New management algorithms in multiple sclerosis.

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 relapsing–remitting multiple sclerosis including new oral therapies and therapeutic monoclonal antibodies. Recent findings Recent large placebo-controlled trials in relapsing–remitting 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) [2–4]. www.co-neurology.com

Early treatment in CIS consistently reduced conversion to CDMS across treatments [2,5–10], 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: [email protected] Curr Opin Neurol 2014, 27:246–259 DOI:10.1097/WCO.0000000000000096 Volume 27 Number 3 June 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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 relapsing–remitting MS. A review of comparative studies of DMDs for treatment of relapsing–remitting MS is provided. A new treatment algorithm is presented for initiation of therapy and treatment escalation in patients with CIS or relapsing–remitting 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 RELAPSING–REMITTING 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 [14–19,20 ,21 ,22 ,23–26]. 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) [14–16]. The effect on disease activity on MRI was more impressive, typically with reductions of 60–80%. [14–16]. 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 ¼ 0.0002), but a more pronounced effect was seen on disease progression with 36–49% reduction. MRI changes were reduced by 60–70%, 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 [14–16,33]. For glatiramer acetate, self-limiting feeling of chest tightness,

1350-7540 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-neurology.com

247


248

www.co-neurology.com 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

n

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 ¼ 0.25)c 0.16a [7%] (P ¼ 0.70)c

0.22 [44%] (P < 0.001)c 0.29 [29%] (P ¼ 0.01)c

0.17

0.13a [24%] (P ¼ 0.20)c

0.40

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

0.22a [4.5%] (P ¼ 0.0762)

0.16a [32.5%] (P ¼ 0.044)

0.27

0.22a [23.7%] (P ¼ 0.08)

0.20a [29.8%] (P ¼ 0.03)

0.25a

0.22a [12%] (P > 0.05)

0.38a

0.29a [22.0%] (P ¼ 0.07)

0.26a [30.0%] (P ¼ 0.03)

0.35b

0.22b [37.2%] (P ¼ 0.02)

0.28a

0.28a [0%]

0.20a [28.6%] (P ¼ 0.161)

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

0.50

0.39 [22.3%] (P ¼ 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 ¼ 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 ¼ 0.04)

1.27

1.17 [7.8%] (P ¼ 0.01)

0.84 [33.9%] (P ¼ 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 relapsing–remitting multiple sclerosis

Demyelinating diseases

Volume 27 Number 3 June 2014


ALLEGRO

Laquinimod [22 ]

1350-7540 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 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 ¼ 0.001)

0.39

0.30 [23%] (P ¼ 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 ¼ 0.02)

0.17a [32.0%] (P ¼ 0.02)

0.29a

0.17a [42%] (P < 0.001)

0.22

0.08a [63.6%] (P ¼ 0.036)

0.16a

0.11a [49%] (P ¼ 0.01)

0.27a

0.16a [38%] (P ¼ 0.005)

0.18a [33.3%] (P ¼ 0.01)

AFFIRM, Natalizumab Safety and Efficacy in Relapsing–Remitting 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 Relapsing–Remitting Multiple Sclerosis trial; DEFINE, The Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting 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.

d

&

DEFINE

Dimethyl fumarate && [21 ]



249



(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

IFNβ 1b

SC IFNβ 1a Glatiramer Laquinimod IM IFNβ 1a 44 µg/22 µg 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

0

28% P = 0.02

Mitoxantrone Natalizumab Dimethyl IM IFNβ 1a Laquinimod SC IFNβ 1a fumarate 44 µg/22 µg tiw

Teriflunomide

IFNβ 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


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 Volume 27 Number 3 June 2014



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 80–90%. 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 74–82%, 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 1–3% of patients, and a few patients have developed renal failure because of Goodpasture’s 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 ,39,43–46,47 ]. 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


&

&

&&

&

&&

&


251


252

www.co-neurology.com 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


378

386

425


TRANSFORMS

Fingolimod IFNb-1a intramuscular [39]

202


IFNb-1a subcutaneous && [36 ]

426

Intravenous alemtuzumabc

Intravenous alemtuzumabc

CARE MS 2

363 376

Placebo

Alemtuzumab

350


202

359



CARE MS 1

Alemtuzumab

345

338


Intramuscular IFNb-1a 30 mg weekly

339

96

92

n

IFNb-1a subcutaneous & [35 ]

CONFIRM

Dimethyl fumarate & Glatiramer acetate [20 ]

IFNb-1a intramuscular [13]


