Trying to predict the clinical course of MS and treating-2-target

Questions: the MSers perspective

To make an informed decision you need to ask and understand the following questions:

Are you sure that you have MS?

What types of MS do you have?

What prognostic group do you fall into?

What is the risk of not having any treatment?

Do you have active MS?

Am I eligible for treatment with a DMT?

Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?

Question: What prognostic group do you fall into?

Good prognosis Poor prognosis

Young

Female sex

Optic neuritis

Isolated sensory symptom

Full recovery from attack

Long interval to second

relapse

No disability after 5 years

Normal MRI / low lesion load

CSF negative for OCBs

Older age of onset

Male sex

“Multifocal“ onset

Efferent system affected (motor,

cerebellar, bladder)

High relapse rate in the first 2-5 years

Substantial disability after 5 years

Abnormal MRI with large lesion load

Genomic factors (e.g. ApoE4, KIF1B)

CSF positive for OCBs

Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288

Question: What prognostic group do you fall into?

Favourable

Indeterminate

Poor

timeAim of

treatment

Question: Do you have active MS?

vs.

1

2

3

Clinical

MRI

Biomarkers

What is active MS?

2001Clinical

2009Clinical and MRI

2014Clinical or MRI

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

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

Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months

Rapidly-evolving severe MS (RES); two disabling attacks in a 12

month period and MRI evidence of activity during this period.

MS is an autoimmune disease hypothesis

15-20 yearexperiment

“hit hard and early ”

Question: Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?

What is your treatment philosophy?maintenance-escalation vs. induction

survival analysis

BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers,

e.g. NABs?

Monitoring

• MS prognosis based on

clinical and MRI indices

• Life style and goals

• Shared goals for therapy

Rebaseline

Rebaselining:

• IFNβ, natalizumab, fingolimod,

teriflunomide, Dimethyl-

Fumarate=3-6 months

• Glatiramer acetate=9 months

• Alemtuzumab=24 months

Choose a therapeutic strategy

Maintenance-escalation Induction

Choose therapy

X Z

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

Y

• Patient’s preferences?

• Your choice?

NoYes Yes

• Only one licensed induction

therapy at present

Choosing a therapeutic strategy

Maintenance therapies

• Continuous treatment

• Low to very high efficacy

• Reversible

• Perceived to be lower risk

• Examples• Laquinimod, GA, IFN-beta, teriflunomide, BG12,

fingolimod, natalizumab, daclizumab

• Breakthrough disease• Suboptimal or failure to respond

• NEDA reliable metric for efficacy

• Rebound activity• Highly likely

• Can be life threatening

• Pregnancy• Contra-indicated

• No potential for a cure• Rebound

• SPMS & progressive brain atrophy

Induction therapies

• Short-courses or pulsed therapy

• Very high efficacy

• Irreversible

• Perceived to be higher risk

• Examples• Mitoxantrone, cladribine, alemtuzumab, anti-

CD20 (?), BMT

• Breakthrough disease• Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity• Less likely

• Unlikely to be life-threatening

• Pregnancy• Strategy of choice

• Potentially curative• 15-20 year experiment

• BMT, alemtuzumab, cladribine

100 MSers

Who are the

responders?

?

20:80

?

40:60

?

80:20

NEDA as an outcome

1.87

5.29

2.75

2.92

3.41

1.64

2.29

0 1 2 3 4 5 6

Dimethyl fumarate (DEFINE)

Natalizumab (AFFIRM)

Cladribine (CLARITY)

Fingolimod (FREEDOMS)

sc IFN β-1a (DoF)

Teriflunomide (TEMSO)

Alemtuzumab (CARE MS II)

Increase in proportion of NEDA patients relative to comparator

Patients with RRMS over 2 years. Increase in proportion of patients with NEDA versus placebo (except CARE MS II)

All data from post hoc analyses of randomized controlled trials in patients with RRMS. Table adapted from Bevan CJ and Cree BA. JAMA Neurol 2014;71:269-70, with the exception of: TEMSO. Freedman et al. Neurology 2012;78 [Meeting

Abstract s 1]: PD5.007; sc IFN b1-a sc. Data on file; CARE MS II. Coles AJ et al. Lancet 2012;380:1829-39

versus sc IFN b-1a

Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

MS Iceberg –NEDA is not good enough

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers