The Transition From First-Line to Second-Line Therapy in Multiple ...

Curr Treat Options Neurol (2015) 17:25 DOI 10.1007/s11940-015-0354-5

Multiple Sclerosis and Related Disorders (P Villoslada, Section Editor)

The Transition From First-Line to Second-Line Therapy in Multiple Sclerosis Jan Do¨rr, MD* Friedemann Paul, MD Address * NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany Email: [email protected]

* Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Multiple Sclerosis and Related Disorders

Keywords Multiple sclerosis I Treatment I Escalation I Disease modifying drug I Treatment failure I Disease activity I Window of opportunity

Opinion statement Sufficient control of disease activity in multiple sclerosis (MS) patients, particularly in the early phase of the disease, is crucial for the prevention of an unfavorable outcome. While currently available disease modifying drugs are generally clearly assigned as first-line or second-line treatment, no universal guidelines exist that help in the real world setting to decide when and how exactly a transition from first-line to second-line therapy should be initiated. Furthermore, the concept of first and second-line therapies is constantly evolving. In order to facilitate evidence-based decision making in this common situation, we here summarize existing data on the optimization of treatment when the first-line drug needs to be switched. Obviously, a switch of treatment starts with an exploration of the motivation to switch, which usually may be ascribed to either inadequate treatment response or tolerability, safety, or adherence issues. In the latter situation, intra class switching, e.g., from interferon (IFN) beta to glatiramer acetate (GA) or, in case of aversion against injectables, from GA/IFN beta to one of the new orals dimethylfumarate or teriflunomide can be a reasonable option. If treatment failure is the reason for a switch, existing data suggest that escalation to a more powerful drug such as natalizumab, fingolimod or even alemtuzumab is more appropriate. Of note, in some drugs, different formal approvals apply in different countries. For example, while fingolimod is approved as second-line therapy in the European Union, it can be used as first-line drug in the United States and in Switzerland. The flip side of these more powerful drugs might be a less favorable risk-benefit ratio. As long as data are not yet sufficient to allow a direct comparison of efficacy among second-line drugs, the treatment decision should be primarily based on the individual situation and risk profile of the patient.

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Introduction Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) in young adults and is characterized by both demyelination and early neurodegeneration [1•, 2, 3]. More recent network-based research suggests disrupted functional and structural brain connectivity as another hallmark of MS [4]. In about 80–90 %, MS starts off with a relapsing-remitting (RR) course with relapses occurring on average once every 2 years. Pathophysiologically, this phase of the disease is dominated by autoimmunemediated inflammatory attacks to the CNS leading to focal inflammation, demyelination, and axonal damage; clinically, this phase is characterized by episodes of rather focal CNS dysfunctions of variable degree which respond to anti-inflammatory treatment and usually remit after resolution of the inflammation. The frequency and severity of relapses is amenable to various disease modifying drugs (DMD), and the risk to develop relevant permanent disability at this stages is relatively low [1•]. After a highly variable period of time, ranging from very few to 25 years or even longer, however, the occurrence of acute relapses is replaced by a gradually increasing permanent disability. In this phase of the disease, termed secondary progressive (SP) MS, inflammation usually takes a back seat, and the scenario is dominated by the neurodegenerative component in combination with an exhaustion of the capacity of the CNS to compensate for loss of function [5•]. Currently

available DMDs are only effective as long as residual inflammatory activity is present. Generally, SPMS is by far more difficult to treat than RRMS. In line with the clinical experience, several studies have convincingly shown that while the duration to reach a moderate permanent disability, defined by a score of 3 to 4 on the original 10-point disability status scale (DSS) [6], is highly variable among patients, the time to further progress to a DSS of 6 is remarkably homogenous and irrespective of both the time to reach a DSS of 3 and the occurrence of relapses [7, 8••]. Thus, disability progression in MS appears to follow a two-stage process in which only the first phase is dependent on focal inflammation. Given the primarily anti-inflammatory capacity of current DMDs, this observation has direct implication for the treatment strategies in MS as it suggests a Bwindow of opportunity^ during the first phase, i. e., roughly until a DSS of 3 is reached. However, current DMDs are often only partially effective, and many patients show continuing disease activity or breakthrough disease while on first-line DMD treatment. Other patients develop intolerable side effects that require cessation of treatment. A major challenge in MS therapy is the optimization of drug treatment in order to prevent even these patients from progression into the second phase of the disease outside the window of opportunity. However, algorithms when and how to optimize treatment in the real world setting still need to be established.

