The n e w e ng l a n d j o u r na l of m e dic i n e

clinical therapeutics

Fingolimod for Multiple Sclerosis

Daniel Pelletier, M.D., and David A. Hafler, M.D.

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the authors’ clinical recommendations.

A 37-year-old man with multiple sclerosis was evaluated for consideration of oral im-
munotherapy. Six years earlier, he had reported acute monocular visual disturbance.
The diagnosis of multiple sclerosis was subsequently confirmed by means of exami-
nation of cerebrospinal fluid, which revealed an increased IgG index and oligoclonal
banding, and by abnormal results on magnetic resonance imaging (MRI). There was
no family history of multiple sclerosis. Daily injections of glatiramer acetate were ini-
tiated at the time of diagnosis, but two consecutive annual brain MRI scans revealed
substantial disease activity. He was then switched to interferon beta therapy, but this
treatment was discontinued after the patient had two episodes of acute neurologic
worsening. Monthly natalizumab therapy was then considered, but a test for JC virus
antibodies was positive. Neurologic examination showed disk pallor and visual acu-
ity of 20/40 in the right eye, partial internuclear ophthalmoplegia, wide-based gait,
and posterior column deficits in both legs. The patient was referred to a specialist in
multiple sclerosis for consideration of oral fingolimod therapy.

The Cl inic a l Probl em

Multiple sclerosis is an inflammatory disease of the central nervous system that From the Yale Multiple Sclerosis Center,
shares several genetic variants with other autoimmune diseases. It affects approxi- Departments of Neurology and Immu-
nobiology, Yale School of Medicine, New
mately 400,000 people in the United States and 2.5 million people worldwide, with Haven, CT. Address reprint requests to
a prevalence of approximately 1 case per 1000 persons in white populations (ratio Dr. Pelletier at the Department of Neu-
of females to males, >2:1).1 The vast majority of patients with multiple sclerosis rology, 15 York St., LLCI-709, P.O. Box
208018, New Haven, CT 06520-8018, or
(approximately 85%) have a relapsing form of the disease at onset (relapsing–remit- at daniel.pelletier@yale.edu.
ting course). More than half of these patients have increasing and sustained dis-
ability between the acute attacks and make a transition to secondary progressive N Engl J Med 2012;366:339-47.
Copyright © 2012 Massachusetts Medical Society.
multiple sclerosis within 10 to 20 years after diagnosis.2,3
The life expectancy of patients with multiple sclerosis is reduced; in one study
(Canadian registry),4 life expectancy was reduced by 4 to 7 years, and in another
(Danish registry),5 it was reduced by up to 10 to 12 years. A patient’s quality of life
is markedly affected by physical symptoms, including fatigue, pain, and difficulty
with mobility, and by problems with social functioning and impaired mood and
affect. The costs of drugs and other medical care for patients with multiple scle-
rosis are substantial; in the United States alone, the costs have been estimated at
$14 billion per year.6 The total mean annual direct and indirect costs (associated with
loss of work and productivity) per patient, in 2004 dollars, are $47,215.

PATHOPH YSIOL O GY A ND EFFEC T OF THER A PY

Multiple sclerosis is an autoimmune disease in which lymphocytes migrate out of

lymph nodes into the circulation, cross the blood–brain barrier, and aggressively

