Update on treatments in multiple sclerosis

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To cite this article: Michel L, et al. Update on treatments in multiple sclerosis. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.02.008 Presse Med. 2015; //: ///

MULTIPLE SCLEROSIS

on line on www.em-consulte.com/revue/lpm www.sciencedirect.com

Quarterly Medical Review 1

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Update on treatments in multiple sclerosis

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Laure Michel, Catherine Larochelle, Alexandre Prat

Available online:

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Université de Montréal, faculté de médecine, centre de recherche du CHUM, département de meuroscience, unité de recherche en neuro-immunologie, H2X0A9 Montréal, Canada

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Correspondence:

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Alexandre Prat, CRCHUM, 900, rue Saint-Denis, 9e étage, H2X0A9 Montréal, Québec, Canada. [email protected]

Environmental factors in multiple sclerosis Vasiliki Pantazou et al., Lausanne, Switzerland The autoimmune concept of multiple sclerosis Bryan Nicol et al., Nantes, France Advanced imaging tools to investigate multiple sclerosis pathology Benedetta Bodini et al., Paris, France Update on clinically isolated syndrome Éric Thouvenot, Nîmes, France Update on rehabilitation in multiple sclerosis Cécile Donzé, Lille, France Update on treatments in multiple sclerosis Laure Michel et al., Montreal, Canada Treatment of multiple sclerosis in children and its challenges Sona Narula et al., Philadelphia, United States

Summary While there is no cure for multiple sclerosis (MS), numerous disease-modifying drugs are now available to treat MS patients. In fact, the therapeutic strategies are now more and more complex, directly impacting the management of patients. Despite the good safety profile of the first-line immunomodulatory drugs, the clinical response is often suboptimal. Important questions remain about the right timing to switch for a second-line agent and whether escalation therapy is an appropriate therapeutic strategy. In this review, we conducted a systematic search by PubMed using the terms: treatment, multiple sclerosis, therapeutic, DMT and treatment response. Randomized trials and reviews addressing MS, DMTs and management strategies were selected and included in this review. Herein, we present the currently approved and emerging drugs used for the treatment of MS with their relative benefit/risk profiles, and their respective positions in the therapeutic arsenal. We then focused on the different therapeutic strategies and criteria available to evaluate the response to disease-modifying therapies (DMTs).

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ecent decades have seen considerable advances in our understanding of the natural history of multiple sclerosis (MS). Correlations between different clinical or radiological inflammatory parameters in the early phase of the disease and the long-term cumulative deficits in the chronic phase of the disease are now well established. From a radiological point of view, T2 lesion load at the beginning of MS is predictive of the disability at 5 years [1] and 20 years [2]. From a clinical point of view, the interval between the first two relapses as well as the number of relapses during the first two years are associated with a shorter duration to attain EDSS (Expanded Disability Status Scale) 3 or 4, and 6 or 7 [3,4]. Active control of the early inflammatory phase of the disease is therefore considered to prevent or delay the late progression phase. While there is no cure for MS, numerous disease-modifying drugs are now available to treat MS patients, making the appropriate choice of therapy more and more complex. Despite the good safety profile of the first-line immunomodulatory drugs, the clinical response is often suboptimal. Important questions remain about the right timing to switch for a second-line agent and whether escalation therapy is an

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In this issue

tome xx > n8x > xx 2015 http://dx.doi.org/10.1016/j.lpm.2015.02.008 © 2015 Elsevier Masson SAS. All rights reserved.

LPM-2734

To cite this article: Michel L, et al. Update on treatments in multiple sclerosis. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.02.008

L. Michel, C. Larochelle, A. Prat

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appropriate therapeutic strategy. Herein, we present the currently approved and emerging drugs used for the treatment of relapsing MS, focusing on the different therapeutic strategies and criteria available to evaluate the response to diseasemodifying therapies (DMTs).

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Methods

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We conducted this review using a comprehensive search of PubMed with the following search terms: treatment, multiple sclerosis, therapeutic, DMT and treatment response. Randomized trials and reviews addressing MS, DMTs and management strategies were selected and included in this review.

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Medication approved for the treatment of MS

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Approved disease-modifying treatments in multiple sclerosis are detailed below [5–54] and summarized in electronic supplement (annex 1).

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Glatiramer acetate

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Glatiramer acetate (GA) is an immunomodulatory agent and a synthetic copolymer made of four distinct amino acids randomly assembled: Glutamic acid, Lysine, Alanine and Tyrosine. GA 20 mg sub-cutaneously (SC) every day is approved for the treatment of both relapsing-remitting MS (RR-MS) and clinically isolated syndrome (CIS). GA does not affect the number of circulating lymphocytes but switches lymphocyte polarization from a pro-inflammatory TH1 to an anti-inflammatory TH2 profile. Recently, generic GA formulation trial GATE concluded to similar efficacy as compared to Copaxone® [55]. The lower frequency regimen of GA 40 mg SC 3 weekly (tiw) has demonstrated superiority to placebo at 6 and 12 months both in terms of annualized relapse rate (ARR) and cumulative number of active lesions. GA 40 mg SC tiw displayed the same safety profile as the 20 mg daily formulation, leading to its acceptance by the FDA [12]. GA is a generally well-tolerated and safe injectable medication with no known drug interactions. Local post-injection reaction is the most frequent adverse event. GA is considered to be a safe DMT even in early pregnancy [56–59], although most clinicians will stop the use of any DMT, including GA, during the childbearing period. There is no apparent impact of paternal exposure to GA on birth outcome or child health [60,61]. Finally, while anti-GA IgG antibodies form in most patients, they do not seem to affect drug efficacy [62].