Treatment Currently, 13 different drugs with ten different active components are licensed in the European Union (EU) and the United States (US) for the treatment of MS. Based on their formal approval by the respective authorities, for example, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and their individual risk-benefit profile, these drugs can be categorized into first-line, second-line, and third-line treatment (Table 1). Of note, formal approvals do not necessarily coincide in different countries. For example, while FDA approved fingolimod as a first-line treatment, the EMA labeled fingolimod as second-line therapy except in patients with highly active disease in which fingolimod can be used as first-line also in the EU. Alemtuzumab in contrast is labeled by the FDA as third-line therapy in Bpatients who have had an inadequate response to two or more drugs indicated for the treatment of MS^, whereas according to the EMA label, alemtuzumab can be used as first-line therapy in the EU. However, in light of the more serious risk profile, most

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Table 1. Drugs approved in the EU and USA for the treatment of MS Active compound (brand name)

EU approval

US approval

IFN beta 1a (Avonex, Rebif, Plegridy) IFN beta 1b (Betaferon/Betaseron, Extavia) Glatiramer acetate (Copaxone) Dimethylfumarate (Tecfidera) Teriflunomide (Aubagio) Fingolimod (Gilenya)

First-line First-line

First-line First-line First-line First-line First-line First-line

Alemtuzumab (Lemtrada) Mitoxantrone (Ralenova)

First-line First-line First-line Second-line, first-line in highly active patients Second-line, first-line in highly active patients Formally first-line, used as second-line Formally second-line, used as third-line

Azathioprin

Formally second-line, used as third-line

Natalizumab (Tysabri)

Second-line Third-line Formally first-line use possible, used as third-line Not approved

Abbreviations: EU European Union, US United States, IFN interferon, MS multiple sclerosis

European MS experts also consider alemtuzumab rather a second-line option than a drug for routine first-line therapy [9]. Likewise, according to the labels, mitoxantrone could be used as first-line (FDA) or second-line (EMA) treatment. In light of its unfavorable benefit-risk ratio, in particular, the well-known cardiotoxic potential [10, 11] and the risk of treatment-related leukemia [12] on the one hand, and the availability of other drugs on the other hand, mitoxantrone has recently become less frequently prescribed [13]. Today, mitoxantrone is used rather as a third-line option or in SPMS, in which fingolimod, natalizumab, or alemtuzumab are not approved, and will therefore not be considered in this review. To make the situation even more complicated, the pivotal trials of fingolimod and natalizumab focused on the setting of a first-line therapy [14–17], and neither of both has in fact been formally tested in large-scale trials in the setting of breakthrough disease in MS patients on firstline medication. Thus, the EMA label for fingolimod and both FDA and EMA labels for natalizumab are in fact not backed up by appropriate efficacy data and rather reflect the supposed risk-benefit profile of both drugs than a proven capacity to stabilize active disease under first-line treatment. The most commonly used treatment strategy is the sequential DMD monotherapy [18]. Based on preferentially shared decision making between patient and physician [19], a first-line treatment is initiated and accompanied by surveillance of relapse rate, disability progression, MRI activity, tolerability, safety, and adherence. The ultimate therapeutic goal is a complete remission of clinical and MRI activity in the absence of any tolerability or safety issues. However, many patients experience episodes with variable degree of disease activity during treatment. The first challenge is to decide when to declare failure of first-line treatment and to reconsider the treatment scheme. The second challenge is to decide whether switch to another first-line therapy or to escalate to a more effective but possibly less safe drug. From this sequential monotherapy approach, the question arises, whether failure of a first-line DMD needs to

