Treatment uncertainties in a crowded MS landscape

Dr Nikos Evangelou

Clinical Assoc. Professor of Neurology

Nottingham University

UK

Conflict of Interest

• I have received research funding from Novartis, Biogen, Teva

• Participated in clinical trials for Biogen, Merck, Novartis,

• Participated in advisory boards for Biogen, Genzyme, Teva, Roche

• Received hospitality from Biogen, Teva, Genzyme, Merck, Roche

Apology- Explanation

Thessaloniki

Bristol

Oxford, UK

Nottingham

interferon-b

(Betaferon/Extavia

Avonex

Rebif)

pegylated interferon

(Plegridy)

glatiramer acetate

(Copaxone)

teriflunomide

(Aubagio)

dimethyl fumarate

(Tecfidera)

fingolimod

(Gilenya)

cladribine

daclizumab

(Zynbryta)

natalizumab

(Tysabri)

alemtuzumab

(Lemtrada)

ocrelizumab

(Ocrevus)

Miss S- 2010

• 23 years old student from India , single, no family

• Presented with optic neuritis

• MRI typical MS lesions

• Bit more fatigued but no clear relapse.

• 3 new MRI Lesions at 12 months

Miss S- 2010

• 23 years old student from India , single, no family

• Presented with optic neuritis

• MRI typical MS lesions

• Bit more fatigued but no clear relapse.

• 3 new MRI Lesions at 12 months

What is the best treatment ?

Miss S- 2010

• 23 years old student from India , single, no family

• Presented with optic neuritis

• MRI typical MS lesions

• Bit more fatigued but no clear relapse.

• 3 new MRI Lesions at 12 months

What is the best treatment ?

What is the best treatment approach ?

• Copaxone started , but 6 month later bad relapse

• Patient worried , new scan showed new lesions

• Action?

• Escalated to fingolimod

• 12 months later, new ataxic relapse, residual disability , some cognitive concerns

• JCV positive

• Escalated to Tysabri

• Continues on Tysabri , no relapse

• Fallen, fractured arm , prolonged rehabilitation

• Some decline, walks slowly now with Rolator

• Worried about JCV, couldn’t sleep the other night

• Action?

Unacceptable variation of practice not based on patient preference

Strong opinions not based on evidence

Consider- compare with the secondary prevention of stroke: treatment of hypertension, cessation of smoking, statins,

antiplatelet agents, lifestyle modification, revascularisation of internal carotid

In more than 30% of MS-relapses,pre-relapse function is not regained

Le Page E,t al. Lancet 2015;386:974-981

1. Cutter et al. 2013 P07.118 AAN San Diego

2013: n=196, placebo group

FREEDOMS

disability maintained to end of study2

Years

NNT=25

Weinshenker BG, et al. Brain 1989; 112:1419–1428.

Pat

ien

ts (

%)a

Time from onset of MS (years)

0 10 20 30 40 50

100

80

60

40

20

0

0–1 attacks in first 2 years

2–4 attacks in first 2 years

≥ 5 attacks in first 2 years

DSS, Disability Status Scale.a The percentage of patients not having reached DSS 6 is shown after stratification according to the

number of attacks in the first 2 years from onset of MS. The difference between the groups is significant (p < 0.0001).

Patients with chronically progressive MS were excluded.

