T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Oral Fingolimod or Intramuscular Interferon
`for Relapsing Multiple Sclerosis
`Jeffrey A. Cohen, M.D., Frederik Barkhof, M.D., Giancarlo Comi, M.D.,
`Hans-Peter Hartung, M.D., Bhupendra O. Khatri, M.D., Xavier Montalban, M.D.,
`Jean Pelletier, M.D., Ruggero Capra, M.D., Paolo Gallo, M.D.,
`Guillermo Izquierdo, M.D., Klaus Tiel-Wilck, M.D., Ana de Vera, M.D.,
`James Jin, Ph.D., Tracy Stites, Ph.D., Stacy Wu, M.D., Shreeram Aradhye, M.D.,
`and Ludwig Kappos, M.D., for the TRANSFORMS Study Group*
`
`Abstr act
`
`Background
`Fingolimod (FTY720), a sphingosine-1-phosphate–receptor modulator that prevents
`lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on
`imaging in a phase 2 study involving patients with multiple sclerosis.
`
`Methods
`In this 12-month, double-blind, double-dummy study, we randomly assigned 1292
`patients with relapsing–remitting multiple sclerosis who had a recent history of at
`least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or
`0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple scle-
`rosis) at a weekly dose of 30 μg. The primary end point was the annualized relapse
`rate. Key secondary end points were the number of new or enlarged lesions on T2-
`weighted magnetic resonance imaging (MRI) scans at 12 months and progression
`of disability that was sustained for at least 3 months.
`
`Results
`A total of 1153 patients (89%) completed the study. The annualized relapse rate was
`significantly lower in both groups receiving fingolimod — 0.20 (95% confidence inter-
`val [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the
`0.5-mg group — than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001
`for both comparisons). MRI findings supported the primary results. No significant
`differences were seen among the study groups with respect to progression of dis-
`ability. Two fatal infections occurred in the group that received the 1.25-mg dose of
`fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis.
`Other adverse events among patients receiving fingolimod were nonfatal herpesvi-
`rus infections, bradycardia and atrioventricular block, hypertension, macular ede-
`ma, skin cancer, and elevated liver-enzyme levels.
`
`Conclusions
`This trial showed the superior efficacy of oral fingolimod with respect to relapse
`rates and MRI outcomes in patients with multiple sclerosis, as compared with in-
`tramuscular interferon beta-1a. Longer studies are needed to assess the safety and
`efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)
`
`The authors’ affiliations are listed in the
`Appendix. Address reprint requests to
`Dr. Cohen at Mellen Center U-10, Neuro-
`logic Institute, Cleveland Clinic, 9500
`Euclid Ave., Cleveland, OH 44195, or at
`cohenj@ccf.org.
`
`*The members of the Trial Assessing In-
`jectable Interferon versus FTY720 Oral
`in Relapsing–Remitting Multiple Scle-
`rosis (TRANSFORMS) study group are
`listed in the Supplementary Appendix,
`available with the full text of this article
`at NEJM.org.
`
`This article (10.1056/NEJMoa0907839)
`was published on January 20, 2010, at
`NEJM.org.
`
`N Engl J Med 2010;362:402-15.
`Copyright © 2010 Massachusetts Medical Society.
`
`402
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2035
`
`

`

`Oral Fingolimod or Interferon for Relapsing Multiple Sclerosis
`
`Oral fingolimod (FTY720) is a sphin-
`
`gosine-1-phosphate–receptor modulator.
`After phosphorylation, fingolimod acts as
`a functional antagonist of the sphingosine-1-phos-
`phate type 1 receptor, inducing receptor internal-
`ization and rendering T and B cells insensitive to
`a signal necessary for egress from secondary lym-
`phoid tissues.1,2 The resulting redistribution to
`lymph nodes reduces recirculation of autoaggres-
`sive lymphocytes to the central nervous system.3-5
`Also, fingolimod is lipophilic, readily crosses the
`blood–brain barrier, and is phosphorylated with-
`in the central nervous system.6 Through interac-
`tion with sphingosine-1-phosphate receptors on
`neural cells, fingolimod may have neuroprotec-
`tive or reparative effects.6-9
`Fingolimod effectively treats experimental au-
`toimmune encephalomyelitis, an animal model of
`multiple sclerosis.1,10,11 In a 6-month, phase 2
`study involving patients with relapsing multiple
`sclerosis,12 daily oral fingolimod at a dose of 5.0
`or 1.25 mg significantly reduced the number of
`gadolinium-enhancing lesions seen on magnetic
`resonance imaging (MRI) and the relapse rate,
`as compared with placebo. In an extension study,
`clinical and MRI benefits were maintained for up
`to 5 years, and no new safety issues were identi-
`fied.13,14
`In this 12-month, phase 3, multicenter, ran-
`domized, double-blind, double-dummy, parallel-
`group study, called the Trial Assessing Injectable
`Interferon versus FTY720 Oral in Relapsing–
`Remitting Multiple Sclerosis (TRANSFORMS), we
`compared the efficacy and safety of fingolimod
`with that of intramuscular interferon beta-1a, an
`established therapy for multiple sclerosis.
