Multiple Sclerosis and Related Disorders (2014) 3, 355363

Available online at www.sciencedirect.com

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

Effect of prior treatment status and reasons

for discontinuation on the efcacy and safety
of ngolimod vs. interferon -1a
intramuscular: Subgroup analyses of the Trial
Assessing Injectable Interferon vs. Fingolimod
Oral in RelapsingRemitting Multiple Sclerosis
(TRANSFORMS)
B.O. Khatria,n, J. Pelletierb, L. Kapposc, H.-P. Hartungd, G. Comie,
F. Barkhoff, P. von Rosenstielg, X. Mengh, A. Grinspanh,1,
R. Hashmonayh, J.A. Coheni, on behalf of the
TRANSFORMS Study Group
a

The Regional MS Center, Center for Neurological Disorders, Wheaton Franciscan Health Care, 3237 S. 16th
Street, Milwaukee, WI 53215, USA
b
CHU La Timone, CRMBM-CNRS 6612, Marseille, France
c
University Hospital, Petersgraben 4, Basel 4031, Switzerland
d
Heinrich Heine University, Moorenstr 5, Dusseldorf 40225, Germany
e
Universit Vita-Salute San Raffaele, Milan 20123, Italy
f
VU Medical Center, P.O. Box 7057, Amsterdam 1007 MB, The Netherlands
g
Novartis Pharma AG, Kirschgarten Site, Basel 4002, Switzerland
h
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA
i
Mellen Center, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Received 9 July 2013; received in revised form 13 November 2013; accepted 20 November 2013

Corresponding author. Tel.: +1 414 385 1801; fax: +1 414 385 1899.
E-mail addresses: bokhatri@aol.com (B.O. Khatri), jean.pelletier@mail.ap-hm.fr (J. Pelletier), lkappos@uhbs.ch (L. Kappos),
Hans-Peter.Hartung@uniduesseldorf.de (H.-P. Hartung), comi.giancarlo@unisr.it (G. Comi), f.barkhof@vumc.nl (F. Barkhof),
philipp.von_rosenstiel@novartis.com (P. von Rosenstiel), Xiangyi.meng@novartis.com (X. Meng),
augustogrinspan@hotmail.com (A. Grinspan), ronny.hashmonay@novartis.com (R. Hashmonay), cohenj@ccf.org (J.A. Cohen).
1
Present address: Teva Pharmaceuticals, 41 Moores Road, Frazer, PA, USA.
2211-0348/$ - see front matter & 2014 Published by Elsevier B.V.
http://dx.doi.org/10.1016/j.msard.2013.11.006

356

B.O. Khatri et al.

KEYWORDS
Disease-modifying
therapy;
Fingolimod;
Interferon;
Multiple sclerosis;
Sphingosine
1-phosphate receptor
modulator;
Relapse rate

1.

Abstract
Background: Fingolimod demonstrated superior efcacy compared with interferon -1a

intramuscular in relapsing multiple sclerosis. The impact of treatment history on ngolimod

efcacy is unknown.
Objectives: This post-hoc analysis of phase 3 TRANSFORMS data compared the efcacy and
safety of ngolimod and interferon -1a intramuscular among patient subgroups dened by
prior treatment history.
Methods: Annualized relapse rate and safety of once-daily oral ngolimod 0.5 mg, 1.25 mg, or
once-weekly interferon -1a 30 g intramuscular for 12 months were analyzed in 1292 patients
with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior
disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic
effect), and prior disease-modifying therapy duration.
Results: Compared with interferon -1a intramuscular, ngolimod 0.5 mg signicantly reduced
annualized relapse rate in patients who were treatment naive, received prior interferon- treatment,
discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior
disease-modifying therapy duration of Z1 year (Pr0.05, all comparisons). Similar trends were
observed in patients with prior glatiramer acetate treatment. Signicant reductions were also seen
with ngolimod 1.25 mg for treatment-naive and prior interferon--treated patients.
Conclusions: This analysis demonstrates superiority of ngolimod over interferon -1a intramuscular
regardless of prior (interferon-) treatment and prior treatment efcacy and duration. ClinicalTrials.
gov identier: NCT00340834.
& 2014 Published by Elsevier B.V.

