Future efficacy measures for Multiple Sclerosis
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Transcript of Future efficacy measures for Multiple Sclerosis
Efficacy measures of the future: what to expect and accept?
Professor Gavin Giovannoni
Blizard Institute, Barts and The London School of Medicine and Dentistry
Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.
Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
Defining the therapeutic target
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions
DAF1,2
NEDA is a sensitive 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
The modified Rio score can predict disability progression and response to IFN-β therapy
*No qualifying relapses or confirmed EDSS progression; †Percentage calculated using total number of patients with a particular modified Rio score at Week 48; ‡No clinical activity, gadolinium-enhancing lesions, or new/enlarging T2 lesions. EDSS, Expanded Disability Status Scale
Outcomes after 1 year of IFN-β treatment Modified Rio score
≤5 new T2 lesions and 0 relapses 0
≤5 new T2 lesions and 1 relapse, or >5 new T2 lesions and 0 relapses 1
≤5 new T2 lesions and ≥2 relapses, or >5 new T2 lesions and 1 relapse 2
>5 new T2 lesions and ≥2 relapses 3
Higher modified Rio score predicts greater risk of progression1
Modified Rio score at Week 48 (REGARD)
Clinical activity-free* at Week 96 n (%)†2
Disease activity-free at Week 96 n (%)‡2
Yes No Yes No
0 (n=156) 121 (77.6) 35 (22.4) 53 (34.0) 103 (66.0)
1 (n=42) 3 (7.1) 39 (92.9) 0 42 (100)
2 (n=5) 0 5 (100) 0 5 (100)
Total (N=203) 124 79 53 150
Wo
rse
nin
g d
ise
ase
1. Sormani MP et al. Mult Scler J 2013;19:605-12 2. Freedman M et al. Mult Scler J 2013;19(Suppl. 1):262 [P610]
Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014
*As measured by modified Rio score. EDSS, Expanded Disability Status Scale; RRMS, relapsing–remitting MS; tiw, three times weekly
Faster disability progression seen in patients with worse Rio-defined disease activity*
Kaplan–Meier cumulative incidence curves of time to confirmed EDSS progression by modified Rio score in patients with RRMS receiving sc IFN β-1a 44 µg tiw
156 42
155 41
151 39
144 33
138 27
No. of patients at risk: Rio score 0 Rio score 1
Baseline Week 24 0.0
0.1
0.2
Cu
mu
lati
ve in
cid
en
ce
0.3
0.4
0.5
Week 48 Week 72 Week 96
O (n=156) 1 (n=42)
Rio score group
Time to 3-month EDSS confirmed progression
Freedman M et al. Mult Scler J 2013;19(Suppl. 1):262 [P610]
Slide courtesy Prof. Mark Freedman, EFNS-ENS Istanbul 2014
Yes, 72
No, 28
Relapse reporting
• Most common reasons for not reporting their most recent relapse to a specialist MS team were: – ‘Mild relapse so not felt necessary’ 5/28 (18%) – ‘Saw or spoke to their GP’ 4/28 (14%)
• Most common reasons for not seeking healthcare support were: – ‘Felt I could manage’/mild relapse 18/42 (43%) – ‘Nothing that they can do to help’ 8/42 (19%)
Duddy M, et al. ECTRIMS 2013. P590.
N = 101
Yes, 46
No, 54
N = 102
Patients who have ever experienced an MS relapse and
not contacted a healthcare professional
Patients reporting most recent relapse to a specialist MS team
Pseudo-relapses • “I think I know what causes pseudo-relapes, but I don’t know how to define
them!”
• Too many patients with transient, or intermittent, symptoms have active MRI scans (Gd+ lesions)
• What about non-classical symptoms?
– Cognitive relapse
– Fatigue
– Narcolepsy
– Well described transient syndromes, e.g. Lhermitte’s, flexor spasms
• NOT ("the appearance of new symptoms, or the return of old symptoms, for a period of 24 hours or more – in the absence of a change in core body temperature or infection“)
– Trial protocols are more restrictive and require patients to move on the EDSS and/or FS (one FS by at least 2 points or two FS by at 1 point)
– The above creates protocol and non-protocol defined relapses.
Normal neurological examination
No disability
Minimal disability
Moderate disability
Relatively severe disability
Disability precludes full daily activities
Assistance required to walk Restricted
to a wheelchair
Restricted to bed or chair Confined
to bed
Death
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0
EDSS
Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
Neurology 1983; 33:1444–1452.