EVIDENCE

IFNb-1a subcutaneous

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

INCOMIN

IFNb-1b

Treatment arms


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 ¼ 0.25)b [17%] (NS) 0.16a [7%] (P ¼ 0.70)b

0.22 [44%] (P < 0.001)b [24%] (NS) 0.29 [29%] (P ¼ 0.01)b

0.29

0.30 [3.3%] (P ¼ 0.828)

0.09a

0.12a [25.0%] (P ¼ 0.117)

0.06a [25.3%] (P ¼ 0.25)d

0.16 [51.5%] (P < 0.01)d 0.33

0.07a [15.2%] (P ¼ 0.50)d

0.21a

0.13a [42%] (P ¼ 0.008)

0.11a

0.08a [30%] (P ¼ 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 ¼ 0.20)b [18%] (NS)

0.20 [51%] (P < 0.001)b [31%] (NS)

0.40

0.15a

0.13a [13%] (P ¼ 0.51)

0.30a

0.13a [44%] (P ¼ 0.005)

Disability progression [relative reduction] (P value)

0.64

0.54 [15.6%] (P ¼ 0.093)

0.7

0.5 [28.6%] (P ¼ 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 relapsing–remitting multiple sclerosis




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


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 ¼ 0.03)d

0.26 [3.8%] (P ¼ 0.59)

–

0.13a

0.11a [25.8%] (P ¼ 0.127)b [7.6%] (P ¼ 0.74)d

0.26 [25.9%] (P ¼ 0.007)b [7.1%] (P ¼ 0.389)d d

0.10a [31.3%] (P ¼ 0.044)b

0.28 [17.6%] (P ¼ 0.075)b

0.34

0.21a

0.25a [19.3%] (P ¼ 0.68)

0.71

0.70 [1.4%] (P ¼ 0.91)

0.21a

0.27a [22.2%] (P ¼ 0.68)e

0.36 [5.5%] (P ¼ 0.79)e 0.34

0.22a [4.5%] (P ¼ 0.71)e

0.33 [2.9%] (P ¼ 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 Relapsing–Remitting Multiple Sclerosis trial; DMSG, Danish Multiple Sclerosis Group; EDSS, Expanded Disability Status Scale; EVIDENCE, Evidence for Interferon Dose Response: European–North American Comparative Efficacy; Gdþ, 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 Relapsing–Remitting 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]


BEYOND

IFNb-1b Glatiramer acetate [44]




253


254


SIMCOMBIN [53]

ACT [52]

NORMIMS [51]

MECOMBIN [50]

SENTINEL [49]

&&

COMBI Rx [48 ]

Trial name/study group (reference number)

339 338


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 þ placebo

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

74

64

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

66

158

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

143

Intramuscular IFNb-1a 30 mg weekly þ oral methylprednisolonef

582

Intramuscular IFNb-1a 30 mg weekly þ placebo

499

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

250


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

250

n


Treatment arms

Mean baseline EDSS

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

0.12 [8%] (P ¼ 0.27)d

0.14 [23%] (P ¼ 0.35)

0.19

0.53

0.40 [25%]

0.43a [8.1%] (P ¼ 0.953)

0.37a

Not studied

0.23 [57%] (see belowi)

0.40 [25%]

0.25a

0.16a [36.0%] (P ¼ 0.29)

0.28g

0.26g [7%] (P ¼ 0.57)

0.29a

0.59

0.22 [62.7%] (P ¼ 0.013)

0.33

0.21 [36.4%] (P ¼ 0.002)

0.33

0.23a [20.7] (P ¼ 0.02)

0.25a

0.11 [31%] (P ¼ 0.025)c

0.38 [53.1%] (P ¼ 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 relapsing–remitting multiple sclerosis




41

IFNbj þ placebo

155

37

IFNbj þ oral teriflunomide 7 mg daily

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

38

IFNbj þ oral teriflunomide 14 mg daily

149

55

Subcutaneous glatiramer acetate 20 mg daily þ placebo

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

55

Subcutaneous glatiramer acetate 20 mg daily þ 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 ¼ 0.37)

0.34

0.14 [33%] (P ¼ 0.436)

0.14 [58%] (P ¼ 0.101)

0.67

0.40 [40%] (P ¼ 0.237)

0.04g [57%] (P ¼ 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 relapsing–remitting 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 þ glatiramer acetate. e Intramuscular IFNb-1a, intramuscular IFNb-1a þ 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]




255



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 ,49–56]. 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 RELAPSING–REMITTING 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+

(IFNβ – 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 relapsing–remitting 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





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 [58–60]. 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



