
`this article at NEJM.org.
`
`This article (10.1056/NEJMoa0909494)
`was published on January 20, 2010, at
`NEJM.org.
`
`N Engl J Med 2010;362:387-401.
`Copyright © 2010 Massachusetts Medical Society.
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`387
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on October 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Fingolimod (fty720) is an oral sphin-
`
`gosine-1-phosphate–receptor modulator1 that
`is currently being evaluated for the treatment
`of multiple sclerosis. There is evidence that fin-
`golimod acts by preventing lymphocyte egress from
`lymph nodes.2,3 This leads to a reduced infiltration
`of potentially autoaggressive lymphocytes into the
`central nervous system.4,5 Preclinical findings also
`suggest that fingolimod may promote neuropro-
`tective and reparative processes within the central
`nervous system through modulation of sphin-
`gosine-1-phosphate receptors expressed on neu-
`ral cells.6-12
`A 6-month, phase 2, placebo-controlled study13
`and its open-label extension study14 showed sus-
`tained suppression, for up to 5 years, of both re-
`lapse and inflammatory activity in patients re-
`ceiving fingolimod. Furthermore, in a recently
`completed, 12-month, phase 3 study involving pa-
`tients with relapsing–remitting multiple sclerosis
`(TRANSFORMS [Trial Assessing Injectable Inter-
`feron vs. FTY720 Oral in RRMS]; ClinicalTrials
`.gov number, NCT00340834), reported elsewhere
`in this issue of the Journal, fingolimod reduced
`the relapse rate and disease activity as measured
`with the use of magnetic resonance imaging
`(MRI), as compared with a once-weekly, intra-
`muscular injection of interferon beta-1a at a dose
`of 30 μg.15
`In our phase 3, double-blind, placebo-controlled
`study, called FREEDOMS (FTY720 Research Eval-
`uating Effects of Daily Oral therapy in Multiple
`Sclerosis), we investigated the effects of daily fin-
`golimod treatment for 24 months on the relapse
`rate, disability progression, and MRI measures of
`inflammation, burden of disease, and tissue de-
`struction in patients with relapsing–remitting mul-
`tiple sclerosis.
`
`Methods
`
`Study Oversight
`Steering-committee members (listed in the Sup-
`plementary Appendix, available with the full text
`of this article at NEJM.org) collaborated with the
`sponsor, Novartis Pharma, to develop the proto-
`col and monitor the ongoing study. Data were
`collected by the investigators and analyzed by the
`sponsor. All the authors had access to the data,
`participated in the data analysis and interpreta-
`tion, and wrote the manuscript. All authors vouch
`for the accuracy and completeness of the data and
`
`the statistical analysis. All authors participated in
`the writing of the manuscript and approved the
`final manuscript before submitting it for publi-
`cation.
`
`Patients
`Key eligibility criteria were an age of 18 to 55 years;
`a diagnosis of multiple sclerosis, according to the
`revised McDonald criteria16; a relapsing–remitting
`course17; one or more documented relapses in the
`previous year or two or more in the previous
`2 years; and a score of 0 to 5.5 on the Expanded
`Disability Status Scale (EDSS; which ranges from
`0 to 10, with higher scores indicating greater dis-
`ability).18 Key exclusion criteria were relapse or
`corticosteroid treatment within 30 days before
`randomization, active infection, macular edema,
`diabetes mellitus, immune suppression (drug- or
`disease-induced), or clinically significant systemic
`disease. Interferon-beta or glatiramer acetate ther-
`apy had to have been stopped 3 or more months
`before randomization.
`The study was conducted in accordance with
`the International Conference on Harmonisation
`Guidelines for Good Clinical Practice19 and the
`Declaration of Helsinki.20 The protocol was ap-
`proved by each site’s institutional review board;
`patients gave written informed consent before any
`study-related procedures were performed.
