This meeting has been initiated, organised and funded by Merck

Professor Gavin GiovannoniBarts and The London School of Medicine & Dentistry

Expert opinions on switching:Treatment algorithms

Disclosures

Over the last 15 years, I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from:

Abbvie, Almirall, Atara Bio, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals

Learning objectives

ObjectiveTo provide sufficient information on specific DMT sequences and help attendees develop a strategy for managing the associatedrisks with particular sequences

Questions to considerDrawing upon the available evidence and guidance on MS DMT sequencing, explore what the existing data suggest are the logical sequences of MS DMTs

Establish which specific sequences are useful/successful

Outline the differences between continuous immunosuppression and discontinuous immunosuppression. Establish how this informs treatment sequencing

Explore other factors that may influence treatment sequencing. How might these affect the treatment algorithm?

OutcomesExplore sequences for the following populations:

● Sequencing due to lack of efficacy (of another DMT)

● Sequencing due to risk (AE)

● Sequencing due to lifestyle decision (e.g. family planning)

● Stopping DMT’s due to SPMS

AE, adverse event; DMT, disease-modifying therapy; SPMS, secondary progressive multiple sclerosis.

Mitoxantrone*2000 (RMS/SPMS)

Evolving therapeutic landscape

*Licensed in the US, Germany, Austria and France#Unlicensed

BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation; IFN, interferon; IM, intramuscular; RMS, relapsing multiple sclerosis;RRMS, relapsing-remitting multiple sclerosis; R-SPMS, relapsing-secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; SC, subcutaneous

1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018

SC IFN beta-1b1995 (RMS)

IM IFN beta-1a1997 (RMS)

BMT/HSCT#

1997 (RMS)

SC IFN beta-1a1998 (RMS)

Glatiramer acetate20 mg/mL2003 (RMS)

Natalizumab2006 (RRMS)

Fingolimod2011 (RRMS)

Alemtuzumab2013 (RRMS)

Teriflunomide2013 (RRMS)

Dimethyl fumarate2014 (RRMS)

Peginterferon beta-1a2014 (RRMS)

Glatiramer acetate40 mg/mL2015 (RMS)

Daclizumab2016 (RMS)

Oral cladribine2017 (RMS)

Ocrelizumab2018 (RMS/PPMS)

Draft treatment algorithm for multiple sclerosis disease-modifying therapies

ABN NHS England, DraftPlease note the ordering of drugs within each category is alphabetical and not intended to indicate a heirarchy of treatment

Switch due to disease activity Switch due to intolerance

Rescue therapyfor continuedinflammatory activitywhilst on second-linetherapy

Second-line therapyfor disease activitywhilst on first-linetherapy

First-line therapy

Presentation

Alternative first-linetherapy due tointolerance

No treatment

Beta-interferon

No treatment

Beta-interferon

Alemtuzumab, rarely

See note 9Beta-interferon

Glatiramer acetateTeriflunomide

Dimethyl fumarate

Alemtuzumab

No changeAlemtuzumab

CladribineDaclizumab

NatalizumabAutologous haematopoietic stem cell transplant

Beta-interferon

Dimethyl fumarate

Alemtuzumab, but see note 7

Glatiramer acetate

Teriflunomide

Alemtuzumab

Cladribine

Natalizumab

AlemtuzumabCladribineFingolimod

Natalizumab(Daclizumab)

Alemtuzumab

Cladribine

Natalizumab

(Daclizumab)

Clinically isolatedsyndrome with

multiple MRI lesions

Clinically isolatedsyndrome & MRI activity,

i.e. McDonald MS

RRMS:1 relapse in 2 years AND

radiological activity

RRMS:2 significant relapses

in last 2 years

Rapidly evolvingsevere MS

Alemtuzumab

Cladribine

Fingolimod

(Daclizumab)

Highlyactive MS

CSF, cerebrospinal fluid; Gd, gadolinium.

