1 New MS treatments and updates on established treatments

Transcription

1 Teaching Course 1 Disease modifying treatment Chairs: R.J. Fox (Cleveland, US) L. Kappos (Basel, CH) 1 New MS treatments and updates on established treatments R.J. Fox (Cleveland, US) 2 Assessing and mitigating risks: the right treatment for the right patient S. Vukusic (Lyon, FR) 3 Defining what is working: choosing a therapeutic strategy L. Kappos (Basel, CH)

2 New MS Treatments and Updates on Established Treatments Robert J. Fox, MD Staff Neurologist, Mellen Center for Multiple Sclerosis Vice-Chair for Research, Neurological Institute Cleveland Clinic, Cleveland, OH, USA Disclosures: Dr. Fox receives personal consulting fees from Actelion, Biogen, Genentech, Novartis, Mallinckrodt, MedDay, Teva, and Xenoport; serves on clinical trial steering committees for Biogen Idec and Novartis; serves on the Scientific Advisory Board for MedDay; and serves on the editorial boards of Neurology and Multiple Sclerosis Journal. RJ Fox, New MS Treatments and Updates on Established Treatments Page 1 of 6

3 Introduction Prior to a few years ago, initial long-term treatment of MS usually involved an injectable therapy (interferon-β1 or glatiramer acetate). In a mostly unpredictable fashion, some patients would display complete control of disease, whereas others would continue to have disease activity as measured by a combination of clinical relapses and new lesions on MRI. Searches for accurate predictive biomarkers have been largely unsuccessful, and so clinicians have had very limited tools to personalize treatment choices to maximize efficacy. The development of natalizumab heralded the era of highly effective antiinflammatory therapies. With such high efficacy, predictors of treatment response are generally unnecessary. The high efficacy of natalizumab, however, also came with a price the risk of progressive multi-focal leukoencephalopathy (PML). A potentially fatal brain infection, PML was initially estimated to occur at a rate of approximately 1:1000 in patients treated with natalizumab over 18 months. Mitoxantrone is another potent MS therapy with significant risks of cardiac injury and lymphoproliferative disorders including leukemia, and so this therapy is now infrequently used. In the last several years, three oral therapies have become clinically available fingolimod, teriflunomide, and dimethyl fumarate. All three therapies have relatively good efficacy and tolerability, and reasonable safety profiles. With more than ten approved therapies currently available, and more pending regulatory review, the choice of MS therapy has become increasingly challenging. Currently, there are no established guidelines for choosing an initial long-term MS disease modifying therapy for relapsing MS. Like with other medical therapies, the choice of treatment should be guided by the balance of efficacy and risk, along with patient tolerability and convenience. Several new therapies have become available, which expand the available treatment options. In addition, the high cost of MS disease modifying therapies necessitates incorporation of local payer policies into choice of therapy. Efficacy With the exception of the recent oral therapies, there have been few head-to-head trials of different MS disease modifying (DMT) therapies. For the injectable therapies (interferon-β; glatiramer acetate), many clinicians feel that their efficacy across patient populations is more similar than different. 1 However, the population-based efficacy studies should not be blindly applied to individual patients, as one patient may respond to one injectable therapy after insufficiently responding to another therapy. Given their similar population-based efficacies, choice of injectable therapy should probably be driven predominantly by expected side-effect profile, patient choice, and clinician familiarity with the particular injectable therapy. The development of oral therapies appears to bring with them a general increase in efficacy and tolerability. Fingolimod and dimethyl fumarate (DMF) both reduce annualized relapse rates by about 50% and MRI measures of active inflammation by 71-90%. 2 In head-to-head studies against injectable therapies, both were found to be superior in reducing relapses and/or MRI disease activity, although the comparison in the DMF study was post-hoc. Teriflunomide also reduces annualized relapse rate and MRI measures of disease activity, with what appears to be similar efficacy to injectable RJ Fox, New MS Treatments and Updates on Established Treatments Page 2 of 6