`
`Methods
`
`Patients
`Patients were eligible to participate in the study
`if they were between 18 and 55 years of age, had
`received a diagnosis of multiple sclerosis that met
`the revised McDonald criteria,15 had disease with
`a relapsing–remitting course,16 had had at least
`one documented relapse during the previous year
`or at least two documented relapses during the
`previous 2 years, and had a score of 0 to 5.5 on
`the Expanded Disability Status Scale (EDSS)
`(ranging from 0 to 10, with higher scores indi-
`cating a greater degree of disability).17 Other
`exclusion criteria were a documented relapse or
`corticosteroid treatment within 30 days before ran-
`
`domization, active infection, macular edema, im-
`munosuppression (either drug- or disease-induced),
`and clinically significant coexisting systemic dis-
`ease. Previous recent therapy with either any type
`of interferon beta or glatiramer acetate was not a
`criterion for exclusion.
`The study was conducted in accordance with
`the International Conference on Harmonisation
`Guidelines for Good Clinical Practice18 and the
`principles of the Declaration of Helsinki.19 The
`protocol was approved by the institutional review
`board at each study site. All patients provided
`written informed consent before any study-related
`procedure was performed.
`
`Study Oversight
`A steering committee consisting of academic in-
`vestigators collaborated with the sponsor (No-
`vartis Pharma) to design the study and monitor
`its conduct. Data were collected by the site inves-
`tigators and analyzed by the sponsor. All the au-
`thors had access to all data, participated in all
`analyses and their interpretation, wrote the man-
`uscript, and decided to submit the manuscript
`for publication. The authors attest to the com-
`pleteness and accuracy of the data and the analy-
`ses. During the study, the investigators, participat-
`ing institutions, and sponsor agreed to maintain
`confidentiality of the data.
`
`Study Design
`Patients were randomly assigned to 12 months of
`treatment with oral fingolimod, at a daily dose of
`either 1.25 or 0.5 mg, or intramuscular interferon
`beta-1a (Avonex, Biogen Idec), at a weekly dose of
`30 μg. Randomization was performed centrally in
`blocks of six within each site and was stratified
`according to site. Study-group assignments were
`performed with the use of an interactive voice-
`response system. At each site, a treating neurolo-
`gist supervised medical management. A specially
`trained and certified20 examining neurologist de-
`termined EDSS scores at scheduled and unsched-
`uled visits. The examining neurologist or a trained
`technician calculated Multiple Sclerosis Function-
`al Composite (MSFC) scores, which included the
`average of scores on the timed 25-foot walk, the
`9-hole peg test, and the paced auditory serial-addi-
`tion test with a 3-second interstimulus interval.
`Each of these scores was converted to a z score on
`the basis of the combined study population at
`baseline as the reference population, with higher
`scores indicating improvement.21
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`403
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`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`During the trial, patients, study personnel, MRI
`evaluators, steering-committee members, and the
`study statistician were unaware of study-group as-
`signments and leukocyte counts. Capsules, sy-
`ringes, and packaging materials for active and
`placebo treatments were indistinguishable. Pa-
`tients were instructed to cover injection sites at
`visits and not to discuss adverse events with clini-
`cal evaluators. An independent physician moni-
`tored patients after the first dose of the oral study
`drug was administered and was instructed not to
`discuss heart-rate changes with patients or study
`personnel. Employees of the sponsor working in-
`dependently of the study team monitored first-
`dose safety data. An independent data and safety
`monitoring board evaluated overall safety in the
`fingolimod phase 3 program. No interim efficacy
`analysis was performed.
`
`Study Procedures
`Safety assessments were conducted during screen-
`ing, at baseline, and at months 1, 2, 3, 6, 9, and
`12. EDSS scores were determined every 3 months,
`and MSFC scores every 6 months. Standardized
`MRI scans were obtained at screening and at 12
`months and were analyzed centrally by the Image
`Analysis Center in Amsterdam.