No evidence of disease activity: NEDA-4

No evidence of disease activity defined as:1,2

No relapses

No sustained disability progression

No MRI activity

No new or enlarging T2 lesions

No Gd-enhancing lesions

Treat-2-target

1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Normalisation of brain atrophy rates

Normalisation of CSF neurofilament levels

Alem, alemtuzumab; Clad, cladribine tablets; Dac, daclizumab; DMF, dimethyl fumarate; Fingo, fingolimob; GA, glatiramer acetate; *HSCT, Hematopoietic stem cell transplantation (not licensed in the UK for MS);IFN beta, interferon-beta; NABs, neutralising antibodies; NEDA, no evident disease activity; Nz, natalizumab; Rx, treatment; Teri, teriflunomide; T2T, treating-to-target

Barts-MS T2T NEDA algorithm

Choose therapy

Define the individual’s MS

Choose a therapeutic strategy

Maintenance-escalation Immune reconstruction therapy (IRT)

Choose therapy

Nz/DacFingo/DMF/TeriIFN beta/GA HSCT*CladAlem

Initiate switch or Escalate Rx Complete course/Re-treat

Re-baseline Re-baseline

Monitoring Monitoring

Treatment failure? Breakthrough disease

Yes No No Yes

What is an immune reconstitution therapy or IRT?

An immune reconstitution therapy (IRT) is, by definition,given as a short course, i.e. intermittently and not continuously,

and has the ability to induce long-term remission and insome cases the possibility of a cure

*In multiple sclerosis, inflammatory activity typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and or Gd-enhancing lesions)Gd, gadolinium; IRT, immune reconstitution therapy; MRI, magnetic resonance imaging

Please note that an IRT is not given continuously and additional courses of the therapyare only given if there is a recurrence of inflammatory activity*

What is a maintenance therapy?

*In multiple sclerosis, inflammatory activity typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and or Gd-enhancing lesions)Gd, gadolinium; MRI, magnetic resonance imaging

A maintenance therapy is, by definition, given continuously,without an interruption in dosing, and although it has the

ability to induce long-term remission it cannot result in a cure

Please note that maintenance therapy is given continuously and if while on therapythere is a recurrence of, or ongoing, inflammatory activity*, it is an indication that there is a suboptimal response

Mitoxantrone*2000 (RMS/SPMS)

Maintenance vs IRT

*Licensed in the US, Germany, Austria and France#Unlicensed

BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation; IFN, interferon; IM, intramuscular; IRT, immune reconstitution therapy; RMS, relapsing multiple sclerosis;RRMS, relapsing-remitting multiple sclerosis; R-SPMS, relapsing-secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; SC, subcutaneous

1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018

SC IFN beta-1b1995 (RMS)

IM IFN beta-1a1997 (RMS)

BMT/HSCT#

1997 (RMS)

SC IFN beta-1a1998 (RMS)

Glatiramer acetate20 mg/mL2003 (RMS)

Natalizumab2006 (RRMS)

Fingolimod2011 (RRMS)

Alemtuzumab2013 (RRMS)

Teriflunomide2013 (RRMS)

Dimethyl fumarate2014 (RRMS)

Peginterferon beta-1a2014 (RRMS)

Glatiramer acetate40 mg/mL2015 (RMS)

Daclizumab2016 (RMS)

Oral cladribine2017 (RMS)

Ocrelizumab2018 (RMS/PPMS)

IRTsMaintenance treatments

The following are not licensed for MS in the UK: laquinimod, daclizumab, mitoxantrone, anti-CD20 therapies, and BMT. BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation;GA, glatiramer acetate; IFN, interferon; IRTs, immune reconstitution therapies; NEDA, no evidence of disease activity; SPMS, secondary progressive multiple sclerosis

Maintenance therapies vs immune reconstitution therapies (IRTs)

Continuous treatmentAdherence potential problem

Low to very high efficacy

Reversible

Perceived to be lower riskCumulative, or increased, risk with time

ExamplesGA, IFN beta, teriflunomide, BG12, fingolimod,natalizumab, daclizumab, anti-CD20