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 The n e w e ng l a n d j o u r na l
target putative myelin antigens in the central ner-
vous system, causing inflammation, demyelin-
ation, neuroaxonal injury, astrogliosis, and ulti-
mately neurodegeneration.7 Lymphocyte migration
out of lymph nodes is dependent on engagement
of a G protein–coupled receptor, S1P1, which is
present on the surface of the lymphocyte.8-10 The
ligand for this receptor, the lipid sphingosine
S1P, is found predominantly in the serum and
lymph. A gradient in the concentration of S1P
(low in the lymph node and higher in the circula-
tion) induces the migration of lymphocytes from
the lymph node into the circulation (Fig. 1A).
Fingolimod, also known as FTY720, is struc-
turally similar to S1P. Fingolimod is phosphory-
lated in vivo after oral ingestion and can then
engage four of the five known S1P receptors
(S1P1, S1P3, S1P4, and S1P5). In lymph nodes,
fingolimod initially acts as an agonist of the
S1P1 receptor and then becomes a highly potent
functional antagonist, leading to internalization
of S1P1 receptors on lymph-node T cells11,12 (Fig.
1B). As a result, lymphocytes no longer respond
to the gradient of S1P and remain sequestered in
the lymph node.
Although patients with multiple sclerosis who
are treated with fingolimod have a decrease in
the total mean lymphocyte count, the effects on
lymphocyte subsets are rather specific: the drug
blocks the exit of naive and central memory
lymphocytes, but not effector memory T cells,
from the lymph node.13,14 This effect appears to
be a consequence of the fact that naive T cells
and central memory cells, but not effector mem-
ory cells, express the chemokine receptor CCR7,
which induces homing to the lymph nodes. As a
consequence, these cells recirculate to the lymph
nodes and are sequestered there, with effector
memory cells representing the major T-cell popu-
lation in the blood of patients being treated with
fingolimod. These circulating effector memory
cells may have a suppressive function, down-
regulating the autoimmune response.15 Thus,
fingolimod may work both by sequestering auto-
reactive T cells in the secondary lymph nodes
and by enhancing the functionality and frequency
of potent circulating regulatory T cells.
Other studies suggest that fingolimod may
also have a direct effect on the central nervous
system, since sphingolipids and S1P receptors
are expressed on oligodendrocytes, astrocytes,
microglial cells, and neurons (Fig. 2). Although
this effect is still debated,16 it is possible that
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of m e dic i n e
fingolimod modulates the survival of human
oligodendrocyte progenitor cells, potentially af-
fecting myelin repair17,18 and astrocyte prolifera-
tion, migration, and gliosis.19 In addition, the
S1P signaling pathway could have neuroprotec-
tive effects, as shown in preliminary in vitro
studies.20,21
CL INIC A L E V IDENCE
The efficacy of oral fingolimod for the treatment
of multiple sclerosis was investigated in two large,
phase 3, double-blind, randomized trials involv-
ing patients with relapsing–remitting disease.
Patients with progressive forms of multiple scle-
rosis were excluded. The FTY720 Research Evalu-
ating Effects of Daily Oral Therapy in Multiple
Sclerosis trial (FREEDOMS; ClinicalTrials.gov
number, NCT00289978) enrolled 1272 patients
who were randomly assigned to receive oral fin-
golimod at a dose of 0.5 mg daily or 1.25 mg
daily or placebo tablets for 2 years.22 Neurologic
evaluations included measures of acute relapses
and disability (as assessed with the use of the
Expanded Disability Status Scale [EDSS]). The
annualized rate of relapse, which was the pri-
mary end point, was 0.18 with the 0.5-mg regi-
men, 0.16 with the 1.25-mg regimen, and 0.40
with placebo (P<0.001 for the comparison of ei-
ther regimen with placebo). The cumulative prob-
ability of progression of disability (confirmed
after 3 months) as assessed on the basis of the
EDSS score was 17.7% with 0.5 mg of fingolimod
and 16.6% with 1.25 mg of fingolimod, as com-
pared with 24.1% with placebo (P = 0.03 and
P = 0.01 for the comparison of the two fingoli-
mod regimens, respectively, with placebo). Fin-
golimod was also associated with a reduction in
the number of new or enlarging lesions on T2-
weighted images and of gadolinium-enhancing
lesions on MRI at year 2. Reductions in whole-
brain volume were smaller with fingolimod than
with placebo at both 12 and 24 months.
The Trial Assessing Injectable Interferon Ver-
sus FTY720 Oral in Relapsing–Remitting Multi-
ple Sclerosis (TRANSFORMS, NCT00340834) en-
rolled 1292 patients who were randomly assigned
to receive oral fingolimod at a dose of 0.5 mg
daily or 1.25 mg daily or intramuscular inter-
feron beta-1a (30 μg weekly for 1 year).23 Several
of the trial participants were already receiving
an interferon regimen, which was potentially a
confounding factor in this study involving an
 clinical ther apeutics

Figure 1. Mechanism of Action of Fingolimod.

