REVIEW

URRENT
C
OPINION

New management algorithms in multiple sclerosis

Per Soelberg Sorensen

Purpose of review
Our current treatment algorithms include only IFN-b and glatiramer as available first-line disease-modifying
drugs and natalizumab and fingolimod as second-line therapies. Today, 10 drugs have been approved
in Europe and nine in the United States making the choice of therapy more complex. The purpose of the
review has been to work out new management algorithms for treatment of relapsingremitting multiple
sclerosis including new oral therapies and therapeutic monoclonal antibodies.
Recent findings
Recent large placebo-controlled trials in relapsingremitting multiple sclerosis have shown efficacy of new
oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the
injectable disease-modifying drugs, IFN-b and glatiramer acetate. In addition, the new oral drugs seem to
have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has
shown superiority to subcutaneous IFN-b 1a, has been approved in Europe, but not yet in the United States.
Summary
In de novo-treated patients, the injectables, IFN-b and glatiramer acetate, will to a great extent be replaced
by the new orals, dimethyl fumarate and teriflunomide. However, patients who are stable on an injectable
with no or minor side-effects could continue their current therapy. Alemtuzumab should be used as a
second-line therapy.
Keywords
disease-modifying drugs, multiple sclerosis, oral therapies, treatment algorithm

INTRODUCTION
Until a few years ago, the treatment of relapsing
remitting multiple sclerosis (RRMS) with diseasemodifying drugs (DMDs) was rather simple. IFN-b
preparations and glatiramer acetate were available
for first-line therapy, and if treatment escalation
was needed, natalizumab and fingolimod were the
only options.
Today, 10 drugs have been approved in Europe
and nine in the United States making the choice
of therapy more complex, and accurate evaluation
of the benefits and risks provided by the different
treatment options becomes critical in making
decisions on therapy for individual patients.

INITIATION OF THERAPY IN CLINICALLY

ISOLATED SYNDROME
Axonal damage occurs early in the disease process,
and a proportion of patients with clinically isolated
syndrome (CIS) already have discrete cognitive dysfunction [1]. A multifocal presentation and baseline
lesion load on MRI predict likelihood of conversion
to clinically definite multiple sclerosis (CDMS) [24].
[Link]

Early treatment in CIS consistently reduced

conversion to CDMS across treatments [2,510],
and early treatment may even reduce long-term risk
of developing permanent disability, relative to later
treatment [11]. Available drugs for treatment of
CIS patients are intramuscular IFN-b 1a (Avonex),
subcutaneous IFN-b 1a (Rebif), subcutaneous IFN-b
1b (Betaferon, Extavia), and glatiramer acetate
(Copaxone).
There are no comparative studies in patients
with CIS, but comparative studies in patients
with RRMS suggest that the frequently injected subcutaneous IFN-b 1a and subcutaneous IFN-b 1b
more effectively prevent the patient from developing CDMS than intramuscular IFN-b 1a [12,13].
Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
Correspondence to Professor Per Soelberg Sorensen, MD, DMSc,
Danish Multiple Sclerosis Center, Department of Neurology 2082,
Rigshospitalet, DK-2100 Copenhagen, Denmark. Tel: +45 3545 2080;
e-mail: pss@[Link]
Curr Opin Neurol 2014, 27:246259
DOI:10.1097/WCO.0000000000000096
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New management algorithms in multi ple sclerosis Sorensen

KEY POINTS

The article gives a review of the recent large placebocontrolled trials reporting the efficacy and safety of the
new oral DMDs and the monoclonal antibody
alemtuzumab in patients with relapsingremitting MS.

A review of comparative studies of DMDs for treatment
of relapsingremitting MS is provided.

A new treatment algorithm is presented for initiation of
therapy and treatment escalation in patients with CIS or
relapsingremitting MS.

Hence, the suggested treatment algorithm for CIS

patients with prognostic factors indicating a very
high risk of developing CDMS would be to choose
either a frequently injected IFN-b or glatiramer
acetate.

TREATMENT OF RELAPSINGREMITTING
MULTIPLE SCLEROSIS
Since 1993, IFN-b has been used for treatment of
RRMS and this together with glatiramer acetate
have been the only approved first-line therapies
for RRMS in the USA and Europe. Recently, the
oral drugs teriflunomide (Aubagio) and dimethyl
fumarate (Tecfidera) were approved in the USA
by US Food and Drug Administration (FDA) and
in the European Union by the European Medicines
Agency (EMA). Natalizumab (Tysabri), fingolimod
(Gilenya), alemtuzumab (Lemtrada), and mitoxantrone are mainly used as second-line therapies
in patients who do not respond satisfactorily
to a first-line therapy. However, alemtuzumab is
approved for active RRMS, and may, like natalizumab and fingolimod, be used as first-line therapy
in patients with very active RRMS. Laquinimod
(Nerventra) is not yet approved in the United States
and is under evaluation in the European Union by
the EMA.

EFFICACY OF AVAILABLE FIRST-LINE

THERAPIES
The clinical efficacy in phase III placebo-controlled
trials of the drugs available for treatment of RRMS
can be seen in Table 1 [1419,20 ,21 ,22 ,2326].
IFN-b has since 1993 been the mainstay in the
treatment of RRMS. IFN-b is administered as intramuscular or subcutaneous injections once or several
times weekly. In pivotal placebo-controlled trials,
IFN-b reduced the annualized relapse rate (ARR)
about 30% and showed a modest reduction in the
time to progression on the Expanded Disability
&

&&

&

Status Scale (EDSS) (Table 1 and Fig. 1) [1416].