`
`Study Design and Randomization
`Patients were randomly assigned, in a 1:1:1 ratio,
`to receive oral fingolimod capsules in a dose of
`0.5 mg or 1.25 mg or matching placebo, once dai-
`ly for 24 months. Randomization was performed
`centrally, with the use of a validated system and
`stratification according to site, with a block size
`of six within each site.
`To ensure that all assessments remained unbi-
`ased regarding the study-group assignments (i.e.,
`unaffected by awareness of them), an independent,
`specially trained and certified21 examining neu-
`rologist determined all the EDSS scores; this
`examining neurologist or a trained technician
`administered the Multiple Sclerosis Functional
`Composite (MSFC; comprising the average of the
`scores on the timed 25-foot walk, the 9-hole peg
`test, and the paced auditory serial-addition test
`with a 3-second interstimulus interval, with each
`converted to a z score [with the combined study
`population at baseline as the reference popula-
`tion], with higher scores representing improve-
`
`388
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`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on October 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`TEVA EX. 1038
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`Oral Fingolimod in Relapsing Multiple Sclerosis
`
`ment).22 Another independent physician monitored
`patients for 6 or more hours after administration
`of the first dose of the study drug. MRI scans
`were analyzed at a central MRI evaluation center by
`radiologists who were unaware of the study-group
`assignments, and an independent data and safety
`monitoring board evaluated the safety and over-
`all benefit–risk profiles.
`
`Study Procedures and End Points
`Clinical assessments were performed at screening
`and at randomization (baseline), and study visits,
`including safety assessments, were scheduled at
`2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24
`months after randomization. The EDSS score was
`determined every 3 months, and the MSFC z score
`every 6 months. Standardized MRI scans were ob-
`tained at the screening visit and at 6, 12, and 24
`months and were analyzed centrally at the Mul-
`tiple Sclerosis–MRI Evaluation Center at the Uni-
`versity Hospital in Basel, Switzerland.
`The primary end point was the annualized re-
`lapse rate, defined as the number of confirmed
`relapses per year. Relapses were verified by the
`examining neurologist within 7 days after the on-
`set of symptoms. To constitute a confirmed re-
`lapse, the symptoms must have been accompanied
`by an increase of at least half a point in the EDSS
`score, of one point in each of two EDSS functional-
`system scores, or of two points in one EDSS
`functional-system score (excluding scores for the
`bowel–bladder or cerebral functional systems).
`The key secondary end point was the time to
`confirmed disability progression, defined as an
`increase of one point in the EDSS score (or half
`a point if the baseline EDSS score was equal to
`5.5), confirmed after 3 months, with an absence of
`relapse at the time of assessment and with all
`EDSS scores measured during that time meet-
`ing the criteria for disability progression.
`Other secondary end points included the time
`to a first relapse, time to disability progression
`(confirmed after 6 months), changes in the EDSS
`score and MSFC z score23 between baseline and
`24 months, number of gadolinium-enhancing le-
`sions, proportion of patients free from gadolin-
`ium-enhancing lesions, number of new or enlarged
`lesions on T2-weighted MRI scans, proportion of
`patients free from new or enlarged lesions on T2-
`weighted scans, volumes of hyperintense lesions
`on T2-weighted scans and hypointense lesions on
`T1-weighted scans, change in brain volume be-
`
`tween baseline and 24 months, and safety and
`tolerability measures. Specifications of the ad-
`verse-event monitoring procedure, as defined in
`the study protocol, were the same as those in
`TRANSFORMS and are detailed in the Supplemen-
`tary Appendix, which also provides other method-
`ologic details.
`
`Statistical Analysis
`For the primary end point, on the basis of data
`from a phase 2 study of fingolimod,13,24 the ex-
`pected annualized relapse rate was 0.7 for the
`group receiving placebo and 0.42 for the group
`receiving 1.25 mg of fingolimod, with a common
`standard deviation of 1.06. We calculated that a
`sample of 1250 patients would provide 95% sta-
`tistical power to detect a relative reduction of 40%
`or more in the annualized relapse rate with fingoli-
`mod as compared with placebo, after 24 months.