Afferent naive T cells migrate through lymph nodes, are activated, and egress through an S1P–S1P1-receptor gradient (Panel A). Fingolimod
(red) down-regulates (internalizes) S1P1 receptors on T cells, producing lymphocyte sequestration (Panel B).

active comparative intervention, since some pa- sponse in them. The annualized relapse rate, the
tients may have been randomly assigned to a primary end point, was 0.16 in the group that
therapy that had already failed to effect a re- received 0.5 mg of fingolimod, 0.20 in the group

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 2. Cellular Targets of Fingolimod.

Neurons, oligodendrocytes, astrocytes, and microglia are central nervous system cellular targets of fingolimod. The distribution of S1P
receptors on neural cells is shown. Commas in subscripts denote “and” (e.g., S1P1,3 denotes S1P1 and S1P3).

that received 1.25 mg of fingolimod, and 0.33 in
the interferon group (P<0.001 for the compari-
son of either fingolimod regimen with interfer-
on). No differences were found with respect to
confirmed progression of disability, as assessed
with the use of the EDSS. MRI results supported
the primary findings.
CL INIC A L USE
In September 2010, the Food and Drug Adminis-
tration (FDA) approved fingolimod (0.5 mg given
orally once a day) as a treatment aimed at reduc-
ing the frequency of clinical exacerbations and
delaying the progression of physical disability in
patients with relapsing forms of multiple sclero-
sis. No formal contraindications are described.
Fingolimod was the first oral therapy approved by
the FDA for the treatment of multiple sclerosis.
Although fingolimod has been approved as a
first-line drug for the treatment of multiple scle-
rosis, we strongly believe that this agent should
be reserved as a second-line drug until further
long-term safety investigations have allowed for
the evaluation of the risks of infectious compli-
cations and secondary cancers (see the section
below on adverse effects). A substantial number
of patients with multiple sclerosis have a good
response to first-line drugs that have minimal
side effects; therefore, it seems prudent to initi-
ate treatment with these drugs at the first evi-
dence of a clinically isolated syndrome in a patient
with abnormal MRI findings that are consistent
with a demyelinating process (Fig. 3).25-28 How-