The effect on disease activity on MRI was more
impressive, typically with reductions of 6080%.
[1416]. Brain atrophy was not measured in most
studies, and the effect was not convincing.
Glatiramer acetate (Copaxone) is a mixture
of polypeptides composed of four amino acids.
Glatiramer acetate is administered subcutaneously,
20 mg daily. In placebo-controlled trials, glatiramer
acetate reduced the ARR by 29% and, less convincingly, reduced time to increased disability on
EDSS (Table 1 and Fig. 1) [17]. Glatiramer acetate
also reduced MRI activity but to a lesser extent than
IFN-b. In some but not all studies, brain atrophy was
reduced [27,28].
Teriflunomide (Aubagio) is a dihydrooratate
dehydrogenase inhibitor that causes inhibition
of proliferation of autoreactive B- and T-cells and
is administered orally 14 mg once daily [29]. The
effect of teriflunomide 14 mg daily on relapses,
disease progression, and MRI activity was comparable to that of the injectable first-line therapies
(Table 1 and Fig. 1) [18,19]. The change in brain
parenchymal fraction was not significantly different
[30].
Dimethyl fumarate (BG12) (Tecfidera) reduces
the production and release of inflammatory
molecules and has antioxidant properties [31 ].
Dimethyl fumarate is administered orally as a
240 mg tablet twice daily. The relapse rate was
reduced about 50% and disability progression
by 38% in one trial but not significantly in
another (Table 1 and Fig. 1). The effect in MRI
on gadolinium-enhancing lesions or new or
enlarging T2 lesions was between 80 and 90%
[20 ,21 ].
Laquinimod (Nerventra) is a quinoline-3carboxamide derivative with several immunomodulatory effects [1,32]. Laquinimod is administered
orally as 0.6 mg once daily. The effect on relapses
was disappointingly low (23%; P 0.0002), but
a more pronounced effect was seen on disease
progression with 3649% reduction. MRI changes
were reduced by 6070%, and brain atrophy was
reduced by 43% [22 ].
&

&

&&

&

SAFETY AND CONVENIENCE OF

AVAILABLE FIRST-LINE THERAPIES
The old injectable first-line therapies have an
excellent safety record but require frequent intramuscular or subcutaneous injections. The most
frequent side-effects of IFN-b are injection site
reaction and flu-like symptoms and the occurrence
of neutralizing antibodies [1416,33]. For glatiramer acetate, self-limiting feeling of chest tightness,

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[Link]

247

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248

[Link]
MSCRG

PRISMS

CMSSG

TEMSO

TOWER

Intramuscular
IFNb-1a [15]

Subcutaneous
IFNb-1a [16]

Glatiramer
acetate [17]

Teriflunomide [18]

Teriflunomide [19]

CONFIRM

MSSG

IFNb-1b [14]

Dimethyl
&
fumarate [20 ]

Trial
name/study
group

Active drug
[reference number]

363

Placebo

345
359
350
363

Oral dimethyl fumarate

240 mg  2 daily
Subcutaneous glatiramer
acetate 20 mg daily
Placebo

388

Placebo
Oral dimethyl fumarate
240 mg  3 daily

407

Oral teriflunomide 7 mg
daily

370

365

Oral teriflunomide 7 mg
daily
Oral teriflunomide 14 mg
daily

358

Oral teriflunomide 14 mg
daily

126

Placebo

187

Placebo
125

189

Subcutaneous IFNb-1a
22 mg three times per
week
Subcutaneous glatiramer
acetate 20 mg daily

184

Subcutaneous IFNb-1a
44 mg three times per
week

143

Placebo

123

Placebo
158

125

Subcutaneous IFNb-1b
1.6 MIU every other day
Intramuscular IFNb-1a
30 mg weekly

124

Subcutaneous IFNb-1b
8 MIU every other day

Treatment arms

2.6

2.6

2.6

2.5

2.7

2.7

2.7

2.7

2.7

2.7

2.4

2.8

2.4

2.5

2.5

2.3

2.4

2.8

2.9

3.0

Mean
baseline
EDSS

0.13a [21%] (P 0.25)c

0.16a [7%] (P 0.70)c

0.22 [44%] (P < 0.001)c

0.29 [29%] (P 0.01)c

0.17

0.13a [24%] (P 0.20)c

0.40

0.21
0.20 [51%] (P < 0.001)c

0.22a [4.5%] (P 0.0762)

0.16a [32.5%] (P 0.044)

0.27

0.22a [23.7%] (P 0.08)

0.20a [29.8%] (P 0.03)

0.25a

0.22a [12%] (P > 0.05)

0.38a

0.29a [22.0%] (P 0.07)

0.26a [30.0%] (P 0.03)

0.35b

0.22b [37.2%] (P 0.02)

0.28a

0.28a [0%]

0.20a [28.6%] (P 0.161)

Disability progression
[relative reduction]
(P value versus placebo)

0.50

0.39 [22.3%] (P 0.18)

0.32 [36,3%%] (P < 0.001)