Breakthrough diseaseSuboptimal or failure to respondNEDA reliable metric for efficacy

Rebound activityHighly likelyCan be life-threatening

Pregnancy

No potential for a cureReboundSPMS and progressive brain atrophy

Maintenance therapies IRTs

Short-courses or pulsed therapyAdherence seldom a problem

High to very high efficacy

Irreversible

Perceived to be higher riskFrontloading of risk or reduced risk with time

ExamplesNon-selective: mitoxantrone, alemtuzumab, BMT/HSCTSemi-selective: cladribine (minimal impact on innate immunity)

Breakthrough diseaseMarker for retreatmentNEDA unreliable to assess efficacy

Rebound activityLess likelyUnlikely to be life-threatening

Pregnancy

Potentially ‘curative’?15–20 year experiment

What is active MS?

2001Clinical

2009Clinical and MRI

2014Clinical or MRI

Inactive MS: no relapses orMRI activity in the last 24 months

Active MS: relapses in the last 12 or 24 monthsand/or MRI activity in the last 12 months

Highly active MS: relapses in thelast 12 months and MRI

activity in the last 12 months

Rapidly-evolving severe MS (RES):two disabling attacks in a

12-month period andMRI evidence of activity during

this period

MRI, magnetic resonance imaging

What is active MS?

2001Clinical

2009Clinical and MRI

2014Clinical or MRI

Inactive MS: no relapses or MRI activity in the last 24 months (NEDA)

MRI, magnetic resonance imaging; NEDA, no evidence of disease activity

Active MS: relapses in the last 12 or 24 monthsand/or MRI activity in the last 12 months

Highly active MS: relapses in thelast 12 months and MRI

activity in the last 12 months

Rapidly-evolving severe MS (RES):two disabling attacks in a

12-month period andMRI evidence of activity during

this period

100 MSers

Who are the responders?

20:80

?

40:60

?

80:20

?

2.36

2.692.54

2.38 2.36 2.39

3.13 3.073.22 3.24 3.21 3.15

2.9

2.69 2.722.84 2.85 2.79

0

0.5

1

1.5

2

2.5

3

3.5

4

Me

an E

DSS

sco

re

Original placebo

Original natalizumab

Original placebo, now on natalizumab

Natalizumab STRATA: stable EDSS scores for up to 5 years

Kappos L, et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France: P520.

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

treatment gap*

*p<0.0001; EDSS, Expanded Disability Status Scale

n=380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

Feederstudy

baseline

Feederstudyend

Safetystudyend

STRATAbaseline

STRATA48 weeks

STRATA96 weeks

STRATA144 weeks

STRATA192 weeks

STRATA240 weeks

Alem, alemtuzumab; Clad, cladribine tablets; Dac, daclizumab; DMF, dimethyl fumarate; Fingo, fingolimob; HDA, high disease activity; GA, glatiramer acetate;*HSCT, hematopoietic stem cell transplantation (not licensed in the UK for MS); IFN beta, interferon-beta; Nz, natalizumab; RES, rapidly-evolving severe; Teri, teriflunomide

Treatment ladder

HDA/RES

IFN beta

Teri

GA

DMF

Alem

Nz Clad

Fingo

Alem

Clad

Nz

Dac HSCT*

RES

Fingo Clad

Alem

Nz

Level 1

Level 2

Level 3

EDSS

IFN beta NatalizumabJun 2000 May 2014

6.0

3.5 3.5

EDSS, Expanded Disability Status Scale; IFN, interferon

17 year-old girl, myelitis

Jun 2000

Natalizumab

Jan 2008

Clumsy left hand

Jan 2002

Pins and needles in legs

Oct 2003

Right optic neuritis

Mar 2004

Brainstem syndrome;diplopia and ataxia

Dec 2007

Cervical cord relapse;weak left arm with pain

Jan 2008

NEDA (no evidence of disease activity)

Feb 2008 to May 2014

Bladder dysfunction

Mild urinary frequency

Depression, anxietyand fatigue

No depression, anxiety or fatigue

Reduced mobility Fully mobile

Residual deficits:

• Walking distance >500 m

• Unable to run

• Exercise induces intermittent sensory symptoms in left arm

• Mild urinary frequency

1st year university. Left optic neuritis

Feb 2001

IFN beta

Feb 2001

MRI – progressive brain atrophy

Is this patient in long-term remission?

