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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)

Teaching Course 1 Disease modifying treatment - …...Teaching Course 1 Disease modifying treatment Chairs: R.J. Fox (Cleveland, US) L. Kappos (Basel, CH) 1 New MS treatments and updates

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Page 1: Teaching Course 1 Disease modifying treatment - …...Teaching Course 1 Disease modifying treatment Chairs: R.J. Fox (Cleveland, US) L. Kappos (Basel, CH) 1 New MS treatments and updates

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)

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RJ Fox, New MS Treatments and Updates on Established Treatments Page 1 of 6

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.

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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 anti-

inflammatory 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

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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 post-

marketing 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 2014.

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.

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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, anti-

glomerular 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

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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:

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1. Fox RJ, Arnold DL. Seeing injectable MS therapies differently: they are more

similar than different. Neurology 2009;72:1972-3.

2. Phillips JT, Fox RJ. BG-12 in multiple sclerosis. Semin Neurol 2013;33:56-65.

3. 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;19:1092-9.

5. 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;87:957-8.

6. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with

relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled

phase 3 trial. Lancet 2012;380:1829-39.

7. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as

first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised

controlled phase 3 trial. Lancet 2012;380:1819-28.

8. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in

relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-

controlled trial. Lancet 2013;381:2167-75.

9. Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus Interferon Beta-1a

in Relapsing Multiple Sclerosis. N Engl J Med 2015;373:1418-28.

10. Oh J, Saidha S, Cortese I, et al. Daclizumab-induced adverse events in multiple

organ systems in multiple sclerosis. Neurology 2014;82:984-8.

11. Cortese I, Ohayon J, Fenton K, et al. Cutaneous adverse events in multiple

sclerosis patients treated with daclizumab. Neurology 2016;86:847-55.

12. 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; 2015. p. PS190.

13. 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; 2015. p. PS 228.

14. 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; 2016.

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Assessing and mitigating risks –

The right treatment for the right patient

ECTRIMS Teaching Course #1 “Disease Modifying Treatment”

Wednesday October 14th, 2016

Sandra VUKUSIC, MD PhD1-4

1 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 – 69677 BRON cedex – France e-mail: [email protected] Tel: +33 4 72 35 75 22 – Fax: +33 4 72 35 75 25 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.

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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 (RMPs) 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

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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-RMP 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

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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 RMP was requested from the manufacturer as approval was given before 2005. 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?

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Table 1

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Table 2

Drug Identified risks EMA Risk mitigation recommendations

Interferons bêta

Hepatic dysfunction Liver enzymes if clinical signs

Hematological abnormalities Complete Blood Count (no details)

Depression Patient information

Clinical vigilance

Thrombotic microangiopathy Clinical vigilance

Pregnancy 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

RMP No

Drug Identified risks EMA Risk mitigation recommendations

Glatiramer acetate

No No

Pregnancy Limited informartion - no signal

Insufficient animal data

Contraindicated during pregnancy

RMP No

Drug Identified risks EMA Risk mitigation recommendations

Fingolimod

Bradyarrythmia ECG - Blood pressure prior to initiation

6-hour monitoring at first dose and re-introduction

Infections Complete Blood Cell Count

prior to initiation, at Month 3 and yearly or if signs of infection thereafter

stop if lymphocytes <0,2.109/l

VZV vaccine prior to initiation

if seronegative or no confirmed history of chickenpox

PML Baseline MRI

MRI follow-up according to local recommendations

Macular oedema Ophtalmologic evaluation at month 3-4 or anytime if visual symptoms

Hepatic dysfunction Liver function (no details)

prior to initiation, at month 1, 3, 6, 9 and 12 and periodically thereafter

Elevated blood pressure Clinical vigilance

Basal cell carcinoma Dermatological evaluation

prior to initiation and yearly thereafter

Pregnancy Limited informartion

Reproductive toxicity in animals

Contraindicated during pregnancy

Active contraception - Stop FTY 2 months prior to conception

RMP Restricted indication "Highly active RRMS"

Physician information pack

- SPC

- Checklist prior to prescription

- Information on Pregnancy Exposure Registry

- Patient reminder card

Prospective cohort study assessing the incidence of cardiovascular events

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Drug Identified risks EMA Risk mitigation recommendations