`Relapse was defined as new, worsening, or re-
`current neurologic symptoms that occurred at least
`30 days after the onset of a preceding relapse, that
`lasted at least 24 hours without fever or infection,
`and that were accompanied by an increase of at
`least half a point on the EDSS or an increase of at
`least one point in two functional-systems scores
`or of at least two points in one functional-system
`score (excluding changes in bowel or bladder func-
`tion and cognition). Potential relapses triggered
`an unscheduled visit and were confirmed by the
`treating neurologist on the basis of blinded ex-
`amination by the examining neurologist. Progres-
`sion of disability was defined as a one-point in-
`crease in the EDSS score (or a half-point increase
`for patients with a baseline score ≥5.5) that was
`confirmed 3 months later in the absence of re-
`lapse. Additional methodologic details are avail-
`able in the Supplementary Appendix, available
`with the full text of this article at NEJM.org.
`
`Study End Points
`The primary efficacy end point was the annual-
`ized relapse rate, which was defined as the num-
`ber of confirmed relapses during a 12-month pe-
`riod. The two key secondary end points were the
`
`number of new or enlarged hyperintense lesions
`on T2-weighted MRI scans at 12 months and the
`time to confirmed disability progression.
`
`Statistical Analysis
`We based our sample-size estimates on a phase 2
`trial of fingolimod12 and a phase 3 trial of inter-
`feron beta-1a,22 which showed an annualized re-
`lapse rate of 0.33 for a 1.25-mg dose of fingolimod
`and of 0.55 for interferon beta-1a, a common stan-
`dard deviation of 0.9, and 57 study-drug discon-
`tinuations per year per group. Using the Wilcoxon–
`Mann–Whitney rank-sum test, we estimated that
`an enrollment of 425 patients per study group
`would be needed to provide a power of 90% at a
`two-sided significance level of 0.05.
`To control for type I errors, multiplicity adjust-
`ment was applied to testing for comparisons
`between fingolimod and interferon beta-1a in a
`hierarchical order, according to the dose of fin-
`golimod, for the study end points. Each test was
`performed at a significance level of 0.05. However,
`the lower-rank testing was performed only when
`every higher-rank test indicated statistical signifi-
`cance.
`The modified intention-to-treat cohort, which
`consisted of all patients who underwent random-
`ization and received at least one dose of a study
`drug, was the primary focus for efficacy and
`safety analyses. The study was designed to test the
`null hypothesis that there would be no significant
`differences in the annualized relapse rate between
`either of the fingolimod groups and the interfer-
`on group with the use of a negative binomial re-
`gression model with adjustment for study group,
`country, number of relapses in the previous 2 years,
`and baseline EDSS score. These prespecified co-
`variates were based on exploratory analyses of the
`phase 2 study data.12 Heterogeneity in efficacy ac-
`cording to whether patients had undergone previ-
`ous therapy was tested as a post hoc analysis with
`the use of the same negative binomial regression
`model, with the addition of the interaction term
`for therapy during the study and before baseline.
`Additional details concerning statistical methods
`are available in the Supplementary Appendix.
`
`R esults
`
`Study Population
`From May 2006 through September 2007, a total
`of 1292 patients underwent randomization at 172
`clinical centers in 18 countries. Of these patients,
`
`404
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`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`
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`

`

`ORAL FINGOLIMOD OR INTERFERON FOR RELAPSING MULTIPLE SCLEROSIS
`
`
`
`1573 Patients were assessed for eligibility
`
`231 Were excluded
`
`1292 underwent randomization
`
`426 Were assigned to receive
`fingolimod, 1.25 mg
`
`431Were assigned to receive
`fingolimod, 0.5 mg
`
`435 Were assigned to receive
`interferon beta-1a
`
`F 4Werenottreated
`
`% 2werenottreated
`
`
`429 Were included in the modified
`431 Were included in the modified
`intention-totreat and
`intentionto-treat and
`safety populations
`safety populations
`
`398 Completed 12-mo followup
`31 Discontinued follow-up
`9 Had an adverse event
`9Withdrew consent
`3 Had unsatisfactory therapeutic
`effect
`6 Had abnormal laboratory value
`3 Had abnormal test result