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 clinical ther apeutics
ever, considering the apparent benefits from the
greater clinical efficacy of the agents affecting
T-cell migration (natalizumab and fingolimod)
and the consequences of chronic inflammation
of the central nervous system associated with
multiple sclerosis, we recommend a relatively low
threshold for initiating second-line therapies
when permanent clinical signs of central nervous
system injury are present. Natalizumab therapy
has been shown to be associated with an in-
creased risk of progressive multifocal leukoen-
cephalopathy, and this risk has been shown to
correlate with the presence of anti–JC virus anti-
bodies.29-31 Therefore, we recommend that the
choice between natalizumab and fingolimod be
based principally on the results of tests for these
antibodies.
We further recommend that intravenous im-
munosuppressive agents (e.g., cyclophosphamide),
monoclonal-antibody therapies (e.g., rituximab or
alemtuzumab), or other maintenance oral immu-
nosuppressants (e.g., methotrexate, mycopheno-
late, or azathioprine), which are not FDA-approved
for the treatment of multiple sclerosis, should
now be considered as third-line options that
would be appropriate for consideration only af-
ter the patient has had an inadequate response
to or side effects from fingolimod and natalizu­
mab. Mitoxantrone, an approved therapy that is
still used by some clinicians specializing in the
care of patients with multiple sclerosis, is no
longer a treatment option in our clinical prac-
tice, mainly because of the long-term risk of
leukemia associated with this agent.32
Before the initiation of fingolimod therapy,
several specific laboratory tests and other assess-
ments should be performed. These include mea-
surement of total and differential leukocyte
counts, aminotransferase levels, bilirubin levels,
and varicella–zoster antibody titers (if negative,
vaccination 1 month before initiation of fingoli-
mod therapy should be considered); electrocardi-
ography (especially if any personal or familial
cardiovascular risk factors are present); and spi-
rometry (if pulmonary risk factors are present).
For patients who present with electrocardio-
graphic abnormalities, referral to a cardiologist
is recommended before the initiation of fingoli-
mod therapy. Special attention should be given
to patients who have evidence of atrioventricular
conduction block and to patients who are taking
drugs known to alter conduction (e.g., psycho-
tropic agents, beta-blocker drugs, and calcium-
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Relapsing–remitting MS or
clinically isolated syndrome
(with abnormal MRI scan)
Interferon beta or glatiramer acetate
with yearly MRI monitoring
Clinically and Inadequate response:
radiologically stable ≥1 relapse or new
white-matter lesions
on MRI, or both
Natalizumab if Fingolimod if positive
negative for JC for JC virus antibodies
virus antibodies
Figure 3. Decision-Making Therapeutic Algorithm, Including Newly Approved
Fingolimod, for Patients with Relapsing Forms of Multiple Sclerosis (MS).
An abnormal MRI scan was one that showed evidence of lesion dissemina-
tion in space (not necessarily dissemination in time) according to the criteria
in Polman et al.24
channel blockers).33 Referrals to ophthalmolo-
gists and dermatologists are recommended, at
least until the actual risk of macular edema and
skin cancer is known (see the section on adverse
effects).
No adjustments of the dose of fingolimod are
necessary in patients who have mild or moderate
hepatic or renal impairment or in those who are
elderly. However, caution is warranted in these
populations. Patients undergoing dialysis or plas-
mapheresis do not have enhanced removal of
fingolimod from the blood, and therefore do not
require dose adjustment.
The patient’s vital signs must be monitored
for 6 hours after the first oral dose is adminis-
tered, to detect any decrease in the heart rate.
The drug should be discontinued if bradycardia
is documented. The observation of vital signs
does not require hospitalization and can be per-
formed in an outpatient clinical office. No other
immediate reactions have been reported. The pa-
tient should then be reevaluated clinically every
month to assess the response to treatment, as
well as to observe any side effects. Measurement
of leukocyte counts and aminotransferase and
bilirubin levels should be repeated every 3 months.
A repeat ophthalmologic evaluation should be
343
 The n e w e ng l a n d j o u r na l
performed 3 months after the initiation of fin-
golimod therapy and every 6 months thereafter;
annual dermatologic evaluations are also recom-
mended.
As with several other FDA-approved therapies
for multiple sclerosis, the safety and efficacy of
fingolimod have not been evaluated formally in
children. In addition, there are no data from
adequately controlled studies of fingolimod ther-
apy in pregnant women; therefore, it is a preg-
nancy category C drug, and we do not recom-
mend its use during pregnancy. Women with
multiple sclerosis who could become pregnant
should use effective contraception during treat-
ment and for 2 months after discontinuation of
treatment. It has been shown that fingolimod is
excreted in the milk of rodents; therefore, the
drug should be discontinued for at least 2 months,
or not initiated at all, in women who wish to
breast-feed.
Discontinuation of fingolimod, for reasons
such as pregnancy, lack of therapeutic response,
or undesirable side effects, does not require ta-
pering of the dose. If a patient interrupts fingol­
imod therapy for more than 2 weeks and then
resumes treatment, monitoring of vital signs for
6 hours is again necessary.
The yearly wholesale price of fingolimod, as
currently listed, is approximately $52,200.34 Addi-
tional costs for services related to administration
of the first dose (e.g., 6-hour monitoring of vital
signs), referral visits, and tests associated with
monitoring vary considerably according to the lo-
cal medical care environment and geographic area.
A DV ER SE EFFEC T S
The safety profile of oral fingolimod therapy in
patients with multiple sclerosis is derived from
large pharmacologic databases and from phase 2,
phase 3, and extension studies.22,23,35,36 Further-
more, a risk-evaluation and mitigation strategy
(REMS) has been developed to educate patients
and providers about the long-term risks. However,
unlike the case with natalizumab (and perhaps
unfortunately), there is no mandatory monitor-
ing program for fingolimod. It is important that
clinicians familiar with fingolimod and the po-
tential complications associated with it monitor
patients and actively report cases of unexpected
adverse events.
One death has been reported in the post-
marketing period after the administration of a
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of m e dic i n e
single dose of fingolimod.37 As of this writing,
the exact cause of death has not been deter-
mined, and the role of fingolimod can neither