`With this sample size, using a log-rank test and
`a two-sided α level of 0.05 (assuming a study-dis-
`continuation rate of 25%13), we calculated that
`the study would have a statistical power of more
`than 90% to detect an absolute difference be-
`tween the two groups of 12% in the proportion
`of patients with disability progression (confirmed
`after 3 months) at month 24, which was expected
`to be approximately 30% in the placebo group.
`Both the intention-to-treat population and the
`safety population included all patients who had
`undergone randomization. The study tested two
`null hypotheses: that there were no differences in
`the annualized relapse rate between the group re-
`ceiving fingolimod at a dose of 1.25 mg and the
`group receiving placebo or between the group re-
`ceiving fingolimod at a dose of 0.5 mg and the
`group receiving placebo. The aggregate annual-
`ized relapse rate was estimated by means of a
`negative binomial regression model with adjust-
`ment for study group, country, number of relapses
`within 2 years before baseline, and EDSS score at
`baseline. The time to relapse or progression was
`estimated with the use of the Kaplan–Meier meth-
`od.25 The times to disability progression (con-
`firmed after 3 or 6 months) were compared in
`the main analysis by means of the log-rank test
`and in the supportive analysis by means of a Cox
`proportional-hazards model with adjustment for
`study group, country, baseline EDSS score, and
`age. To control for a type I statistical error, a pro-
`spectively planned, hierarchical testing procedure
`was used to compare fingolimod with placebo re-
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`389
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`The New England Journal of Medicine
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`
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`
`TEVA EX. 1038
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`garding the primary and key secondary end points,
`in the following order: the annualized relapse rate,
`first in association with 1.25 mg of fingolimod
`and next in association with 0.5 mg of fingolimod,
`and then the time to disability progression (con-
`firmed after 3 months), first with 1.25 mg of
`fingolimod and next with 0.5 mg of fingolimod.
`Each test was performed with a significance level
`of 0.05. However, the next test was performed only
`when the preceding test was statistically signifi-
`cant. Missing data were not imputed.
`Safety analyses were summarized by means of
`descriptive statistics; inferential significance test-
`ing was not performed. Statistical details for other
`end points are provided in the Supplementary Ap-
`pendix.
`
`R esults
`
`Study Population
`From January 2006 through August 2007, a total
`of 1272 patients were randomly assigned to a study
`group (Fig. 1) at 138 centers in 22 countries (see
`the Supplementary Appendix for a list of the cen-
`ters and principal investigators). Baseline charac-
`teristics were similar across the three study groups
`(Table 1). In total, 1033 patients (81.2%) completed
`the 24-month study, with 945 (74.3%) still receiv-
`ing the assigned study drug. The study drug was
`discontinued in proportionately fewer patients in
`the group receiving 0.5 mg of fingolimod (18.8%)
`than in the group receiving 1.25 mg of fingoli-
`mod (30.5%) or in the placebo group (27.5%).
`Reasons for study-drug discontinuation are listed
`in Figure 1.
`
`Efficacy
`All clinical and MRI-related efficacy end points
`significantly favored both doses of fingolimod over
`placebo, and there were no significant differences
`in efficacy between the two fingolimod doses
`(Table 2).
`
`Relapse
`The aggregate annualized relapse rate (the pri-
`mary end point) was lower with fingolimod at a
`dose of 0.5 mg (0.18) and fingolimod at a dose of
`1.25 mg (0.16) than with placebo (0.40), represent-
`ing relative reductions of 54% and 60%, respec-
`tively, in the annualized relapse rate (Table 2). As
`compared with placebo, both doses of fingolimod
`
`reduced the annualized relapse rate among pa-
`tients who had not previously received disease-
`modifying treatment as well as among those who
`had been treated previously (P<0.01 for all com-
`parisons). In the fingolimod groups as compared
`with the placebo group, the time to a first relapse
`was longer (Fig. 2A), the risk of relapse was re-
`duced, and proportionately more patients re-
`mained free of relapse during the 24-month period
`(Table 2).