Introduction

Until recently, interferon (IFN) and glatiramer acetate (GA)

were the only approved rst-line disease-modifying therapies
(DMTs) for multiple sclerosis (MS). Prior studies have shown that
most patients will experience disease activity on these compounds: 6275% will relapse and 2027% will worsen by 1 point
on the Expanded Disability Status Scale (EDSS) within 2 years
(The IFNB Multiple Sclerosis Study Group, 1993; Jacobs et al.,
1996; Johnson et al., 1995; PRISMS (Prevention of Relapses and
Disability by Interferon beta-1a Subcutaneously in Multiple
Sclerosis) Study Group, 1998). Not surprisingly, reported discontinuation rates after 13 years of IFN treatment range from
23% to 55%; for GA, discontinuation rates tend to be lower, but
still range widely, from 9% to 57% (Haas and Firzlaff, 2005;
Kleinman et al., 2010; Milanese et al., 2005; Reynolds et al.,
2010; Ruggieri et al., 2003; Wong et al., 2011). One study of
treatment adherence reported an unsatisfactory therapeutic
response in 1648% of IFN discontinuations and 25% of GA
discontinuations (Milanese et al., 2005). Intolerable side effects
are another important reason for DMT discontinuation, accounting for 1050% of IFN discontinuations and 16% of GA discontinuations (Milanese et al., 2005; Ruggieri et al., 2003).
Because IFN and GA responses vary among patients, with
relatively high rates of failure and intolerable side effects,
there remains a need for additional therapeutic options that
are effective and well-tolerated.
Fingolimod is an oral sphingosine 1-phosphate modulator
approved in North America and Europe to treat relapsing MS at
a dose of 0.5 mg once daily. Its approval was based on efcacy
and safety demonstrated in 2 pivotal trials. In the 2-year phase
3 Fingolimod Research Evaluating Effects of Daily Oral Therapy
in Multiple Sclerosis (FREEDOMS) study, the annualized relapse
rate (ARR) was signicantly lower with once-daily treatment
with ngolimod 0.5 mg ( 54%; Po0.001) or ngolimod 1.25 mg
( 60%; Po0.001) compared with placebo (Kappos et al.,

2010). In the 12-month, phase 3 Trial Assessing Injectable

Interferon vs. Fingolimod Oral in RelapsingRemitting Multiple
Sclerosis (TRANSFORMS) study, the ARR was signicantly lower
with once-daily ngolimod 0.5 mg ( 52%; Po0.001) or ngolimod 1.25 mg ( 38%; Po0.001) compared with once-weekly
intramuscular (IM) injection of IFN-1a 30-g (Cohen et al.,
2010). Previous subgroup analyses of TRANSFORMS study data
showed that ngolimod 0.5 mg signicantly reduced ARR in
treatment-naive patients (P=0.002) and in patients with prior
DMT treatment (Po0.001), as well as in subgroups by baseline
disease characteristics (Cohen et al., 2013).
To conrm the clinical benet of ngolimod across
treatment history subgroups, additional post-hoc analyses
of the TRANSFORMS trial data were conducted to compare
the efcacy and safety of ngolimod and IFN-1a IM in IFNor GA-naive patients and in patients switching from prior
IFN or GA therapy, as well as those who discontinued prior
DMT for unsatisfactory treatment response or intolerable
side effects. The impact of prior DMT treatment duration on
efcacy and safety was also examined.

2.
2.1.

Material and methods

Study design and patient population

TRANSFORMS was a 12-month, phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled trial,
with
optional
extension
(ClinicalTrials.gov
number,
NCT00340834) (Cohen et al., 2010). A total of 1292 patients
with relapsing MS were randomly assigned to receive, with
equal probability, once-daily ngolimod 0.5 mg (the dose
approved by the United States Food and Drug Administration
and other health authorities) or 1.25 mg or once-weekly
interferon -1a IM 30 g for 12 months. The detailed study
methodology was previously published in accordance with

Subgroup analyses of the TRANSFORMS study

357

2.3.

CONSORT guidelines (Cohen et al., 2010). The study was

conducted in accordance with the International Conference
on Harmonisation Guidelines for Good Clinical Practice and the
Declaration of Helsinki. The protocol was approved by each
site's institutional review board and all patients gave written
informed consent.

2.2.

In the core TRANSFORMS study, statistical analyses were

conducted in the intent-to-treat (ITT) population using a
negative binomial regression model adjusted for treatment,
country, the number of relapses within 2 years prior to
enrollment, and baseline EDSS (Cohen et al., 2010). For the
subgroup populations, ARRs with associated condence intervals and ARR ratios with associated P values were estimated
using a negative binomial regression model adjusted for
treatment, subgroup variable, and treatment-by-subgroup
variable interaction. AE data refer to treatment-emergent
events, regardless of causality.

Study endpoints and subanalysis groups

The primary efcacy variable in the TRANSFORMS core study

was ARR, dened as the number of conrmed relapses during a
12-month period. Conrmed relapse criteria included symptoms
accompanied by one of the following: an increase of at least
half a point in the EDSS score, 1 point increases in each of
2 EDSS functional system scores, or of 2 points in one EDSS
functional system score (excluding scores for bowel-bladder or
cerebral functioning systems). Secondary efcacy endpoints
included time to disability progression conrmed at 3 months
and MRI outcomes, including brain atrophy. Safety was assessed
through adverse event (AE) reporting. Post-hoc analyses of the
TRANSFORMS core study data were performed to evaluate ARR
in subgroups of patients based on prior use of IFN therapy,
prior use of GA therapy, discontinuation of prior DMT due to
unsatisfactory therapeutic effect, discontinuation of prior DMT
for AEs, and duration of prior DMT.
Table 1

Statistical analysis

3.