number of relapses in first two years can predict disability progression

5602 potentially eligible

4986 with eligible baseline819 not RR at entry

592 ineligible or untreated

6 no baseline EDSS

16 age at onset unknown

18 age at onset unknown

4862year 10 analysis cohort

124 no valid EDSS after baseline

follow up (total cohort): mean 8.7yr

median 10yr

follow up (RRMS only) : mean 8.9yr

median 10yr

4217 RR baseline

645 SP baseline

4157excluding

switchers to non-scheme

drugs Duddy et al. 2016 ECTRIMS London

BCMSn=898

RR SP

735 163

RSSn=4862

RR SP

4217 645

age at eligibility (mean)37.2

35.8 43.5

39.438.3 46.4

age at onset (mean)29.2

28.6 32.1

30.630.5 31.4

female (%) 74.2 74.8

disease duration (yr)7.9

7.2 11.4

8.77.7 15.0

relapses last 2 years (mean) 2 .9 3.0

EDSS baseline (mean)2.44

1.98 4.48

3.403.07 5.54

MSSS3.91

3.39 6.25

5.044.81 6.48

baseline characteristics: BCMS vs RSS

total cohort: EDSS (Markov)comparison to control

cha

nge in

EDSS

years

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

2

0 2 4 6 8 10

control RSS

7% reduction

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4 5 6 7 8 9 10

all patients

untreated

RSS

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4 5 6 7 8 9 10

RRMS at baseline

YEAR

reaching EDSS 6.0

results provisional

RRMS only: EDSS (Markov)comparison to control

cha

nge in

EDSS

years

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

2

0 2 4 6 8 10

control RSS

14%

reduction

The number/volume of lesions correlates to long term disability/ reaching progressive MS

Brain. 2008;131(3):808-817

start low and escalate start high(er), stay high?de-escalate

reboot

InterferonscopaxoneteriflunomideDMFfingolimod

AlemtuzumabOcrelizumabNatalizumab?Cladribine

AHSCT

first choices in the new world

patients with more active disease use oneof natalizumab or alemtuzumab.

real world comparisons has valueAND LIMITATIONS

Spelman et al. 2017 AAN Boston P6.372

PPV of NEDA at 2 years for progression of disability at 7 years was 78 %

MS therapy: marathon or sprint?

Speed regarding:• Diagnosis

• Therapy start

• Optimization

Endurance regarding:• Long-term safety

• Long-term effectiveness

• Adherence

MARATHONSPRINT

Age of patients (years)

Start of MS (middle age)1

RIS? CIS RRMS SPMS?

Diagnosis 3.5 years2

Therapy

Activity on T2 lesions- or Gad

Yearly brain scans of MS

19 2534

45

CIS RRMS SPMS 1 SPMS 2

What about different scanners, different field strengths, different radiologists, different day of the week ….

Cortical lesions

Number of

cortical

lesions

Intra-cortical

(IC)

Mixed

cortical –

subcortical

(C/SC)

3T FLAIR 71 27 44

3T DIR 120 63 57

7T MP-RAGE 97 38 59

3T DIR

3T FLAIR

7T MP-RAGE3T DIR

3T FLAIR

7T MP-RAGE

7T MP-RAGE3T FLAIR 3T DIR

When should we escalate to monoclonal ? UK guidelines

when there is clinical evidence of high-disease activity despite treatment.

rapid new MRI lesion acquisition, in the absence of clinical relapses, rarely may indicate sufficient disease activity to consider escalation to monoclonal antibodies rarely, despite there being no clear evidence base for this.

Unless a zero tolerance policy is established for any new clinical or radiological activity due to MS as our threshold for adequate versus inadequate therapy, the presence of the new MR lesion is not necessarily

connoting a loss of efficacy

Sormani MSJ 2016

Choice talk

• Step back

• Offer choice

• Justify choice (preferences matter)

• Check reaction

• Defer closure

Option talk

• Check knowledge

• List options

• Describe options (explore preferences)

• Harms and benefits

• Provide decision support

• Summarize

Decision talk

• Focus on preferences

• Elicit a preference

• Move to a decision

• Offer review

Initial preferences Informed preferences

Elwyn G, et al. J Gen Intern Med 2012; 27:1361–1367.

Shared decision-making

2 crucial questions in MS

• Which is the best treatment strategy?

• How to use MRI in treatment decisions ?

Randomized autologoushematopoietic stem cell

transplantation vs. Alemtuzumab for patients with relapsing

remitting Multiple Sclerosis

(RAM-MS)50 patients with MS in Scandinavia are being treated yearly with HSCT,

over 100 MS patients from Norway have gone abroad for this treatment in privatehospitals.

Only treatment strategy clinical trials will give us the answer

Thank you