Yes – I do an EDSS whenever I see a patient 14 25%
Yes – I do an EDSS annually 10 18%
Yes – I occasionally do an EDSS 20 36%
No – I never do an EDSS 3 5%
Other 9 16% Yes – I do an EDSS whenever I see a
patient [14] Yes – I do an EDSS
annually [10]
Yes – I occasionally do an EDSS [20]
No – I never do an EDSS [3]
Other [9]
Survey of UK MSologists
Schmierer K, et al. ABN 2014; Unpublished.
Clinical – In your routine MS clinical practice, do you use the EDSS?
Clinical – If you do an EDSS in your routine clinical practice, do you walk the patients to assess their walking distance?
Yes [9]
No [20]
Sometimes [22]
Other [5] Yes 9 16%
No 20 36%
Sometimes 22 39%
Other 5 9%
Validating a novel web-based method to capture disease progression outcomes in MS
P-EDSS, physician or actual EDSS. The midpoint of the diamonds is the mean difference between the two EDSS scores, the upper and lower lines within the diamonds are the 95% CI. The width of the diamond indicates the sample size, the dots the actual values. The horizontal line at 0.46 indicates the mean difference between the two scores. The graph indicates the greater variation at lower EDSS scores, with greater agreement at scores > 5. Leddy S, et al. J Neurol 2013; 260:2505–2510.
ORIGINAL COMMUNICATION
we
b-
EDSS
– P
-ED
SS s
core
P-EDSS score
–4
–3
–2
–1
0
1
2
3
4
0 1 1.5 2 2.5 3 3.5 4 4.5 5.5 6 6.5 7 8
Monitoring your own disease
http://www.patientslikeme.com/
Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
Differential Diagnosis
MRI
Evoked Potentials
Lumbar puncture
Blood Tests
Diagnostic Criteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain Swallowing
Spasticity Falls
Balance problems Insomnia
Restless legs Fertility
Clinical trials
Gait
Pressure sores
Oscillopsia
Emotional lability
Seizures
Gastrostomy
Rehab
Suprapubic catheter Intrathecal
baclofen
Physio- therapy
Speech therapy
Occupational Therapy
Functional neurosurgery
Colostomy
Tendonotomy
Studying
Employment Relationships
Travel
Vaccination
Anxiety
Driving
Nurse specialists
Family counselling
Relapses
1st line
2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease progression
DMTs
Side Effects
Advanced Directive
Exercise
Diet
Alternative Medicine
Pregnancy Breast Feeding
Research
Insurance
Visual loss
Palliative Care
Assisted suicide
Social services
Legal aid
Genetic counselling
Prevention
Diagnosis
DMT Symptomatic
Therapist
Terminal
Counselling An holistic approach to MS
Intrathecal phenol
Fractures
Movement disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
Brain Health
Cognitive Reserve
Sudden death
Suicide
OCD
Narcolepsy
Apnoea Carers
Respite
Hospice
Respite
Dignitas
Advanced Directive
Rhiztomy
Rhiztomy
Wheelchair
Walking aids
Blood/Organ donation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
Web Resources
Pathogenesis
Double vision
What is MS?
NEDA
T2T OCT
Neurofilaments
JCV status Pharma
Anaesthesia
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices)
DAF1,2
Treating-2-target
Choosing therapy
X Y Z
Define the Individual’s MS
No
Treatment failure? Yes
• Patient’s preferences?
• Your choice?
Individual measures:
• Evidence of disease activity?
• Tolerability/safety?
• Adherence?
• Drug or inhibitory markers?
Monitoring
• MS prognosis
• Life style and goals
• Shared goals for therapy
Rebaseline
Rebaseline:
• IFNβ, natalizumab, fingolimod,
teriflunomide, DMF=3-6 months
• Glatiramer acetate=9 months
• Alemtuzumab=24 months
DMF=dimethyl fumarate.
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
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment-effect on atrophy correlates with treatment-effect on disability
Sormani et al. Ann Neurol 2014;75:43–49.
Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions
and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials
(13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0% Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
-0.40%
-0.56%
-0.43%
-0.24%
P=0.004†
P=0.002†
†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
AFFIRM Study: natalizumab and brain atrophy
Mean
(S
E)
perc
en
tag
e c
han
ge i
n B
PF
Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2 years
Fingolimod 0.5 mg (n = 356)
Placebo (n = 329)
***
*
**
6 0 12 24
Time (months)
0
-0.4
-0.8
-1.2
-1.6
-2.0
−38%
vs placebo p<0.001
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
TRANSFORMS, 1 year
0 12
Time (months)
0.0
-0.4
-0.6
-1.0
IFNb-1a IM (n = 359)
Fingolimod 0.5 mg (n = 368)
−40%
vs IFNb-1a IM p<0.001
*** -0.2
-0.8
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
Reduction in brain atrophy on alemtuzumab
Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting
Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies
Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5
Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8
AAN 2014
Blitz S65-008
1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal
Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering,
Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre,
Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a
Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)
Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF
For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)
Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)
Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e, %
(9
5%
CI)
Year No. of Patients 371 367 351 323
% Change from Previous Year – –0.59% –0.25% –0.19%
Me
dia
n C
ha
ng
e F
rom
Ba
se
lin
e, %
(9
5%
CI)
Year 428 414 405 359
– –0.48% –0.22% –0.10%
No. of Patients
% Change from Previous Year
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
0 1 2 3
-1 .5 0
-1 .2 5
-1 .0 0
-0 .7 5
-0 .5 0
-0 .2 5
0 .0 0
AAN 2014
Blitz S65-008
CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity
The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3
MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of
Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium;
MRI=magnetic resonance imaging; Y=year
No. of Patients 359 370 336 356 370 325 354 369 326
Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3
Pro
po
rtio
n o
f P
ati
en
ts,
% (
95
% C
I)
0
20
40
60
80
100
Gd-enhancing
lesion-free
New/enlarging
T2 lesion-free
MRI
activity-free
% MRI Activity Free in Treatment-Naive
Patients (CARE-MS I)
% MRI Activity Free in Patients Who
Relapsed on Prior Therapy (CARE-MS II)
No. of Patients 412 421 364 405 423 361
Gd-enhancing
lesion-free
New/enlarging MRI
activity-free
402 414 361
Pro
po
rtio
n o
f P
ati
en
ts,
% (
95
% C
I)
0
20
40
60
80
100
Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3
T2 lesion-free
Patients were treated with alemtuzumab 12 mg at baseline and 12 months later
Re-treatment in Year 3 was administered upon recurrence of disease activity
18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated with
alemtuzumab in Year 3; <3% were treated with another DMT in Year 3
AAN 2014
Blitz S65-008
Rheumatoid arthritis End-stage joint disease
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates
DAF1,2
Natalizumab and Functional Benefit – Double-blind, Placebo-controlled Study (AFFIRM)
1. Phillips JT et al., Mult Scler 2011;17:970-979; 2. Munschauer F et al., ECTRIMS Meeting September 9–12, 2009, Dusseldorf, Germany,
P434; 3. Balcer LJ et al., J Neurol Sci 2012;318:119-24; 4. Weinstock-Guttmanen B et al., J Neurol 2012;259:898–905.
Compared with placebo, Natalizumab showed sustained improvement in
• EDSS1
• Upper limb2
• Walking2
• Vision3
and reduced the risk of progression of cognitive deficit4
-0.30.20.71.21.72.22.73.23.74.2
0.5 5
Hazard Ratio (95% Confidence Interval)
0.5 1.0 1.5 2.0 3.0 4.0 5.0
Favours placebo Favours natalizumab
Cognitive deficit – PASAT-3 (P=0.013)
Vision – 1.25% low contrast acuity (P=0.014)
Vision - 2.5% low contrast acuity (P=0.012)
Timed 25-foot walk (P=0.028)
9-hole peg test (P=0.044)
EDSS (P=0.006)
Favours natalizumab Favours placebo
Alemtuzumab improved pre-existing disability
CARE-MS II
aSecondary endpoint; defined as decrease of ≥1 EDSS point lasting at least 6 months, assessed in patients
with baseline EDSS ≥2.0. bTertiary endpoint. cMeasured by SRD score in relapsing patients.
Coles AJ, et al. Lancet. 2012;380:1829-1839.
IFNB-1a 44 μg Alemtuzumab12 mg
‒0.17
P<0.0001
+0.24
ED
SS
Sco
re, m
ea
n
3.25
3.00
2.75
2.50
2.25
Follow-Up Month
0 3 6 9 12 15 18 21 24
40
30
20
10
0
Pa
tie
nts
With
6-M
on
th S
RD
(%
)
29%
13%
P=0.0002
Mean EDSS Change From Baselinea SRDb
Follow-Up Month
0 3 6 9 12 15 18 21 24
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device)
DAF1,2
Re-defining the therapeutic window
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Window of therapeutic efficacy
Theoretical model: treat early and effectively
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease Onset
Dis
abili
ty
Time is brain
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Window of therapeutic efficacy
Tur et al. Arch Neurol. 2011 Nov;68(11):1421-7.