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be proven in any patient before moving to a second-line therapy or whether treatment could be started with a second-line DMD, based on the individual risk profile? With respect to the best option for a transition from first-line to second-line treatment in MS, three crucial questions need to be considered: why is change of treatment considered? When is the time for a change? How to transit from first-line to second-line treatment? These questions will be referred to in the next sections, followed by a short description of the characteristics of standard second-line medications.

Why is change of treatment considered? Typically, two situations may call for a change from first-line to second-line treatment: poor response to and tolerability/safety issues with the first-line drug. Virtually all first-line DMDs including the injectables interferon (IFN) beta and glatiramer acetate (GA) as well as the orals dimethylfumarate (DMF) and teriflunomide (TF) are only partially effective as demonstrated both in prospective clinical trials and Breal life^ surveys [20, 21]. A typical example of poor response to first-line treatment is a patient with ongoing relapses and/or disability progression and/or new or enlarging lesions on MRI. Before truly insufficient effectiveness of the DMD is declared, other reasons for treatment failure such as poor adherence to the drug should be explored and discussed with the patient. Whatever reason, insufficient response to first-line treatment should not be tolerated for the following reasons: (i) a window of opportunity to influence the disease course by DMDs may be in the early disease phase [7, 8••]; (ii) associations exits between early relapse rate and future disability or conversion to SPMS [7, 22, 23]; associations also exist between ongoing disease activity despite IFN beta treatment and unfavorable long-term outcomes [24•, 25]; and (iv) beneficial effects of switching treatments have been reported [26]. When a treatment switch is considered because of tolerability or safety aspects, the different labels by the EMA and FDA need to be accounted for. As an example, the FDA label allows the use of natalizumab in patients Bunable to tolerate an alternate MS therapy^ while switching to natalizumab because of intolerability of alternate drugs is not covered by the EMA label.

When is the time for a change? The ostensibly simple answer to the question when to change treatment is: whenever treatment failure becomes evident. The real life situation, however, is much more complex. Standardized definitions for treatment failure that are applicable not only in the setting of clinical trials but also in the clinical routine as well as algorithms for stepping-up in treatment escalation still need to be established. In the era of first generation DMDs, a relevant reduction of the relapse rate in comparison to the pre-treatment period was considered an acceptable achievement. In light of the availability of more powerful DMDs, ongoing though reduced clinical disease activity is hardly a sufficient treatment success. But how long should be waited before treatment failure is established? In the EU, treatment failure of first-line DMDs as a prerequisite for treatment escalation to fingolimod or natalizumab has been defined as ongoing high disease activity in spite of at least 1 year of adequately performed therapy with a