4 therapies. Direct, head-to-head studies are needed to clarify how the efficacy compares between these three oral disease modifying therapies. Similar to studies of injectable therapies, clinical practice-based studies comparing fingolimod and DMF suggest that their efficacy is more similar than different. 3 There are different approaches to MS therapy choice, including gradual escalation (i.e. start with the safest therapy, and then gradually escalate intensity, if needed) and maximal efficacy (i.e. start with the strongest therapy, and then consider decreasing intensity of therapy later). The optimal approach to most effectively manage MS over several decades is not yet known. Safety / Risk Mitigation In parallel to developing more effective MS disease modifying therapies has been progress mitigating the risks of treatment complications. Risk mitigation strategies identify the risk of therapies based on individual patient characteristics. Some risk characteristics are identified in phase III trials, but others are recognized only after postmarketing phase IV studies and general clinical use. Further complicating treatment choices, some risk factors are not static but can change over time, which secondarily change the risk-benefit profile of a treatment for an individual patient. Through risk stratification, clinicians can now personalize treatment. 4 Progressive multifocal leukencephalopathy (PML) is a rare serious risk of several MS therapies. The risk of PML was originally estimated to be about 1:1000 over 18 months in all patients using natalizumab. Risk stratification has allowed that estimate to be tailored to individual patient characteristics, and so now PML varies between 1:X and 1:XX, depending upon several factors. Age may be a risk factor for PML related to DMF and fingolimod, since cases of PML with those therapies have developed in patients older than the population in which those therapies are generally used. 5 Risk assessment and mitigation is discussed in detail in the next talk. New Therapies Two new therapies have received recent regulatory approval, and a third is pending regulatory approval. These therapies are increasing the treatment options available for patients with relapsing forms of MS. Effective therapies for progressive MS remain elusive. Alemtuzumab. CD52 is an anonymous surface protein expressed by T-cells, B-cells, monocytes, and eosinophils. Alemtuzumab is a monoclonal antibody that targets CD52, and administration leads to rapid, profound, and prolonged lymphocyte depletion, with gradual reconstitution of cells with altered cell profile and function. Previously approved for CLL, it was approved for relapsing forms of MS in Alemtuzumab is given by slow intravenous infusion daily for five days; then after one year, treatment is repeated daily for 3 days. Premedication with histamine blockers (both H1 and H2) and corticosteroids reduces infusion reactions. Antiviral prophylaxis reduces the incidence of herpetic infections. Monitoring for 2 hours post infusion helps identify and manage infusion reactions. RJ Fox, New MS Treatments and Updates on Established Treatments Page 3 of 6

5 Phase 3 trials of alemtuzumab have found that it reduces ARR by 50-54% relative to interferon, and reduces progression of disability by 30-42%. 6,7 Side-effects include an increased rate of nasopharyngitis, UTI, and herpes viral infections. There is an increased rate of humoral-mediated autoimmune reactions (i.e. thyroiditis, thrombocytopenia, antiglomerular membrane disorder, and agranulocytosis). There may also be an increased rate of some rare cancers. Risk mitigation strategies include antihistamines and corticosteroids for infusion reactions, antiviral prophylaxis for herpetic viral infections, and blood and urine monitoring for signs of humoral autoimmune reactions. Because of its risks, alemtuzumab not generally considered as a first-line treatment option for MS. Daclizumab. The Interleukin(IL)-2 receptor is a heterotrimetric complex with 3 transmembrane subunits. Several of the subunits are shared with other IL receptors. The IL-2 receptor appears to function in the proliferation and differentiation of immune cells, including T- cells, B-cells, and NK cells; elimination of self-reactive T-cells; and maintenance of T- regulatory cells. Daclizumab is a humanized (90% human; 10% mouse) monoclonal antibody which binds to the IL-2R alpha chain, blocking IL-2 binding and signaling. Without IL-2 receptor signaling, T-cell and B-cell activation by IL-2 is hinhibited, and IL-2 receptor expression is down-regulated on activated T-cells. Daclizumab is an old therapy, having been approved as Zenepax in 1997 (FDA) and 1999 (EMEA) for prevention of renal allograft rejection. It is the third monoclonal antibody to receive regulatory approval, and is the first humanized and first against a cytokine receptor. For MS, daclizumab is given as a monthly subcutaneous injection. Phase 3 trials of daclizumab found that it reduced ARR by 45% compared with IFNβ. 8,9 There was also a 54% reduction in new or enlarging T2 lesions, although no difference in disability progression compared with IFNβ. 9 Side-effects include a slightly increased rate of infections, including nasopharyngitis; elevated liver enzymes; and cutaneous reactions. Eczema is very common, although most patients require no specific treatment. More severe rashes can be appear like psoriasis, although biopsies show features of eczematous dermatitis. 10,11 Summary: Daclizumab has good efficacy and the convenience of monthly SQ administration. Disadvantages include safety concerns, particularly liver injury and skin reactions; and monthly liver monitoring. The principal indication appears to be relapsing MS patients who have failed several other MS therapies. Ocrelizumab. CD20 is a 297 amino acid membrane-associated phosphoprotein expressed on pre-b-cells and B-cells, but not on stem cells or plasma cells. CD20 is not shed and does not cause substantial international when bound. Several anti-cd20 antibodies have developed by a variety of manufacturers. To varying degrees, they all selectively deplete B cells bearing the CD20 surface marker via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis. Rituximab is an anti-cd20 monoclonal antibody that causes rapid and profound depletion of B-cells. A phase II trial in RRMS found that rituximab treated was RJ Fox, New MS Treatments and Updates on Established Treatments Page 4 of 6

