Multiple Sclerosis and Related Disorders (]]]]) ], ]]]]]]

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journal homepage: www.elsevier.com/locate/msard

Fingolimod in relapsing multiple sclerosis:

An integrated analysis of safety ndings
Ludwig Kapposa,n, Jeffrey Cohenb, William Collinsc, Ana de Verac,
Lixin Zhang-Aubersonc, Shannon Ritterd, Philipp von Rosenstielc,
Gordon Francisd
a

Neurology, Department of Medicine, Clinical Research and Biomedicine, University Hospital,

Petersgraben 4, CH-4031 Basel, Switzerland
b
Neurological Institute, The Mellen Center for Multiple Sclerosis Treatment and Research,
Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
c
Novartis Pharma AG, CH-4056 Basel, Switzerland
d
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07849-1080, USA
Received 5 December 2013; received in revised form 28 February 2014; accepted 17 March 2014

KEYWORDS
Fingolimod;
Multiple sclerosis;
Safety;
Adverse events;
Cardiovascular
events;
Pooled analysis

Abstract
Background: Fingolimod 0.5 mg once daily is the rst approved oral therapy for relapsing
multiple sclerosis (MS).

Objective: To report integrated long-term safety data from phase 2/3 ngolimod studies.
Methods: Descriptive safety data are reported from the FTY720 Research Evaluating Effects of
Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, doubleblind study comparing ngolimod 0.5 mg and 1.25 mg with placebo, and an All Studies group
(patients who received ngolimod 0.5 mg (n =1640) or 1.250.5 mg (n =1776) in phase 2/3
studies and associated extensions). Relevant post-marketing experience, up to December 2011,
is included.
Results: The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with
ngolimod and placebo in FREEDOMS. In the All Studies group, ngolimod 0.5 mg was associated
with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular
block on treatment initiation, minor blood pressure increases, frequent (9%) but generally
asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections
(including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to
AEs were similar with ngolimod 0.5 mg and placebo.

Abbreviations: AV, atrioventricular; FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; HPS,
haemophagocytic syndrome; LRTI, lower respiratory tract infection; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy; PRES, posterior reversible encephalopathy syndrome; S1PR, sphingosine 1-phosphate receptor; TRANSFORMS, Trial Assessing
Injectable Interferon Versus FTY720 Oral in RelapsingRemitting Multiple Sclerosis; ULN, upper limit of normal
n
Corresponding author. Tel.: +41 61 2654464.
E-mail address: ludwig.kappos@usb.ch (L. Kappos).
http://dx.doi.org/10.1016/j.msard.2014.03.002
2211-0348/& 2014 Published by Elsevier B.V.

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

L. Kappos et al.
Conclusion: The safety prole of ngolimod has been well characterized in this large combined
trial population. Although infrequent SAEs can occur, there is no increased risk of infections,
malignancies or serious cardiovascular events versus placebo.
& 2014 Published by Elsevier B.V.

1.

Introduction

Fingolimod (FTY720; Gilenyas, Novartis Pharma AG, Basel,

Switzerland) is the rst of a new class of therapeutic compounds the sphingosine 1-phosphate receptor (S1PR) modulators (Brinkmann et al., 2010; Chun and Hartung, 2010). It is
approved as a once-daily oral therapy at 0.5 mg for the
treatment of relapsing forms of multiple sclerosis (MS) in
many countries (European Medicines Agency, 2011; US Food
and Drug Administration, 2010). S1PRs are expressed in many
tissues, including cells of the immune, cardiovascular and
central nervous systems (Brinkmann, 2007). In the immune
system, modulation of S1PRs by ngolimod results in the
retention of circulating lymphocytes in the lymph nodes, with
a reversible reduction of peripheral blood lymphocyte counts
to approximately 30% of pre-treatment values, which is
postulated to reduce recirculation of autoreactive lymphocytes and to prevent inltration into the central nervous
system (Brinkmann et al., 2010; Chun and Hartung, 2010).
Fingolimod treatment specically retains nave T cells and
central memory T cells in the lymph nodes, while largely
sparing effector memory T cells (Mehling et al., 2008; Pham
et al., 2008), which are important in immune surveillance
(Lanzavecchia and Sallusto, 2000).
Fingolimod has demonstrated superior efcacy to placebo
as well as to the approved rst-line therapy, intramuscular
(IM) interferon beta-1a (Avonexs, Biogen Idec, Weston, MA,
USA) in a phase 2 study and three phase 3 studies: FTY720
Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS), FREEDOMS II and Trial Assessing
Injectable Interferon Versus FTY720 Oral in Relapsing
Remitting Multiple Sclerosis (TRANSFORMS) in relapsing MS
(Calabresi et al., in press; Cohen et al., 2010; Comi et al.,
2010; Kappos et al., 2006, 2010; Khatri et al., 2011).
Here, we report safety data from an integrated analysis
of FREEDOMS, FREEDOMS II, TRANSFORMS, the single MS
phase 2 study and their extensions. In addition, we report
deaths from the clinical development programme and postmarketing setting from May 2003 to December 2011, as well
as other post-marketing safety cases of particular interest.

2.
2.1.