0.54

0.37 [31.2%] (P < 0.001)

0.37 [31.5%] (P < 0.001)

1.68

1.19 [29.2%] (P 0.007)

2.56

1.82 [28.9%] (P < 0.005)

1.73 [32.4%] (P < 0.005)

0.82

0.67 [18.3%] (P 0.04)

1.27

1.17 [7.8%] (P 0.01)

0.84 [33.9%] (P 0.0001)

ARR over 2 years

[relative reduction]
(P value versus placebo)

Table 1. Randomized, placebo-controlled phase III trials of disease-modifying therapies in patients with relapsingremitting multiple sclerosis

Demyelinating diseases

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ALLEGRO

Laquinimod [22 ]

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MIMS

AFFIRM

FREEDOMS

FREEDOMS 2

Mitoxantrone [23]

Natalizumab [24]

Fingolimod [25]

Fingolimod [26]
358
355

Oral fingolimod 0.5 mg

daily
Placebo

418

Placebo
370

425

Oral fingolimod 0.5 mg

daily
Oral fingolimod 1.25 mg
daily

429

2.5

2.5

2.5

2.5

2.3

2.4

2.3

315

4.7
2.3

64
627

4.5

2.6

2.6

2.5

2.4

2.4

60

Oral fingolimod 1.25 mg

daily

Intravenous natalizumab
300 mg every 4 weeks
Placebo

Intravenous mitoxantrone
12 mg/m2 every 3 months
Placebo

556

Placebo

408

Placebo
550

410

Oral dimethyl fumarate

240 mg  2 daily
Oral laquinimod 0.6 mg
daily

416

Oral dimethyl fumarate

240 mg  3 daily

0.40

0.21 [47.5%] (P < 0.001)

0.20 [50.0%] (P < 0.001)

0.40

0.18 [55.0%] (P < 0.001)

0.16 [60.0%] (P < 0.001)

0.73

0.23 [68.5%] (P < 0.001)

1.02

0.35 [65.7%] (P 0.001)

0.39

0.30 [23%] (P 0.002)

0.36

0.17 [52.7%] (P < 0.001)

0.19 [47.2%] (P < 0.001)

0.29a

0.25a [12.4%] (P > 0.05)

0.22a [25.2%] (P > 0.05

0.25a

0.18a [28.0%] (P 0.02)

0.17a [32.0%] (P 0.02)

0.29a

0.17a [42%] (P < 0.001)

0.22

0.08a [63.6%] (P 0.036)

0.16a

0.11a [49%] (P 0.01)

0.27a

0.16a [38%] (P 0.005)

0.18a [33.3%] (P 0.01)

AFFIRM, Natalizumab Safety and Efficacy in RelapsingRemitting Multiple Sclerosis; ALLEGRO, Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis trial; ARR, annualized relapse rate;
CONFIRM, Comparator and an Oral Fumarate in RelapsingRemitting Multiple Sclerosis trial; DEFINE, The Determination of the Efficacy and Safety of Oral Fumarate in RelapsingRemitting MS; EDSS, Expanded
Disability Status Scale; FREEDOMS, FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis; MIMS, Mitoxantrone in Multiple Sclerosis; MIU, million international units; MSCRG, Multiple Sclerosis
Collaborative Research Group; PRISMS: Prevention of Relapses and Disability by Interferon b-1a Subcutaneously in Multiple Sclerosis; MSSG, The IFNB Multiple Sclerosis Study Group; CMSSG: The Copolymer 1
Multiple Sclerosis Study Group; TEMSO, Teriflunomide Multiple Sclerosis Oral trial; TOWER, The Efficacy and Safety of Teriflunomide in Patients with Relapsing MS.
a
3 months confirmed progression in EDSS score.
b
6 months confirmed progression in EDSS score.
c
Compared with placebo.
d
50% of the patients had secondary progressive multiple sclerosis.

&

DEFINE

Dimethyl fumarate
&&
[21 ]

New management algorithms in multi ple sclerosis Sorensen

[Link]

249

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Demyelinating diseases

(a)

Relapse rate reduction vs placebo (%)

70
68%
P < 0.001

60

66%
P = 0.001

55%
P < 0.001

50

53%
48%

P < 0.001

P < 0.001

44%

40

P < 0.001

32%

34%

30

P = 0.0001

32%a

32%
P < 0.001

29%

29%

P < 0.001

P = 0.007

P = 0.002a

20

22%
P = 0.002

18%
P = 0.04

10

0
Natalizumab Mitoxantrone Fingolimod

Dimethyl
fumarate

Teriflunomide

IFN 1b

SC IFN 1a
Glatiramer Laquinimod IM IFN 1a
44 g/22 g tiw
acetate

Results (intent to treat) from separate clinical studies cannot be directly compared; afor patients completing 2 years in the study.

(b)
Disability progression reduction vs placebo (%)

70

64%
P = 0.036

60

63%a
P = 0.05

53%a
50

P = 0.001

49%a
P = 0.002

40

42%
P < 0.001

38%
P < 0.001

30

37%a
P = 0.02

36%

29%a

P = 0.01

P = 0.01

30%
P = 0.03

20

21%
P = 0.25

30%

29%

P = 0.03

P = 0.161

22%
P = 0.07

10

28%
P = 0.02

Mitoxantrone Natalizumab Dimethyl IM IFN 1a Laquinimod SC IFN 1a

fumarate
44 g/22 g tiw

Teriflunomide

IFN 1b

12%

12%

P > 0.05

P > 0.05

Fingolimod

Glatiramer
acetate

Results (intent to treat) from separate clinical studies cannot be directly compared; afor patients completing 2 years in the study.