Results

3.1.

Patients

A total of 1292 patients were randomly assigned to treatment. Demographic and baseline clinical characteristics
for all patient subgroups are shown in Tables 1 and 2.
The majority of patients (57.6%) had received treatment
with a DMT prior to enrollment; 218 patients (17.0%) had a
history of treatment with multiple DMTs.

Baseline patient demographics and clinical characteristics by treatment subgroup (randomized population).

Characteristic

Age, years
Female, n (%)
Duration of MS, years
Relapses in previous
1 year, n
Relapses in previous
2 years, n
EDSS score
Gd + lesions, n
T2 lesion volume, mm3
Patients free of
Gd + lesions, n (%)

IFN-naive patients

IFN-treated patients

Fingolimod
0.5 mg
(n= 212)

Fingolimod
1.25 mg
(n = 217)

IFN-1a IM
(n = 228)

Fingolimod
0.5 mg
(n= 219)

Fingolimod
1.25 mg
(n = 209)

IFN-1a IM
(n= 207)

35.8
130
3.36
1.6

35.0
144
3.25
1.6

35.0
155
3.27
1.5

37.6
152
6.23
1.5

36.6
149
5.97
1.4

37.1
140
6.73
1.4

(8.8)
(61.3)
(4.75)
(0.8)

2.1 (1.1)
1.94
1.20
4338
134

(1.21)
(3.53)
(6078)
(64.1)

(8.4)
(66.4)
(4.89)
(0.9)

2.1 (1.1)
1.99
2.04
4980
119

(1.18)
(6.13)
(5771)
(56.4)

(8.1)
(68.0)
(5.00)
(7.9)

2.1 (1.1)
1.93
1.20
4212
135

(1.23)
(3.23)
(4691)
(61.1)

(8.7)
(69.4)
(4.63)
(1.5)

2.48 (2.9)

2.25 (1.3)

2.53
0.76
5971
154

2.45
0.91
5197
151

(1.37)
(1.85)
(7065)
(70.6)

GA-naive patients

Age, years
Female, n (%)
Duration of MS, years
Relapses in previous
1 year, n
Relapses in previous
2 years, n
EDSS score
Gd + lesions, n

(8.3)
(71.3)
(4.52)
(0.8)

(1.40)
(2.58)
(6170)
(75.1)

(8.4)
(67.6)
(5.33)
(0.8)

2.4 (1.4)
2.46
0.91
5695
133

(1.24)
(2.25)
(6567)
(65.2)

GA-treated patients

Fingolimod
0.5 mg
(n= 374)

Fingolimod
1.25 mg
(n = 359)

IFN-1a IM
(n = 368)

Fingolimod
0.5 mg
(n = 67)

Fingolimod
1.25 mg
(n= 57)

IFN-1a IM
(n= 67)

36.5
24
4.49
1.5

35.7
237
4.03
1.5

35.7
245
4.37
1.4

38.0
41
7.00
1.5

35.9
56
7.48
1.6

37.6
50
7.99
1.8

(9.0)
(64.4)
(4.88)
(1.2)

(8.4)
(66.0)
(4.53)
(0.8)

(8.1)
(66.6)
(5.02)
(0.7)

(7.3)
(71.9)
(4.50)
(0.9)

(8.6)
(83.6)
(5.73)
(1.1)

(9.3)
(74.6)
(6.59)
(1.1)

2.3 (2.3)

2.2 (1.1)

2.2 (1.1)

2.4 (1.2)

2.3 (1.4)

2.8 (1.8)

2.16 (1.30)
0.99 (2.91)

2.14 (1.29)
1.37 (4.80)

2.12 (1.26)
1.12 (2.98)

2.77 (1.41)
0.75 (1.40)

2.60 (1.37)
0.88 (1.99)

2.55 (1.22)
2.14 (4.64)

358

B.O. Khatri et al.

Table 1. (continued )
T2 lesion volume,
mm3
Patients free of
Gd + lesions, n (%)

4990 (6596)

4867 (5777)

4926 (5850)

6364 (6882)

6225 (6789)

4910 (4895)

252 (67.9)

236 (68.2)

224 (62.0)

36 (64.3)

34 (51.5)

44 (68.8)

Discontinued prior DMT owing to

unsatisfactory therapeutic effect

Age, years
Female, n (%)
Duration of MS, years
Relapses in previous
1 year, n
Relapses in previous
2 years, n
EDSS score
Gd + lesions, n
T2 lesion volume,
mm3
Patients free of
Gd + lesions, n (%)

Fingolimod
0.5 mg
(n= 41)

Fingolimod
1.25 mg
(n= 54)

IFN-1a IM
(n = 45)