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Interferons beta

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Interferons b (INFb) are immunomodulatory medications approved for the treatment of RR-MS, CIS and secondary progressive (SP)-MS patients. IFNbs have a limited capacity to reduce the number of circulating lymphocytes. Both IFNb-1a and IFNb-1b are considered safe injectable therapeutic options with limited drug interactions. The most frequent adverse events of IFNb treatment are benign but annoying flu-like

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symptoms (30–60% of patients) that can be alleviated by the use of acetaminophen or ibuprofen [6,63], and liver enzyme abnormalities. Long-term discontinuation rate of standard formulations of IFNb is over 20% across all marketed agents [6,63]. The new pegylated IFNb-1a formulation, which is administered at a dose of 125 mg SC every two weeks, has demonstrated superiority to placebo in terms of relapse rate, EDSS score and radiological parameters [26] (ATTAIN study extension for longterm dose frequency ongoing) and will hopefully improve adherence. As for GA, recent observational studies have shown that IFNb are relatively safe before or during pregnancy, but some conflicting data suggests a potentially increased rate of spontaneous abortion and of preterm birth in women taking IFNb during pregnancy [57,64–68]. No apparent significant impact of paternal exposure is reported [60,61]. Patients on IFNb can develop neutralizing Abs (Nabs) against IFNb. However, the use of Nabs titer to guide clinical decision in case of suboptimal response is becoming less relevant in the view of the many therapeutic options now available [13,69]. However, recent guidelines suggest that high titers of Nabs 12–24 months after initiating therapy should guide to a switch from IFNb to another class of DMT, even in the absence of significant disease activity [70,71].

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Teriflunomide

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Teriflunomide is an oral DMT approved for the treatment of RRMS [72]. As inhibitor of pyrimidine synthesis, teriflunomide is known to reduce the number of circulating leukocytes, but displays a relatively good safety profile [27]. Significant adverse events include hepatotoxicity and infections, which seem to be more frequent than with GA or IFNb. Immunization during teriflunomide therapy is efficient, but live vaccines should be avoided [62]. Numerous drug interactions are reported, including with warfarin, CYP inducers, substrates of CYP2C8 and many other medications such as some of the oral anti-diabetic agents, statins and antibiotics (EMA website). In view of the drug interaction profile and the reported risk of peripheral neuropathies, teriflunomide should be used with caution in diabetic patients, as is leflunomide [73]. Moreover, teriflunomide is labeled as a teratogenic medication (class X) [74] in women and possibly also in men. As elimination of teriflunomide can take up to two years, accelerated elimination using cholestyramin 8 g tid for 11 days or activated charcoal 50 g bid for 11 days is therefore warranted before conception for both females and males. A similar clearance regimen is suggested before switching from teriflunomide to another DMT with immunosuppressive properties [60,74].

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Dimethylfumarate

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Dimethylfumarate (DMF) is an oral immunomodulatory DMT approved for the treatment of RR-MS and CIS patients (FDA, Health Canada and EMA website). DMF has the capacity to reduce the number of circulating lymphocytes, and lymphopenia can

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To cite this article: Michel L, et al. Update on treatments in multiple sclerosis. Presse Med. (2015), http://dx.doi.org/10.1016/j. lpm.2015.02.008 Update on treatments in multiple sclerosis

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be significant in some individuals. Administration of live attenuated vaccines is not recommended during therapy. DMF has no known drug interactions and demonstrate an intermediate risk of adverse events. Although rare, the use of DMF can be associated with the development of progressive multifocal leukoencephalopathy (PML), an opportunistic demyelinating viral disease of the CNS, in both MS and in psoriasis [34,75]. Gastrointestinal symptoms (abdominal discomfort or pain and diarrhea) as well as flushing are seen in more than 25% of patients during the first trimester of therapy, leading to discontinuation in 12–16% of patients as compared to 10–13% for placebo [76]. Animal studies suggest some adverse impact of DMF on developing fetuses [60,76]. A washout period of 1 month is recommended before conception, although DMF is virtually eliminated from the circulation after 24 h.

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Fingolimod

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Fingolimod is a Sphingosine-1-Phosphate receptor agonist and a generally well-tolerated oral DMT. Fingolimod reduces the number of circulating lymphocytes. In view of potential serious cardiac, hepatic, infectious and ocular complications, treatment with fingolimod requires significant work-up and monitoring and needs to be used with caution in patients with a history of cardiac or ocular disease, including diabetic patients [75,77]. Numerous drug interactions with other medication and natural products, mainly antiarrhythmic agents and immunosuppressants are reported and limit the clinical use of fingolimod. Congenital malformations are reported to be more frequent in fetuses exposed to fingolimod and a washout period of 2 months before pregnancy is indicated [78,79]. Administration of live attenuated vaccines is not recommended during therapy [62]. Noteworthy, rebound activity or MS reactivation after discontinuation of fingolimod has been observed, albeit this phenomenon is relatively rare [77].