FIGURE 1. (a) Comparison of relapse rate reductions. Data from respective placebo-controlled pivotal trials. (b) Comparison
of reduction in disability progression in EDSS. Data from respective placebo-controlled pivotal trials. EDSS, Expanded
Disability Status Scale; IM, intramuscular.

dyspnea, and palpitations together with injection

site reactions are the most frequent side-effects [17].
The new first-line oral therapies appeared well
tolerated in the phase III trials, but side-effects
included hair-thinning and gastrointestinal symptoms for teriflunomide and flushing and gastrointestinal symptoms for dimethyl fumarate that in
addition needs to be taken as one tablet twice daily
[18,21 ].
&&

250

[Link]

EFFICACY OF AVAILABLE SECOND-LINE

THERAPIES
Natalizumab and fingolimod are approved in the
European Union by the EMA as second-line therapy
in patients with high disease activity despite
treatment with IFN-b or as first-line therapy in
rapidly evolving severe RRMS. In the United States,
natalizumab is generally recommended for patients
who have had an inadequate response to, or are
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New management algorithms in multi ple sclerosis Sorensen

unable to tolerate, an alternate multiple sclerosis

therapy, whereas fingolimod is approved for the
treatment of patients with relapsing multiple
sclerosis, lately revised with specific recommendations for monitoring patients and with new
contraindications for use of fingolimod in certain
patients. Mitoxantrone is approved by the US FDA
for treatment of worsening RRMS and secondary
progressive multiple sclerosis (SPMS).
Natalizumab (Tysabri) is a humanized monoclonal antibody directed against a4-integrin that
inhibits lymphocyte migration across the blood
brain barrier. Natalizumab is administered intravenously, 300 mg at 4-week intervals. Natalizumab
reduced the clinical relapse rate by 68% and
confirmed progression of disability on EDSS by
42% [24]. MRI activity was reduced by 8090%.
Also brain atrophy was significantly decreased in
the second year (Table 1).
Fingolimod (Gilenya), a sphingosine-1-phosphate (S1P) analog, decreased circulating lymphocyte count in the peripheral blood [34]. Fingolimod
is administered as a 0.5-mg tablet taken once
daily. In the placebo-controlled trials, fingolimod
decreased the relapse rate by approximately 50%.
Confirmed EDSS progression decreased 37% in one
study, whereas no statistical significant difference
was seen in another. MRI activity was reduced by
7482%, and brain volume loss was reduced by 34%
[25,26].
Alemtuzumab is a humanized monoclonal
antibody against CD52 that causes a long-lasting
depletion of lymphocytes and monocytes. Alemtuzumab is administered intravenously, 12 mg daily
for 5 days and after 12 months 12 mg daily for 3 days.
It has never been tested in large placebo-controlled
trials but only compared with subcutaneous IFN-b
1a (see below) [35 ,36 ].
Mitoxantrone is a strong immunosuppressant
that when administered 12 mg/m2 intravenously
at 3 month intervals reduced the ARR by 60% and
progression of disability on EDSS by 64% [23].
&

&&

SAFETY AND CONVENIENCE OF

AVAILABLE SECOND-LINE THERAPIES
Natalizumab therapy can cause progressive multifocal leukoencephalopathy (PML), and postmarketing more than 400 patients have encountered
this serious opportunistic infection [37]. Today, risk
stratification is possible as the presence of the
John Cunningham virus (JCV) can be determined
by measurement of anti-JCV antibodies in the blood
[38 ]. Mild lymphocytosis, hepatotoxicity, and infusion reactions were reported in a small proportion
of patients often associated with the presence of
&

neutralizing antibodies occurring in 6% of the

patients with abolition of the therapeutic efficacy
[24].
The presence of S1P receptors in many body
tissues explains a number of unwarranted effects
of fingolimod. After the first dose of fingolimod,
bradycardia and atrioventricular conduction block
occurred in less than 2% of patients. Other sideeffects were macula edema, elevated liver function
tests, increased risk of infections, and hypertension
[25,35 ]. Fatal herpes virus infections have been
reported in a few patients [35 ,39].
Alemtuzumab causes frequently infusionrelated side-effects and is associated with increased
frequency of generally mild-to-moderate infections.
Immune-mediated hypothyroidism or hyperthyroidism occurs in more than 30% of patients
treated with alemtuzumab [35 ,36 ], idiopathic
thrombocytopenia has been detected in 13%
of patients, and a few patients have developed
renal failure because of Goodpastures syndrome
[35 ,36 ,40].
Mitoxantrone causes chemotherapy-induced
reversible bone marrow suppression and nausea.
Amenorrhea was reported in more than 20% of
fertile women. Risk of cardiotoxicity increases with
the cumulative dose of mitoxantrone, and therefore
the maximum cumulative dose is restricted to
120 mg/m2. Therapy-related acute leukemia with
a mortality of about 40% occurs in up to 1% of
patients, often several years after discontinuation
of mitoxantrone [41,42].
&