Dec 2007 Jul 2010 Jul 2013

Pregnancy in multiple sclerosis

Vukusic S, et al. Brain. 2004;127:1353–1360

Delivery

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1 2 3 4 1 2 3 1 2 3 4 5 6 7 8

Trimestersbefore pregnancy

Trimestersduring pregnancy

Trimestersafter pregnancy

Pregnancy

An

nu

al r

esp

on

se r

ate

a. Total number of administrations over the first 12 months of treatment; b. 10 tablets refers to a patient weighing 50 – <60 kgIFN, interferon; sc, subcutaneous; SmPC, Summary of Product Characteristics

Treatment burden

1. Rebif® EU SmPC; 2. Copaxone® SmPC; 3. Aubagio® EU SmPC; 4. Tecfidera® EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Mavenclad EU SmPC;10. Ocrevus EU SmPC

Natalizumab5

Teriflunomide3

Dimethyl fumarate4

Fingolimod6

Alemtuzumab7

Daclizumab8

Cladribine9

Glatiramer acetate2

sc IFN beta-1a1

Ocrelizumab10

12 Totala10 118 96 74 52 3Pre-dose 1

Month

156

365

365

730

12

365

5

12

10b

3

Adherence

In MS, patients with long gaps in treatment are at greater risk of relapse thanmore adherent patients1

Lower adherence to MS therapy is associated with a higher risk of relapse2

1. Al-Sabbagh A, et al. J Neurol 2008;255(Suppl. 2):S79; 2. Steinberg SC, et al. Clin Drug Invest 2010;30:89–100

MPR, Medication Possession Ratio

Good adherenceis important for

optimising outcomes

0.90

≥80

An

nu

al r

esp

on

se r

ate

0.95

1.00

1.05

1.10

1.15

<80 <75 <70 <65 <60

MPR (%)

Comparison of relapse risk ratios bylevel of adherence in patients with MS2

Patients could have reported more than one reason for non-adherence. When counting injection-related reasons for non-adherence, each patient was counted only once.GAP, Global Adherence Project

Forgetfulness is a primary cause of non-adherence

Devonshire V, et al. Eur J Neurol 2011;18:69–77

0

Re

aso

ns

for

mis

sin

g o

ne

or

mo

re in

ject

ion

s

Patients (%)

Pregnancy/planned pregnancyNot confident in treatment benefits

Financial reasonsNobody available to administer

Did not feel need for injectionDid not pick up medicine

DepressionWeakness

Skin reactionInjection anxiety

Dosing schedule difficult/inconvenientHeadache

Pain at injection siteFlu-like symptoms

FatigueOther

Tired of taking injectionsForgot to administer

10 20 30 40 50 60

1%2%2%

3%4%

5%6%

8%9%

10%10%10%

12%13%

15%17%

20%50%

Psychological factors– forgetfulness and complacency –

impact adherence

Observational GAP study

NB. Screening for latent infections, in particular TB and hepatitis B/C, must be performed prior to initiation of cladribine in Year 1 and 2. Numbers indicate the number of blood tests. CV, cardiovascular; DMT, disease-modifying therapy; hypersens., hypersensitivity; MRI, magnetic resonance imaging; SmPC, Summary of Product Characteristics; TB, tuberculosis.

DMT monitoring burden

1. Rebif® EU SmPC; 2. Copaxone® UK PI; 3. Aubagio® EU SmPC; 4. Tecfidera EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Mavenclad EU SmPC.