Fingolimod
0.5 mg
(n = 390)

Fingolimod
1.25 mg
(n= 372)

IFN-1a IM
(n= 390)

37.2
25
6.99
1.6

34.0
44
7.11
1.8

36.5
29
8.41
1.7

36.7
257
4.59
1.5

36.0
249
4.21
1.5

35.9
266
4.52
1.4

(8.3)
(61.0)
(4.50)
(1.0)

(8.7)
(81.5)
(4.50)
(1.1)

(8.1)
(64.4)
(5.92)
(1.0)

(8.9)
(65.9)
(4.89)
(1.2)

(8.3)
(66.9)
(4.85)
(0.8)

(8.3)
(68.2)
(5.24)
(0.8)

3.0 (1.8)

2.6 (1.5)

3.0 (1.9)

2.2 (2.2)

2.1 (1.1)

2.2 (1.1)

2.60 (1.38)
0.71 (1.15)
7120 (7529)

2.81 (1.59)
1.77 (4.21)
8212 (9115)

2.76 (1.30)
0.89 (1.56)
6102 (6108)

2.20 (1.32)
1.01 (2.93)
4963 (6518)

2.13 (1.24)
1.45 (4.85)
4635 (5224)

2.12 (1.24)
1.08 (2.91)
4784 (5654)

27 (65.9)

34 (65.4)

28 (62.2)

261 (67.6)

236 (65.6)

240 (63.2)

Discontinued prior DMT owing to AE

Age, years
Female, n (%)
Duration of MS, years
Relapses in previous
1 year, n
Relapses in previous
2 years, n
EDSS score
Gd + lesions, n
T2 lesion volume,
mm3
Patients free of
Gd + lesions, n (%)

Discontinued prior DMT for reason other

than unsatisfactory therapeutic effect
(includes DMT-naive patients)

Discontinued prior DMT for reason other

than AE (includes DMT-naive patients)

Fingolimod
0.5 mg
(n= 59)

Fingolimod
1.25 mg
(n= 47)

IFN-1a IM
(n = 51)

Fingolimod
0.5 mg
(n = 372)

Fingolimod
1.25 mg
(n= 379)

IFN-1a IM
(n= 384)

37.5
45
7.09
1.5

36.4
35
8.28
1.5

37.2
43
7.41
1.6

36.6
237
4.46
1.5

35.7
258
4.11
1.5

35.8
252
4.60
1.4

(9.3)
(76.3)
(5.59)
(0.9)

(8.4)
(74.5)
(6.14)
(0.8)

(8.9)
(84.3)
(5.13)
(0.9)

(8.7)
(63.7)
(4.68)
(1.2)

(8.4)
(68.1)
(4.52)
(0.9)

(8.2)
(65.6)
(5.40)
(0.8)

2.4 (1.4)

2.3 (1.4)

2.5 (1.3)

2.3 (3.3)

2.2 (1.2)

2.2 (1.2)

2.65 (1.35)
1.19 (2.80)
5996 (6423)

2.86 (1.28)
1.00 (2.08)
4287 (3867)

2.64 (1.25)
0.96 (2.47)
4637 (4963)

2.17 (1.31)
0.94 (2.81)
5037 (6675)

2.13 (1.29)
1.55 (5.01)
5185 (6171)

2.13 (1.25)
1.07 (2.85)
4961 (5806)

38 (64.4)

30 (65.2)

30 (61.2)

250 (67.9)

240 (65.6)

238 (63.3)

AE=adverse event; DMT =disease-modifying therapy; EDSS=Expanded Disability Status Scale; GA=glatiramer acetate; Gd+ =gadolinium-enhancing; IFN =interferon beta; IM=intramuscular; MS=multiple sclerosis. All values are mean (SD) unless otherwise noted.

3.2. IFN-naive patients vs. those who received

prior IFN
Approximately 50% of patients had previously received IFN
therapy (Table 1). Patients previously treated with IFN had a
longer duration of MS than IFN-naive patients (6.31 years vs.
3.29 years, respectively), as well as higher EDSS scores (2.48 vs.
1.95), and greater mean baseline T2 lesion volume (5631 mm3
vs. 4506 mm3). Fingolimod 0.5 mg and 1.25 mg signicantly
reduced ARR compared with IFN-1a IM in patients with prior
IFN treatment ( 58% and 39%, respectively, Po0.0001 and
P=0.0069; Figs. 1 and 2). Fingolimod 0.5 mg and 1.25 mg were

also superior to IFN-1a IM in patients with no previous IFN

treatment ( 43% and
41%, respectively (P=0.0092 and
P=0.0131).