&

&

&

&&

&&

COMPARATIVE HEAD-TO-HEAD STUDIES

OR ACTIVE COMPARATOR TRIALS
There are a number of randomized, double-blind
head-to-head studies comparing two first-line therapies (Table 2) [12,13,20 ,35 ,36 ,39,4346,47 ].
Two studies indicated that weekly IFN-b 1a was less
efficacious than subcutaneous IFN-b 1a or subcutaneous IFN-b 1b [12,13], whereas this was not
found in a study comparing weekly subcutaneous
IFN-b 1a and subcutaneous IFN-b 1b [45]. In the
COMBI Rx study, glatiramer acetate was superior to
intramuscular IFN-b 1a regarding the ARR (Table 3)
[48 ]. Oral fingolimod was superior to intramuscular IFN-b 1a on annual relapse rate but not on
disability progression [39], whereas teriflunomide
7 mg was inferior and 14 mg equal to subcutaneous
IFN-b 1a [47 ].
A number of studies have compared one drug
with another used as the reference treatment arm
in open label assessor-blinded trials. Two studies
found no difference in clinical endpoints between
glatiramer acetate and subcutaneous IFN-b 1a or

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&

&

&&

&

&&

&

[Link]

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252

[Link]
REGARD

IFNb-1a subcutaneous [43]

Subcutaneous glatiramer
acetate 20 mg daily

435

Intramuscular IFNb-1a
30 mg weekly
Subcutaneous IFNb-1a
44 mg three times per
week

Glatiramer acetate

431

Oral fingolimod 0.5 mg

daily

378

386

425

Oral fingolimod 1.25 mg

daily

TRANSFORMS

Fingolimod
IFNb-1a intramuscular [39]

202

Subcutaneous IFNb-1a
44 mg three times per
week

IFNb-1a subcutaneous
&&
[36 ]

426

Intravenous alemtuzumabc

Intravenous alemtuzumabc

CARE MS 2

363
376

Placebo

Alemtuzumab

350

Subcutaneous glatiramer
acetate 20 mg daily

202

359

Oral dimethyl fumarate

240 mg  2 daily

Subcutaneous IFNb-1a
44 mg three times per
week

CARE MS 1

Alemtuzumab

345

338

Oral dimethyl fumarate

240 mg  3 daily

Intramuscular IFNb-1a
30 mg weekly

339

96

92

IFNb-1a subcutaneous
&
[35 ]

CONFIRM

Dimethyl fumarate
&
Glatiramer acetate [20 ]

IFNb-1a intramuscular [13]

Subcutaneous IFNb-1a
44 mg three times per
week

EVIDENCE

IFNb-1a subcutaneous

Subcutaneous IFNb-1b
250 mg every other day
Intramuscular IFNb-1a
30 mg weekly

INCOMIN

IFNb-1b

Treatment arms

IFNb-1a intramuscular [12]

Trial name

Active drugs
[reference number]

2.3

2.4

2.2

2.2

2.2

2.7

2.7

2.0

2.0

2.6

2.6

2.6

2.5

2.3

2.3

2.0

2.0

Mean
baseline
EDSS

0.13a [21%] (P 0.25)b

[17%] (NS)
0.16a [7%] (P 0.70)b

0.22 [44%] (P < 0.001)b

[24%] (NS)
0.29 [29%] (P 0.01)b

0.29

0.30 [3.3%] (P 0.828)

0.09a

0.12a [25.0%] (P 0.117)

0.06a [25.3%] (P 0.25)d

0.16 [51.5%] (P < 0.01)d

0.33

0.07a [15.2%] (P 0.50)d

0.21a

0.13a [42%] (P 0.008)

0.11a

0.08a [30%] (P 0.22)

0.20 [39.4%] (P < 0.01)d

0.52

0.26 [48.4%] (P < 0.001)

0.39

0.18 [54.9%] (P < 0.001)

0.17

0.13a [24%] (P 0.20)b

[18%] (NS)

0.20 [51%] (P < 0.001)b

[31%] (NS)

0.40

0.15a

0.13a [13%] (P 0.51)

0.30a

0.13a [44%] (P 0.005)

Disability progression
[relative reduction]
(P value)

0.64

0.54 [15.6%] (P 0.093)

0.7

0.5 [28.6%] (P 0.03)

ARR over 2 years

[relative reduction]
(P value)

Table 2. Randomized head-to-head or active comparator trials of disease-modifying therapies in patients with relapsingremitting multiple sclerosis

Demyelinating diseases

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BRAVO

Laquinimod

111
109
104

Oral teriflunomide 7 mg
daily
Subcutaneous IFNb-1a
44 mg three times per
week

450

Placebo
Oral teriflunomide 14 mg
daily

447

Intramuscular IFNb-1a
30 mg weekly

434

158

Subcutaneous IFNb-1b
250 mg every other day
Oral laquinimode 0.6 mg
daily

448

Subcutaneous glatiramer
acetate 20 mg daily
143

897

Subcutaneous IFNb-1b
250 mg every other day

Subcutaneous IFNb-1a
22 mg weekly

899

Subcutaneous IFNb-1b
500 mg every other day

4.7

4.5

2.7

2.6

2.7

2.8

3.0

2.3

2.5

2.3

0.22

0.41 [46.3%] (P 0.03)d

0.26 [3.8%] (P 0.59)