Blood Test Ophthalmology CV monitoring MRI Urinalysis

Renal function and cardiac function to be monitored in cases of renal impairment and pre-existing cardiac disorder, respectively

IFN beta-1a

Glatirameracetate2

Teriflunomide3

Dimethylfumarate4

Natalizumab5

Fingolimod6

Alemtuzumab7

Daclizumab8

Cladribine9

Pre-doseFirstdose

Month1

Month2

Month3

Month4

Month5

Month6

Month7

Month8

Month9

Month10

Month11

Month12

Immuno-suppression

TB screening

Infusionreaction

Vigilancefor skin

reactions

×2 ×2

×2

×3

×2

×2 ×2 ×3

×2

×2 ×2 ×3

×2

×2 ×2 ×3

×2

×3×3

×2×2×2×2

×2

×2×2×2

Hypersens.

×2

×3

TB screening×3

TB screening

Immunosuppression

Definition:Immunosuppression is a reduction of the activation or efficacy of the immune system

This definition refers to short-term/intermittent (induction) and long-term persistent immunosuppression (maintenance)

Immunomodulatory (not immunosuppressive)Interferon-betaGlatiramer acetate

Immunomodulatory (possibly immunosuppressive)TeriflunomideDaclizumab

ImmunosuppressiveMitoxantroneNatalizumab (selective compartment)Fingolimod and other S1P modulatorsDimethyl fumarateAlemtuzumabOcrelizumab (anti-CD20)1

Cladribine (purine analogue)

For a drug to be considered an immunosuppressantit should:

1. Cause significant lymphopenia

2. Be associated with opportunistic infections

3. Reduce the antibody response to vaccines

4. Be associated with secondary malignancies

1. Ocrevus EU SmPC.

Continuous(e.g. fingolimod, natalizumab)

Short-term(e.g. alemtuzumab, cladribine)

Immunosuppression

PML, progressive multifocal leukoencephalopathy

1. Persistent immunosuppression

2. Risk increases with time (cumulative)a. Increased risk of PML (complex pathogenesis)b. Increased risk of other opportunistic infectionsc. Increased risk of secondary malignancy

3. Live vaccines contraindicated

4. High risk of exotic infectionsa. Dengueb. Zikac. Etc

5. Pregnancy not recommended

6. Long-term burden of pharmacovigilance

1. Short-term immunosuppression

2. Short-term risk (front-loaded)a. Low risk of PMLb. Low risk of other opportunistic infectionsc. Low risk of secondary malignancy

3. Live vaccines not necessarily contraindicated

4. Low risk of exotic infections if travel occursafter immune reconstitution

5. Pregnancy opportunity post immune reconstitution

6. Less of a pharmacovigilance burden

Immunosuppression

PML, Progressive multifocal leukoencephalopathy; PCP, Pneumocystis carinii pneumonia; TB, tuberculosis

Continuous(e.g. fingolimod, natalizumab)

Short-term(e.g. alemtuzumab, cladribine)

Listeria TB PCP

ZosterNocardia

Frontloadingrisk

Cumulativerisk

Global natalizumab PML riskestimate by treatment epoch

(as of Feb. 28, 2017)TYSABRI PML risk estimates by treatment epoch

Basal cell carcinoma

1. Biogen, on file. https://medinfo.biogen.com/secure/download?doc=workspace%3A%2F%2FSpacesStore%2Fded9df8f-d785-444a-ae89-888bef72aa7e&type=pmldoc&path=null&dpath=null&mimeType=null

Derisking immunosuppression

CSF, cerebrospinal fluid; FBC, full blood count; LFTs, liver function tests; U&E, urea and electrolytes;HIV, human immunodeficiency virus; VZV, varicella zoster virus; TB, tuberculosis; LP, lumbar puncture; DMTs, disease-modifying therapies;IRTs, immune reconstitution therapies; PCP, Pneumocystis carinii pneumonia; TFTs, thyroid function tests; PML, progressive multifocal leukoencephalopathy; MRI, magnetic resonance imaging