6 associated with a 91% reduction in enhancing lesions, and a 56% reduction in ARR. The manufacturer then decided to further develop a more humanized anticd20 antibody ocrelizumab in MS. Phase III trials of ocrelizumab in relapsing MS found that it was associated with a 46% reduction in ARR, and 40% reduction in sustained progression of disability. 12 A phase III trial of ocrelizumab in young patients with early-stage PPMS found that it slowed the progression of disability by 24%, although the majority of the benefit was observed in the first 12 weeks of the trial. 13 Additionally, patients with gadolinium enhancing lesions were more likely to demonstrate slowed progression of disability compared to those without gadolinium enhancing lesions. 14 Side-effects of rituximab and ocrelizumab include infusion reactions; nasopharyngitis, sinusitis, bladder infections. Both relapsing and progressive MS studies observed an increased incidence of cancers, although overall rate was low and cancer is not a signal reported from other trials of ocrelizumab in autoimmune disorders (i.e. systemic lupus and rheumatoid arthritis). Placement of New Therapies The appropriate placement of these new therapies in the MS treatment algorithm is not yet established. Due to their side-effect profile, alemtuzumab and daclizumab are typically relegated to patients who have sub-optimally responded or not tolerated two or more MS therapies. The optimal location of ocrelizumab in the treatment algorithm is not yet clear, although some argue that its side-effect profile makes it a reasonable first-line therapy. Patient Preference Patients are an important partner in the choice of MS therapies. Several aspects of therapy can influence patient preference, including expected side-effects, expected benefit of the therapy, and expected course of the disease if left untreated. Tolerance to risk can impact patient preference for therapy, and risk tolerance varies greatly across the MS patient population. Payor Influence MS disease modifying therapies are very expensive, which make local health system policies regarding MS therapy coverage an important factor in the choice of MS therapy. Different systems have taken different approaches to managing these costs, and payer policies will impact a clinician s ability to utilize different therapies. Conclusion There are many MS therapies available for treatment of RRMS. Contemporary developments with current therapies focus on management of risk, including risk stratification and risk minimization. New therapies available or expected to be available in the future include alemtuzumab, daclizumab, and ocrelizumab. Each of these therapies has its own benefit and risk profile. The optimal sequencing of MS therapies has yet to be established. References: RJ Fox, New MS Treatments and Updates on Established Treatments Page 5 of 6

7 1. Fox RJ, Arnold DL. Seeing injectable MS therapies differently: they are more similar than different. Neurology 2009;72: Phillips JT, Fox RJ. BG-12 in multiple sclerosis. Semin Neurol 2013;33: Hersh CM, Love TE, Cohn S, et al. Comparative efficacy and discontinuation of dimethyl fumarate and fingolimod in clinical practice at 12-month follow-up. Multiple Sclerosis and Related Disorders 2016;In Press Accepted manuscript. 4. Ontaneda D, Fox RJ. Multiple sclerosis treatment: risk mitigation. Continuum (Minneap Minn) 2013;19: Ontaneda D, Fox RJ, Brosseau MSG, Stobbe G, Wundes A. Natalizumab-related PML 2 weeks after negative anti-jcv antibody assay / Author response. Neurology 2016;87: 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: 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: Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebocontrolled trial. Lancet 2013;381: Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med 2015;373: Oh J, Saidha S, Cortese I, et al. Daclizumab-induced adverse events in multiple organ systems in multiple sclerosis. Neurology 2014;82: Cortese I, Ohayon J, Fenton K, et al. Cutaneous adverse events in multiple sclerosis patients treated with daclizumab. Neurology 2016;86: Hauser SL, Comi GC, Hartung H, et al. Efficacy and safety of Ocrelizumab in relapsing multiple sclerosis - results of the interferon-beta-1a-controlled, double-blind, Phase III OPERA I and II studies. In: European Committee for treatment and Research in Multiple Sclerosis (ECTRIMS); 2015; Barcelona, Spain; p. PS Montalban X, Hemmer B, Rammohan K, et al. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis - results of the placebo-controlled, double-blind, Phase III ORATORIO study. In: European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015; Barcelona, Spain; p. PS Wolinski JS. Efficacy of ocrelizumab in patients with Primary Progressive Multiple Sclerosis with and without T1 gadolinium-enhancing lesions at baseline in a Phase III, placebo-controlled trial. In: The Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS); 2016; New Orleans, LA; RJ Fox, New MS Treatments and Updates on Established Treatments Page 6 of 6