0.13a

0.11a [25.8%] (P 0.127)b

[7.6%] (P 0.74)d

0.26 [25.9%] (P 0.007)b

[7.1%] (P 0.389)d
d

0.10a [31.3%] (P 0.044)b

0.28 [17.6%] (P 0.075)b

0.34

0.21a

0.25a [19.3%] (P 0.68)

0.71

0.70 [1.4%] (P 0.91)

0.21a

0.27a [22.2%] (P 0.68)e

0.36 [5.5%] (P 0.79)e

0.34

0.22a [4.5%] (P 0.71)e

0.33 [2.9%] (P 0.42)e

ARR, annualized relapse rate; BEYOND, Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in Multiple Sclerosis Patients; BRAVO, Benefit-Risk Assessment of AVonex and LaquinimOd trial; CARE MS,
Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis trial; CONFIRM, Comparator and an Oral Fumarate in RelapsingRemitting Multiple Sclerosis trial; DMSG, Danish Multiple Sclerosis Group; EDSS,
Expanded Disability Status Scale; EVIDENCE, Evidence for Interferon Dose Response: EuropeanNorth American Comparative Efficacy; Gd, Gadolinium-enhancing; INCOMIN, Independent Comparison of Interferon;
REGARD, Rebif Versus Glatiramer Acetate in Relapsing Multiple Sclerosis Disease; TENERE, Teriflunomide versus Subcutaneous Interferon beta-1a in Patients with Relapsing Multiple Sclerosis; TRANSFORMS, Trial
Assessing Injectable Interferon versus FTY720 Oral in RelapsingRemitting Multiple Sclerosis.
a
3 months confirmed progression in EDSS score.
b
Comparison with placebo.
c
Intraveneous alemtuzumab 12 mg daily for 5 days and after 12 months 12 mg daily for 3 days.
d
Comparison with IFNb 1a.
e
Comparison with glatiramer acetate.

Teriflunomide
&
IFNb-1a intramuscular [47 ]

TENERE

DMSG

IFNb-1b
IFNb-1a [45]

IFNb-1a intramuscular [46]

BEYOND

IFNb-1b
Glatiramer acetate [44]

New management algorithms in multi ple sclerosis Sorensen

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254

[Link]

SIMCOMBIN [53]

ACT [52]

NORMIMS [51]

MECOMBIN [50]

SENTINEL [49]

&&

COMBI Rx [48 ]

Trial name/study group

(reference number)

339
338

Intramuscular IFNb-1a
30 mg weekly

2.3

2.3

2.9

2.7

76
70

2.8

2.5

2.5

2.3

2.0

2.0

2.5

2.4

1.9

1.9

2.0

66

Intramuscular IFNb-1a
30 mg weekly

Intramuscular IFNb-1a 30 mg
weekly placebo

Intramuscular IFNb-1a 30 mg
weekly methotrexate and
placebo
Intramuscular IFNb-1a 30 mg
weekly and methotrexate

74

64

Subcutaneous IFN-1a 44 mg
three times per week placebo
Intramuscular IFNb-1a 30 mg
weekly oral methotrexate
20 mg weekly and intravenous
methylprednisolone 1000 mg
bimonthly and placebo

66

158

Intramuscular IFNb-1a
30 mg weekly placebo
Subcutaneous IFNb-1a
44 mg three times per
week oral
methylprednisoloneh

143

Intramuscular IFNb-1a
30 mg weekly oral
methylprednisolonef

582

Intramuscular IFNb-1a
30 mg weekly placebo

499

Intramuscular IFNb-1a
30 mg weekly subcutaneous
glatiramer acetate 20 mg daily
589

250

Subcutaneous glatiramer
acetate 20 mg daily

Intramuscular IFNb-1a 30 mg
weekly Intravenous
natalizumab 300 mg every
4 weeks

250

Intramuscular IFNb-1a
30 mg weekly

Treatment arms

Mean
baseline
EDSS

0.24a (10%] (P > 0.20)e

0.12 [8%] (P 0.27)d

0.14 [23%] (P 0.35)

0.19

0.53

0.40 [25%]

0.43a [8.1%] (P 0.953)

0.37a

Not studied

0.23 [57%] (see belowi)

0.40 [25%]

0.25a

0.16a [36.0%] (P 0.29)

0.28g

0.26g [7%] (P 0.57)

0.29a

0.59

0.22 [62.7%] (P 0.013)

0.33

0.21 [36.4%] (P 0.002)

0.33

0.23a [20.7] (P 0.02)

0.25a

0.11 [31%] (P 0.025)c

0.38 [53.1%] (P 0.001)

0.22a [13%] (P > 0.20)b

Disability progression
[relative reduction]
(P value)

0.16

ARR ovher 2 years

[relative reduction]
(P value)

Table 3. Randomized combination trials or placebo-controlled add-on trials of disease-modifying therapies in patients with relapsingremitting multiple sclerosis

