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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
2.
2.1.
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
3
Fingolimod 5.0 mg
Fingolimod 1.25 mg
Fingolimod 0.5 mg
Placebo
Interferon beta-1a IM 30 g
once weekly
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.
3.
3.1.
Results
Study population
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
Fingolimod
1.25/0.5 mgb
(n = 1776)
Fingolimod
0.5 mg
(n = 1640)
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
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.
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
3.3.
Cardiovascular effects
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
5
Higher with placebo
Fingolimod 0.5 mg
(n = 425)
Musculoskeletal stiffness
Placebo
(n = 418)
Somnolence
0.002
0.016
0.125
64
512
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.
3.4.
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
Event, n (%)
At least one AE
Any serious AE
Deatha
AE leading to study drug
discontinuationb
Abnormal laboratory value
leading to study drug
discontinuation
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)
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.
Table 3
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
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)
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.
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
3.7.
Lymphopenia
3.8.
Malignancies
4.
Discussion
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
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.
Contributions
Appendix A.
5.
Conclusions
Supplementary information
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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
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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