`
`Disability
`The time to disability progression, with confirma-
`tion either after 3 months (the key secondary end
`point) or after 6 months, was longer with both
`fingolimod doses than with placebo (Fig. 2B and
`Table 2). Fingolimod reduced the risk of disabil-
`ity progression, confirmed after 3 months, over the
`24-month study period (hazard ratios, 0.68 for the
`1.25-mg dose and 0.70 for the 0.5-mg dose). The
`cumulative probability of disability progression
`(confirmed after 3 months) was 17.7% for 0.5 mg
`of fingolimod, 16.6% for 1.25 mg of fingolimod,
`and 24.1% for placebo. Regarding disability pro-
`gression that was confirmed after 6 months, the
`risk was also reduced with fingolimod over the
`24-month study period (hazard ratio, 0.60 with
`the 1.25-mg dose and 0.63 for the 0.5-mg dose),
`and the cumulative probability of progression was
`12.5% for 0.5 mg of fingolimod, 11.5% for 1.25 mg
`of fingolimod, and 19.0% for placebo. During the
`study period, the EDSS scores and MSFC z scores
`remained stable or improved slightly in the fingoli-
`mod groups and worsened in the placebo group
`(Table 2).
`
`MRI-Related End Points
`Patients in either fingolimod group had signifi-
`cantly fewer gadolinium-enhancing lesions than
`those in the placebo group at 6, 12, and 24 months,
`as well as fewer new or enlarged lesions on
`T2-weighted MRI scans at 24 months (Table 2).
`Proportionately more patients in the fingolimod
`groups than in the placebo group were also free
`from gadolinium-enhancing or new or enlarging
`lesions at these time points (Table 2 and Fig. 2C).
`The median volume of lesions on T2-weighted
`scans decreased between baseline and month 24
`with fingolimod but increased with placebo.
`During the 24-month study period, changes
`in the volume of hypointense lesions on T1-weight-
`
`390
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on October 20, 2016. For personal use only. No other uses without permission.
`
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`
`TEVA EX. 1038
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`Oral Fingolimod in Relapsing Multiple Sclerosis
`
`1564 Patients were assessed for eligibility
`
`292 Were excluded
`212 Did not meet inclusion criteria
`41 Declined to participate
`45 Were excluded for other reasons
`
`1272 Underwent randomization
`
`429 Were assigned to receive
`1.25 mg of fingolimod daily and
`were included in intention-
`to-treat and safety analyses
`
`425 Were assigned to receive
`0.5 mg of fingolimod daily and
`were included in intention-
`to-treat and safety analyses
`
`418 Were assigned to receive
`placebo and were included in
`intention-to-treat and safety
`analyses
`
`96 Discontinued the study
`30 Withdrew consent
`22 Had an adverse event
`20 Had an abnormal laboratory
`value
`13 Had an unsatisfactory
`therapeutic effect
`5 Had a protocol violation
`3 Were lost to follow-up
`2 Had an abnormal test
`procedure result
`1 Died
`131 Discontinued the study drug
`32 Had an abnormal laboratory
`value
`31 Had an adverse event
`30 Withdrew consent
`18 Had an unsatisfactory
`therapeutic effect
`8 Had a protocol violation
`6 Had an abnormal test result
`3 Had administrative problems
`2 Were lost to follow-up
`1 Died
`333 Completed the study
`298 Were still receiving the
`study drug
`35 Had discontinued the
`study drug
`
`56 Discontinued the study
`17 Withdrew consent
`13 Had an adverse event
`9 Had an abnormal laboratory
`value
`6 Had an unsatisfactory
`therapeutic effect
`5 Had a protocol violation
`5 Were lost to follow-up
`1 Had an abnormal test
`procedure result
`80 Discontinued the study drug
`20 Had an abnormal laboratory
`value
`15 Had an adverse event
`17 Withdrew consent
`8 Had an unsatisfactory
`therapeutic effect
`8 Had a protocol violation
`3 Had an abnormal test result
`3 Had administrative problems
`6 Were lost to follow-up
`369 Completed the study
`345 Were still receiving the
`study drug
`24 Had discontinued the
`study drug
`
`86 Discontinued the study
`28 Withdrew consent
`18 Had an adverse event
`1 Had an abnormal laboratory
`value
`25 Had an unsatisfactory
`therapeutic effect
`4 Had a protocol violation
`7 Were lost to follow-up
`1 Had an abnormal test
`procedure result
`2 Died
`115 Discontinued the study drug
`5 Had an abnormal laboratory
`value
`24 Had an adverse event
`31 Withdrew consent
`36 Had an unsatisfactory
`therapeutic effect
`5 Had a protocol violation
`3 Had an abnormal test result
`4 Had administrative problems
`5 Were lost to follow-up
`2 Died
`332 Completed the study
`303 Were still receiving the
`study drug
`29 Had discontinued the
`study drug
`
`Figure 1. Enrollment, Randomization, and Follow-up of Study Patients.