DimethylfumarateHepatic dysfunction Creatinine, urea, urinanalysis + ALT, AST

Renal dysfunction prior to initiation, at month 3 and 6, every 6 to 12 months thereafter

Lymphopenia Complete Blood cell Count

prior to initiation, every 3 months therafter

stop if lymphocytes <0,5.109/l persisting for more than 6 monthsPML Baseline MRI

MRI follow-up according to local recommendations

Pregnancy Limited information

Reproductive toxicity in animals

Not recommended during pregnancy

Active contraception - Benefit vs risk to be discussed individually

RMP No

Drug Identified risks EMA Risk mitigation recommendations

Teriflunomide

Hepatic dysfunction ALT, AST

prior to initiation, every 2 weeks in the first 6 months, every 8 weeks after

Hematological abnormalities Complete Blood cell Count

prior to initiation, if clinical symptoms therafter

Blood pressure Before initiation and periodically thereafter

Pregnancy Limited information in humans

Reproductive toxicity in animals

Contraindicated during pregnancy

Active contraception - Accelerated elimination procedure if desire of

pregnancy

RMP Educational programme

- SPC

- Educational material for professionals

- Educational card for patients

Pregnancy registry

Drug Identified risks EMA Risk mitigation recommendations

Natalizumab

PML 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

Infections Clinical vigilance

Herpes, Varicella zoster

Pregnancy Limited information - no signal (355 pregnancies)

Reproductive toxicity in animals

Benefit vs risk to be discussed individually

RMP Restricted indication "Highly active RRMS"

Physician information pack

- SPC

- Physician information

- Patient alert card

- Treatment initiation and continuation forms

- Treatment discontinuation form

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Assessing and mitigating risks ECTRIMS Teaching Course 06/09/2016

Page 8/9

Drug Identified risks EMA Risk mitigation recommendations

Alemtuzumab

Autoimmunity

- Immune thrombocytopenic

purpuraComplete Blood cell Count

prior to initiation

monthly therafter until 48 months after the last infusion

- Nephropathies (including anti-

GBM disease)Serum creatinine, urinanalysis

prior to initiation

monthly therafter until 48 months after the last infusion

- Thyroid disorders TSH

prior to initiation

monthly therafter until 48 months after the last infusion

- Other autoimmune cytopenia Complete Blood cell Count

as above

Infusion-assicated reactions Premedication

Infections

- VZV Prophylaxis with aciclovir during 1 month after each course

- HPV HPV screening annually in female patients

Pregnancy Limited information

Reproductive toxicity in animals

Active contraception for 4 months after each course

Benefit vs risk to be discussed individually

RMP Extended indication (restricted by some national agencies)

Physician educational pack

- SPC

- Healthcare professional guide

- Prescriber check list

- Patient guide

- Patient alert card

Drug Identified risks EMA Risk mitigation recommendations

Daclizumab

Hepatic dysfunction ALT, AST, bilirubine prior to initiation

ALT, AST monthly thereafter and up to 4 months after last dose

Skin reactions Clinical vigilance

Depression Clinical vigilance

Infections Screening for active TB if past history or endemic area

Lymphopenia Complete Blood cell count

every 3 months

Pregnancy Limited information

No reproductive toxicity in animals

Benefit vs risk to be discussed individually

RMP Hepatic risk management guide

Patient card

Page 16: Teaching Course 1 Disease modifying treatment - …...Teaching Course 1 Disease modifying treatment Chairs: R.J. Fox (Cleveland, US) L. Kappos (Basel, CH) 1 New MS treatments and updates

Assessing and mitigating risks ECTRIMS Teaching Course 06/09/2016

Page 9/9

Drug Identified risks EMA Risk mitigation recommendations

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/m2

Myelosuppression Complete Blood cell Count

Acute myeloid Leukemia prior to initiation, at time and 10 days following each administration

Myelodysplastic syndrome if clinical signs

Pregnancy Genotoxic

Contraindicated during pregnancy

Active contraception for 4 months in women and 6 months in men

RMPRestricted 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...."