`1 Was lost to follow-up
`
`335 Completed study on study drug
`13 Completed study offstudy drug
`44 Discontinued study drug
`16 Had an adverse event
`9 Withdrew consent
`2 Had administrative problem
`5 Had unsatisfactory therapeutic
`effect
`7 Had abnormal laboratory value
`4 Had abnormal test result
`1 Had protocolviolation
`
`386 Completed 12-mo follow-up
`45 Discontinued follow-up
`9 Had an adverse event
`16 withdrew consent
`3 Had administrative problem
`7 Had unsatisfactory therapeutic
`effect
`1 Had abnormal laboratory value
`3 Had abnormal test result
`4Were lost to followup
`2 Had protocol violation
`
`380 Completed study on study drug
`6 Completed study off study drug
`51 Discontinued study drug
`12 Had an adverse event
`16 Withdrew consent
`3 Had administrative problem
`7 Had unsatisfactory therapeutic
`effect
`3 Had abnormal laboratory value
`4 Had abnormal test result
`4 Were lost to follow-up
`2 Had protocol violation
`
`
`
`420 Were included in the modified
`intention-totreat and
`safety populations
`
`369 Completed lZ-mo followup
`51 Discontinued follow-up
`26 Had an adverse event
`11Withdrew consent
`3 Had unsatisfactorytherapeutic
`effect
`4 Had abnormal laboratory value
`4 Had abnormal test result
`lWas lost to follow-up
`2 Died
`
`358 Completed study on study drug
`11 Completed study off study drug
`62 Discontinued study drug
`32 Had an adverse event
`10 Withdrew consent
`1 Had administrative problem
`5 Had unsatisfactory therapeutic
`effect
`8 Had abnormal laboratory value
`3 Had abnormal test result
`1 Was lost to fol low-up
`l Died
`1 Had a condition no longer
`requiring study drug
`
`
`
`Figure l. Enrollment and Outcomes.
`The numbers of patients who discontinued a study drug include all those in the modified intention-to-treat population, regardless of
`whether they completed the 12-month follow-up.
`
`12 were excluded before receiving any study drug
`or undergoing any safety or efficacy assessments
`because they did not meet eligibility criteria (Fig. 1).
`Baseline characteristics were similar across the
`
`study groups and were consistent with a popula-
`tion of patients with clinically active, relapsing—
`remitting multiple sclerosis (Table 1). In all, 1153
`patimts (89%) completed the study, and 1123 (87%)
`
`N ENGLJ MED 3615 mimosa
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`rsanuanv 4, 2010
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`
`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
`
`Table 1. Baseline Characteristics of the Patients.*
`
`Characteristic
`
`Demographic characteristics
`
`Age — yr
`
`Mean
`
`Median (range)
`
`Female sex — no. (%)
`
`White race — no. (%)†
`
`Clinical characteristics
`
`Interval from onset of symptoms to randomization — yr
`
`Mean
`
`Median (range)
`
`Relapses in previous yr — no.
`
`Mean
`
`Median (range)
`
`Relapses in previous 2 yr — no.
`
`Mean
`
`Median (range)
`
`EDSS score‡
`
`Fingolimod
`
`Interferon Beta-1a
`(N = 435)
`
`1.25 mg (N = 426)
`
`0.5 mg (N = 431)
`
`35.8±8.4
`
`36.7±8.8
`
`36 (18–54)
`
`37 (18–55)
`
`293 (68.8)
`
`404 (94.8)
`
`282 (65.4)
`
`404 (93.7)
`
`36.0±8.3
`
`36 (18–55)
`
`295 (67.8)
`
`408 (93.8)
`
`7.3±6.0
`
`6 (0–33)
`
`1.5±0.9
`
`1 (0–7)
`
`2.2±1.2
`
`2 (1–8)
`
`7.5±6.2
`
`6 (0–34)
`
`1.5±1.2
`
`1 (0–20)
`
`2.3±2.2
`
`2 (1–40)
`
`7.4±6.3
`
`6 (0–40)
`
`1.5±0.8
`
`1 (0–6)
`
`2.3±1.2
`
`2 (1–12)
`
`2.24±1.33
`
`2.19±1.26
`
`Mean
`
`Median (range)
`
`Treatment history§
`
`Any therapy — no. (%)
`
`Any interferon beta
`
`Glatiramer acetate
`
`Natalizumab
`
`MRI findings¶
`
`Patients with no gadolinium-enhancing lesions on
`T1-weighted images — no./total no. (%)
`
`No. of gadolinium-enhancing lesions on T1-weighted
`images
`
`Mean
`
`Median (range)
`Volume of lesions on T2-weighted images — mm3
`Mean
`
`Median (range)
`Normalized brain volume — cm3
`Mean
`
`Median (range)
`
`2.21±1.31
`
`2.0 (0–5.5)
`
`249 (58.5)
`
`209 (49.1)
`
`67 (15.7)
`
`3 (0.7)
`
`2.0 (0–5.5)
`
`2.0 (0–5.5)
`
`238 (55.2)
`
`219 (50.8)
`
`57 (13.2)
`
`4 (0.9)
`
`245 (56.3)
`
`207 (47.6)
`
`67 (15.4)
`
`1 (0.2)
`
`270/412 (65.5)
`
`288/427 (67.4)
`
`268/425 (63.1)
`
`1.49±4.77
`
`0 (0–66)
`
`0.98±2.81
`
`0 (0–29)
`
`1.06±2.80
`
`0 (0–36)
`
`5085±5962
`
`5170±6642
`
`4924±5711
`
`3096 (0–38,870)
`
`2382 (0–46,280)
`
`2901 (0–38,712)
`
`1526.2±76.4
`
`1524.1±83.9
`
`1526.7±77.9
`
`1528 (1300–1794) 1526 (1185–1862)
`
`1533 (1231–1762)
`
`* Plus–minus values are means ±SD. None of the between-group comparisons were significant.