`Among the 292 patients who were assessed for eligibility but were not enrolled, some were excluded for more than one
`reason. For one patient receiving 1.25 mg of fingolimod daily who completed the study while receiving the study drug,
`the status was incorrectly recorded by the investigator as having discontinued the study while still receiving the study drug.
`AUTHOR:
`Kappos
`RETAKE:
`1st
`Patients who discontinued the study drug include those who discontinued the study; the correct status is shown here.
`2nd
`FIGURE:
`1 of 2
`3rd
`Revised
`events (Table 3); the events were mild to moder-
`ed scans favored both doses of fingolimod over
`ARTIST:
`MRL
`SIZE
`ate in severity in 82% of patients receiving 0.5 mg
`placebo (Table 2). In addition, reductions in brain
`6 col
`4-C
`H/T
`Line
`Combo
`TYPE:
`33p9
`of fingolimod, 77% of those receiving 1.25 mg of
`volume were smaller with fingolimod.
`AUTHOR,PLEASENOTE:
`fingolimod, and 77% of those receiving placebo.
`Figurehasbeenredrawnandtypehasbeenreset.
`Adverse events that led to discontinuation of the
`Adverse Events
`Pleasecheckcarefully.
`study medication (including abnormal laboratory-
`Similar proportions of patients (93 to 94%) in the
`JOB: 361xx
`ISSUE:
`2-04-10
`test results) were more common with fingolimod
`three study groups were reported to have adverse
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`391
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Table 1. Baseline Characteristics of the Patients, According to Study Group.*
`
`Characteristic
`
`Age — yr
`
`Mean
`
`Median (range)
`
`Female sex — no. (%)
`
`Disease and treatment history
`
`Time from first MS symptom to randomization — yr
`
`Mean
`
`Median (range)
`
`Relapses — no.
`
`Within previous yr
`
`Mean
`
`Median (range)
`
`Within previous 2 yr
`
`Mean
`
`Median (range)
`
`EDSS score†
`
`Fingolimod
`
`1.25 mg
`(N = 429)
`
`0.5 mg
`(N = 425)
`
`Placebo
`(N = 418)
`
`37.4±8.9
`
`36.6±8.8
`
`38.0 (17–55)
`
`36.0 (18–55)
`
`295 (68.8)
`
`296 (69.6)
`
`37.2±8.6
`
`37.0 (18–55)
`
`298 (71.3)
`
`8.4±6.9
`
`6.9 (0–37)
`
`8.0±6.6
`
`6.6 (0–35)
`
`8.1±6.4
`
`7.0 (0–32)
`
`1.5±0.8
`
`1.0 (0–6)
`
`2.1±1.3
`
`2.0 (1–10)
`
`1.5±0.8
`
`1.0 (0–5)
`
`2.1±1.1
`
`2.0 (1–11)
`
`1.4±0.7
`
`1.0 (0–6)
`
`2.2±1.2
`
`2.0 (1–10)
`
`2.5±1.3
`
`Mean
`
`Median (range)
`
`2.4±1.4
`
`2.0 (0–5.5)
`
`No history of disease-modifying treatment — no. (%)
`
`259 (60.4)
`
`2.3±1.3
`
`2.0 (0–5.5)
`
`244 (57.4)
`
`2.0 (0–5.5)
`
`249 (59.6)
`
`Features on MRI‡
`
`Absence of gadolinium-enhancing lesions — no. (%)
`No. of gadolinium-enhancing lesions on T1-weighted
`images
`
`Mean
`
`Median (range)
`Volume of lesions on T2-weighted images — mm3
`Mean
`
`Median (range)
`Volume of hypointense lesions on T1-weighted images
`— mm3
`
`257 (60.6)
`
`263 (62.0)
`
`262 (63.0)
`
`1.8±4.7
`
`0 (0–50)