8 Assessing and mitigating risks The right treatment for the right patient #1 Disease Modifying Treatment Wednesday October 14th, 2016 Sandra VUKUSIC, MD PhD Service de Neurologie A and Fondation Eugène Devic EDMUS contre la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, F-6977, France; 2 Centre des Neurosciences de Lyon, INSERM 1028 et CNRS UMR5292, Equipe Neuro-oncologie et Neuro-inflammation, Lyon, F-69003, France; 3 Université de Lyon, Lyon, F-69003, France; 4 Université Lyon 1, Lyon, F-69003, France; Correspondance to: Prof. Sandra VUKUSIC Service de Neurologie A Hôpital Neurologique Pierre Wertheimer 59 boulevard Pinel BRON cedex France sandra.vukusic@chu-lyon.fr Tel: Fax: Financial Disclosure Statement Dr. Vukusic has received consulting and lecturing fees, travel grants and research support from Bayer- Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, Sanofi Aventis and Teva Pharma. Page 1/9

9 If there is still no cure for MS, disease-modifying treatments (DMTs) have become available since the early 1990s. Interferon beta and glatiramer acetate first demonstrated efficacy in preventing the recurrence of relapses, and, to some extent, in delaying disability accumulation. If not so convenient in daily life, because of sub-cutaneous or intramuscular administration and injection-related adverse effects, data on their long term safety is up to now very reassuring. In particular, there is no more concern on their risk of increasing cancer or opportunistic infections. Since 2005, MS treatment has been entering a new era, with arrival of drugs that are more effective, but at the cost of rare but severe risks, as opportunistic infections, cancers or other auto-immune diseases. Natalizumab, first monoclonal antibody marketed for MS, is responsible for cases of Progressive Multifocal Leukoencephalopathy (PML) in around 3 persons per 1000 treated for more than two years. Other drugs are or will become available, with concerns on their safety that cannot be ruled out by clinical trials only. This is the case for oral drugs, like fingolimod, dimethylfumarate and teriflunomide and for other monoclonal antibodies (alemtuzumab, rituximab, ocrelizumab, daclizumab ) or IV immunosuppressants (mitoxantrone). Year 2005 was also a crucial time-point in drug surveillance. In response to several affairs leading to the withdrawal of drugs due to unexpected side effects discovered after dissemination on the market, drug regulation agencies modified their mainly passive pharmacovigilance strategy and imposed the concept of a mandatory pro-active approach to post-marketing surveillance, through the Risk Management Plans (s) in Europe and Risk Evaluation and Mitigation Strategies (REMs) in the United States. The widening of the DMT arsenal for MS, the introduction of the notion of life-threatening risks balanced with greater efficacy, as well as the new legal framework, have modified neurological practice: 1. towards patients, who deserve to be informed about the benefits and the risks of the different drugs that may be proposed to them; 2. towards neurologist colleagues, who may need a shared decision process, with expert MS centres or concertation meetings; and 3. towards regulation agencies and industrials, with a more active implication in post-marketing surveillance of new drugs. From a drug s life At the time of marketing authorization, relatively limited information is known about the safety of a drug. This is due to many facts, directly related to the design of clinical trials: 1- the limited number of subjects (hundreds to 1-2 thousands), compared to the much larger number of patients in which it Page 2/9