Baseline Infusion DMTs and IRTs Monitoring

1. FBC: leukocytes/platelets

2. LFTs, U&E, urine

3. Pregnancy tests

4. Immunoglobin levels

5. Serum protein electrophoresis

6. Serologya. HIV 1/2b. Hepatitis B/Cc. VZVd. Syphilise. TB Elispot/Quantiferon assay

7. Cervical smear

8. Vaccinations

9. MRI

10. LP (CSF analysis)

11. Listeria prophylaxis

1. Infusion reactionsa. Corticosteroidsb. Anti-histaminesc. Anti-pyretics

2. Antibioticsa. Anti-herpesb. Listeria/PCP prophylaxis

1. Bloodsa. FBC: leukopeniab. TFTs, LFTs, U&E, …

2. Urinea. Autoimmuneb. Renal dysfunction

3. MRIa. Disease activityb. PML

4. Infectiona. Serologyb. CSF

5. Disease activity

6. Pregnancy

7. Malignancya. Skin, cervical, breastb. Etc.

The following are not licensed for MS in the UK: laquinimod, daclizumab, mitoxantrone, anti-CD20 therapies, and BMT. BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation;GA, glatiramer acetate; IFN, interferon; IRTs, immune reconstitution therapies; NEDA, no evidence of disease activity; SPMS, secondary progressive multiple sclerosis

Maintenance therapies vs immune reconstitution therapies (IRTs)

Continuous treatmentAdherence potential problem

Low to very high efficacy

Reversible

Perceived to be lower riskCumulative, or increased, risk with time

ExamplesGA, IFN beta, teriflunomide, BG12, fingolimod,natalizumab, daclizumab, anti-CD20

Breakthrough diseaseSuboptimal or failure to respondNEDA reliable metric for efficacy

Rebound activityHighly likelyCan be life-threatening

Pregnancy

No potential for a cureReboundSPMS and progressive brain atrophy

Maintenance therapies IRTs

Short-courses or pulsed therapyAdherence seldom a problem

High to very high efficacy

Irreversible

Perceived to be higher riskFrontloading of risk or reduced risk with time

ExamplesNon-selective: mitoxantrone, alemtuzumab, BMT/HSCTSemi-selective: cladribine

Breakthrough diseaseMarker for retreatmentNEDA unreliable to assess efficacy

Rebound activityLess likelyUnlikely to be life-threatening

Pregnancy

Potentially ‘curative’?15–20 year experiment

Case study 1

42 year-old journalist, married with 2 children,

War correspondent – frequent travel to Afghanistan, Ukraine, Iraq and Syria

Diagnosed RRMS late 2014:

Initial symptoms of sensory symptoms in feet and Lhermitte’s phenomenon

Treated with dimethyl fumarate (Tecfidera)

Two disabling attacks in 2015 – ataxia and spinal cord lesion with weak legs

Diagnosis:

Rapidly-evolving severe (RES) MS

Treatment:

Eligible for fingolimod, natalizumab and alemtuzumab

Natalizumab contraindicated as found to be JCV-seropositive (index 1.86)Offered fingolimod – was not keen about long-term immunosuppression Interested in HSCT (not eligible under local guidelines) or alemtuzumab

Major concerns about monitoring and accessing urgent treatment when abroadas war correspondent

Joint decision to treat him with parenteral cladribine* (two cycles given Jan/Feb 2016 and 2017)

*Only cladribine tablets are licensed for the treatment of MSHSCT, haematopoietic stem cell transplantation; JCV, JC virus; RRMS, relapsing-remitting multiple sclerosis

Vaccinations

Gilenya EU SmPC

Vaccination

During and for up to two months after treatment with GILENYA,vaccination may be less effective. The use of live attenuatedvaccines may carry a risk of infections and should therefore beavoided (see sections 4.4 and 4.8).