`
`1.6±5.6
`
`0 (0–84)
`
`1.3±2.9
`
`0 (0–26)
`
`6829±8491
`
`6128±7623
`
`6162±7085
`
`3557 (0–47,734)
`
`3303 (0–47,148)
`
`3416 (0–37,148)
`
`Mean
`
`Median (range)
`
`Normalized brain volume — ml
`
`Mean
`
`Median (range)
`
`2114±3220
`
`1898±2854
`
`1962±3131
`
`860 (0–25,886)
`
`814 (0–22,378)
`
`811 (0–20,956)
`
`1511±86
`
`1521±83
`
`1512±85
`
`1515 (1217–1764)
`
`1529 (1144–1734)
`
`1515 (1230–1723)
`
`* Plus–minus values are means ±SD. There were no significant between-group differences at baseline for any characteris-
`tic. MS denotes multiple sclerosis.
`† The Expanded Disability Status Scale (EDSS) ranges from 0 to 10, with higher scores indicating greater disability.
`‡ MRI data were available for 424 patients in each of the fingolimod groups and for 416 patients in the placebo group.
`The means and medians were calculated on the basis of all images, not just those showing lesions.
`
`392
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`Oral Fingolimod in Relapsing Multiple Sclerosis
`
`<0.001
`
`<0.001
`
`<0.001
`
`216/332 (65.1)
`
`331/369 (89.7)
`
`<0.001
`
`0.0 (0–21)
`
`1.1±2.4
`
`332
`
`0.0 (0–8)
`
`0.2±0.8
`
`369
`
`0.01
`
`0.02
`
`–0.06±0.57
`
`0.03±0.39
`
`–0.01 (–3.8 to 5.5)
`
`0.07 (–2.1 to 1.2)
`
`0.002
`
`0.01
`
`0.01
`
`0.02
`
`0.03
`
`0.002
`
`0.006
`
`0.004
`
`0.02
`
`0.01
`
`0.0 (–3.0 to 3.5)
`
`0.0 (–3.0 to 3.5)
`
`0.13±0.94
`
`0.00±0.88
`
`81.0±2.0 (77.1 to 84.9)
`
`0.63 (0.44 to 0.90)
`
`75.9±2.2 (71.7 to 80.2)
`
`0.70 (0.52 to 0.96)
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`45.6±2.5 (40.7 to 50.6)
`
`0.48 (0.39 to 0.61)
`
`<0.001
`
`<0.001
`
`0.40 (0.34 to 0.47)
`
`0.18 (0.15 to 0.22)
`
`Fingolimod, 0.5 mg,
`
`vs. Placebo
`
`Fingolimod, 1.25 mg,
`
`vs. Placebo
`
`0.5 mg (N = 425)
`
`P Value
`
`Placebo (N = 418)
`
`308/343 (89.8)
`
`0.0 (0–11)
`
`0.2±1.1
`
`343
`
`0.05 (–2.4 to 1.3)
`
`0.01±0.40
`
`0.0 (–3.0 to 4.0)
`
`–0.03±0.88
`
`Absence of gadolinium-enhancing lesions at 24 mo — no./
`
`total no. (%)§§‖‖
`
`Median (range)
`
`Mean¶¶
`
`No. of patients with data
`
`No. of gadolinium-enhancing lesions at 24 mo§§
`
`Measures of inflammatory activity or scar formation
`
`MRI-related secondary end points‡‡
`
`Median (range)
`
`Mean††
`
`MSFC z score at 24 mo
`
`Median (range)
`
`Mean††
`
`EDSS score at 24 mo
`
`87.5±1.6 (84.3 to 90.7)
`
`88.5±1.6 (85.3 to 91.6)
`
`Percent (95% CI)¶
`
`0.60 (0.41 to 0.86)
`
`Hazard ratio for fingolimod vs. placebo (95% CI)**
`
`Absence of disability progression, confirmed after 6 mo,
`
`during the 24-mo period§
`
`82.3±1. 9 (78.6 to 86.1)
`
`83.4±1.9 (79.7 to 87.1)
`
`Percent (95% CI)¶
`
`0.68 (0.50 to 0.93)
`
`Hazard ratio for fingolimod vs. placebo (95% CI)**
`
`Key secondary end point: absence of disability progression, con-
`
`firmed after 3 mo, during the 24-mo period§
`
`Disability-related secondary end points