`† Race was self-reported.
`‡ Scores on the Expanded Disability Status Scale (EDSS) range from 0 to 10, with higher scores indicating a greater de-
`gree of disability.
`§ Patients may have received more than one treatment before study entry.
`¶ All MRI findings were based on all images that could be evaluated.
`
`406
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`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`
`
`

`

`Oral Fingolimod or Interferon for Relapsing Multiple Sclerosis
`
`continued to receive the assigned study drug.
`A slightly greater proportion of patients assigned
`to fingolimod at a dose of 1.25 mg discontinued
`treatment or study participation because of adverse
`events, as compared with the other two groups.
`Other reasons for discontinuation were equally
`distributed among the study groups.
`
`Efficacy
`Relapse
`Table 2 summarizes the relapse rates, MRI out-
`comes, and results with respect to disability pro-
`gression. There was a significantly greater re-
`duction in the annualized relapse rates in both
`fingolimod groups than in the interferon group.
`Other relapse-related measures also significantly
`favored fingolimod, including the proportion of
`patients who were relapse-free, the proportion with
`multiple relapses, and the time to the first re-
`lapse (Fig. 2). There was no significant difference
`in the magnitude of the treatment effect between
`patients who had previously undergone disease
`treatment and those who had not.
`
`MRI Outcomes
`Patients in the two fingolimod groups had signifi-
`cantly fewer new or enlarged hyperintense lesions
`on T2-weighted images and gadolinium-enhanc-
`ing lesions on T1-weighted images at 12 months
`than did those in the interferon group. The mean
`percent reduction in brain volume from baseline
`to 12 months was significantly lower in the two
`fingolimod groups than in the interferon group.
`Changes in the volume of lesions on unenhanced
`T2- or T1-weighted images at 12 months did not
`differ significantly among the study groups.
`
`Disability
`Confirmed disability progression was infrequent
`in all the study groups. There were no significant
`differences in the time to the progression of dis-
`ability or in the proportion of patients with con-
`firmed progression among the study groups.
`
`Adverse Events
`Serious Events
`Adverse events were reported for similar propor-
`tions of patients in the three study groups, rang-
`ing from 86 to 92% (Table 3). Of these events, 87
`to 90% were mild or moderate in severity. Serious
`adverse events and those leading to the discontinu-
`ation of a study drug were most frequent in the
`patients assigned to fingolimod at the 1.25-mg
`
`dose. The most common serious events in this
`group were bradycardia and atrioventricular block.
`All such events were observed after the first ad-
`ministration of fingolimod, and most were asymp-
`tomatic but were reported as serious adverse events
`because protocol-defined discharge criteria at
`6 hours were not met, leading to mandatory hos-
`pitalization. All other serious adverse events oc-
`curred in fewer than four patients (<1%) in any
`study group.
`There were two deaths during the trial, both
`in the group assigned to fingolimod at a dose of
`1.25 mg. One of these deaths was caused by dis-
`seminated primary varicella zoster infection in a
`patient with no history of chicken pox and a nega-
`tive baseline varicella zoster antibody titer who was
`exposed to a child with chicken pox during an
`8-day course of corticosteroids (intravenous and
`then oral methylprednisolone) for a relapse of mul-
`tiple sclerosis. Fingolimod was discontinued af-
`ter 317 days of therapy, and intravenous antiviral
`therapy was started, but the patient died 3 days
`later. The second death was caused by herpes sim-
`plex encephalitis, which developed after 339 days
`of fingolimod therapy. A 3-day course of intrave-
`nous methylprednisolone was initially adminis-
`tered for suspected relapse of multiple sclerosis,
`followed by antiviral therapy starting 1 week af ter
`presentation. The patient died approximately
`2 months later.