Materials and methods

Analysis groups

Results are reported from the following two analysis groups:

the FREEDOMS group, which included all patients enrolled in
the 2-year core phase of FREEDOMS (Kappos et al., 2010)
(ClinicalTrials.gov identier NCT00289978), and the All
Studies group, which was an integrated analysis of safety
data from all patients who received once-daily ngolimod
in the 6-month, placebo-controlled, phase 2 core study

(1.25 mg or 5.0 mg; ClinicalTrials.gov identier NCT00333138),

the 2-year phase 3 core studies (FREEDOMS, FREEDOMS II
[0.5 mg or 1.25 mg; ClinicalTrials.gov identier NCT00355134])
and the 1-year phase 3 core study TRANSFORMS (0.5 mg or
1.25 mg; ClinicalTrials.gov identier NCT00340834), and their
completed long-term extensions.
Following approval of ngolimod 0.5 mg, all patients receiving ngolimod 1.25 mg in study extensions were switched
to ngolimod 0.5 mg (this group was referred to in the All
Studies analysis as ngolimod 1.250.5 mg). Patients remained
in study extensions until 31 March 2011 (database lock) or until
the cut-off for the ongoing FREEDOMS II extension (Figure 1).
Patients were then transferred to the ongoing, long-term
observational safety study 2399 (ClinicalTrials.gov identier
NCT01281657).
Study methodologies for FREEDOMS, FREEDOMS II, TRANSFORMS and the phase 2 study have been previously reported
in accordance with CONSORT guidelines (Cohen et al., 2010;
Kappos et al., 2006, 2010; Khatri et al., 2011). The study
design and entry criteria for FREEDOMS II closely match
those of FREEDOMS. The FREEDOMS group provides a 24month, placebo-controlled comparison with ngolimod, and
the All Studies group provides ngolimod safety data from a
larger population with longer follow-up. Data describing
cardiovascular effects following treatment initiation come
only from the phase 3 studies because data on these effects
were not collected in a compatible manner during the phase
2 core study. All deaths are reported for patients exposed to
ngolimod during May 2003December 2011, including clinical trials and post-marketing data.
2.1.1. Outcome measures and analyses
Results are reported for the safety population, comprising
all patients who received at least one dose of study drug. Safety
analyses were summarized by means of descriptive statistics;
numerical (not statistical) differences are described. The
proportions of patients experiencing adverse events (AEs)
and serious AEs (SAEs) are reported for the FREEDOMS group
and the All Studies group (with a focus on the ngolimod
1.250.5 mg and 0.5 mg groups). Also reported in more detail
are the following AEs of special interest: treatment initiation
effects (pooled data from phase 3 studies only), infections,
hypertension and notable increases in blood pressure, macular
oedema, malignancies, liver enzyme effects and lymphopenia
(FREEDOMS group; All Studies group). Patients were required
to interrupt dosing if lymphocyte counts fell below a threshold
(o0.1  109/L initially, later increased to o0.2  109/L at the
request of the regulatory agency, but not due to any safety
signal). Dosing could resume once lymphocyte counts reached
0.6  109/L. Due to a potential risk for teratogenesis, as seen
in animals, ngolimod is not recommended for use in women
who are, or want to become, pregnant. Full details of pregnancy outcomes and pregnancy risks are reported elsewhere

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

Fingolimod in relapsing multiple sclerosis

3
Fingolimod 5.0 mg
Fingolimod 1.25 mg
Fingolimod 0.5 mg

Placebo
Interferon beta-1a IM 30 g
once weekly

Phase 2 study (2201)

Core phase

Optional extension
a
b
b

a
Phase 3 TRANSFORMS
Core phase

Optional extension

All studies
analysis group
n = 3553

b
b

Phase 3 FREEDOMS
Core phase
FREEDOMS
analysis group
n = 1272

Optional
extension
b
b

Phase 3 FREEDOMS II
Core phase

Optional
extension
b
b

Randomization

Month 6

Month 12

Month 24

Figure 1 Analysis groups. (a) Patients who were initially randomized to ngolimod 5.0 mg during the phase 2 core study or
extension were switched to ngolimod 1.25 mg during months 1524 of the extension phase, then to ngolimod 0.5 mg between
months 24 and 60. (b) All patients received ngolimod 0.5 mg in study extensions following approval of this dose. The All Studies
analysis group includes all patients who switched from placebo or interferon beta-1a IM to ngolimod in the extension phases; the
pooled treatment groups were ngolimod 0.5 mg (n =1640), ngolimod 1.250.5 mg (n =1776), ngolimod 5.01.250.5 mg (n =137,
which included all patients who received ngolimod 5.0 mg only or ngolimod 5.0 mg then ngolimod 1.25 mg, before receiving ngolimod
0.5 mg). The FREEDOMS analysis group included patients receiving ngolimod 0.5 mg (n=425), ngolimod 1.25 mg (n=429) or placebo
(n=418). FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; IM, intramuscular; TRANSFORMS, Trial
Assessing Injectable Interferon Versus FTY720 Oral in RelapsingRemitting Multiple Sclerosis.

(Karlsson et al., 2014), but otherwise are not further addressed

in this article.
Additional methodological information for the studies in
this analysis, including details of study oversight, inclusion
and exclusion criteria, and blinding and randomization are
provided in the Supplementary data.

3.
3.1.

Results
Study population

Baseline characteristics of patients in the phase 3 studies

and the phase 2 study were similar among treatment groups
(Calabresi et al., in press; Cohen et al., 2010; Kappos et al.,
2006, 2010). The All Studies group comprised 3553 patients
with MS, with 9070 patient-years of exposure to ngolimod,
and included some patients with more than 7 years of

exposure in the phase 2 extension study (as of 31 March

2011) (Table 1).

3.2. Incidence of adverse events and serious

adverse events
In the FREEDOMS group, the overall relative risk of AEs
(Figure 2) and the proportions of patients who experienced
AEs and SAEs were similar with both doses of ngolimod and
placebo; the occurrence remained similar in the larger
patient population exposed to ngolimod 0.5 mg in the All
Studies group (Table 2). Fingolimod 1.250.5 mg was associated with a higher proportion of SAEs than ngolimod
0.5 mg in the All Studies group. The relative risk of liver
enzyme elevations, migraine, lymphopenia, bronchitis, back
pain and diarrhoea was slightly higher with ngolimod
0.5 mg than with placebo (Figure 2). A similar proportion

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

L. Kappos et al.

Table 1

Overall exposure to ngolimod after randomization in the All Studies group.