10 might be used in daily practice; 2- the restricted population evaluated in trials in term of age, gender and ethnicity, but also in terms of co-morbidities and associated treatments; 3- the restricted conditions of use, strictly defined by the study protocol; 4- the relatively short duration of follow-up. Pre-marketing studies are therefore insufficient to detect rare adverse events (<1/1000), especially in populations that are not or insufficiently studied in clinical trials. The number of patients treated in real life settings, not selected by restrictive per-protocol inclusion and exclusion criteria and exposed for years to the drugs, might then reveal soon or late unexpected and sometimes severe adverse events. Pharmacovigilance aims at detecting such events, but it still might be difficult to define whether they are above the threshold of events happening within the general population, not in relation with the drug. A Risk Management Plan is defined as a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks relating to medicinal products, including the assessment of the effectiveness of those interventions (EMEA/CHMP/96268/2005). This strategy introduces new activities - as detection, evaluation, minimization, communication - to set a proactive and systematic approach, always challenged with benefits, in order to optimize the benefit/risk balance of the drug, all along its life. The aim of this risk management system is to ensure that the benefits of a particular medicine exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole. The EU- contains two parts, describing risk detection (Safety Specifications and pharmacovigilance plan), and risk minimization activities (including an evaluation of the need for risk minimization activities and a risk minimization plan). Three levels of risks are defined: 1-important identified risks (safety issues that could impact the benefit/risk balance, with a causative association with the drug, established by temporal relation or biological plausibility for example), 2-important potential risks (safety issues that could be related to the drug but need to be confirmed) and 3-important missing information (safety concerns for which no or insufficient information is available at the time of authorization, for example at-risk populations). When no concerns have arisen in pre-marketing clinical trials, spontaneous reporting through the pharmacovigilance system may be sufficient. However, additional activities may be needed. There is a wide range of designs for post-authorization studies. Some of them have already been used in MS: prescription event monitoring in the TOUCH program in the United States or exposure registries in Europe. Exposure registries may also be dedicated to the study of a particular population, the most Page 3/9

11 common situation being exposure during pregnancy. Table 1 provides a comparison of characteristics of different study designs aiming at evaluating the safety of a drug. In some countries, where MS specific databases exist, neurologists actively contribute to the post-marketing surveillance through the national MS registries, which offer the possibility to study not only the effectiveness and risks of a given drug, but also the interplay with the use of other drugs. This is of particular interest as this data is usually missing in clinical trials. For interferons and glatiramer acetate in the late 90s, surveillance was limited to pharmacovigilance reporting. Mitoxantrone received FDA approval in 2000 and sometimes later in European countries for aggressive MS. Rapidly, regulatory agencies issued an alert about the dose-cumulative potential of cardiotoxicity and, in some countries, about the risk of leukaemia. Cardiac and haematologic surveillance were recommended but not mandatory and were not collected in a post-marketing study. No was requested from the manufacturer as approval was given before This point has to be underlined, as some may think that new drugs are more dangerous than oldest ones, only because of the particular surveillance they are committed to. We present here in Table 2 an overview of MS drugs risk mitigation recommendations by the European Medicine Agency. to a patient s centered decision process As neurologists, we have to transpose those data collected through the drug s life into information that will help us evaluate the benefit/risk balance in a patient s life. That means taking into account many other parameters: - related to the patient: extreme ages (no or poor data in younger and older ones), co-medications, comorbidities, desire of pregnancy - related to MS course: risk of starting a treatment, risk of not starting a treatment, risk of stopping a treatment (especially for those were a rebound can be feared) - related to the successive use of drugs in an individual patient, that can have similar adverse events, as infections and cancer. The most striking situation today is the risk of PML when stopping natalizumab because of the presence of risk factors. What is the best timing to switch to avoid a potential rebound? To avoid the risk of starting a new drug when PML is already developing (13% of PML cases are diagnosed after natalizumab cessation)? To avoid a cumulative risk when using other drugs that have a prolonged impact on the immune defence? Page 4/9

12 Table 1 Page 5/9

13 Table 2 Interferons bêta Hepatic dysfunction Liver enzymes if clinical signs Hematological abnormalities Depression Thrombotic microangiopathy Complete Blood Count (no details) Patient information Clinical vigilance Clinical vigilance Limited information - might be an increased risk of aborption Initiation is contraindicated during pregnancy Benefits on MS course should be weighted against possible increased risk of spontaneous aborption No Glatiramer acetate No No Limited informartion - no signal Insufficient animal data Contraindicated during pregnancy No Fingolimod Bradyarrythmia Infections PML Macular oedema Hepatic dysfunction Elevated blood pressure Basal cell carcinoma ECG - Blood pressure prior to initiation 6-hour monitoring at first dose and re-introduction Complete Blood Cell Count prior to initiation, at Month 3 and yearly or if signs of infection thereafter stop if lymphocytes <0, /l VZV vaccine prior to initiation if seronegative or no confirmed history of chickenpox Baseline MRI MRI follow-up according to local recommendations Ophtalmologic evaluation at month 3-4 or anytime if visual symptoms Liver function (no details) prior to initiation, at month 1, 3, 6, 9 and 12 and periodically thereafter Clinical vigilance Dermatological evaluation prior to initiation and yearly thereafter Limited informartion Reproductive toxicity in animals Contraindicated during pregnancy Active contraception - Stop FTY 2 months prior to conception Restricted indication "Highly active RRMS" Physician information pack - SPC - Checklist prior to prescription - Information on Exposure Registry - Patient reminder card Prospective cohort study assessing the incidence of cardiovascular events Page 6/9