`Two additional patients who received fingoli-
`mod at a dose of 1.25 mg died after the study
`ended. One patient, who had a baseline EDSS score
`of 5.0 at 3 years after the onset of disease, discon-
`tinued fingolimod after 11 months because of
`neurologic deterioration. Progressive multifocal
`leukoencephalopathy was ruled out. The patient’s
`condition continued to decline, aspiration pneu-
`monia developed, and the patient died 6 months
`after study discontinuation. The other patient died
`from metastatic breast cancer 10 months after
`discontinuing fingolimod.
`
`Infections
`The overall incidence of infection was similar
`across the study groups (ranging from 51 to 53%),
`whereas serious infections occurred in 0.2 to 1.7%
`of patients (Table 3). The only serious infections
`that were reported in more than one patient were
`appendicitis and herpesvirus infections. Among
`patients assigned to receive fingolimod, herpes-
`virus infections were diagnosed in 23 patients in
`the 1.25-mg group (5.5%) and 9 patients in the
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` 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
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`286/354 (80.8)
`
`337/374 (90.1)
`
`321/352 (91.2)
`
`165/361 (45.7)
`
`204/372 (54.8)
`
`168/350 (48.0)
`
`Patients with no gadolinium-enhancing lesions on T1-weighted
`
`images — no./total no. (%)
`
`Patients with no new or enlarged lesions on T2-weighted images
`
`— no./total no. (%)
`
`0 (0 to 24)
`
`0.51±1.86
`
`1 (0 to 63)
`
`2.6±5.8
`
`9 (2.1)
`
`30 (7.0)
`
`90 (20.9)
`
`302 (70.1)
`
`0 (0 to 11)
`
`0.23±0.97
`
`0 (0 to 38)
`
`1.7±3.9
`
`1 (0.2)
`
`11 (2.6)
`
`63 (14.7)
`
`354 (82.5)
`
`0 (0 to 6)
`
`0.14±0.58
`
`1 (0 to 26)
`
`1.5±2.7
`
`2 (0.5)
`
`19 (4.5)
`
`61 (14.5)
`
`338 (80.5)
`
`Median (range)
`
`Mean
`
`Gadolinium-enhancing lesions on T1-weighted images — no.
`
`Median (range)
`
`Mean
`
`New or enlarged lesions on T2-weighted images — no.
`
`MRI outcome§
`
`≥3 relapses
`
`2 relapses
`
`1 relapse
`
`0 relapse
`
`<0.001
`
`69.3 (64.8 to 73.8)
`
`82.6 (79.0 to 86.3)
`
`79.8 (75.9 to 83.7)
`
`Patients with no confirmed relapse — % (95% CI)‡
`
`0.53 (0.43 to 0.65)
`
`0.26 (0.19 to 0.34)
`
`0.33 (0.26 to 0.42)
`
`0.31 (0.22 to 0.41)
`
`0.15 (0.10 to 0.23)
`
`0.17 (0.11 to 0.25)
`
`Rate for patients who had previous disease-modifying therapy
`
`— no. (95% CI)
`
`Rate for patients who had no previous disease-modifying
`
`therapy — no. (95% CI)†
`
`Patients with confirmed relapse — no. (%)
`
`<0.001
`
`<0.001
`
`0.33 (0.26 to 0.42)
`
`0.16 (0.12 to 0.21)
`
`0.20 (0.16 to 0.26)
`
`Annualized relapse rate (primary end point) — no. (95% CI)
`
`vs. Interferon Beta-1a
`Fingolimod, 0.5 mg,
`
` vs. Interferon Beta-1a
`Fingolimod, 1.25 mg,
`
`0.5 mg (N = 429)
`
`1.25 mg (N = 420)
`
`P Value
`
`Interferon Beta-1a
`
`(N = 431)
`
`Fingolimod
`
`Relapse
`
`End Point
`
`Table 2. Clinical and MRI Results at 12 Months.*
`
`<0.001
`
`0.01
`
`<0.001
`
`<0.001
`
`0.37
`
`<0.001
`
`0.004
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`408
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`
`
`

`

`Oral Fingolimod or Interferon for Relapsing Multiple Sclerosis
`
`* Plus–minus values are means ±SD. Data are for the modified intention-to-treat population, which consisted of all patients who underwent randomization and received at least one dose
`
`of a study drug.