3.3. GA-naive patients vs. those that received

prior GA
A total of 179 patients had received prior GA, constituting a
minority of all treatment subgroups (1316%). Overall, patients
with a history of GA treatment had longer mean duration of MS
(7.52 years), higher EDSS score (2.63), and greater mean T2

Subgroup analyses of the TRANSFORMS study

359

Table 2 Baseline patient demographics and clinical characteristics by duration of prior disease-modifying therapy
(randomized population).
Characteristic

Age, years
Female, n (%)
Duration of MS, years
Relapses in previous
1 year, n
Relapses in previous
2 years, n
EDSS score
Gd + lesions, n
T2 lesion volume,
mm3
Patients free of Gd +
lesions, n (%)

r1 year

No prior treatment
Fingolimod
0.5 mg
(n =184)

Fingolimod
1.25 mg
(n= 170)

IFN-1a IM
(n= 186)

Fingolimod
0.5 mg
(n = 64)

Fingolimod
1.25 mg
(n = 55)

IFN-1a IM
(n= 64)

35.5
113
2.61
1.6

35.2
106
2.44
1.6

34.8
123
2.49
1.5

35.9
36
3.60
1.6

33.4
47
3.95
1.8

35.3
46
3.39
1.4

(8.9)
(61.4)
(3.77)
(0.8)

(8.4)
(62.4)
(4.30)
(0.8)

(7.9)
(66.1)
(4.02)
(0.7)

(6.9)
(73.4)
(4.87)
(1.0)

(8.7)
(71.9)
(3.77)
(0.8)

2.1 (1.0)

2.1 (1.1)

2.1 (1.0)

2.2 (1.1)

2.3 (1.2)

2.3 (1.1)

1.85 (1.17)
1.10 (3.15)
4010 (5920)

1.95 (1.20)
1.92 (6.37)
4534 (5565)

1.84 (1.19)
1.31 (3.50)
4302 (4925)

2.36 (1.16)
1.36 (4.05)
6503 (6904)

2.24 (1.25)
1.69 (4.19)
6030 (6963)

2.22 (1.16)
0.68 (1.24)
4132 (4122)

120 (66.3)

98 (59.4)

107 (59.4)

33 (60.0)

39 (60.9)

40 (63.5)

413 years

Age, years
Female, n (%)
Duration of MS, years
Relapses in previous
1 year, n
Relapses in previous
2 years, n
EDSS score
Gd + lesions, n
T2 lesion volume,
mm3
Patients free of Gd +
lesions, n (%)

(8.9)
(65.5)
(4.81)
(0.7)

43 years

Fingolimod
0.5 mg
(n =80)

Fingolimod
1.25 mg
(n= 86)

IFN-1a IM
(n= 75)

Fingolimod
0.5 mg
(n = 111)

Fingolimod
1.25 mg
(n = 101)

IFN-1a IM
(n= 108)

36.9
56
4.50
1.4

35.7
66
4.27
1.4

35.6
50
5.13
1.4

39.1
76
9.46
1.5

38.3
70
8.62
1.3

38.5
75
9.70
1.4

(9.0)
(70.0)
(3.35)
(1.0)

(9.4)
(76.7)
(3.25)
(0.9)

(8.6)
(66.7)
(4.48)
(0.8)

(8.1)
(68.5)
(4.47)
(1.9)

(8.0)
(69.3)
(4.53)
(0.8)

(7.9)
(69.4)
(5.75)
(0.9)

2.5 (1.5)

2.4 (1.3)

2.6 (1.3)

2.4 (1.2)

2.3 (1.2)

2.3 (1.1)

2.23 (1.34)
0.81 (2.02)
4602 (5825)

2.05 (1.26)
1.22 (3.20)
5247 (6512)

2.24 (1.25)
0.80 (2.24)
4692 (5578)

2.82 (1.41)
0.70 (1.78)
6818 (7728)

2.78 (1.41)
0.88 (2.65)
5262 (5402)

2.68 (1.25)
0.99 (2.37)
6643 (7365)

55 (68.8)

56 (67.5)

54 (72.0)

80 (72.1)

77 (77.0)

67 (63.2)

DMT=disease-modifying therapy; EDSS=Expanded Disability Status Scale; Gd+ =gadolinium-enhancing; IFN =interferon beta;
IM=intramuscular; MS=multiple sclerosis. All values are mean (SD) unless otherwise noted.

lesion volume (5814 mm3) compared with GA-naive patients

(4.30 years, 2.12, and 4930 mm3, respectively). Compared with
IFN-1a IM, ngolimod 0.5 mg and 1.25 mg signicantly reduced
ARR in GA-naive patients by 56% and 42%, respectively
(Pr0.0005; Figs. 1 and 2). Fingolimod 0.5 mg and 1.25 mg
numerically reduced ARR compared with IFN-1a IM by 28% and
31%, respectively, in patients with prior GA treatment
(P=0.2804 and P=0.2118).