be confirmed nor ruled out.
There were two deaths reported during the
TRANSFORMS trial, both in the group assigned
to the higher-dose fingolimod regimen. In one of
these patients, a primary disseminated herpes zos-
ter infection developed after the patient was ex-
posed to chicken pox during the course of intra-
venous methylprednisolone treatment for a relapse
of multiple sclerosis; the second patient had her-
pes simplex encephalitis. It is not clear whether
fingolimod contributed to the deaths, since both
cases involved the use of glucocorticoids in the
context of a clinical relapse; however, given the
mechanism of action of fingolimod, it is highly
plausible that these deaths were attributable to
fingolimod therapy. There was also a slight
increase in the incidence of mild infections,
mainly infections of the lower respiratory tract
(bronchitis and pneumonia) (FREEDOMS study)
and herpesvirus infections (primarily among pa-
tients receiving 1.25 mg of fingolimod).
The most common serious adverse effects re-
ported in previous studies were cardiovascular
events, including bradycardia (in 1 to 3% of pa-
tients) and first-degree or second-degree atrio-
ventricular block (in <1%). Most of these events
were asymptomatic, were observed during the
administration of the first oral dose, resolved
within 24 hours, and did not recur despite the
continuation of therapy. These changes probably
reflect the effects of fingolimod on the S1P re-
ceptors on atrial myocytes.38 In addition, a mild
dose-dependent increase in systolic and diastolic
blood pressure was observed over the course of
2 years.
Macular edema was confirmed by ophthal-
mologic evaluation in less than 1% of the pa-
tients. Most of the cases of macular edema were
asymptomatic and resolved within months after
discontinuation of fingolimod therapy.
Localized skin cancers (basal-cell carcinoma
and melanoma)39 and breast cancers were re-
ported more frequently in the groups receiving
either high-dose or low-dose fingolimod than in
the group receiving interferon beta-1a in the
TRANSFORMS trial. Long-term follow-up stud-
ies are needed to clarify the actual risk of cancer.
There were mild dose-dependent decreases in
lung function, as assessed by means of forced
expiratory maneuvers; decreases in exhaled vol-
 clinical ther apeutics
umes were observed within the first month after
the initiation of therapy, and there were no sub-
sequent reductions. These effects on pulmonary
function could reflect the mechanism of action
of fingolimod on the S1P receptors on smooth-
muscle cells and endothelial barrier cells.40
As expected, peripheral-blood lymphocyte
counts were reduced by approximately 75% from
baseline after the first month. Asymptomatic
elevations in liver enzyme levels (e.g., alanine
aminotransferase) were seen more frequently in
patients receiving fingolimod than in those re-
ceiving either interferon beta-1a or placebo. En-
zyme levels returned to the normal range in all
patients, even in those who continued to take
fingolimod.
Fingolimod has been shown to be teratogenic
in rodents.41 In humans, several pregnancies have
been reported among women receiving fingoli-
mod, but because the number of pregnancies is
low, no firm conclusions can be drawn. The es-
tablishment of a pregnancy registry should help
define the risk of fingolimod to fetuses.
A r e a s of Uncer ta in t y
The risks of adverse effects with fingolimod, es-
pecially in the long term, remain uncertain. The
risks include severe infections, such as dissemi-
nated and central nervous system herpetic infec-
tion; effects on immune surveillance (a possible
increase in the risk of progressive multifocal leu-
koencephalopathy, toxoplasmosis, or neoplasms);
and effects on the reproductive system after long-
term use. Long-term (5-to-10-year) controlled ex-
tension studies are necessary, since such risks
cannot be addressed adequately in short-term
studies.
It remains unclear whether fingolimod has a
direct effect on oligodendrocytes, astrocytes, and
neurons in vivo (as suggested in Fig. 2). If so,
fingolimod could have the potential to offer
primary neuroprotection and help prevent fur-
ther disability. To address this issue, fingolimod
is currently being evaluated in a 3-year, multi-
center, phase 3 study involving patients with
primary progressive multiple sclerosis.42,43
Additional direct comparisons of fingolimod
with other available therapies for multiple sclero-
sis are crucial. For example, clinicians must often
decide between natalizumab and fingolimod for
patients who are having suboptimal responses
to current injectable therapies. Establishing the
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minimal effective dose of fingolimod in clinical
trials could also minimize the risk of adverse
events and improve the risk-to-benefit ratio.
Guidel ine s
Currently, there are no established clinical guide-
lines, published by national or international neu-
rologic societies, for the use of fingolimod in
patients with multiple sclerosis. We believe that
until additional long-term safety data are avail-
able, fingolimod therapy should be considered
only for patients who have had recent inflamma-
tory disease activity (one or more relapses or new
white-matter lesions on MRI within the past year)
and those who do not benefit from or cannot
tolerate alternative disease-modifying therapies.
We also recommend that patients not have taken
immunosuppressive medications or received a
natalizumab infusion within 3 months before the
initiation of fingolimod therapy (6 months if the
patient has received long-term intravenous im-
munosuppression with agents such as mitoxan-
trone or cyclophosphamide). No specific washout
period is needed after cessation of glatiramer ac-
etate or beta-interferon therapy. Other FDA-
approved medications for the treatment of multiple
sclerosis should not be initiated until 2 months
after discontinuation of fingolimod therapy, to
allow for elimination of fingolimod and normal-
ization of lymphocyte counts and to minimize
the risk of additive immunosuppressive effects.
Until additional safety data are available, patients
receiving fingolimod therapy who have lympho-
cyte counts of less than 200 cells per cubic mil-
limeter should discontinue therapy; resumption
of therapy may be considered after normalization
of the lymphocyte count.
R ec om mendat ions
Fingolimod is a reasonable therapeutic option for
the patient described in the vignette. The diagno-
sis of multiple sclerosis is firmly established, and
the patient has evidence of disease activity de-
spite the use of both interferon and glatiramer
acetate therapies in the past. Moreover, his neu-
rologic examination is worrisome because there
are signs of permanent injury to the central ner-
vous system after incomplete recovery from sev-
eral attacks affecting his spinal cord, brain stem,
vision, and gait. A discussion about natalizumab
therapy is certainly appropriate in this clinical
345
 The n e w e ng l a n d j o u r na l of m e dic i n e