Immunisations

In a randomised, open label study of 60 patients with relapsingMS there was no significant difference in the humoral immuneresponse to a recall antigen (tetanus toxoid) and only slightlyslower and reduced humoral immune response to a neoantigen(keyhole limpet haemocyanin) was observed in patients whowere treated with TYSABRI for 6 months compared to anuntreated control group. Live vaccines have not been studied.

Tysabri EU SmPC

Vaccines

It is recommended that patients have completed local immunisationrequirements at least 6 weeks prior to treatment with LEMTRADA.The ability to generate an immune response to any vaccine followingLEMTRADA treatment has not been studied.

The safety of immunisation with a live viral vaccine following a courseof LEMTRADA treatment has not been formally studied in controlledclinical trials in MS and should not be administered to MS patientswho have recently received a course of LEMTRADA.

Varicella zoster virus antibody testing/vaccinationAs for any immune modulating medicinal product, before initiatinga course of LEMTRADA treatment, patients without a history ofchickenpox or without vaccination against varicella zoster virus (VZV)should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to treatment initiationwith LEMTRADA. To allow for the full effect of the VZV vaccinationto occur, treatment with LEMTRADA should be postponed to 6 weeksfollowing vaccination.

Lemtrada EU SmPC

Live or live attenuated vaccines

Treatment with MAVENCLAD should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccinesbecause of a risk of active vaccine infection. Vaccination with live or attenuated live vaccines should be avoided during andafter cladribine treatment as long as the patient’s white blood cell counts are not within normal limits. Mavenclad EU SmPC

Case study 2

48 year-old woman (born 1969),married, two children, employed as a counsellor

1996: Probable first symptoms with mild transient sensory symptoms in legs

2001: Diagnosed with MS after an episode of weakness in right hand

2003: Right optic neuritis

2004: Weakness in legs with bladder involvement

2005–2007: CLARITY study (active treatment)

2008–2010: CLARITY EXTENSION (placebo)

2005–2015: NEDA, EDSS 3.0 (stable), walking unrestricted

April 2015: Numbness and pain right side of face, MRI new T2 lesion in brainstem

Refused platform DMTs(interferon-beta, glatiramer acetate, dimethyl fumarate, teriflunomide, alemtuzumab)

Treated with parenteral cladribine, June 2015*

*Only cladribine tablets are licensed for the treatment of MS DMTs, disease-modifying therapies; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; MS, multiple sclerosis; NEDA, no evidence of disease activity

*p<0.05, **p<0.001, ***p<0.0001 study drug vs comparator. NEDA values are calculated from individual studies; conclusions drawn from comparing NEDA values should be done so with caution.NEDA defined as no relapses, no 3-month confirmed CDP, and no new T1 Gd+ lesions and no new enlarging or enlarged T2 lesions on cranial MRI (except CLARITY, CARE-MS I and CARE-MS II: based on no 6-month CDP).CDP, confirmed disability progression; Gd+, gadolinium-enhancing; IFN, interferon; IM, intramuscular; MRI, magnetic resonance imaging; NEDA, no evidence of disease activity; SC, subcutaneous.

48 48 47

3937

33 32

2528

23

2925

17

7

13 14 14 15 14

0

10

20

30

40

50

60

NEDA rates in Phase 3 trials

1. Traboulsee A, et al. Neurology 2016;86 [PL02.004]; 2. Giovannoni G, et al. Lancet Neurol 2011;10:329‒337; 3. Cohen AJ, et al. Lancet 2012;380:1819–1828; 4. Havrdova E, et al. Lancet Neurol 2009;8:254‒260;5. Bevan CJ, Cree BA. JAMA Neurol 2014;71:269‒270; 6. Coles AJ, et al. Lancet 2012;380:1829–1839; 7. Kappos L, et al. AAN 2016:115; 8. Giovannoni G, et al. Neurology 2012;78: PD5.005; 9. Freedman M, et al. Neurology 2012;78:PD5.007