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Natalizumab Natalizumab (NTZ) is a humanized monoclonal Ab directed at the adhesion molecule VLA-4. It is a well-tolerated DMT, which displays no significant drug interactions, but should not be used in combination with other DMT or immunosuppressors. NTZ is associated with a non-negligible risk (overall risk of 1/200, as of September 2014) of serious infections, especially the JC virusinduced PML. Twenty to 25% of patients developing PML have died, and survivors remain with mild to severe disability ([80], Biogen-Idec). PML risk stratification can be achieved by using two independent predictive factors in patients JCV (+): the previous exposure to immunosuppressive agents, and the duration of treatment with natalizumab (see table I) (FDA and EMA website). The anti-JCV Abs index may also help to differentiate patients with a higher risk of PML (index above 1.5) but only in patients without prior use of immunosuppressive drugs [81]. In case of seropositivity, most experienced MS specialists will discontinue NTZ therapy after two years of treatment. NTZ is


TABLE I Estimation of the risk of PML in natalizumab (NTZ) treated patients Duration of NTZ therapy (months)

Prior IS exposure No

Yes

0.7 (0.5–1)

1.8 (1.1–7.2)

25—48

5.3 (4.4–6.2)

11.2 (8.6–14.3)

49–72

6.1 (4.8–7.8)

Insufficient data

0–24

Risk estimates are expressed per 1000 treated patients (95% CI) and were updated September 1, 2013. For JCV negative patients: risk is estimated at 0.1 per 100. IS: immunosuppressive drugs; JCV: JC virus; PML: progressive multifocal leukoencephalopathy.

not recommended during pregnancy, but fetuses exposed to NTZ during first trimester display no major health issues so far [82]. Moreover, NTZ has been used for highly active MS during third trimester, resulting in transient mild to moderate hematologic abnormalities in the newborns and one subclinical bleeding complication [83]. NTZ cessation can be associated with severe MS reactivation or MS rebound activity and necessitates a close monitoring [84,85]. Introduction of a new immunomodulatory agent less than 2 months after last infusion is therefore now recommended (see section on washout).

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Alemtuzumab

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Alemtuzumab is a monoclonal antibody directed against CD52. Alemtuzumab is given IV for a total of 8 days over 2 years and is associated with infusion reactions in virtually all patients. Slow (over 4 h) infusion and premedication with methylprednisolone 1 g for the initial 3 days of each course of treatment, and with acetaminophen and diphenhydramine, is recommended to decrease the severity of these infusion reactions [86]. Alemtuzumab is associated with herpes exacerbations; acyclovir 200 mg bid or equivalent for 1 month starting on the first day of each treatment course is recommended. Autoimmunity is the major drawback of alemtuzumab, with as much as 48% of patients developing clinical autoimmune disease in a long-term follow-up study [87]. Graves' hyperthyroidism, hypothyroidism and subacute thyroiditis are the most frequent autoimmune disorders, found in 34–41% of patients [87,88]. Autoimmune cytopenias and nephropathies are rare but also reported. Frequent infections are nasopharyngitis, urinary tract infections, upper respiratory tract infection, sinusitis, oral herpes, influenza and bronchitis as well as oral and vaginal candidiasis. Serious infections included appendicitis, gastroenteritis, pneumonia, herpes zoster and dental infection. Most patients will develop antibodies to alemtuzumab without any observed clinical impact. Due to the incidence of serious autoimmune and infectious complications, patients who may not be fully committed to

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the prolonged and demanding monitoring after alemtuzumab infusions should not receive the drug. Pregnancy should be avoided for at least 4 months following infusion of alemtuzumab; outside of this period, fertility and pregnancy do not seem affected by previous alemtuzumab treatment [87]. Administration of live attenuated vaccines is not recommended during therapy.

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Mitoxantrone

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Mitoxantrone is a type 2 topoisomerase inhibitor with proven efficacy in MS with very active disease [52,89]. Mitoxantrone conveys a risk of serious irreversible adverse effects including heart failure and acute leukemia. To limit the morbidity of the drug, the maximum dose per month is 20 mg, and the maximal cumulative lifetime dose is 120 mg or 72 mg/m2. Nevertheless, incidence of cardiotoxicity on echocardiogram is estimated at 4.1% (assessed on left ventricular fraction < 50%) [90] or 14% [91] (assessed as a 10% reduction of left ventricular ejection fraction). Incidence of leukemia ranges between 0.25–0.8% [91–96]. Mitoxantrone is teratogenic and can cause persistent amenorrhea especially in women older than 25 years old [94,97]. Moreover, previous exposure to mitoxantrone increases the risk of PML in individuals on NTZ (see NTZ section) and probably on other immunosuppressive DMTs. Taken together, the long-term effects of mitoxantrone warrant caution when considering mitoxantrone early in the course of the disease. Administration of live attenuated vaccines is not recommended during therapy.

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Comparison of DMTs

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First-line agents

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In RR-MS patients, four classes of DMTs are actually available as first-line therapies: interferons beta and glatiramer acetate, injectable DMTs available for more than 15 years, and teriflunomide and dimethylfumarate, newcomer oral DMTs (annex 1). Comparison of the different IFNb formulations, although not based on reliable double-blinded head-to-head trials, seems to favor SC preparations regarding efficacy as well as incidence of flu-like symptoms, while injection site reactions and development of Nabs would be less frequent with IM preparation [6,63,98,99]. The IFNb-1a SC formulation might be associated with higher although very rare incidence of thrombotic microangiopathy [100,101]. Differences between the IFNb formulations are however generally not considered clinically significant. While comparison studies were either post-hoc, unblinded or small, and are therefore arguably reliable, no significant difference in terms of clinical and radiological efficacy has been demonstrated between IFNb and GA [63,98,99,102–105]. A recent phase III study (TENERE) has demonstrated similar impact of teriflunomide 14 mg and IFNb on MS clinical activity as defined by the time to first relapse and the annualized relapse rate in a cohort of 324 patients [31]. For DMF, the phase III trial

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(CONFIRM) compared DMF to placebo and GA to placebo [36]. Post-hoc comparisons of DMF versus GA revealed significant differences concerning the MRI criteria with a superiority of DMF over GA. However, this study was not designed to test the superiority or non-inferiority of DMF compared to GA. The choice of a first-line agent will therefore be guided by the profile of side effects, the patients' convenience but also by the desire of pregnancy. Combination strategies are widely used in other medical fields such as rheumatology or cancer. In MS however, the CombiRx study has analyzed the effect of the association of IFNb-1a and GA and has found no significant advantage of the combination therapy over the others arms [102]. Moreover, even if the association of therapies with different mechanisms of actions would seem attractive in theory, safety and costs remain major concerns.

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Second- and third-line agents

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Fingolimod, natalizumab and alemtuzumab are agents that have proven therapeutic superiority to selected first-line agents. Mitoxantrone has also proved to be superior to IFNb, but as an induction therapy [89] (see section on induction therapy). The TRANSFORMS study has demonstrated the superior efficacy of oral fingolimod as compared with IFNb-1a in terms of relapse rates and MRI outcomes in a cohort of 1153 patients [41]. No clinical trial has compared the efficacy of NTZ over first-line medication. SENTINEL has demonstrated the higher efficacy of adding NTZ to IFNb-1a, as compared to IFNb-1a alone in a cohort of MS patients who presented a treatment failure under IFNb-1a [45]. Significant adverse events, including 2 cases of PML, however occurred and combination is therefore contra-indicated. As compared to IFNb-1a, alemtuzumab significantly reduced the risk of disability by 42% in CARE MSII and by 75% in CAMMS223, and also significantly reduced the relapse rate by 49 to 69% in these different studies. An extended long-term follow-up with a median of 7 years follow-up revealed an improvement or stability of the disability in 60% of patients [87]. Comparative analyses of the efficacy of 2nd line agents have not been performed. In one multicenter observational study of MS patients treated with either by NTZ or fingolimod, treatment outcomes were similar, however the baseline characteristics of the patients were different [106]. Another observational study comparing NTZ versus fingolimod was recently published [107]. The authors selected only patients for whom JCV serology was used to decide treatment to ensure similar baseline characteristics. Adjusted analyses found significant differences favoring NTZ concerning clinical and MRI criteria. No studies have yet compared NTZ vs. alemtuzumab.

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Therapeutic strategies

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Initiating therapy with DMTs: a shared decision

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Two contrasting treatment strategies exist when initiating treatment with DMTs in MS: escalation and induction. Decisions

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regarding the best therapeutic plan for individual MS patient are based on past and current disease activity (clinical relapses, new/enlarging or enhancing lesions on MRI), on burden of disease (cognitive status, EDSS, total lesion load, brain atrophy) but also by the profile of adverse events of the different DMTs, the patient's preference and the neurologist's experience. In this section, we will review the different general therapeutic strategies used in MS and their indications.

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Therapeutic escalation

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Therapeutic escalation (figure 1) is underpinned by a strong rationale that treatment has to start with drugs considered safe before moving to more "aggressive'' therapies which are more efficient but carry a risk of potentially severe or irreversible adverse events. This strategy is probably most suitable for patients presenting with early MS, with low to moderate disease activity and burden of disease, and expressing concerns regarding the safety profile of second- and third-line therapies. In these patients, it seems reasonable to start with DMTs displaying a good safety profile, and to be ready to switch to a different agent in case of lack of tolerance or of efficacy. This strategy requires to monitor clinically and radiologically the patient to

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identify early signs of breakthrough disease that would be considered as a suboptimal response or a treatment failure. Indeed, one of the keys of success in the escalation therapy is most likely to be able to identify not only a failure of treatment but also a suboptimal response that can predict a less favorable evolution of the disease.

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How to define a suboptimal response of treatment? As treatment may be especially beneficial early in the course of MS, rapid identification of non-responders is crucial to determine the need for a therapeutic switch. The evaluation of the response to therapy relies on outcome measures that may directly or indirectly reflect the progression of a disease. A clear and consensual definition of a lack of response to the immunomodulatory drugs in MS does not exist, but numerous studies have suggested some criteria [108–117]. In 2006, Rio et al. have evaluated the clinical criteria, which would allow early identification of non-responders to IFNb, and then could be used to predict the long-term disability status at 6 years. They analyzed different criteria based on relapses, disability progression, or both [118]. In this study, after two years of treatment the proportion of non-responders ranged

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Figure 1 Escalation therapy in multiple sclerosis patients Three approved lines of therapies can be proposed in multiple sclerosis. The first-line agents include safe immunomodulatory drugs (interferons, glatiramer acetate and teriflunomide). In case of failure, different second-line agents can be proposed depending of the level of concern (LOC): in case of low/medium LOC: a switch for dimethyl fumarate, fingolimod or another first-line drug can be legitimate, in case of medium/high LOC, an escalation for natalizumab or mitoxantrone is recommended. A third-line therapy is now available with alemtuzumab and can be proposed in case of suboptimal response with a second-line drug. Some experimental therapies can sometimes be proposed in some selected patients with highly active and refractory disease.