`
`70.4±2.3 (66.0 to 74.8)
`
`74.7±2.2 (70.4 to 78.9)
`
`Percent (95% CI)¶
`
`0.38 (0.30 to 0.48)
`
`Hazard ratio for fingolimod vs. placebo (95% CI)‖
`
`0.16 (0.13 to 0.19)
`
`Annualized relapse rate over 24 mo (95% CI)†‡
`
`Absence of relapse during the 24-mo period§
`
`Relapse-related secondary end points
`
`1.25 mg (N = 429)
`
`Fingolimod
`
`Primary end point
`
`End Point
`
`Table 2. Clinical and MRI End Points, According to Study Group.*
`
`n engl j med 362;5 nejm.org february 4, 2010
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`393
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`<0.001
`
`0.002
`
`0.03
`
`0.001
`
`0.006
`
`0.003
`
`–0.57 (–5.60 to 2.43)
`
`–0.34 (–6.24 to 1.90)
`
`–0.67±1.07
`
`329
`
`–0.37±0.81
`
`356
`
`–0.56 (–3.89 to 2.78)
`
`–0.38 (–8.11 to 2.40)
`
`–0.65±1.05
`
`358
`
`–0.50±1.05
`
`383
`
`–0.29 (–4.02 to 2.57)
`
`–0.14 (–5.62 to 2.25)
`
`–0.34±0.73
`
`383
`
`–0.22±0.81
`
`395
`
`0.01
`
`0.02
`
`1.59 (–100.0 to 5285.3)
`
`0.00 (–100.0 to 1037.1)
`
`50.7±388.3
`
`305
`
`8.8±76.3
`
`346
`
`<0.001
`
`<0.001
`
`8.61 (–84.5 to 1378.7)
`
`33.8±106.9
`
`339
`
`10.6±103.5
`
`368
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`72/339 (21.2)
`
`5.0 (0 to 99)
`
`9.8±13.2
`
`339
`
`187/370 (50.5)
`
`0.0 (0 to 107)
`
`2.5±7.2
`
`370
`
`–0.38 (–5.40 to 2.24)
`
`–0.42±0.83
`
`327
`
`–0.30 (–4.91 to 4.34)
`
`–0.44±1.08
`
`371
`
`–0.12 (–4.71 to 3.37)
`
`–0.21±0.86
`
`384
`
`–0.20 (–100.0 to 888.4)
`
`12.2±85.5
`
`317
`
`Median (range)
`
`Mean¶¶¶
`
`No. of patients with data
`
`Change in brain volume, 12 to 24 mo — %
`
`Median (range)
`
`Mean¶¶¶
`
`No. of patients with data
`
`Change in brain volume, baseline to 12 mo — %
`
`Median (range)
`
`Mean¶¶¶
`
`No. of patients with data
`
`Change in brain volume, baseline to 6 mo — %
`
`Median (range)
`
`Mean§§§
`
`No. of patients with data
`
`–1.69 (–100.0 to 1828.5)
`
`–3.10 (–68.2 to 221.5)
`
`1.6±30.7
`
`343
`
`175/337 (51.9)
`
`0.0 (0 to 41)
`
`2.5±5.5
`
`337
`
`Change in volume of hypointense lesions on T1-weighted
`
`images, baseline to 24 mo — %
`
`Measures of tissue damage or loss
`
`Median (range)
`
`Mean§§§
`
`No. of patients with data
`
`Change in lesion volume on T2-weighted images, baseline
`
`to 24 mo — %
`
`Absence of new or enlarged T2-weighted lesions at 24 mo —
`
`no./total no. (%)***‡‡‡
`
`Median (range)
`
`Mean†††
`
`No. of patients with data
`
`No. of new or enlarged lesions on T2-weighted images, base-
`
`line to 24 mo***
`
`394
`
`n engl j med 362;5 nejm.org february 4, 2010
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`The New England Journal of Medicine
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`Downloaded from nejm.org on October 20, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2010 Massachusetts Medical Society. All rights reserved.