`
`† Among patients receiving fingolimod, P values for the interaction between therapy during the study period and before baseline, as compared with the interferon group, were 0.49 for
`
`∥ Scores on the Multiple Sclerosis Functional Composite (MSFC) are expressed as z scores, with higher scores indicating improvement in disability.
`¶ Scores on the Expanded Disability Status Scale (EDSS) range from 0 to 10, with higher scores indicating a greater degree of disability.
`§ All MRI outcomes were based on all images that could be evaluated.
`‡ Values are Kaplan–Meier estimates from the analysis of time to first relapse.
`
`the 1.25-mg group and 0.81 for the 0.5-mg group.
`
`Median (range)
`
`Mean
`
`Change from baseline in MSFC z score∥
`
`Median (range)
`
`Mean
`
`Change from baseline in EDSS score¶
`
`92.1 (89.4 to 94.7)
`
`94.1 (91.8 to 96.3)
`
`93.3 (90.9 to 95.8)
`
`Patients with no confirmed disability progression — % (95% CI)‡
`
`<0.001
`
`<0.001
`
`–0.45±0.73
`
`–0.31±0.65
`
`–0.30±0.65
`
`–0.40 (–3.40 to 2.60)
`
`–0.20 (–3.70 to 2.00)
`
`–0.20 (–2.90 to 2.20)
`
`0.17
`
`0.09
`
`15.0±70.3
`
`24.1±127.3
`
`34.7±122.3
`
`1.2 (–100.0 to 636.4)
`
`4.4 (–100.0 to 1291.8)3.2 (–100.0 to 2061.1)
`
`Disability
`
`Median (range)
`
`Mean
`
`Change from baseline in brain volume — %
`
`Median (range)
`
`Mean
`
`Change from baseline in volume of hypointense lesions on
`
`T1-weighted images — %
`
`0.63
`
`0.48
`
`10.4±42.8
`
`9.9±37.3
`
`6.7±31.0
`
`3.0 (–60.7 to 494.1)
`
`6.2 (–100.0 to 318.2)
`
`2.9 (–76.1 to 247.1)
`
`Median (range)
`
`Mean
`
`<0.001
`
`<0.001
`
`0 (0 to 2238)
`
`50.68±198.16
`
`0 (0 to 1359)
`
`22.61±111.59
`
`0 (0 to 1442)
`
`19.54±109.10
`
`Median (range)
`
`Mean
`
`Volume of gadolinium-enhancing lesions on T1-weighted images
`
`— mm3
`
`Change from baseline in volume of hyperintense lesions on
`
`T2-weighted images — %
`
`0.02
`
`0.06
`
`0.25
`
`0.02
`
`0.50
`
`–0.01 (–5.30 to 1.70)
`
`0.20 (–2.10 to 4.70)
`
`0.06 (–1.90 to 3.60)
`
`<0.001
`
`–0.03±0.48
`
`0.04±0.42
`
`0.08±0.46
`
`0 (–2.0 to 3.0)
`
`0 (–3.0 to 2.5)
`
`0 (–3.0 to 5.0)
`
`0.01±0.78
`
`–0.08±0.79
`
`–0.11±0.90
`
`n engl j med 362;5 nejm.org february 4, 2010
`
`The New England Journal of Medicine
`
` Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`409
`
`
`
`

`

`
`
`30
`70
`
`5 90
`g
`i
`3;
`60
`i
`g 50
`0
`
`0
`
`Ofingolimod, 0.5 mg
`Oi-‘tngolimod, 1.25 mg
`O Interferon
`50
`
`100
`
`33%
`30%
`699g
`
`200
`
`250
`
`300
`
`350
`
`150
`
`Days to first Relapse
`
`Figure 2. Annualized Relapse Rate at 12 Months and the Time to the First
`Relapse.
`Panel A shows the annualized rate ofrelapse from baseline to 12 months,
`with adjustment for study group, country, number of relapses in the previ-
`ous 2 years, and baseline disability score. Panel B shows Kaplan—Meier es-
`timates ofthe time to the first relapse, indiating the proportion of relapse-
`free patients (P<0.001 for both comparisons with interferon).