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from 7 to 49% of patients depending on the stringency of the criteria used. Criteria based on disability progression (increase of at least one EDSS step confirmed at 6 months) showed higher sensitivity, specificity and accuracy for notable disability after 6 years of treatment than relapse-based criteria. Therefore, disability progression is probably more relevant than relapse rate to define a failure of IFNb. As regards radiological criteria, different studies have suggested that the presence of gadolinium-enhancing lesions or of new T2 lesions while on IFNb therapy predicts poor long-term response to treatment and future clinical worsening [2,117,119–122]. In the same way, the analysis of the longitudinal relationship between MRI lesions and clinical course over a period of 20 years has revealed that the change in the volume of lesions during the first years of the disease is correlated with disability after 20 years [2]. Current recommendations of EMA concerning second-line drugs include some definitions of "non-responders''. MS patients are considered as non-responders if after one year of treatment with IFNb they presented at least one relapse in the previous year while on therapy and at least nine T2 lesions or one gadoliniumenhancing lesion on brain MRI (EMA website). Apart from the EMA, several formal monitoring strategies and algorithms have been proposed. The Canadian Multiple Sclerosis Working Group (CMSWG) has published in 2004 and 2013 practical guidelines to categorize patients with MS receiving DMT by level of concern (LOC) [69]. In these guidelines, relapse occurrence, EDSS progression and MRI evolution are monitored and the LOC is described as none, low, medium or high. A change of treatment should be considered if there is a high level of concern in any one domain, a medium level of concern in any two domains, or a low level of concerns in the three domains. In the revised recommendations, the CMSWG also suggests to test

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cognitive functions using the Symbol Digit Modalities Test at least every two or three years. The International Working Group for Treatment Optimization in MS has also formulated some guidelines concerning suboptimal response [123,124]. They recommend waiting at least 6 to 12 months to assess efficacy. The monitoring strategy focuses on the usual parameters (relapse, disability and MRI) to categorize patients in one of 3 levels of concern (table II). The timing of follow-up visit is usually every six months, or every 3 months in case of important signs of disease activity. The first MRI following initiation of treatment can be performed at one year to evaluate disease activity and also the long-term prognosis.

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Management of treatment failure Suboptimal response to a first-line DMT warrants either a lateral/transversal switch in some cases with low to moderate LOC (from one first-line immunomodulatory treatment to another one) or a vertical switch (therapeutic escalation) in more aggressive cases with moderate to high LOC (from a first-line to a second- or third-line therapy).

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Transversal switch Switching from a first-line DMT to a different first-line DMT can represent an acceptable strategy after treatment failure or lack of tolerability [125–128] (figure 1). There are few data available concerning the benefit of these switches. Recently, a Spanish observational study has reported the clinical outcome after switching from a first-line DMT because of a treatment failure in 180 patients [129]. Half of these patients switched to another first-line drug, the other half to a second-line therapy. Concerning the "first-line switch'' (i.e. IFNb/IFNb, IFNb/GA, GA/IFNb), all the groups presented a significant reduction of their ARR after the switch and more than 60% of patients showed an absence of clinical disease activity. Therefore, it

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TABLE II Summary of the criteria used to define a suboptimal response to interferon in MS patients

Clinical criteria MRI criteria

Others criteria

Levels of concerns

Canadian Multiple Sclerosis Working Group (CMSWG)

International Working Group for treatment optimization in MS

Relapses (rate, severity, recovery) Progression (EDSS, time 25 foot walk)

Relapses (rate, severity) Progression (EDSS over 2 years)

New Gd+ enhancing lesions/year New T2 lesions/year

New Gd+ lesions New T2 lesions New T1 hypointense lesions

Cognition with SDMT before and every 2 or 3 years Neutralizing Abs

Depression, fatigue Pain, spasticity Sexual dysfunction Quality of life, cognition

Low/medium/high

Noteworthy/worrisome/actionable

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EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; SDMT: Symbol Digit Modalities Test.


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seems that in MS patients with a low to medium level of concern, offering a transversal switch from one first-line DMT to another is an adequate option. Vertical switch (escalation) For patients in whom a worrisome breakthrough of disease activity has occurred while on first-line therapy, escalation to more aggressive but often less innocuous second-line drugs such as fingolimod, NTZ or mitoxantrone can be considered (figure 1). The choice of therapy will be guided by different determinants: the level of concern (LOC) regarding the risk of MS worsening, the potential adverse events associated with the medications and the age and medical history of the patient. If the LOC is deemed low to medium, escalation to fingolimod is a legitimate option. Fingolimod has proven its superiority as compared to IFNb-1a in the TRANSFORMS study (see "comparisons of DMTs''). In the extension study [130], patients who had been treated first with IFNb-1a were reassigned after one year to fingolimod for one year. The relapse rate, the number of new T2 lesions and the number of gadolinium-enhancing lesions decreased significantly after switching, as compared to the year under IFNb-1a. Moreover, post-hoc subgroup analyses of FREEDOMS and TRANSFORMS [131,132] have revealed that in patients who were considered non-responders to previous IFNb therapy (defined by both relapses and MRI activity), fingolimod significantly reduced the ARR as compared to IFNb-1a or placebo. Recently, an interesting retrospective study in MS patients switching from IFNb to GA or fingolimod in a real-world setting has reported that patients who switched to fingolimod were significantly less likely to experience relapses than those who switched to GA [133]. Whether these results can be generalized to all first-line DMTs remains unknown. Post-marketing studies are needed to answer these questions. In case of medium or high LOC, more aggressive therapies such as NTZ and mitoxantrone are valuable second-line options. NTZ has indeed been approved in case of failure of IFNbs or GA, while the chemotherapeutic agent mitoxantrone is approved for MS patients (RR and SP-MS) with rapidly worsening disease. There are currently no randomized prospective controlled studies comparing NTZ in monotherapy to other DMTs. Several observational studies have reported the efficacy of NTZ in patients presenting a suboptimal response to IFNb or GA [128,134–137]. These studies conclude to a clinical and radiological improvement after switching from IFNb or GA to NTZ. For mitoxantrone, two published randomized clinical trials [52,53] have analyzed the benefit of mitoxantrone therapy versus placebo in rapidly worsening RR and SP-MS. Edan et al. showed a significant benefit in 42 MS patients after 6 months of treatment, based on analysis of MRI criteria, relapses and EDSS score. A prospective study comparing a 3 years of treatment with NTZ to 6 months on mitoxantrone followed by a maintenance therapy with any first-line DMD is currently ongoing in RR-MS patients (IQALY-SEP study).


Alemtuzumab has also demonstrated its efficacy in patients showing breakthrough MS activity on first-line DMTs. In CARE MS II, non-responders to IFNb or GA were assigned to alemtuzumab (12 or 24 mg), IFNb-1a or placebo [48]. A statistically significant reduction in ARR, sustained disability, and new enhanced lesions over 24 months was observed in favor of alemtuzumab versus IFNb-1a. However, in light of the high incidence of significant secondary autoimmune diseases following treatment with alemtuzumab, the authors would rather consider it as a third-line agent.

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Induction therapy

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When? Immunosuppressive or immune ablative medications currently available for the treatment of MS patients are associated with serious and irreversible side effects. Induction strategy is therefore generally reserved to patients with very active and aggressive disease. Indeed, in this group of patients, the risk of rapidly progressive and definitive disability outweighs that of adverse events associated with more intense immunosuppression or immunoablation. Once disease control has been achieved, a maintenance therapy with a safer drug is performed. Early inflammatory activity (clinical and radiological) is strongly related to the risk of long-term disability and with future development of SP-MS [2,4,138]. Epidemiological data suggest that MS present a two stage course: a first phase where focal inflammation influence disability progression, and a second phase during which disability progression seems less dependent on focal inflammation [4]. MS patients who present frequent relapses and an important accumulation of T2 lesions during the first years of the disease become disabled more quickly, as compared to patients who do not [2,4,138]. In this group of active MS patients, an induction therapy needs to be considered.

482 483

Which drug? In MS, induction has been studied using different drugs: mitoxantrone, NTZ, alemtuzumab and fingolimod. Mitoxantrone A first randomized clinical trial has assessed in 1997 the shortterm benefits of a six-month treatment by mitoxantrone vs. placebo in a small group of patients with very active RR-MS or SP-MS [52]. Mitoxantrone significantly decreased the relapse rate, the number of enhancing lesions, and also provided some improvement in the EDSS score. A phase III trial published in 2002 has confirmed these results in SP-MS and RR-MS patients with active and relatively severe disease [53]. Another randomized clinical trial published in 2011 has compared a six-month induction with mitoxantrone followed by a maintenance therapy with IFNb-1b to a treatment by IFNb-1b, in a group of active RR-MS patients. The 3-year risk of sustained worsening of disability was reduced by 65% in the mitoxantrone group, and the ARR and T2 lesions accumulation were also significantly

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reduced [89]. Similar data were obtained when using the GA instead of IFNb [139]. The induction strategy by mitoxantrone followed by GA was found to be safe and effective with a sustained decrease of MRI activity.

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Natalizumab AFFIRM and SENTINEL studies have shown that NTZ was effective both as monotherapy and in combination with IFNb in patients with relapsing MS. A post-hoc analysis was conducted to determine the efficacy of NTZ in patients who presented a highly active disease (i.e. 2 relapses in the year before study and > 1 Gd+ on MRI) [140]. They found that NTZ significantly reduced the risk of disability progression by 64% and relapse rate by 81% in treatment-naïve patients with highly active disease and by 58% and 76%, respectively, in patients with highly active disease despite IFNb-1a treatment. These results pointed to the important efficacy of NTZ in rapidly worsening RR-MS.

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Fingolimod As for NTZ, fingolimod has two main indications: failure on first-line DMTs and rapidly worsening RR-MS patients. Indeed, subgroup analyses of ARR and confirmed disability progression over 24 months have been performed in the FREEDOMS study. Subgroups were defined according to demographic and disease characteristics but also to response to previous therapy. The authors have shown that in treatment-naïve patients with rapidly evolving severe disease, ARR was significantly reduced on fingolimod by 67% versus placebo over 24 months [131]. However, the risk of disability progression was not significantly lower in the fingolimod group as compared to placebo. Overall, this sub-analysis suggested that rapidly worsening RR-MS patients could directly benefit from fingolimod as firstline therapy.

540 541 542 543 544 545 546 547 548 549 550 551 552 553 554

Alemtuzumab Alemtuzumab is also foreseen as a good candidate for induction therapy in MS. In a phase II randomized double-blinded trial published in 2008 comparing alemtuzumab to IFNb-1a [141], alemtuzumab has significantly reduced the rate of sustained accumulation of disability by 75% as compared to IFNb-1a as well as the ARR and the lesion burden. The 5-year extension phase has demonstrated a 72% lower risk of accumulation of disability and a reduction of 69% in ARR as compared to IFNb-1a [48]. The phase III study CARE MS I has found a superiority of alemtuzumab as compared to IFNb-1a over 2 years with respect to ARR (decrease of 55%) and to MRI outcomes [49]. However, even if the risk of disability lasting for at least 6 months was lower in the alemtuzumab group compared with interferon beta 1a, the difference was not statistically significant. The incidence of serious and persisting adverse events following use of alemtuzumab limits its use as an induction agent to a selected population of patients presenting with an unusually aggressive disease course, and only after careful

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consideration of the risks and benefits of alemtuzumab as compared to other DMTs.

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Which drug in relay? After induction therapy, the question of maintenance therapy remains an important problem. In two distinct trials, the efficacy of maintenance therapy with IFNb [89] or GA [139,142] has been evaluated following induction with mitoxantrone. Both trials have reported a good and persistent efficacy after 3 years [89] and 15 months of treatment [139,142]. As for NTZ, the central issue remains the risk of rebound MS activity immediately following discontinuation of NTZ [143,144]. It remains actually unclear which drug should be used and within which time period it would need to be initiated to suppress rebound activity without leading to overwhelming CNS immunosuppression. Recently, a randomized non-blinded placebo-controlled study (RESTORE) has evaluated disease activity in patients undergoing discontinuation of NTZ, as well as the clinical efficacy of IFNb-1a, GA or methylprednisolone (MP) to prevent rebound activity. Placebo-treated patients showed a clinically significant increase in MRI activity (46%) and in relapses (17%) within 4–12 weeks after discontinuation of NTZ. While IFNb-1a appeared to be efficient to control MRI-based indices of disease activity (MRI recurrence: 7%), when compared to GA (MRI recurrence: 53%) or MP (MRI recurrence: 40%) [144], none of IFNb, GA or MP was beneficial in terms of controlling clinical relapses. Additional studies have recently confirmed the risk of important rebound disease activity following NTZ discontinuation [145–147]. Finally, as RESTORE was not designed nor powered to compare the efficacy of immunomodulatory drugs, larger controlled studies are needed. A randomized blinded clinical trial (Kappos L., TOFINGO, oral presentation ECTRIMS 2013) has investigated the effect of different washout periods (8, 12 or 16 weeks) on clinical and MRI disease activity in patients switching from NTZ to fingolimod. The preliminary results have confirmed that a shorter washout period is associated with a lower risk of clinical and MRI disease recurrence. In addition, a recent study has demonstrated that the relay of NTZ with fingolimod resulted in a slight increase of the ARR (from 0.26 to 0.38) and that the patients with a washout period of less than 2 months presented a significantly lower risk of relapse as compared to those with longer washout periods [147]. Therefore, fingolimod seems to be an interesting therapy in relay of NTZ, and shorter washout periods protect against rebound disease activity. One of the biggest challenges in the therapeutic management of RR-MS patients is to choose the most effective drug at the best time for each patient. For clinically and radiologically aggressive RR-MS, induction strategy with classical second-line therapies seems to be the most efficient strategy. In the other groups of patients, escalation can be successfully applied to minimize the incidence of serious adverse events. However,

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there is a relative lack of evidence to determine if the use of induction strategy could be widen to include other patients at risk of developing significant disability.

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The washout: when and how?

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With the arrival of new therapies in MS, the timing of relay from one DMT to another has become a crucial issue for MS caregivers when switching is required (table III). There does not seem to be major issues concerning the switch from IFNbs or GA to other therapies. No washout period is required before starting another treatment, even for secondline drugs. Concerning teriflunomide, the EMA recommend no washout period when switching from teriflunomide to IFNb or GA. However, if a switch to other therapies is decided, such as fingolimod, NTZ or others immunosuppressive drugs, a washout period of 3.5 months needs to be respected (=5 half-lives of teriflunomide) or an accelerated elimination procedure has to be performed. For DMF and fingolimod, the recommended washout period is the time necessary to recover a normal white blood cells count, usually between one and two months, although it can be longer [148].

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What's new in term of treatment?

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Emerging therapies are currently under investigation and can, in some selected cases, be considered as an alternative treatment. We chose to briefly summarize three of them: daclizumab, antiCD20 Abs, and hematopoietic stem cell transplantation.