257



Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics, and Biotechnology for health.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Potagas C, Giogkaraki E, Koutsis G, et al. Cognitive impairment in different MS subtypes and clinically isolated syndromes. J Neurol Sci 2008; 267:100– 106. 2. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357:1576–1582. 3. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131 (Pt 3):808–817. 4. Tintore M, Rovira A, Rio J, et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006; 67:968–972. 5. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebocontrolled trial. Lancet 2009; 374:1503–1511. 6. Comi G, De SN, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012; 11:33–41. 7. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343:898–904. 8. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67:1242–1249. 9. Kinkel RP, Kollman C, O’Connor P, et al. IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Neurology 2006; 66:678–684. 10. Sorensen PS. Early-stage multiple sclerosis. What are the treatment options? Drugs 2005; 64:2021–2029. 11. Kinkel RP, Dontchev M, Kollman C, et al. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance. Arch Neurol 2012; 69:183–190. 12. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002; 359:1453–1460. 13. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE trial. Neurology 2002; 59:1496–1506. 14. Duquette P, Girard M, Despault L, et al. Interferon beta-1b is effective in relapsing–remitting multiple-sclerosis – clinical-results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43: 655–661. 15. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 1996; 39:285– 294. 16. PRISMS (Prevention of Relapses, Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised doubleblind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352:1498–1504. 17. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45:1268– 1276. 18. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011; 365: 1293–1303. 19. Kappos L, Comi G, Confavreux C, et al. The efficacy and safety of teriflunomide in patients with relapsing MS: results from TOWER, a phase III, placebo-controlled study. Presented at: Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2012, abstract 153. Mult Scler J 2012; 18 (S4):50–51.

258


20. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367:1087– 1097. A confirmatory placebo-controlled trial of dimethyl fumarate showing superiority to placebo and with glatiramer acetate as comparative treatment arm. 21. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral && BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367:1098–1107. A large placebo-controlled phase III trial that reports the efficacy and safety of dimethyl fumarate showing significant effects of dimethyl fumarate 240 mg twice or three times daily on relapse rate and disease progression. 22. Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod & for multiple sclerosis. N Engl J Med 2012; 366:1000–1009. Phase III placebo-controlled trial of laquinimod showing a modest reduction in relapse rate, but a larger effect on disease progression. 23. Hartung HP, Gonsette R, Konig N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360:2018–2025. 24. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899–910. 25. Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362:387– 401. 26. Peter C, Ernst-Wilhelm R, Douglas G, et al. Efficacy and safety of fingolimod in patients with relapsing–remitting multiple sclerosis (RRMS): results from an additional 24-month double-blind, placebo-controlled study (FREEDOMS II study). Neurology 2012; 79:E90–E91. 27. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, doubleblind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49:290–297. 28. Rovaris M, Comi G, Rocca MA, et al. Short-term brain volume change in relapsing–remitting multiple sclerosis: effect of glatiramer acetate and implications. Brain 2001; 124 (Pt 9):1803–1812. 29. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS: teriflunomide. Clin Immunol 2012; 142:49–56. 30. Wolinsky JS, Narayana PA, Nelson F, et al. Magnetic resonance imaging outcomes from a phase III trial of teriflunomide. Mult Scler 2013; 19:1310– 1319. 31. Phillips JT, Fox RJ. BG-12 in multiple sclerosis. Semin Neurol 2013; 33: & 56–65. A review of the mechanism of action and therapeutic efficacy of dimethyl fumarate. 32. Bruck W, Wegner C. Insight into the mechanism of laquinimod action. J Neurol Sci 2011; 306:173–179. 33. Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of antiinterferon-beta antibody measurements in multiple sclerosis – report of an EFNS task force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005; 12:817–827. 34. Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate – modifiers of lymphocyte migration. N Engl J Med 2006; 355:1088–1091. 35. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a & as first-line treatment for patients with relapsing–remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380:1819–1828. An open label assessor-blinded phase III study of alemtuzumab compared with subcutaneous IFN-b 1a in de novo-treated patients showing superiority of alemtuzumab regarding relapse rate but not disease progression. 36. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with && relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380:1829–1839. An open label assessor-blinded phase III study of alemtuzumab compared with subcutaneous IFN-b 1a in patients failing first-line therapies showing superiority of alemtuzumab regarding both relapse rate and disease progression. 37. Hartung HP. New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 2009; 8:28–31. 38. Sorensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive & multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012; 18:143–152. A review of risk stratification for PML using measurement of JCV antibodies, prior use of immunosuppressant, and duration of natalizumab therapy. 39. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362:402–415. 40. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78:1069–1078. 41. Marriott JJ, Miyasaki JM, Gronseth G, O’Connor PW. Evidence report: the efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010; 74:1463–1470. 42. Martinelli V, Cocco E, Capra R, et al. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology 2011; 77:1887– 1895. &