`
`
`
`who received the 1.25mg dose (0 9%) and in three
`patients who received the 0.5-mg dose (0.7%). Symp-
`toms resolved within 24 hours without treatment.
`There were no cases of syncope. Second-degree
`atrioventricular block was reported during the first
`day of treatment in four patients receiving fingoli-
`mod — three in the 1.25-mg group (0.7%) and
`one in the 0.5-mg group (0.2%). ’IWO patiatts in the
`1.25-mg group had mild symptoms (intermittent
`dyspnea and dizziness in one patient and chest
`pain and palpitations in the other patient), which
`resolved within 24 hours without treatment. No
`significant effect on heart rate or atrioventricular
`conduction was observed with continued adminis-
`tration ofthe drug. Increases in mean arterial pres-
`sure oocurred in both fingolimod groups (3 mm Hg
`in the 1.25-mg group and 2 mm Hg in the 0.5-mg
`group) during the first 6 months and remained
`stable between 6 and 12 months.
`
`Ophthalmologic Events
`Macular edema was confirmed on central review
`in six patients receiving fingolimod — four in the
`1.25-mg group (1%) and two in the 0.5—mg group
`(0.5%). In three patients, the macular edema was
`asymptomatic and diagnosed by ophthalmologic
`examination. Five of the six cases were detected
`within 4 months after the start oftherapy. The ede-
`ma resolved within 3 months after discontinuation
`of fingolimod in four patients, was unchanged
`1 month after discontinuation in one patiatt, and
`was reduced 8 months after discontinuation in
`one patient. Mean visual acuity and retinal thick—
`ness were similar across the study groups and
`remained stable over the 12-month study period.
`
`Neoplasms
`Ten localized skin cancers were reported, and all
`were successfully excised: five basal-cell carcino-
`mas in the fingolimod groups (two in the 1.25-mg
`group and three in the 0.5—mg group) and one in
`the interferon group; three melanomas (all lim-
`ited to the epidermis) in the group receiving the
`0.5-mg dose of fmgolimod; and one squamous-
`cell carcinoma in the interferon group. Of the 10
`skin cancers, 8 were diagnosed at the first study
`examination by a dermatologist 4 to 12 months
`after enrollment. Breast cancer was reported in
`two patients in each of the fingolimod groups;
`three cases were diagnosed within 4 months after
`the initiation of the drug, and one was diagnosed
`11 months after enrollment.
`
`Tl: NEW ENGLAND JOURNAL of MEDICINE
`
`A
`
`0.6
`
`0.5
`
`0.4
`
`'l
`E
`2 £
`5: g 03
`"i 2
`it? 020.1
`0.0
`
`Interferon
`Fingolimod,
`Fingolimod,
`
`(N=431)
`0.5 mg
`1.25 mg
`(N=429)
`(N=420)
`
`B
`
`100
`
`
`
`
`0.5-mg group (2.1%), as well as in 12 patients in
`the interferon group (2.8%). In 41 of these 44
`patients (93%), the infections were mild.
`
`Cardiovascular Events
`There was a transient, dose-dependent reduction
`in the heart rate that developed within 1 hour after
`the initial administration of fmgolimod, which is
`consistent with the findings in previous clinical
`trials.1’~13v13 Mean maximal decreases were reached
`
`after 4 to 5 hours of 12 beats per minute in the
`group that received the 1.25-mg dose and 8 beats
`per minute in the group that received the 0.5-mg
`dose, with the changes starting to attenuate within
`6 hours after the first administration ofthe drug.
`Most patients had asymptomatic reductions in the
`heart rate ofless than 20 beats per minute. Mild-
`m—moderate symptomatic bradycardia after the first
`dose offingolimod was reported in four patients
`
`410
`
`N ENGLJ mo 361;; NEJM.ORG
`
`FEBRUARY 4, 2010
`
`The New England Journal of Medicine
`
`Copyright © 2010 Massachusetts Medical Society All rights reserved
`
`

`

`Oral Fingolimod or Interferon for Relapsing Multiple Sclerosis
`
`Pulmonary Events
`A mild reduction (2 to 3%) in the mean forced ex-
`piratory volume in 1 second (FEV1) was observed
`in both fingolimod groups at 1 month, with no
`further reductions thereafter. No changes in lung
`volumes or diffusion capacity were seen.
`
`Laboratory Measurements
`Reflecting fingolimod’s mechanism of action, pe-
`ripheral-blood lymphocyte counts were reduced af-
`ter 1 month by 77% in the group that received the
`1.25-mg dose of fingolimod and by 73% in the
`group that receive