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TABLE III Durations of wash out periods required after a treatment switch in MS patients Treatment 1

Treatment 2

Washout

IFN or GA

Any drug

No washout required

Any drug

IFN or GA

No washout required

NTZ

FTY Teriflunomide DMF

< 2 months after discontinuation of NTZ

Teriflunomide

FTY NTZ Alemtuzumab

Accelerated elimination procedure or 3.5 months

Teriflunomide NTZ Alemtuzumab

When lymphocytes level are returned to normal levels (1 to 2 months)

Alemtuzumab NTZ FTY

When lymphocytes level are returned to normal levels

FTY

DMF

DMF: dimethylfumarate; FTY: fingolimod; GA: glatiramer acetate; IFN: interferons; MS: multiple sclerosis; NTZ: natalizumab.


Daclizumab

649

Daclizumab is a humanized monoclonal Ab directed against the a chain of the IL-2 receptor, a molecule up-regulated on activated T cells. This drug has been used for more than 10 years in the prevention of kidney transplant rejection. Studies showed that CD25 antagonism was responsible for an expansion of CD56bright NK regulatory cells, resulting in decreased T cell activation [149]. The CHOICE phase II placebo-controlled trial has shown that daclizumab in combination with IFNb was effective at reducing the number of new gadolinium-enhancing lesions at 6 months [150]. The SELECT trial has compared a 52-week treatment by monthly daclizumab 150 mg or 300 mg to placebo in 600 patients with active RR-MS [151]. Treatment with daclizumab has resulted in a 50 to 54% reduction of ARR as compared to placebo. In the MRI sub-study performed in 309 patients, there was a 69 to 78% reduction of new or enlarging gadolinium-enhancing lesions in daclizumab-treated patients, when compared to placebo-treated patients. The most common adverse events reported were nasopharyngitis, upper respiratory tract infection and headache. Four malignancies were reported in the study: one in the placebo group and three in the daclizumab-treated groups. DECIDE, a phase III trial designed to evaluate the safety and efficacy of once monthly subcutaneous administration of daclizumab as compared to IFNb-1a is ongoing.

650

Rituximab/ocrelizumab/ofatumumab

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Rituximab is a human/murine monoclonal Ab directed against CD20, a B cell marker. It was the first B cell depletion therapy used for treatment of MS. Despite the good results of different studies [152–154], the development program has been suspended. Ocrelizumab is a recombinant monoclonal humanized anti-CD20 Ab. This Ab is structurally similar to rituximab, but as a humanized molecule it is expected to be less immunogenic and to present a more favorable benefit-risk profile. In a phase II study, 218 relapsing MS patients were randomized to receive either placebo, low dose (600 mg) IV ocrelizumab, high dose (2000 mg) IV ocrelizumab, or IFNb-1a [155]. The study has demonstrated a significant reduction in the number of new gadolinium-enhancing lesions in both ocrelizumab groups as compared to placebo or to IFNb. ARR was respectively 80% and 73% lower in the 600 mg and 2000 mg groups when compared to placebo. Only the 600 mg group presented a significantly lower ARR when compared to IFNb. Recently, ofatumumab (a second generation humanized monoclonal Ab against CD20), has been tested in a randomized doubleblind placebo-controlled study [156]. Thirty-eight patients have received 2 infusions of 100 mg, 300 mg, or 700 mg of ofatumumab or placebo at two weeks interval. At week 24, significant reductions of new gadolinium-enhancing lesions and new T2 lesions were observed in the treated groups (all doses).

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There are currently three large phase III trials underway, one in PP-MS patients (ORATORIO) and two in relapsing MS patients (OPERA I and II).

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Autologous hematopoietic stem cell transplantation (AHSCT)

705

In recent years, intense immunosuppression followed by infusions of autologous hematopoietic stem cells has been the subject of several studies in patients with RR-MS. The aim of this treatment is first to eradicate the autoreactive cells, and then to restore the hematopoietic system. Only results from phase I/II trials are currently available, and there is no data coming from prospective comparative studies [157–173]. However, AHSCT appears to be very effective in some selected MS cases with relapsing-remitting form and/or showing inflammatory MRI activity, who are younger than 40 years and who have a short disease duration [174]. Concerning the safety profile, the mortality rate has been evaluated to 1.3% during the period 2001–2007 [175], mainly due to systemic infections. About 10% of the transplanted patients present autoimmune diseases in the first two years [176]. In the future, AHSCT will probably be considered as an alternative therapy for RR-MS patients with highly active and refractory disease on DMTs.

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Conclusion

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The considerable advances made recently in our understanding of the pathophysiology of MS have allowed the development of many therapies with different mechanisms of actions. The currently approved DMTs present different levels of efficacy and tolerability. Escalation strategy, based on the failure a treatment, has classically been used to treat MS patients. But, it seems more and more legitimate to consider induction therapy with more aggressive DMTs in selected patients populations affected with more severe forms of MS. One of the remaining issues in MS is the early estimation of suboptimal response to first-line DMTs. Clinical and radiological criteria can actually help to detect early suboptimal responders and, in the future, biomarkers and pharmacogenomics will probably guide us to select the most appropriate individualized therapy.

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Disclosure of interest: Laure Michel received honoraria from Novartis and 739 Teva for counseling and conferences. 740 Alexandre Prat received honorarium from Novartis, EMD Serono, TEVA, Q2 741 Sanofi-Genzyme and Biogen for scientific advisory boards and conferences. 742

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