barts health treatment algorithm in a nutshell
TRANSCRIPT
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