14 Dimethylfumarate Hepatic dysfunction Creatinine, urea, urinanalysis + ALT, AST Renal dysfunction prior to initiation, at month 3 and 6, every 6 to 12 months thereafter Lymphopenia PML Complete Blood cell Count prior to initiation, every 3 months therafter stop if lymphocytes <0, /l persisting for more than 6 months Baseline MRI MRI follow-up according to local recommendations Limited information Reproductive toxicity in animals Not recommended during pregnancy Active contraception - Benefit vs risk to be discussed individually No Teriflunomide Hepatic dysfunction Hematological abnormalities Blood pressure ALT, AST prior to initiation, every 2 weeks in the first 6 months, every 8 weeks after Complete Blood cell Count prior to initiation, if clinical symptoms therafter Before initiation and periodically thereafter Limited information in humans Reproductive toxicity in animals Contraindicated during pregnancy Active contraception - Accelerated elimination procedure if desire of pregnancy Educational programme - SPC - Educational material for professionals - Educational card for patients registry Natalizumab PML Infections Herpes, Varicella zoster Anti-JCV antibody prior to initiation - if negative: retest every 6 months - if positive and low index an no prior IS: retest every 6 months after 2 years Baseline MRI and every year for at-risk patients - JCV +/>2 years/prior IS - High JCV index/>2 years additional MRI follow-up every 3 to 6 months with abbreviated protocol Clinical vigilance Limited information - no signal (355 pregnancies) Reproductive toxicity in animals Benefit vs risk to be discussed individually Restricted indication "Highly active RRMS" Physician information pack - SPC - Physician information - Patient alert card - Treatment initiation and continuation forms - Treatment discontinuation form Page 7/9

15 Alemtuzumab Autoimmunity - Immune thrombocytopenic purpura - Nephropathies (including anti- GBM disease) - Thyroid disorders TSH Complete Blood cell Count prior to initiation monthly therafter until 48 months after the last infusion Serum creatinine, urinanalysis - Other autoimmune cytopenia Complete Blood cell Count prior to initiation monthly therafter until 48 months after the last infusion prior to initiation monthly therafter until 48 months after the last infusion as above Infusion-assicated reactions Premedication Infections - VZV Prophylaxis with aciclovir during 1 month after each course - HPV HPV screening annually in female patients Limited information Reproductive toxicity in animals Active contraception for 4 months after each course Benefit vs risk to be discussed individually Extended indication (restricted by some national agencies) Physician educational pack - SPC - Healthcare professional guide - Prescriber check list - Patient guide - Patient alert card Daclizumab Hepatic dysfunction ALT, AST, bilirubine prior to initiation ALT, AST monthly thereafter and up to 4 months after last dose Skin reactions Depression Infections Lymphopenia Clinical vigilance Clinical vigilance Screening for active TB if past history or endemic area Complete Blood cell count every 3 months Limited information No reproductive toxicity in animals Benefit vs risk to be discussed individually Hepatic risk management guide Patient card Page 8/9

16 Mitoxantrone Myocardial toxicity Left Ejection Ventricular Fraction (LEVF) prior to initiation, to each dose and yearly up to 5 years after the last infusion Dose limitation <72 mg/m 2 Myelosuppression Complete Blood cell Count Acute myeloid Leukemia prior to initiation, at time and 10 days following each administration Myelodysplastic syndrome if clinical signs Genotoxic Contraindicated during pregnancy Active contraception for 4 months in women and 6 months in men Restricted indication "Highly active relapsing MS with no alternative treatment" Recently re-evaluated (June 2016) to conceal the initial national procedures "The company will provide educational materials about the use of Novantrone in patients with MS. The educational materials will include a guide and checklist for healthcare professionals informing on the risks of cardiotoxicity and leukemai and how patients should be monitored. Patients will receive a guide to the risks and an alert card..." Page 9/9