37

OPERA I1

Ocrelizumaba

vsSC IFN

beta-1a

OPERA II1

Ocrelizumaba

vsSC IFN

beta-1a

CLARITY2

Cladribine tablets

vsplacebo

CARE-MS I3

Alemtuzumab vs

SC IFNbeta-1a

AFFIRM4

Natalizumabvs

placebo

FREEDOMS5

Fingolimod vs

placebo

CARE-MS II6

Alemtuzumab vs

SC IFNbeta-1a

DECIDE7

Daclizumab vs

IM IFNbeta-1a

DEFINE8

Dimethylfumarate

vsplacebo

TEMSO9

Teriflunomidevs

placebo

Pat

ien

ts a

chie

vin

g N

EDA

(%

)

*** *** *** * *** ** *** *** * **

27

NEDA, no evident disease activity; NEDA-2, clinical only (relapse-free and progression-free); NEDA-3, clinical and focal MRI activity;NEDA-4/5, clinical and focal MRI activity free and normalising brain atrophy loss and normalisation of CSF neurofilament levels.Alem, alemtuzumab; Clad, cladribine tablets; Dac, daclizumab; DMF, dimethyl fumarate; Fingo, fingolimod; GA, glatiramer acetate; IFN, interferon; Nz, natalizumab; Teri, teriflunomide

“Flipping the pyramid in MS”

Inactive

MS diseaseactivity

Active

Highly-active

Rapidly-evolvingsevere

NEDA-1/2Clinical activity

NEDA-3Focal MRI activity

NEDA-4/5Brain atrophy and

CSF neurofilament levels

Conventionalstep-care

Rapidescalation

Earlytop-down

IFN beta/GA/Teri/DMF

IFN beta/GA/Teri/DMF

Nz/Alem/Fingo/Dac/Clad

Fingo/Dac/Clad Fingo/Dac/Clad

Nz/Alem Nz/Alem

A new classification of disease-modifying therapies for RMS

Maintenance/escalation therapy (MET) Immune reconstitution therapy (IRT)

Chronic therapy that is maintained and/orescalated over time resulting in

immune function only during active treatment

Short course therapy resulting in long-termqualitative changes in immune function

Immunomodulation … Immunosuppression Semi-selective IRT (SIRT)

IRT that semi-selectivelyaffects the adaptive

immune systeme.g. cladribine

Non-selective IRT (NIRT)

IRT that affects boththe innate & adaptive

immune systemse.g. alemtuzumab

MET that results incontinuous

immunomodulatione.g. interferon-beta,glatiramer acetate

MET that results incontinuous

immunosuppressione.g. fingolimod, ocrelizumab

Derisked METe.g. natalizumab, dimethyl fumarate,

teriflunomide, daclizumabRMS, relapsing multiple sclerosis

It is not only benefits and risks

LymphopaeniaCardiac issuesHepatic issues

PregnancyWorkTravelOthers

PML, progressive multifocal leukoencephalopathy

Drug–drug interactionsCarry-over/rebound/sequencing

InactiveActiveHighly-active/rapidly-evolving severe

Personal factors

Drug effects

ImmunosuppressionPML riskOther

Monitoring frequency

ComorbiditiesAdherence

Safety profileTolerability

Patient profile

Potentialdrug issues

Disease activity/prognosis

Conclusions

Changing therapeutic landscape; more complex – more choice

DMTs are either maintenance or IRTs● IRTs (semi-selective or non-selective)

DMTs immunomodulatory and/or immunosuppressive● Long-term/maintenance vs short-term/induction

Risks of MS vs benefits of treatment vs risks of treatment

De-risking treatments● Baseline screening● Monitoring● Timely switching● Switch from maintenance (cumulative) to induction (front-loaded) risk

DMT specific knowledge

Databasing (pharmacovigilance monitoring, pregnancy, registries)

Can we really implement an algorithm?

What about stopping criteria?

DMTs, disease-modifying therapies; IRTs, immune reconstitution therapies; MS, multiple sclerosis