Fingolimod
5.0/1.25/0.5 mga,b
(n= 137)

Fingolimod
1.25/0.5 mgb
(n = 1776)

Fingolimod
0.5 mg
(n = 1640)

Total All Studies

group
(n = 3553)

Patients by exposure intervals, n (%)

Z6 months
Z1 year
Z2 years
Z3 years
Z5 years
Z7 years

118 (86.1)
108 (78.8)
96 (70.1)
85 (62.0)
65 (47.4)
11 (8.0)

1538 (86.6)
1400 (78.8)
1068 (60.1)
708 (39.9)
75 (4.2)
19 (1.1)

1484 (90.5)
1360 (82.9)
1083 (66.0)
717 (43.7)
0 (0)
0 (0)

3140 (88.4)
2868 (80.7)
2247 (63.2)
1510 (42.5)
140 (3.9)
30 (0.8)

Patient-years of exposurec

566.2

4385.3

4118.9

9070.4

Exposure duration, days

Mean
Median

1509.6
1542

901.9
890

917.3
966

932.4
930

FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; TRANSFORMS, Trial Assessing Injectable
Interferon Versus FTY720 Oral in RelapsingRemitting Multiple Sclerosis.
Fingolimod exposure in the phase 2 study, and FREEDOMS, FREEDOMS II, TRANSFORMS studies and their ongoing extensions up to the
cut-off of 31 March 2011. Duration of exposure was dened as the number of days on ngolimod, starting from the day of initiation of
randomized study medication until the day of last dose; days when a patient did not take ngolimod (e.g., temporary interruption of
randomized study medication) were excluded. Patients randomized to control drug were included once they had converted to
ngolimod in open-label extensions.
a
Patients initially randomized to ngolimod 5.0 mg during the phase 2 core study or extension were switched to ngolimod 1.25 mg
during months 1524 of the extension phase, and between months 24 and 60 were switched to ngolimod 0.5 mg following assessment
of the relative benet-to-risk prole of both doses.
b
Patients initially randomized to 1.25 mg during the phase 3 core studies or extensions were switched to ngolimod 0.5 mg following
assessment of the relative benet-to-risk prole of both doses.
c
Patient-years of exposure was calculated as the sum of the number of days on study drug for all patients divided by 365.25.

of AEs leading to study drug discontinuation occurred with

placebo and ngolimod 0.5 mg, but at a higher frequency in
patients receiving ngolimod 1.25 mg/1.250.5 mg (FREEDOMS
group and All Studies group; Table 2). The most common
reason for discontinuation due to AEs in FREEDOMS was for AEs
related to laboratory tests (ngolimod 0.5 mg, 3.8%; placebo,
1.7%), primarily liver enzyme elevations.

3.2.1. Mortality
No deaths occurred among patients receiving ngolimod
0.5 mg in the FREEDOMS study. For total deaths, data are
presented beyond the cut-off point for the All Studies group
to be more inclusive. Nineteen deaths had occurred, as of
31 October 2011, in the total MS clinical development
programme, which included ongoing, blinded studies in
addition to those in the All Studies group. Of these 19
deaths, four occurred in patients receiving placebo (out of
866 patients with 1305 patient-years of exposure) and two
occurred before randomization. Of the remaining 13 deaths
(out of 3553 patients exposed to ngolimod with 9070
patient-years of exposure), the maximal dose taken was
5 mg for one patient, 1.25 mg for nine patients, and 0.5 mg
for three patients (Supplementary Table 1). Five patients
had ceased medication 336 months before death (one case
each of breast cancer, ovarian adenocarcinoma, lymphoma,
aspiration pneumonia and MS progression with aspiration
pneumonia). Of the remaining eight cases that occurred

while still on therapy, or having recently discontinued

ngolimod treatment, there were three cases of suicide,
and one each of myocardial infarction, road trafc accident,
herpes simplex encephalitis, primary disseminated herpes
zoster and rapidly deteriorating primary progressive MS; see
Supplementary Table 1 for details. In the post-marketing
setting, 18 deaths have been reported as of December 2011
from approximately 25,000 patients treated with ngolimod (15,000 patient-years of exposure) (Supplementary
Table 2). Of these deaths, causes included progressive MS
(n=5), suicide (n=3), myocardial infarction/cardiac arrest
(n=3), sudden unexplained death (n=2; including one
patient within 24 h of receiving rst dose of ngolimod),
drowning (n=2), and one case each of convulsion, culturenegative fungal encephalitis and multi-organ failure; see
Supplementary Table 2 for details.

3.3.

Cardiovascular effects

The effect of ngolimod on heart rate and atrioventricular

(AV) conduction during treatment initiation will be discussed
in full detail in a separate manuscript (DiMarco et al., 2012,
in preparation). Initiation of ngolimod treatment was
associated with transient dose-dependent reductions in
heart rate that returned to baseline levels by 1 month after
treatment initiation. In the 6 h following treatment initiation, symptomatic bradycardia events were observed in

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

Fingolimod in relapsing multiple sclerosis

5
Higher with placebo

Higher with fingolimod 0.5 mg

Overall adverse events

Hepatic enzymes increased
Leukopenia
Lymphopenia
-glutamyltransferase increased
Tinea versicolor
Migraine
Alanine aminotransferase increased
Vision blurred
Bronchitis
Back pain
Hypertension
Diarrhoea
Dyspnoea
Urinary tract infection
Micturition urgency

Fingolimod 0.5 mg
(n = 425)

Musculoskeletal stiffness

Placebo
(n = 418)

Somnolence
0.002

0.016

0.125

64

512

Relative risk (95% CI)

Figure 2 The relative risk of adverse events with ngolimod 0.5 mg compared with placebo in the FREEDOMS group. The relative
risk of each AE was calculated by dividing the incidence of the AE in patients receiving ngolimod 0.5 mg by the incidence of the AE
in patients receiving placebo. AE, adverse event; CI, condence interval; FREEDOMS, FTY720 Research Evaluating Effects of Daily
Oral Therapy in Multiple Sclerosis.