Demyelinating diseases

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41

IFNbj placebo

155

37

IFNbj oral teriflunomide

7 mg daily

Subcutaneous IFNb-1a 44 mg
three times per week placebo

38

IFNbj oral teriflunomide

14 mg daily

149

55

Subcutaneous glatiramer acetate

20 mg daily placebo

Subcutaneous IFNb-1a 44 mg
three times per week oral
minocycline

55

Subcutaneous glatiramer acetate

20 mg daily intravenous
natalizumab 300 mg every
4 weeks

2.0

2.0

2.6

2.4

2,5

2.7

2.6

0.28

0.18 (37.5%] (P 0.37)

0.34

0.14 [33%] (P 0.436)

0.14 [58%] (P 0.101)

0.67

0.40 [40%] (P 0.237)

0.04g [57%] (P 0.29)

0.07g

Not studied

Not studied

ACT, Avonex Combination Trial; ARR, annualized relapse rate; COMBI Rx, Randomized study combining interferon and glatiramer acetate in multiple sclerosis; EDSS, Expanded Disability Status Scale; GLANCE,
Glatiramer Acetate and Natalizumab Combination Evaluation study; MECOMBIN, Methylprednisolone in combination with interferon beta-1a for relapsingremitting multiple sclerosis study; NORMIMS, NORdic trial of
oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis trial; RECYCLINE, Minocycline as add-on therapy to interferon-beta-1a for the treatment of relapsing
remitting multiple sclerosis; SENTINEL, Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis; SIMCOMBIN, Simvastatin as add-on therapy to
interferon beta-1a for relapsing-remitting multiple sclerosis trial; TMSTG, Teriflunomide Multiple Sclerosis Trial Group.
a
3 months confirmed progression in EDSS score.
b
Intramuscular IFNb-1a versus glatiramer acetate.
c
Glatiramer acetate versus intramuscular IFNb-1a.
d
Glatiramer acetate versus intramuscular IFNb-1a glatiramer acetate.
e
Intramuscular IFNb-1a, intramuscular IFNb-1a glatiramer acetate.
f
Oral methylprednisolone 200 mg daily for 5 days every 4 weeks.
g
6 months confirmed progression in EDSS score.
h
Oral methylprednisolone 200 mg daily for 5 days every 4 weeks.
i
Interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both.
j
Any FNb (intramuscular IFNb-1a, subcutaneous IFNb-1a or subcutaneous IFNb-1b).

RECYCLINE [56]

TMSTG [55]

GLANCE [54]

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Demyelinating diseases

subcutaneous IFN-b 1b [43,44]. Alemtuzumab was

found superior to subcutaneous IFN-b 1a in two
studies, one with de-novo treated patients and
one in patients with breakthrough disease on a
first-line drug, regarding relapse rate, but only the
latter on disease progression [35 ,36 ].
Dimethyl fumarate, in a study with glatiramer
acetate as reference treatment arm, showed numerically larger reduction in relapse rate and disease
progression, but the differences were not significantly different [20 ]. Intramuscular IFN-b 1a was
reference arm in a placebo-controlled trial of
laquinimod, and the effect was not statistically
different on relapse rate or disease progression [46].
&

&&

&

COMBINATION TRIALS OR PLACEBOCONTROLLED ADD-ON TRIALS

The number of large-scale combination trials or
placebo-controlled add-on trials has been sparse
and the results overall rather disappointing.
Table 3 gives an overview of larger (n > 100)
double-blind combination studies and placebo-controlled add-on trials [48 ,4956]. The only large
double-blind combination trial did not show any
beneficial effect from the combination of intramuscular IFN-b 1a and glatiramer acetate compared with
each drug alone [48 ].
Only add-on to IFN-b of natalizumab [49]
or monthly courses of methylprednisolone [50,51]
have consistently shown a significant effect on
relapses, but monthly courses of methylprednisolone
&&

&&

First-line therapies

Dimethyl fumarate
Teriflunomidea

TREATMENT ALGORITHM FOR

RELAPSINGREMITTING MULTIPLE
SCLEROSIS
There are only a few head-to-head studies comparing
two first-line therapies or a first-line with a secondline therapy, and none comparing two second-line
therapies. Hence, the treatment algorithm is only
partly based on Class I evidence, and many suggestions are based on Class III or IV (expert opinion)
evidence and may be criticized for being subjective
or even biased. A suggestion of a treatment algorithm
for RRMS is shown in Fig. 2.
Regarding the choice of first-line therapy, it is
necessary to distinguish between de-novo treated
patients and patients already on treatment with a
first-line DMD. Patients who have not previously
received DMDs can choose between oral dimethyl
fumarate or teriflunomide or the injectable IFN-b
preparations or glatiramer acetate. In the randomized, placebo-controlled studies and open label
assessor-blinded trials with a reference treatment
arm, dimethyl fumarate had numerically the
largest reduction of relapse rates, but was not significantly better than glatiramer acetate. Hence,
many patients would probably prefer to start with
dimethyl fumarate, but the twice daily administration might reduce compliance, so if compliance
is an issue teriflunomide might be an attractive

Second-line therapies

Break-through disease
a

are not well tolerated by many patients, and the trials

had a high dropout rate.