3.4. Prior DMT discontinuation owing to

unsatisfactory therapeutic effect
Unsatisfactory therapeutic effect of prior DMT was cited by 140
patients as a reason for participation in TRANSFORMS; more
than 85% of these patients (37/41, 46/54, and 42/45 patients in

the ngolimod 0.5 mg, ngolimod 1.25 mg, and IFN-1a IM

groups, respectively) were considered IFN treatment failures
(i.e., previously treated with IFN and discontinued prior DMT
owing to unsatisfactory treatment effect), so a separate
analysis of IFN failures was not conducted. The subgroup of
patients that did not discontinue prior DMT owing to unsatisfactory therapeutic effect included those who were DMT-naive.
Baseline demographics and disease characteristics were generally comparable among patient subgroups based on unsatisfactory therapeutic response to DMT (Table 1). ARR was
signicantly reduced by ngolimod 0.5 mg compared with
IFN-1a IM in patients who discontinued prior DMT for unsatisfactory therapeutic effect ( 57%; P=0.0369) and in those who
discontinued prior DMT for other reasons ( 50%; Po0.0001;
Fig. 1). Reductions in ARR with ngolimod 1.25 mg vs. IFN-1a
IM were 38% in those who discontinued for unsatisfactory

360

B.O. Khatri et al.

ARR

Subgroup

N*

Fingolimod
0.5 mg

IFN-1a
IM

Reduction
vs IFN-1a , %

Overall

860

0.16

0.33

52

<0.001

Prior IFN

424

0.230

0.543

58

<0.0001

IFN-naive

436

0.188

0.331

43

0.0092

Prior GA

122

0.451

0.623

28

0.2804

GA-naive

738

0.174

0.396

56

<0.0001

Favors Fingolimod 0.5 mg

Favors IFN-1a IM

Treatment history

Reason for prior DMT discontinuation

UTE

86

0.263

0.618

57

0.0369

Reason other than UTE

774

0.204

0.410

50

<0.0001

AE

109

0.402

0.574

30

0.2794

Reason other than AE

751

0.178

0.413

57

<0.0001

No prior treatment

366

0.139

0.306

55

0.0022

119

0.223

0.459

52

0.0556

>13

155

0.227

0.501

55

0.0132

>3

219

0.307

0.585

48

0.0086

Prior DMT duration, y

l
l

l
l
l

0.0

0.2

l
l

0.4

0.6

0.8

1.0

1.2

1.4

1.6

ARR Ratio (95% CI)

Fig. 1 Comparison of annualized relapse rates with ngolimod 0.5 mg (approved dose) or interferon -1a intramuscular in
subgroups based on prior treatment history.

therapeutic effect (P=0.1721) and 40% in those who discontinued for other reasons (P=0.0007; Fig. 2).

AEs were cited as a reason for prior DMT discontinuation by

157 patients. In this analysis, the subgroup of patients that
did not discontinue prior DMT owing to AEs included those
who were DMT-naive. Baseline demographics and disease
characteristics were generally comparable among treatment groups within both patient subgroups (Table 1).
Patients who discontinued prior DMT for AEs had longer
mean duration of MS, as well as higher EDSS scores and
smaller T2 lesion volume than those who discontinued for
other reasons or were treatment-naive. Among patients who
discontinued prior DMT for AEs, ARR was numerically
reduced by ngolimod 0.5 mg and 1.25 mg compared with
IFN-1a IM ( 30%, P = 0.2794; and
16%, P= 0.6142,
respectively; Figs. 1 and 2).

treatment groups, the duration of MS, EDSS scores, and T2

lesion volume increased with greater duration of prior DMT.
Relapse frequency remained relatively stable regardless of
prior treatment duration. The number of Gd-enhancing
lesions at baseline varied among treatment groups and
across treatment duration subgroup categories.
Across all treatment groups, ARRs were generally higher with
increased duration of prior therapy, with the exception of the
subgroup of patients receiving ngolimod 1.25 mg that had
received prior DMT for 43 years. ARR was signicantly reduced
by ngolimod 0.5 mg compared with IFN-1a IM in patients with
no prior treatment with DMT ( 55%; P=0.0022), 413 years
( 55%; P=0.0132), and 43 years ( 48%; Po0.0001) and
trended toward signicance in those who received prior DMT
for r1 year ( 52%; P=0.0556). Reductions in ARR relative to
IFN-1a IM were also seen with ngolimod 1.25 mg: no prior
DMT ( 44%; P=0.0206), r1 year ( 31%; P=0.2572), 413
years ( 23%, P=0.3427), 43 years ( 52%; P=0.0002). These
reductions were statistically signicant in the subgroups of
patients with no prior DMT and those with 43 years of
prior DMT.

3.6.

3.7.