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first-line DMD whereat high disease activity is determined by (i) at least one relapse and at least nine T2-hyperintense lesions or one contrast enhancing lesion or (ii) an unchanged or even increased relapse rate compared to the year before therapy. These definitions, however, raise several questions: for example, how to value an increasing MRI lesion load in a clinically stable patient or how to judge a patient with rare but severe relapses with accrual of permanent disability? The modified Rio score is a validated and easy to handle scoring method for predicting responses to DMDs and integrates the development of new T2 lesions and the occurrence of relapses [27, 28]. A new composite measure for the ultimate goal of complete remission is the concept of Bno evidence of disease activity^ (NEDA) which integrates relapse rate and disability progression on the clinical side and new or enlarging T2- or contrast enhancing lesions on the MRI side [29•]. NEDA means freedom of relapses, freedom of disability progression, and freedom of any MRI activity. This concept is currently expanded to integrate also MS-related brain atrophy. One limitation of both the Rio score and the NEDA concept is the rather crude appraisal of clinical worsening, in particular, the neglect of neuropsychological aspects and fatigue [30]. Therefore, the multiple sclerosis decision model (MSDM), which integrates the domains relapse, disability progression, MRI findings, and neuropsychology including fatigue has recently been suggested as a modification to the NEDA concept. Brain atrophy, however, is not implemented in the MSDM due to the lack of standardized evaluation techniques. The MSDM provides an integrated interpretation algorithm in the style of traffic lights with green meaning Bno change in therapy, reevaluate in 6 months^, yellow calling for a short-term reevaluation and red meaning Bconsider optimization/change of therapy.^ Of note, sole MRI activity will not result in a red signal [31]. Although appealing, such models still have to prove themselves in clinical routine with respect to their eligibility as decision tool for treatment escalation. A recent longitudinal cohort study on NEDA status showed that although 46 % of patients had NEDA after the first year, only about 8 % maintained NEDA after 7 years [32]. According to these data, founding the decision to continue or to change treatment only on the maintenance of NEDA would require treatment escalation in almost every patient within a few years. Unfortunately, this study did not stratify according to DMD treatment and therefore does not provide information on the relative effectiveness of the respective DMDs. In conclusion, in the absence of validated decision tools implementable in daily routine the point in time for transition from first-line to second-line treatment remains an individual decision that allows for the respective clinical and radiographic aspects as well as the individual situation of the patient including comorbidities, risk factors, and available treatment options. Generally, treatment optimization should be done as early as necessary. Apart from obvious cases of treatment failures, new concepts like NEDA or algorithms like MSDM may prove to be helpful.

How to transit from first-line to second-line treatment? Generally, two options exist when the decision to change first-line treatment is made: the patient can be switched either to another first-line therapy with a higher dose or different mode of action (intra class switching) or to a second-

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Curr Treat Options Neurol (2015) 17:25 line therapy (treatment escalation). Generally, class 1 evidences for switching options derived from randomized controlled trials are lacking [33]. Even prospective head-to-head data of different DMDs, which would allow a direct comparison of the efficacy, are sparse. Intra class switching is thus a reasonable option particularly in patients who need switching due to tolerability, adherence, or safety issues. But how is the situation in patients with suboptimal response to a first-line DMD? Should intra class switching also be considered in these patients or should treatment rather be escalated to a probably more powerful but potentially more hazardous drug? According to numerous uncontrolled, mainly retrospective class II/III studies, intra class switching, i.e., from low dose to high dose IFN beta or between IFN beta and GA, can result in a reduction of clinical activity [26, 34–37]. In another study, however, switching from low dose to high dose IFN beta did not result in stabilization of active disease [38]. With respect to the new oral DMDs TF and DMF, the relative efficacy compared to the injectables is an unsolved issue. Efficacy data from the pivotal trials cannot be directly compared due to substantial differences in the cohorts studied. In a phase 3 trial, DMF was more effective in the reduction of relapses than GA. However, GA was included only as an open-label reference arm [39]. In a phase 3 rater-blinded study, TF was equally effective as high dose IFN beta with respect to prevention of relapses [40]. Thus, data are not yet sufficient to argue whether intra class switching from injectable to oral DMDs is reasonable. With respect to escalation therapy, several studies showed that natalizumab effectively stabilized breakthrough disease in first-line treatment non-responders [41–43], and in a pivotal randomized, controlled and double blind trial, fingolimod was more effective than IFN beta in reducing clinical and radiographic disease activity [14]. Direct comparisons of intra class switching and transition to second-line therapy, i.e., treatment escalation to fingolimod or natalizumab provide further evidence that escalation is more effective in the reduction of disease activity [44, 45•, 46]. With respect to alemtuzumab, two randomized controlled trials (phase 2 and 3) demonstrated a superior effect of alemtuzumab compared to high dose IFN beta on both clinical and MRI endpoints in treatment-naive MS patients [47, 48]. In a third trial (phase 3), superiority of alemtuzumab over high dose IFN beta on clinical and MRI parameters of disease activity, including brain atrophy, was confirmed also in patients with active disease under therapy mainly with IFN beta and GA (class I) [49]. In conclusion, increasing evidence suggests that transition to second-line therapy with fingolimod, natalizumab, or even alemtuzumab is probably more effective in stabilizing breakthrough disease than intra class switching which directly leads to the question whether these three drugs are equally effective. Again, head-to-head trials between any of the three drugs are lacking, and direct comparisons of the efficacy demonstrated in the respective pivotal trials are ineligible due to different patient characteristics and study designs. A recent analysis of data from an international, observational, prospectively acquired cohort study suggested that in active disease during treatment with injectable DMDs, switching to natalizumab is more effective than switching to fingolimod in terms of relapse rate and disability burden in the first year after the switch [50]. These short-term data, however, are in disagreement with another Breal world^ study showing similar effectiveness of fingolimod and natalizumab [51]. Thus, currently available data are not sufficient to rate the relative efficacy of fingolimod and natalizumab. Besides efficacy, also safety aspects, in