`
`TEVA EX. 1038
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`

`Oral Fingolimod in Relapsing Multiple Sclerosis
`
`at a dose of 1.25 mg (occurring in 14.2% of pa-
`tients) than with fingolimod at a dose of 0.5 mg
`(occurring in 7.5%) or with placebo (occurring in
`7.7%). Serious adverse events were reported for
`10.1% of patients receiving 0.5 mg of fingolimod,
`11.9% of those receiving 1.25 mg of fingolimod,
`and 13.4% of those receiving placebo. The most
`common serious adverse events, each reported for
`eight patients, were bradycardia, multiple sclero-
`sis relapse, and basal-cell carcinoma. All other seri-
`ous adverse events occurred in four or fewer pa-
`tients (<1%) in any study group. The seven episodes
`of bradycardia in the two fingolimod groups (four
`in the 0.5-mg group and three in the 1.25-mg
`group) were reported during the monitoring period
`after administration of the first dose. Six of these
`events were asymptomatic; the patients continued
`to receive fingolimod and the episodes were re-
`ported as serious adverse events because the pro-
`tocol-defined discharge criteria for the first-dose
`monitoring period were not met.
`Three deaths occurred during the study, two
`with placebo and one with 1.25 mg of fingolimod.
`The causes of death in the placebo group were
`pulmonary embolism and a traffic accident, and
`the cause in the fingolimod group was suicide.
`
`Infections
`The overall incidence of infection was similar in
`the fingolimod and placebo groups (69 to 72%);
`serious infections occurred in 1.6 to 2.6% of pa-
`tients. Urinary tract infection was the only seri-
`ous infection reported in more than one patient
`(reported in two patients in the group receiving
`0.5 mg of fingolimod). Herpesvirus infections were
`reported in similar proportions of patients across
`the three study groups (Table 3). Of these infec-
`tions, herpes zoster was reported in seven patients
`receiving 0.5 mg of fingolimod, three receiving
`1.25 mg of fingolimod, and four receiving place-
`bo. Two cases of herpesvirus infection were clas-
`sified as serious adverse events: one case of genital
`herpes (in a patient receiving 1.25 mg of fingoli-
`mod) and one case of herpes simplex labialis (in
`a patient receiving 0.5 mg of fingolimod).
`Lower respiratory tract infections (including
`bronchitis and pneumonia) were more common
`with fingolimod than with placebo (occurring in
`41 patients [9.6%] receiving 0.5 mg of fingoli-
`mod and 49 patients [11.4%] receiving 1.25 mg
`of fingolimod vs. 25 patients [6.0%] receiving
`placebo).
`
`was measured, and the EDSS score at baseline.
`P values were calculated with the use of the Cox proportional-hazards model with adjustment for study group, country, number of relapses within 2 years before the baseline value
`Plu