3.5. Prior DMT discontinuation owing to adverse

events

Duration of prior DMT

Baseline demographics and clinical characteristics by duration of prior treatment are shown in Table 2. Across

Safety

The overall incidence of AEs was generally similar in subgroups

classied by prior IFN treatment, prior GA treatment, prior

Subgroup analyses of the TRANSFORMS study

361
ARR

Subgroup

N*

Fingolimod
1.25 mg

IFN-1a
IM

Reduction
vs IFN-1a , %

Overall

851

0.20

0.33

38

<0.001

Prior IFN

411

0.333

0.543

39

0.0069

IFN-naive

440

0.194

0.331

41

0.0131

Prior GA

133

0.431

0.623

31

0.2118

GA-naive

718

0.232

0.396

42

0.0005

Favors Fingolimod 1.25 mg

Favors IFN-1a IM

Treatment history

Reason for prior DMT discontinuation

UTE

99

0.381

0.618

38

0.1721

Reason other than UTE

752

0.245

0.410

40

0.0007

AE

97

0.482

0.574

16

0.6142

Reason other than AE

754

0.235

0.413

43

0.0002

No prior treatment

352

0.171

0.306

44

0.0206

128

0.315

0.459

31

0.2572

>13

161

0.385

0.501

23

0.3427

>3

209

0.278

0.585

52

0.0045

Prior DMT duration, y

I
I I

I
I

I
I

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

ARR Ratio (95% CI)

Fig. 2 Comparison of annualized relapse rates with ngolimod 1.25 mg or interferon -1a intramuscular in subgroups based on prior
treatment history.

discontinuation owing to therapeutic effect, prior discontinuation owing to AEs, and duration of prior therapy (Supplementary
Tables 1 and 2). Nausea and diarrhea were more common in
patients who discontinued prior DMT because of AEs than in
those who discontinued prior DMT for other reasons, across all
treatment groups. Pyrexia, myalgia, and u-like illness occurred
in more patients receiving IFN-1a IM than in those receiving
ngolimod; among patients receiving IFN-1a IM, pyrexia and
u-like illness were more common in IFN-naive patients (24.0%
and 44.9%, respectively) than in patients with prior IFN
treatment (11.2% and 28.2%).
The overall incidence of serious AEs was similar across
subgroups (Table 3). None of the subgroups was associated
with increased incidence of serious AEs related to heart
rhythm changes, increased liver enzymes, macular edema,
or infections, with the exception of bradycardia (6.3%) in
patients receiving ngolimod 1.25 mg who had prior treatment duration of r1 year.

4.

Discussion

These analyses show that ngolimod is more effective than

IFN-1a IM in treatment-naive patients and in those who
have received prior DMT. Fingolimod was also more effective than IFN-1a IM in reducing ARR in patients who

previously experienced an unsatisfactory therapeutic

response to DMT. This analysis did not demonstrate superior
efcacy for ngolimod in patients unable to tolerate prior
DMT; however, ngolimod did not introduce any new tolerability concerns in this population. Results from these
analyses are consistent with subgroup analyses of the
FREEDOMS study data, which showed that once-daily ngolimod treatment signicantly reduced ARR when compared
with placebo in patients with a history of IFN or GA
treatment, as well as in patients reporting an unsatisfactory
therapeutic effect of their prior DMT. These analyses had
limitations related to the post hoc design, including a
relatively small sample size for many of the subgroups.
However, despite the fact that the study was not powered
for these analyses, ngolimod-treated patients in some of
these subgroups did show statistically signicant improvements over their IFN-1a IM-treated counterparts.
The overall goal of MS treatment is to reduce the number
of relapses and delay progression of disability over time
while avoiding intolerable side effects. Because signicant
damage occurs early in the disease course, early initiation
of an effective therapy is preferable (Coyle, 2008; Hartung,
2005). The BENEFIT and CHAMPIONS studies showed that
over a 5-year period, early treatment with interferons
reduced the risk of clinically denite MS by 37% and 35%,
respectively, in patients who had an event suggestive of MS,

362

B.O. Khatri et al.

Table 3

Serious adverse events by treatment history subgroup (safety population).

Fingolimod 0.5 mg

Fingolimod 1.25 mg

Placebo

18/218
12/211
5/56
25/373

(8.3)
(5.7)
(8.9)
(6.7)

24/205
21/215
7/67
38/353

(11.7)
(9.8)
(10.4)
(10.8)

15/206
10/225
4/66
21/365

(7.3)
(4.4)
(6.1)
(5.8)

Reason for discontinuation of prior treatment

UTE
3/41
27/388
Reason other than UTEa
AE
4/59
26/370
Reason other than AEa

(7.3)
(7.0)
(6.8)
(7.0)

7/54
38/366
4/47
41/373

(13.0)
(10.4)
(8.5)
(11.0)

3/45
22/386
5/50
20/381

(6.7)
(5.7)
(10.0)
(5.2)

Duration of prior treatment, years

0
r1
413
43

(4.4)
(7.3)
(3.8)
(13.5)

17/169
7/64
10/86
11/101

(10.1)
(10.9)
(11.6)
(10.9)

9/183
5/64
4/75
7/108

(4.9)
(7.8)
(5.3)
(6.5)

Incidence, n/N (%)