9/1640 (0.5%) and 29/1642 (1.8%) patients who received

rst-dose ngolimod 0.5 mg and 1.25 mg, respectively. AV
conduction abnormalities associated with ngolimod rst
dosing were uncommon, typically transient, asymptomatic,
usually did not require treatment and resolved within the rst
24 h on treatment. Second-degree AV blocks, usually Mobitz
type I (Wenckebach) were observed in 2/1640 patients (0.1%)
receiving ngolimod 0.5 mg in clinical trials.
Cardiac disorder AEs were reported in similar proportions
of patients receiving ngolimod 0.5 mg (5.9%; 25/425) or
placebo (5.5%; 23/418) over 24 months in the FREEDOMS
group, and at a higher rate in patients receiving ngolimod
1.25 mg (8.9%; 38/429). No serious cardiovascular events
were observed with ngolimod 0.5 mg in the clinical development programme; three myocardial infarctions occurred
in patients receiving placebo (n= 2) or interferon beta-1a IM
(n= 1), and four in the ngolimod 1.25 mg group.
In the All Studies group, patients treated with ngolimod
experienced small mean increases of 3 mmHg in systolic blood
pressure and 1 mmHg in diastolic blood pressure, which were
evident by month 2, increased to month 6 and were largely
stable thereafter. Notably high or notable increases in systolic

or diastolic blood pressure and hypertension AEs were more

frequently reported for ngolimod 1.250.5 mg than for
ngolimod 0.5 mg (Table 3).

3.3.1. Vascular events

Rare cases of vascular events have occurred in patients
treated with ngolimod 1.25 mg or 5.0 mg in the All Studies
group, including ischaemic and haemorrhagic strokes (n = 3),
peripheral arterial occlusive disease (n= 2) and posterior
reversible encephalopathy syndrome (PRES; n =1). Three
cases of PRES have occurred with ngolimod 0.5 mg, two of
which were reported in the post-marketing setting as of
December 2011; representing a total of three cases in more
than 36,000 patients who have ever received ngolimod.

3.4.

Liver enzyme effects

Dose-dependent increases in alanine aminotransferase (ALT)

levels were observed for ngolimod in the FREEDOMS group
and the All Studies group (Table 3). Liver transaminase

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

L. Kappos et al.

Table 2

Adverse event experience in the FREEDOMS and All Studies groups.

Event, n (%)

At least one AE
Any serious AE
Deatha
AE leading to study drug
discontinuationb
Abnormal laboratory value
leading to study drug
discontinuation

FREEDOMS core study

Placebo
(n= 418)

Fingolimod
0.5 mg
(n= 425)

Fingolimod
1.25 mg
(n = 429)

Fingolimod
0.5 mg
(n= 1640)

Fingolimod
1.250.5 mg
(n = 1776)

387 (92.6)
56 (13.4)
2 (0.5)
24 (5.7)

401 (94.4)
43 (10.1)
0 (0)
15 (3.5)

404 (94.2)
51 (11.9)
1 (0.2)
31 (7.2)

1571
256
4
124

1706
316
8
196

5 (1.2)

20 (4.7)

32 (7.5)

AEs occurring in 410% of patients in any treatment group

Headache
96 (23.0)
107 (25.2)
Nasopharyngitis
115 (27.5)
115 (27.1)
Upper respiratory tract
73 (17.5)
73 (17.2)
infection
ALT increased
16 (3.8)
43 (10.1)
Fatigue
45 (10.8)
48 (11.3)
Back pain
29 (6.9)
50 (11.8)
Cough
34 (8.1)
43 (10.1)
Diarrhoea
31 (7.4)
50 (11.8)
Inuenza
41 (9.8)
55 (12.9)
Lymphopenia

Urinary tract infection

47 (11.2)
34 (8.0)
Serious AEsc
Basal cell carcinoma
Bradycardia
Multiple sclerosis relapse
Urinary tract infection
Non-cardiac chest pain
Back pain
Chest pain
Macular oedema
Epilepsy
Depression
Headache
Lymphopenia
Liver function test
abnormal
First-degree AV block
Second-degree AV block
Palpitations
Vertigo
Cholelithiasis
Appendicitis
Herpes zoster
Malignant melanoma
Breast cancer
Uterine leiomyoma

All Studies

(95.8)
(15.6)
(0.2)
(7.6)

(96.1)
(17.8)
(0.5)
(11.0)

79 (4.8)

117 (6.6)

114 (26.6)
112 (26.1)
62 (14.5)

435 (26.5)
498 (30.4)
314 (19.1)

455 (25.6)
558 (31.4)
358 (20.2)

50
47
45
37
40
40

21

151
176
197
210
223
210
196
199

(9.2)
(10.7)
(12.0)
(12.8)
(13.6)
(12.8)
(12.0)
(12.1)

189
231
239
237
224
207
273
191

(10.6)
(13.0)
(13.5)
(13.3)
(12.6)
(11.7)
(15.4)
(10.8)

(11.7)
(11.0)
(10.5)
(8.6)
(9.3)
(9.3)
(4.9)

2
1
1
0
2
1
0
0
0
1
0
0
1

(0.5)
(0.2)
(0.2)
(0)
(0.5)
(0.2)
(0)
(0)
(0)
(0.2)
(0)
(0)
(0.2)

4
4
2
2
2
2
2
0
0
0
0
0
0

(0.9)
(0.9)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)
(0)
(0)
(0)
(0)
(0)
(0)

1
3
3
0
0
0
0
3
2
2
2
2
2

(0.2)
(0.7)
(0.7)
(0)
(0)
(0)
(0)
(0.7)
(0.5)
(0.5)
(0.5)
(0.5)
(0.5)