New management algorithms in multi ple sclerosis Sorensen 43. Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 2008; 7:903–914. 44. O’Connor P, Filippi M, Arnason B, et al. 250 mug or 500 mug interferon beta1b versus 20 mg glatiramer acetate in relapsing–remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 2009; 8:889– 897. 45. Koch-Henriksen N, Sorensen PS, Christensen T, et al. A randomized study of two interferon-beta treatments in relapsing–remitting multiple sclerosis. Neurology 2006; 66:1056–1060. 46. Vollmer TL, Sorensen PS, Selmaj K, et al. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol 2014; 261:773–783. 47. Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus & subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler 2013. [Epub ahead of print] A large rater-blinded comparative trial showing that the effect of teriflunomide 14 mg daily is comparable to that of subcutaneous IFN-b 1a. 48. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining && interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 2013; 73:327–340. The only large double-blind comparative study showing that the combination of IFN-b and glatiramer acetate did not have significant beneficial effects compared with any of the two drugs administered alone. 49. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911–923. 50. Ravnborg M, Sorensen PS, Andersson M, et al. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebocontrolled, parallel-group trial. Lancet Neurol 2010; 9:672–680. 51. Sorensen PS, Mellgren SI, Svenningsson A, et al. NORdic trial of oral methylprednisolone as add-on therapy to interferon beta-1a for treatment of relapsing–remitting multiple sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol 2009; 8:519–529.

52. Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing–remitting MS. Neurology 2009; 72:535–541. 53. Sorensen PS, Lycke J, Eralinna JP, et al. Simvastatin as add-on therapy to interferon beta-1a for relapsing–remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 2011; 10:691–701. 54. Goodman AD, Rossman H, Bar-Or A, et al. GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study. Neurology 2009; 72:806–812. 55. Freedman MS, Wolinsky JS, Wamil B, et al. Teriflunomide added to interferonb in relapsing multiple sclerosis: a randomized phase II trial. Neurology 2012; 78:1877–1885. 56. Sorensen PS, Sellebjerg F, Lycke J, et al., on behalf of the RECYCLINE Study Investigators. No beneficial effect of minocycline as add-on therapy to interferon-beta-1a for the treatment of relapsing–remitting multiple sclerosis: results of a large double-blind, randomised, placebo-controlled trial. Presented at: Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 2012 abstract P941. Mult Scler J 2012; 18 (S4):431–432. 57. Oh J, Calabresi PA. Emerging injectable therapies for multiple sclerosis. Lancet Neurol 2013; 12:1115–1126. 58. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med 2008; 358:676–688. 59. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011; 378:1779–1787. 60. Sorensen PS, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing–remitting multiple sclerosis: a phase II study. Neurology 2014; 82:573–581. 61. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing–remitting multiple sclerosis (SELECT): a randomised, doubleblind, placebo-controlled trial. Lancet 2013; 381:2167–2175. 62. Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 2010; 9:381–390.



259


Bladder management in multiple sclerosis.

Multiple sclerosis: From new concepts to updates on management.

Spasticity management in multiple sclerosis.

Fatigue Management in Multiple Sclerosis.

Natalizumab in Multiple Sclerosis: Long-Term Management.

New multiple sclerosis phenotypic classification.

Multiple sclerosis: Five new things.

[New therapeutic options in multiple sclerosis].

Multiple sclerosis in New Zealand Māori.

Advances in the management of multiple sclerosis spasticity: multiple sclerosis spasticity nervous pathways.

Current management of relapsing-remitting multiple sclerosis.

Therapeutic Yoga: Symptom Management for Multiple Sclerosis.

Multidisciplinary management of multiple sclerosis symptoms.

[Multiple sclerosis and retroviruses: new findings].

[New and emerging treatments for multiple sclerosis].

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis.

Therapeutic management of severe relapses in multiple sclerosis.

Sexual disorders in men with multiple sclerosis: evaluation and management.

Management of fatigue in persons with multiple sclerosis.

Exercise in the management of persons with multiple sclerosis.

Precision medicine in chronic disease management: The multiple sclerosis BioScreen.

Diagnosis and Management of Multiple Sclerosis in Children.

Interdisciplinary Risk Management in the Treatment of Multiple Sclerosis.

Novel therapeutics in multiple sclerosis management: clinical applications.