Treatment history
Prior IFN
IFN naive
Prior GA
GA naive

8/183
4/55
3/80
15/111

AE=adverse event; GA=glatiramer acetate; IFN=interferon; UTE=unsatisfactory therapeutic effect.

a
Includes treatment-naive patients.

compared with delaying treatment for a median of 23 and

29 months, respectively (Kappos et al., 2009; Kinkel et al.,
2006). In the current analysis, patients without prior IFN or
GA therapy were earlier in their disease course than
patients with prior exposure to these therapies. Although
the short-term or long-term efcacy of ngolimod as
treatment in early MS has not been formally tested, the
superiority of ngolimod over IFN-1a IM in subgroups without prior IFN or GA treatment suggests that ngolimod may
be an appropriate choice of DMT for early treatment.
In patients who do not have a satisfactory response to
initial DMT treatment, switching therapy is a common
approach; however, few data are available to support its
utility (Caon et al., 2006; Carra et al., 2008; Gajofatto
et al., 2009; Rio et al., 2012; Zwibel, 2006). A study of
therapy switch outcomes showed that changing IFN treatments was less effective in relapse reduction than switching
to another class of DMT (e.g., GA to IFN or IFN to GA)
(Carra and Onaha, 2008). The present analyses are consistent with this conclusion, as switching from IFN-1a IM to
ngolimod reduced ARR to a greater extent than further
IFN treatment.

5.

Conclusions

The results of the current analyses support the use of

ngolimod as an effective treatment for patients with
relapsing MS, regardless of prior treatment usage or
duration.

Conict of interest
B.O. Khatri has received research support fees, consultancy
or speaking fees, or grants, in the last 3 years from Bayer,

Biogen Idec, Serono, Novartis, Sano-Aventis, Teva, Genzyme, and Terumo BCT. J. Pelletier has received compensation for serving as advisory board from Novartis, Bayer
Schering, Merck Serono, Sano Aventis, Teva. The University
Hospital Basel as employer of Prof. Kappos has received and
dedicated to research support fees for board membership,
consultancy or speaking, or grants, in the last 3 years from
Actelion, Advancell, Allozyne, Bayer, Bayhill, Biogen Idec,
BioMarin, CSL Behring, Eli Lilly, European Union, GeNeuro,
Genmab, Gianni Rubatto Foundation, Glenmark, Merck
Serono, MediciNova, Mitsubishi Pharma, Novartis, Novartis
Research Foundation, Novo Nordisk, Peptimmune, Roche,
Roche Research Foundation, Sano-Aventis, Santhera, Swiss
MS Society, Swiss National Research Foundation, Teva, UCB,
and Wyeth. H.P. Hartung has received honoraria for consulting and speaking from Bayer Healthcare, Biogen Idec,
Genzyme, Novartis, Roche, Sano-Aventis, and Teva. G. Comi
has received consulting fees for participating on advisory
boards from Novartis, Teva Pharmaceutical Ind. Ltd, SanoAventis, Merck Serono, Bayer Schering, Actelion and
Geneuro and lecture fees from Novartis, Teva, SanoAventis, Merck Serono, Biogen Domp, Bayer Schering and
Serono Symposia International Foundation. F. Barkhof has
served on the editorial boards of the journals Brain,
European Radiology, Neuroradiology, Multiple Sclerosis,
and Radiology, has received compensation personally or to
his institution for consulting work from Bayer-Schering
Pharma, Sano-Aventis, Biogen Idec, Teva, Merck-Serono,
Novartis, Roche, Synthon BV, and Jansen Research, and for
development of educational presentations, including service on speakers' bureaus from Serono Symposium Foundation, and his institution has received grant support from the
Dutch MS Society. P. von Rosenstiel is an employee of
Novartis Pharma AG. X. Meng and R. Hashmonay are
employees of Novartis Pharmaceuticals Corporation. A.

Subgroup analyses of the TRANSFORMS study

Grinspan is a former employee of Novartis Pharmaceuticals
Corporation. J.A. Cohen received personal compensation for
serving as a consultant or speaker from Teva in the past 12
months, and has received research support paid to his
institution from Biogen Idec, Department of Defense, Genzyme, National Institutes of Health, National MS Society,
Novartis, Receptos, Synthon, and Teva.

Acknowledgments
Editorial support for the preparation of this manuscript was
provided by Valerie P. Zediak, PhD, and Erica S. Wehner,
RPh, CMPP, from Complete Healthcare Communications,
Inc., with funding from Novartis Pharmaceuticals Corporation. This work was funded by Novartis Pharmaceuticals
Corporation; the sponsor participated in design, execution,
and interpretation of the post hoc analysis, preparation of
the manuscript, and decision to submit the manuscript.

Appendix A.

Supplementary materials

Supplementary data associated with this article can be

found in the online version at http://dx.doi.org/10.1016/
j.msard.2013.11.006.

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