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particular, the infection risk including progressive multifocal leukoencephalopathy (PML) need to be considered [52]. Data on direct or indirect comparisons between alemtuzumab and fingolimod or natalizumab are currently not available. However, several phase 4 studies are currently underway that compare the impact of natalizumab versus fingolimod on clinical and radiographic outcome parameters in active MS patients (NCT02342704, NCT01981161). For the time being, the individual risk profile of the patient including JC virus status, previous immunosuppressive treatments, comorbidities such as uveitis, cardiac disease, thyroid disease, etc. as well as the patient’s attitude towards treatment options should be decisive for the individual treatment decision.

Pharmacologic treatment & & & & &

&

The ultimate treatment goal of currently available MS drugs is a complete remission of both clinical and radiographic disease activity. The currently favored treatment paradigm is a sequential monotherapy, starting with drugs characterized by moderate effectiveness but high safety, followed by more potent but possibly more risky drugs. In light of a window of opportunity for effective drug intervention, optimization of drug treatment particularly in the early disease phase is of great importance. Intra class switching is probably less effective in the control of active disease than switching to second-line drugs. From an EU perspective, fingolimod, natalizumab, and alemtuzumab are appropriate substance for treatment escalation. In the USA, natalizumab and fingolimod (if not used as first-line drug) can be used for second-line therapy. A prediction of which drug will work best in a given patient is currently not possible.

Class of drugs Fingolimod (US label) Mode of action Standard dosage Contraindications

Sphingosine 1-phosphate receptor modulator. 0.5 mg, orally once daily. Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure; history or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker; baseline QTc interval ≥500 msec; treatment with Class Ia or Class III anti-arrhythmic drugs; pregnancy, lactation.

Main drug interactions

Antineoplastic, immunosuppressive, or immunomodulating therapies; drugs that slow heart rate or atrioventricular conduction (e.g., beta blockers or diltiazem); QT prolonging drugs; vaccines.

Main side effects

Bradyarrhythmia and atrioventricular blocks, infections, macular edema, posterior reversible encephalopathy syndrome, respiratory effects, liver injury.

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Mandatory first dose monitoring of bradyarrhythmia, regular monitoring of white blood count and liver function. One case of PML in a fingolimod-treated patient without any previous immunosuppressive treatment; ophthalmologic evaluation before and 3–4 months after treatment initiation to rule out macular edema, pregnancy category C.

Natalizumab (US label) Mode of action Standard dosage Contraindications Main drug interactions Main side effects

Integrin (VLA-4)-directed antagonistic monoclonal antibody. 300 mg, infused intravenously every 4 weeks. Patients who have or have had PML, patients who have had a hypersensitivity reaction to natalizumab. Immunosuppressant drugs. PML, hypersensitivity, immunosuppression/infections, headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea, and rash.