26
6
13
4
4
3
4
3
2
0
0
3
0

(1.6)
(0.4)
(0.8)
(0.2)
(0.2)
(0.2)
(0.2)
(0.2)
(0.1)
(0)
(0)
(0.2)
(0)

17
24
13
3
1
3
2
9
2
7
4
8
2

(1.0)
(1.4)
(0.7)
(0.2)
(0.1)
(0.2)
(0.1)
(0.5)
(0.1)
(0.4)
(0.2)
(0.5)
(0.1)

0
1
1
0
1
1
0
1
3
0

(0)
(0.2)
(0.2)
(0)
(0.2)
(0.2)
(0)
(0.2)
(0.7)
(0)

0
0
0
0
0
0
0
0
0
1

(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0.2)

1
1
1
0
0
0
0
1
1
0

(0.2)
(0.2)
(0.2)
(0)
(0)
(0)
(0)
(0.2)
(0.2)
(0)

1
1
0
0
7
5
2
4
5
6

(0.1)
(0.1)
(0)
(0)
(0.4)
(0.3)
(0.1)
(0.2)
(0.3)
(0.4)

6
9
5
4
4
5
6
4
5
3

(0.3)
(0.5)
(0.3)
(0.2)
(0.2)
(0.3)
(0.3)
(0.2)
(0.3)
(0.2)

AE, adverse event; ALT, alanine aminotransferase; AV, atrioventricular; FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral
Therapy in Multiple Sclerosis.
a
Deaths in the All Studies group were reported up to the cut-off date of 31 October 2011.
b
Includes events occurring in patients whose primary or secondary reason for discontinuing the study drug was an AE (including
abnormal laboratory ndings).
c
Serious AEs experienced by 41 patient in any ngolimod group in the FREEDOMS group or 42 in any ngolimod group in the All
Studies group.

Fingolimod in relapsing multiple sclerosis

Table 3

Special interest adverse events and laboratory abnormalities.

Event, n (%)

Infections
At least one infection AE
Infections (events per 100
patient-years)a
Any severe infection
Any serious infection
Infections of interest
LRTI and lung infections
Any herpes infection
Herpes infection SAEs
Herpes zoster AEs
Macular oedema
Patients with assessments
Patients with conrmed
macular oedemab
Patients treated for macular
oedemab
Malignancies
Basal cell carcinoma
Squamous cell carcinoma of
the skin
Malignant melanoma
Breast cancer
Cervix carcinoma
Endometrial carcinoma
Prostate cancer
Ovarian epithelial cancer

FREEDOMS core study

Placebo
(n= 418)

Fingolimod
0.5 mg
(n = 425)

Fingolimod
1.25 mg
(n= 429)

Fingolimod
0.5 mg
(n = 1640)

Fingolimod
1.250.5 mg
(n = 1776)

301 (72.0)
128.1

304 (71.5)
126.9

294 (68.5)
123.0

1222 (74.5)
114.7

1291 (72.7)
118.7

13 (3.1)
8 (1.9)

12 (2.8)
7 (1.6)

15 (3.5)
11 (2.6)

93 (5.2)
48 (2.9)

88 (5.4)
61 (3.4)

25 (6.0)
33 (7.9)
0
4 (1.0)

41 (9.6)
37 (8.7)
1 (0.2)
7 (1.6)

49 (11.4)
25 (5.8)
1 (0.2)
3 (0.7)

217 (13.2)
184 (11.2)
6 (0.4)
49 (3.0)

236 (13.3)
200 (11.3)
13 (0.7)
51 (2.9)

413
0 (0)

423
0 (0)

420
7 (1.7)

1612
7 (0.4)

1710
19 (1.1)

0 (0)

0 (0)

5 (1.2)

4 (0.2)

5 (0.3)

10 (2.4)
3 (0.7)
0 (0)

4 (0.9)
4 (0.9)
0 (0)

4 (0.9)
1 (0.2)
1 (0.2)

49 (3.0)
30 (1.8)
1 (0.1)

38 (2.1)
19 (1.1)
1 (0.1)

1
3
1
1
1
0

0
0
0
0
0
0

1
1
0
0
0
0

4
5
0
0
0
1

4
5
0
0
0
0

(0.2)
(0.7)
(0.2)
(0.2)
(0.2)
(0)

Liver enzyme and bilirubin elevationsc

ALT elevation
Z3  ULN
7 (1.7)
Z5  ULN
4 (1.0)
Z10  ULN
0 (0)
Bilirubin
Z1  ULN
39 (9.4)
Increased blood pressure
Systolic blood pressure
Z160 mmHg
Z20 mmHg increase from
baseline
Diastolic blood pressure
Z100 mmHg
Z15 mmHg increase from
baseline
Hypertension AE

All Studies

(0)
(0)
(0)
(0)
(0)
(0)

(0.2)
(0.2)
(0)
(0)
(0)
(0)

(0.2)
(0.3)
(0)
(0)
(0)
(0.1)

(0.2)
(0.3)
(0)
(0)
(0)
(0)

36 (8.5)
8 (1.9)
1 (0.2)

53 (12.5)
13 (3.1)
0 (0)

147 (9.0)
32 (2.0)
3 (0.2)

213 (12.2)
50 (2.9)
7 (0.4)

47 (11.1)

42 (9.9)

142 (8.7)

158 (9.0)

6 (1.4)
76 (18.2)

8 (1.9)
92 (21.6)

19 (4.4)
112 (26.1)

78 (4.8)
560 (34.1)

118 (6.6)
706 (39.8)

17 (4.1)
84 (20.1)

31 (7.3)
93 (21.9)

29 (6.8)
113 (26.3)

125 (7.6)
486 (29.6)

191 (10.8)
597 (33.6)

16 (3.8)

26 (6.1)

27 (6.3)

145 (8.8)

200 (11.3)

AE, adverse event; ALT, alanine aminotransferase; LRTI, lower respiratory tract infection; SAE, serious adverse event; ULN, upper limit
of normal.
a
The incidence of infections per 100 patient-years was calculated as the number of infections divided by the patient-years in the
treatment group, multiplied by 100. The patient-year denominator was dened as the sum of the number of days on study drug for all
patients in each treatment group divided by 365.25.
b
The proportion of patients with macular oedema assessments was used as the denominator.
c
Number of patients with laboratory assessments in the FREEDOMS group: placebo, n=414; ngolimod 0.5 mg, n=424; ngolimod
1.25 mg, n=425. Number of patients with laboratory assessments in the All Studies group: ngolimod 0.5 mg, n=1633; ngolimod
1.25 mg, n=1753.