context. However, we believe that the risk of pro- patient’s clinical course would be monitored
gressive multifocal leukoencephalopathy may be semiannually, and standardized brain MRI stud-
increased considerably, since the patient has pre- ies would be performed annually.
viously been exposed to JC virus, as assessed by
measurement of antiviral antibodies. Unlike some Dr. Pelletier reports receiving consulting fees from Synarc,
practitioners, we no longer use intravenous mito- Bayer, Biogen Idec, Genetech, Teva Neuroscience, EMD Serono,
Novartis, and Revalesio and grant support from Biogen Idec;
xantrone for the treatment of multiple sclerosis and Dr. Hafler, receiving consulting fees from Sanofi-Aventis,
at our center, mainly owing to the long-term risk McKinsey, NKT Therapeutics, Novartis, Biogen Idec, Teva Neuro-
of leukemia. We would offer oral fingolimod af- science, and Pfizer and owning stock options in NKT Therapeu-
tics. No other potential conflict of interest relevant to this article
ter reviewing the risks and benefits for this pa- was reported.
tient and after performing appropriate laboratory Disclosure forms provided by the authors are available with
testing, baseline ophthalmologic and dermato- the full text of this article at NEJM.org.
We thank Dr. Claire Riley and Alyssa Nylander for their criti-
logic evaluations, and other evaluations (includ- cal reading of the manuscript and for assistance with the prepa-
ing electrocardiography) as discussed above. The ration of the manuscript.

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