Special points

Boxed warning for PML, pregnancy category C.

Mode of action

CD52-directed cytolytic monoclonal antibody.

Alemtuzumab Standard dosage

12 mg, infused intravenously for 2 treatment courses: first course: 12 mg/day on 5 consecutive days; second course: 12 mg/day on 3 consecutive days 12 months after first course.

Contraindications

HIV infection.

Main drug interactions

None known.

Main side effects

Special points

Autoimmunity (immune thrombocytopenia, glomerular nephropathies, thyroid disorders), infusion reactions (rash, headache, pyrexia, nausea, urticaria, pruritus, flushing, vomiting), malignancies (thyroid cancer, melanoma, lymphoproliferative disorders and lymphoma), infections. Boxed warning: autoimmunity, infusion reactions, malignancies; premedication with high dose corticosteroids (1000 mg methylprednisolone) immediately prior to infusion and for the first 3 days of each treatment course; anti-viral prophylaxis for herpetic viral infections from the first day of each treatment course for a minimum of 2 months; mandatory laboratory testing and safety monitoring for 48 months; pregnancy category C.

Emerging therapies &

&

Ocrelizumab is a humanized monoclonal anti-CD20 antibody further developed from the chimeric anti-CD20 agent rituximab. Both act by interfering with B cell antigen presentation. Based on promising phase2 data [53], ocrelizumab is currently evaluated in a phase 3 program in RRMS and primary progressive MS. The safety profile suggests the future use of ocrelizumab rather in the setting of treatment escalation than as a first-line drug. Daclizumab is another monoclonal antibody that binds to CD25 and interferes with the interleukin 2-mediated activation of

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lymphocytes. Daclizumab has been shown to be potentially more powerful than low dose IFN beta with an acceptable safety and tolerability profile [54]. Combination therapies with two or even more distinct DMDs are conceptually appealing as they combine different mode of actions to a potentially more powerful treatment strategy. However, combination studies performed so far were rather disappointing as they did not show an advantage of the drug combination over the monotherapy like in the CombiRX trial (IFN beta plus GA) [55•] or resulted in an unfavorable safety profile.

Pediatric considerations Treatment of pediatric MS in general and second-line drug treatment in children in particular is a highly complex situation: drugs approved for treatment of adult MS patient have hardly been formally tested in children with MS. Consequently, data on efficacy and safety of drugs in pediatric MS are sparse, and drugs available for adults are not formally approved for use in children, with the exception of IFN beta and GA which can be used in children from an age of 12 years. The subcutaneous formulation of IFN beta1a is approved even from an age of 2 years. Generally, off-label and empiric treatment of breakthrough disease follows the strategies in adult MS. Efficacy and safety of fingolimod is currently being tested in pediatric MS in a randomized controlled trial (NCT01892722); data are expected by 2018. With respect to natalizumab and alemtuzumab, no data on safety and efficacy in children are available. A comprehensive overview on the treatment of pediatric MS including treatment algorithms has recently been published in this journal [56].

Compliance with Ethics Guidelines Conflict of Interest Jan Dörr declares the receipt of research support from Novartis and Bayer Healthcare, speaker honoraria from Novartis, Teva and Bayer Healthcare, honoraria for advisory from Teva, Genzyme, and Bayer Healthcare, and travel support from Bayer Healthcare and Novartis. Friedemann Paul declares the receipt of speaker honoraria, travel grants, and research grants from Teva, Sanofi Aventis, Bayer Healthcare, Merck Serono, Biogen Idec; MedImmune and Novartis; travel reimbursement and research support by the Guthy Jackson Charitable Foundation; support by the German Research Foundation (DFG Exc 257), the German Ministry of Education and Research (Competence Network Multiple Sclerosis), the Artur Arnstein Foundation and the Werth Foundation of the City of Cologne. Member of the steering committee of the OCTIMS study sponsored by Novartis. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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