L. Kappos et al.

elevations were asymptomatic in most patients and most

frequently occurred within the rst 69 months of treatment.
There were no cases of severe drug-induced hepatotoxicity
during clinical trials or in the post-marketing setting.

3.5.

Macular oedema

No cases of macular oedema occurred in patients receiving ngolimod 0.5 mg in the FREEDOMS group. Conrmed
macular oedema was reported in 0.4% (7/1640) and 1.1%
(19/1776) of patients treated with ngolimod 0.5 mg and
1.250.5 mg, respectively, in the All Studies group (Table 3).
The majority (65%) were diagnosed in the rst 6 months of
receiving ngolimod, with approximately one-third requiring treatment and virtually universal recovery after treatment cessation (Calabresi et al., in press; Cohen et al.,
2010; Kappos et al., 2006, 2010; Zarbin et al., 2011).

3.6.

Infections

In FREEDOMS, the overall incidence of infections was similar

in patients receiving ngolimod 0.5 mg, 1.25 mg or placebo
(Table 3). Serious infections occurred in similar proportions
of patients receiving ngolimod 0.5 mg or placebo, and at a
higher rate with ngolimod 1.25 mg. The incidence of lower
respiratory tract infections (mainly bronchitis) was slightly
increased with ngolimod compared with placebo and
appeared to be dose-dependent (Table 3). For herpes viral
infections, the incidence was similar among patients treated with ngolimod 0.5 mg or placebo, but higher in the
All Studies group, who were given longer follow-up. The
incidence of herpes viral infections reported as SAEs was
low in all treatment groups in FREEDOMS (Table 3). A fatal
primary varicella zoster infection and fatal herpes simplex
encephalitis occurred in two patients who had been treated
with ngolimod 1.25 mg in the All Studies group, and have
been previously reported (Cohen et al., 2010).

3.7.

Lymphopenia

In the All Studies group, after 1 month of treatment the

mean lymphocyte count was reduced by 73% from baseline
values to 0.49  109/L (n = 1505) in the ngolimod 0.5 mg
group and by 77% to 0.41  109/L (n= 1575) in the ngolimod
1.250.5 mg group. Values then remained stable during
chronic treatment. The incidence of lymphopenia as an
AE was higher in the ngolimod 1.250.5 mg group than in
the 0.5 mg group (Table 2). In FREEDOMS 18% of patients
(78/425) on 0.5 mg experienced a mean lymphocyte count
of o0.2  109/L on any single occasion and 0.7% (3/425) had
a count of o0.1  109/L on any single occasion. Re-testing
was conducted at local laboratories, so the number of
patients with conrmed counts below these values (and
thus requiring dose interruption) was not reported. Analysis
of infections by nadir lymphocyte count did not show an
increase in ngolimod-treated patients compared with
placebo (reviewed in detail previously) (Francis et al.,
2014).

3.8.

Malignancies

The overall incidence of malignancies was not increased in

ngolimod-treated patients (0.9% in both dose groups)
compared with patients who received placebo (2.4%) in
the FREEDOMS group, and results were similar for the All
Studies group (Table 3). A trend towards an increased
incidence of basal cell carcinoma has been noticed in the
All Studies group. Three lymphoma cases (cutaneous T-cell
lymphoma, large B-cell non-Hodgkin lymphoma and Epstein
Barr virus-positive B-cell lymphoma) have been reported in
ngolimod-treated patients in the clinical development
programme (up to December 2011) in studies that were
not included in the All Studies group because they were still
ongoing without a cleaned or locked database.

4.

Discussion

The safety prole of ngolimod has been well characterized

in the MS clinical development programme, with the All
Studies group consisting of 3553 ngolimod-treated patients
with MS and more than 9070 patient-years of exposure (as of
31 March 2011). The overall incidence of AEs and SAEs was
similar in patients who received the approved dose of
ngolimod (0.5 mg) in the All Studies and FREEDOMS groups,
and those who received placebo in the FREEDOMS group.
Fingolimod was, however, associated with dose-dependent
increases in the incidence of certain specic AEs, including
transient, mostly asymptomatic reductions in heart rate,
blood pressure increases, macular oedema and liver enzyme
elevations. However, the similar rate of study drug discontinuation due to AEs among patients receiving ngolimod
0.5 mg (All Studies and FREEDOMS groups) and placebo
(FREEDOMS group) indicates that, with the approved
dose, these AEs have a limited impact on tolerability and
adherence.
As of December 2011, 31 deaths have been reported in
more than 30,000 patients exposed to ngolimod since May
2003; 13 occurring in clinical trials (some at doses higher
than the approved 0.5 mg dose) and 18 in the postmarketing setting. No specic pattern of fatalities has been
observed. The incidence of all-cause and cardiovascular
deaths in patients with MS treated with ngolimod are
consistent with an age- and sex-matched general population
(Arias, 2011).
One reported death occurred within the rst 24 h after
taking the rst dose of ngolimod, for which the cause
of death remains uncertain, despite a complete autopsy
examination. This case and 10 other cases (of the total of 31
deaths) of otherwise unexpected or unexplained death
occurred at various times after initiating therapy with
ngolimod. Several of the post-marketing cases lack sufcient information to determine cause of death or relationship to ngolimod therapy. Following review of these cases
and the overall cardiac safety data for ngolimod by the US
Food and Drug Administration and European Medicines
Agency, a relationship between these events and ngolimod
has not been established (European Medicines Agency, 2012;
US Food and Drug Administration, 2011, 2012a, 2012b). The
number of deaths of apparent cardiovascular or unknown
origin is similar to that seen in patients with MS not treated