Break-through disease

Natalizumab

Side-effects

JCV Ab-

Experimental therapies

Side-effects

JCV Ab+

(IFN GLAT)

Fingolimod
Alemtuzumabb

Patients with aggressive MS

Mitoxantrone

Third-line therapies

Suboptimal
effect

Rituximab
Ofatumumab

Intense immunosuppression with

autologous hematopoietic stem
cell transplantation

Natalizumab
JCV AbJCV Ab+

Fingolimod

Side-effects
Suboptimal
effect

Alemtuzumabb

FIGURE 2. Treatment algorithm for relapsingremitting multiple sclerosis. aPatients with low disease activity can choose
between dimethyl fumarate and teriflunomide. With high disease activity dimethyl fumarate should be tried first, and switch
from teriflunomide to dimethyl fumarate appears more logical than the opposite. Women with child-bearing potential, who
plan pregnancy within few years, should probably not choose teriflunomide. In case of side-effects (or suboptimal effect) on
one drug, switch to another drug can be tried, because of different mechanisms of action. bAlemtuzumab should be used after
natalizumab and fingolimod, but before mitoxantrone, owing to the safety profiles. JCV, John Cunningham virus.
256

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New management algorithms in multi ple sclerosis Sorensen

option. For patients who are concerned about any

unknown long-term adverse effects of the new
therapies, the old injectables could still be a
possibility.
The therapeutic response to IFN-b or glatiramer
acetate therapy varies between patients, and
approximately 30% of patients have an excellent
response. Hence, patients who are stable on a firstline DMD with no or only minor side-effects are
advised to stay on their current therapy, whereas
patients with side-effects could switch to dimethyl
fumarate of teriflunomide if they want to avoid
injections.

ESCALATION OF THERAPY
There is an increasing tendency to keep patients
disease-activity free, meaning free of relapses,
disease progression, and MRI activity, and, hence,
in patients with breakthrough disease activity on a
first-line therapy, escalation of therapy should be
considered. Patients with clinical breakthrough are
eligible for treatment with second-line therapies
(EMA) but may also switch to another first-line
therapy if they are concerned about the more
risky second-line therapies. If the patient is JCV
antibody-negative, many would prefer natalizumab
as the second-line treatment, because they regard
natalizumab to be the most powerful treatment,
whereas the majority would be inclined to choose
fingolimod in JCV antibody-positive patients.
If treatment with natalizumab is started in JCV
antibody-positive patients, it should be seriously
reconsidered after 12 and 24 months because
of the increased risk of PML with continued
natalizumab therapy. The EMA has recommended
yearly MRI as a part of PML risk management.
In case of adverse effects, neutralizing antibodies,
or insufficient therapeutic efficacy, an alternative
second-line treatment should be tried. Natalizumab
and fingolimod should usually be tried before
alemtuzumab, but in patients who are JCV antibody
positive and have contraindications against fingolimod, alemtuzumab could be the first choice of a
second-line therapy.
In patients who do not obtain disease control
on first-line therapies and who are afraid of
starting a second-line treatment, cyclic methylprednisolone as add-on to a first-line therapy is
a possibility. Mitoxantrone is also approved for
treatment of RRMS in many countries, but cardiotoxicity and risk of treatment-induced acute
leukemia have reduced the use in RRMS, and today
it is primarily used in the early phase of SPMS
in which no other approved effective treatment
exists [41,42].

Patients who do not respond to the approved

second-line therapies can be treated with experimental therapies such as rituximab, ofatumumab,
or intense immunosuppression with autologous
hematopoietic stem cell transplantation.

EMERGING THERAPIES
Within the next 5 years, we expect new treatments
to be available in Europe and North America.
The use of IFN-b may be prolonged with the introduction of pegylated forms of IFN-b that only
requires injections once or twice monthly [57].
B-cell depleting humanized monoclonal antibodies,
rituximab, ocrelizumab, and ofatumumab, of which
the two former are in phase III studies, have shown
an impressive effect on MRI lesions and relapses and
would be expected to be future important players in
our efforts to control disease activity in multiple
sclerosis [5860]. Daclizumab, which is a humanized monoclonal antibody, modulates interleukin-2
signaling by blocking the alpha subunit (CD25)
of the interleukin-2 receptor, and has shown
promising results in phase II trials either as monotherapy or in combination with IFN-b [61,62].

CONCLUSION
During the last year, treatment of RRMS has
become complex because of the approval of new
oral first-line therapies and very effective monoclonal antibodies. This development will continue
in the next few years with approval of other
additional therapies that will make our current
treatment algorithm even more complicated, but
may render effective personalized treatment with
complete control of disease activity within reach in
the majority of multiple sclerosis patients.
Acknowledgements
None.
Conflicts of interest
Per Soelberg Sorensen received personal compensation
from Biogen Idec, Merck Serono, Novartis, Genmab,
TEVA, Elan, GSK, Bayer Schering and Sanofi-aventis,
Genzyme as member of scientific advisory boards,
steering committees or independent data monitoring
boards in clinical trials, or as speaker at meetings.
He has served as Editor-in-Chief of the European Journal
of Neurology and is currently editorial board member
for Multiple Sclerosis Journal, European Journal of
Neurology, and Therapeutic Advances in Neurological
Disorders. His research unit has received research
support from Biogen Idec, Bayer Schering, Merck Serono,
Sanofi-Aventis and Novartis, the Danish Multiple

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Demyelinating diseases

Sclerosis Society, the Danish Medical Research Council,

and the European Union Sixth Framework Programme:
Life sciences, Genomics, and Biotechnology for health.

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New management algorithms in multi ple sclerosis Sorensen

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