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

Fingolimod in relapsing multiple sclerosis

with ngolimod (US Food and Drug Administration, 2012b).
Nevertheless, as a precautionary measure, revised guidelines relating to the use of ngolimod in patients with
cardiac risk factors, including more rigorous rst-dose
monitoring, have been included in the prescribing information worldwide.
The initiation of ngolimod was associated with a transient, dose-dependent reduction in heart rate, including
infrequent conduction delay, which was usually asymptomatic. These effects are not unexpected because they are
likely to be mediated by modulation of S1PRs in atrial
myocytes, and in sinus and AV nodal cells (Koyrakh et al.,
2005). However, tolerance rapidly develops to these effects
due to internalization of the receptors. Owing to the
potential risk of rhythm disturbances, ngolimod should
not be used in patients with second-degree Mobitz type II or
higher AV blocks, sick-sinus syndrome or sino-atrial heart
block, or in patients with QT prolongation or who are
receiving drugs that have a known association with the
development of torsades de pointes (European Medicines
Agency, 2012; US Food and Drug Administration, 2012a).
Additionally, while there is no clear relationship between
ngolimod and sudden death, patients with cardiac risk
factors (known ischaemic heart disease, congestive heart
failure, history of cardiac arrest, cerebrovascular disease,
uncontrolled hypertension or severe untreated sleep
apnoea) should not be commenced on ngolimod because
signicant bradycardia may be poorly tolerated in these
patients (European Medicines Agency, 2012; US Food and
Drug Administration, 2012a).
The mechanism for the increase in blood pressure is not
completely clear, but is potentially the result of unopposed
natural sphingosine 1-phosphate ligand stimulation of S1PR
type 2/3 (S1P2/3) endothelial receptors, owing to the strong
functional antagonism of S1P1 by ngolimod (Brinkmann
et al., 2010).
The mechanism for the increased incidence of elevations
in liver transaminases with ngolimod 0.5 mg compared
with placebo also remains unclear. Liver enzyme elevations
generally returned to normal or almost normal within a few
months of stopping therapy.
Conrmed macular oedema occurs in less than 0.5% of
patients receiving ngolimod 0.5 mg. Patients with a history
of uveitis have an increased risk of macular oedema (Zarbin
et al., 2011, 2013). The mechanism for the development of
macular oedema in patients receiving ngolimod may also
be related to the role of the S1PR in the regulation of
endothelial barriers (Brinkmann, 2007; Marsolais and Rosen,
2009).
The observed reductions in peripheral blood lymphocyte
counts are an expected pharmacodynamic outcome of
ngolimod therapy, which causes reversible retention of
lymphocytes in the lymph nodes, and these actions are
thought to be integral to the therapeutic effect of ngolimod in MS. This integrated analysis of safety indicates that
ngolimod 0.5 mg does not increase the overall risk of
infections, including those considered severe or serious,
compared with placebo. However, during the clinical trials,
a persistent reduction in mean lymphocyte counts below
0.2  109/L required dose interruption until counts recovered.The lack of effect on overall infection risk may be
related to the selective effect of ngolimod on lymphocyte

9
subsets. Fingolimod treatment specically retains nave T
cells and central memory T cells in the lymph nodes, while
largely sparing effector memory T cells (Mehling et al.,
2008, Pham et al., 2008), which have important roles in
immune surveillance and memory immune responses
(Lanzavecchia and Sallusto, 2000). Although ngolimod leads
to the retention of lymphocytes in the lymph nodes, the
lymphocytes remain functional and retain their ability to
proliferate and differentiate (Brinkmann, 2009; Chun and
Hartung, 2010), as might happen in response to viral or
bacterial infection. However, some questions remain regarding herpes infections. Different incidences were observed
across the phase 2 and 3 studies (Calabresi et al., in press;
Cohen et al., 2010; Kappos et al., 2006, 2010), but in this
integrated analysis, zoster infections were slightly increased
with ngolimod 0.5 mg (3.0%) compared with placebo (1.0%).
Additionally, isolated cases of severe zoster infections have
been reported, including a fatal case of disseminated primary
infection (ngolimod 1.25 mg), a case of polycranial neuritis
(Gross et al., 2012), a case of varicella-related encephalitis
with vasculopathy (Ratchford et al., 2012) and a recent fatal
case of disseminated varicella (data on le). The latter three
cases occurred in patients with presumed previous exposure
to varicella and who had received ngolimod 0.5 mg (Gross
et al., 2012; Ratchford et al., 2012). Antibody status to
varicella zoster virus should be checked before starting
ngolimod. Vigilance for zoster occurrence and then early
treatment is warranted in patients receiving ngolimod.
Beyond the data cut-off dates used in this manuscript,
unexpected serious events of note have been reported.
Three cases of progressive multifocal leukoencephalopathy
(PML) and/or immune reconstitution inammatory syndrome have been reported but all were related to recent
prolonged exposure to natalizumab (Novartis AG, data on
le). A case of PML that began 7 months after ngolimod
therapy initiation in a patient without prior exposure to
natalizumab has been recently reported (Novartis AG, data
on le). Two fatal cases of haemophagocytic syndrome (HPS)
have been reported to Novartis (Novartis AG, data on le).
This rare disorder is characterized by impaired or absent
activity of natural killer cells and cytotoxic T cells, leading
to cytokine dysregulation with the proliferation and activation of histiocytes (Janka, 2007; Maakaroun et al., 2010).
The clinical presentation is one of multi-organ dysfunction
and haemophagocytosis within the reticuloendothelial
system that is characterized by pancytopenia and organomegaly (Ishii et al., 2007; Maakaroun et al., 2010). Although
not fully understood, HPS appears to be the result of an
uncontrolled immune response triggered by different immune
stimuli, particularly EpsteinBarr virus (de Kerguenec et al.,
2001; Ishii et al., 2007; Janka, 2007, 2012; Maakaroun et al.,
2010). The role of ngolimod in these cases remains uncertain.
As with any immunodulatory agent, the effect of ngolimod on the immune system might confer an increased risk
of malignancy; however, the results of FREEDOMS and the
larger All Studies analysis indicate that the overall incidence
is not increased in patients receiving ngolimod compared
with those receiving placebo. A slight imbalance regarding
basal cell carcinoma continues to be evaluated in the postmarketing setting. The occurrence of three cases of lymphoma in the overall clinical development programme is in
line with epidemiological data reporting the background

Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002

10

L. Kappos et al.

incidence of lymphoma (19.1 cases per 100,000 personyears) (Alexander et al., 2007). However, because of the
low incidence of malignancies and the limited scope and
duration of exposure, rm conclusions on an increased risk
of malignancies with ngolimod cannot yet be drawn.
The major strengths of the present analysis include direct
comparison with placebo in the FREEDOMS group, and the
large number of patients receiving ngolimod at the
licensed dose (0.5 mg, n= 1640) or above in the All Studies
group. The safety data from FREEDOMS II yield similar
results to those of FREEDOMS, with the exception of a
slightly higher rate of basal cell carcinoma and herpes
zoster in the treated groups (Calabresi et al., in press).
The exposure to ngolimod in the All Studies group was over
9070 patient-years, and 140 patients had received the drug
for at least 5 years without the emergence of new AEs of
interest. Given the exposure to ngolimod, the incidence of
any event not observed to date will be less than 1 in 3300
patient-years (Eypasch et al., 1995; Hanley and LippmanHand, 1983). An important caveat of the All Studies analysis
is the absence of a control group, necessitating indirect
comparisons with 2-year data from the placebo arm of the
FREEDOMS study.

supported by non-restricted grants from one or more of these

companies and by grants from the Swiss MS Society, the Swiss
National Research Foundation, the European Union, and the
Gianni Rubatto, Novartis and Roche Research Foundations.
Dr. Cohen has received personal compensation for serving
as a Consultant or Speaker from EMD Serono, Genzyme,
Innate Immunotherapeutics and Novartis. Dr. Cohen has
received research support paid to his institution from
Biogen Idec, Consortium of MS Centers, US Department of
Defense, Genzyme, US National Institute of Health, National
MS Society (USA), Novartis, Receptos, Synthon and Teva.
Drs. Collins, de Vera, Zhang-Auberson and von Rosenstiel
are employees of Novartis Pharma AG, Basel, Switzerland.
Dr. Francis and S. Ritter are employees of Novartis
Pharmaceutical Corporation, East Hanover, NJ, USA.

Contributions

This large-scale analysis provides further information

regarding the safety prole of ngolimod. The approved
dose is generally well tolerated in patients with relapsing
MS, although infrequent SAEs can occur. Additional longterm observation of the safety prole, in particular monitoring of infections, malignancies and cardiovascular complications in the post-marketing setting, will be obtained via
post-approval, long-term follow-up and safety studies, and
pharmacovigilance. This will help to consolidate the safety
prole of this therapy further.

The authors take full responsibility for the content of the

paper. All authors had full access to all the study data. All
authors were involved in the interpretation of the data and
the writing of the paper, and the decision to submit the
manuscript for publication.
All authors were involved in analysis and interpretation of
the data, and drafting and revising the manuscript for
content. W. Collins, A. de Vera, G. Francis, P. von Rosenstiel, J. Cohen and L. Kappos were involved in the design
and concept of studies included in this analysis.
The authors thank the patients and investigators who took
part in the studies contributing to the analyses presented
here. They thank Lee Anne Carroll of Novartis Pharmaceuticals, and Sarah Grifths and Carolyn Brechin of Oxford
PharmaGenesis Ltd for editorial assistance, collating the
comments of authors and other named contributors, and
editing the paper for submission. Such editorial help was
funded by Novartis Pharma AG.

Role of funding source

Appendix A.

The study was funded by Novartis Pharma AG, Basel,

Switzerland.

Supplementary data associated with this article can be

found in the online version at http://dx.doi.org/10.1016/
j.msard.2014.03.002.

5.

Conclusions

Supplementary information

Conict of interest statements

Prof. Kappos has participated as Principal Investigator, Member
or Chair of planning and steering committees or advisory boards
in corporate-sponsored clinical trials in MS and other neurological diseases. The sponsoring pharmaceutical companies for
these trials include Actelion, Advancell, Allozyne, BaroFold,
Bayer Health Care Pharmaceuticals, Bayer Schering Pharma,
Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab,
GeNeuro SA, Genmark, GlaxoSmithKline, Lilly, Merck Serono,
MediciNova, Novartis, Novo Nordisk, Peptimmune, Sano-Aventis, Santhera, Roche, Teva, UCB and Wyeth. Prof. Kappos has
also received funding for speaker activities in the form of nonrestricted educational grants from several of the above listed
companies. Honoraria and other payments for all these activities have been exclusively used for funding of research in his
department. Research and the clinical operations (nursing and
patient care services) of the MS Center in Basel have been

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Please cite this article as: Kappos L, et al. Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety ndings. Multiple
Sclerosis and Related Disorders (2014), http://dx.doi.org/10.1016/j.msard.2014.03.002