Motor system to legs
Cerebellar or balance systems
Bladder Therapeutic window 1
Therapeutic window 2
Therapeutic window 3
Upper limbs
Sensory
Cognition
Vision
Etc.
Therapeutic window 4
Therapeutic window 5
Therapeutic window 6
Therapeutic window 7
Therapeutic window 8, etc….
Diagnosis of Progressive MS
Effective DMTs could still target the remaining windows of therapeutic opportunity for individual
neurological systems
The Asynchronous Progressive MS hypothesis
Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial
Chataway Lancet 2014; 383: 2213–21.
Normal neurological examination
No disability
Minimal disability
Moderate disability
Relatively severe disability
Disability precludes full daily activities
Assistance required to walk Restricted
to a wheelchair
Restricted to bed or chair Confined
to bed
Death
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0
EDSS
Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
Neurology 1983; 33:1444–1452.
Ceiling and floor effects
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
Zajicek et al. Lancet Neurol 2013; 12: 857–65.
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(E
DS
S p
rog
ressio
n)
Treatment group
Active
Placebo
Slides courtesy of John Zajicek.
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(E
DS
S p
rog
ressio
n)
Baseline EDSS score
4
4.5
5
5.5
6
6.5
Slides courtesy of John Zajicek.
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
0 200 400 600 800 1000 1200
0.0
0.2
0.4
0.6
0.8
1.0
Time to EDSS progression (days)
P(E
DS
S p
rog
ressio
n)
Treatment group
Active
Placebo
Log rank test P = 0.01
Slides courtesy of John Zajicek.
Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial
Long-term effect of early treatment with IFNB-1b after CIS: 5-yr active extension of the phase 3 BENEFIT trial
Kappos et al. Lancet Neurol 2009; 8: 987–97.
3 6 9 12 24
EDSS
0
TIME
Active (no progression)
Placebo (confirmed progression)
Delayed Recovery
Equal exit EDSS
Therapeutic strategies
Proof of concept Trials
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
Phase 2A study of natalizumab in progressive MS: CSF markers of axonal damage and demyelination (2° endpoint)
Slide courtesy of Romme Christensen, ECTRIMS 2012. Oral presentation 170.
NIND Mean +/- 95% CI
p=0.03
CSF
Ne
uro
fila
men
t lli
ght
ng/
L
p=0.048
CSF
MB
P n
g/m
l
NIND Mean +/- 95% CI
Natalizumab → SPMS (ASCEND STUDY) ClinicalTrials.gov ID: NCT01416181
Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis
Kuhle et al. submitted for publication Fingolimod → PPMS (INFORMS STUDY)
ClinicalTrials.gov ID:NCT00731692
Siponimod → SPMS (EXPAND STUDY)
ClinicalTrials.gov ID: NCT01665144
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device) Normalisation of CSF neurofilament levels
DAF1,2
38 year old woman with left optic neuritis
sTE fFLAIR images
Baseline 52 weeks
Hickman et al. Neuroradiology 2001;43:123-8.
Trapp et al. N Engl J Med 1998.
Acute mono-focal lesion
Acute neuroprotection
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device) Normalisation of CSF neurofilament levels Normalisation of retinal nerve fibre layer thinning (OCT)
DAF1,2
Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-p75NTR
GAP-43
NCAM
Neuregulin
Slide courtesy of Klaus Schmierer.
Agents in trial
1. GSK239512: histamine H(3)
receptor antagonist
2. BIIB033: anti-LINGO-1
3. Clemastine: anti-histamine
4. IRX4204 & Bexarotene: RXR-
agonists
5. Etc.
No evident disease activity: NEDA
Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Treat-2-target What is NEDA?
× No relapses × No sustained disability progression (EDSS) × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions Patient-related outcomes (PRO or PROMS / Smart Devices) Normalisation of brain atrophy rates Sustained improvement in disability (PROM / Smart Device) Normalisation of CSF neurofilament levels Normalisation of retinal nerve fibre layer thinning (OCT) Improvement in central conduction times (VEPs)
Etc.
DAF1,2
Therapeutic hierarchy
Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
Brain
Health
Initiative
• Smoking
• Exercise
• Diet
• Sleep
• Co-morbidities
• Infections
• Concomitant
medications
Conclusions • Therapeutic target is moving
– NEDA
– PROMS/PROS/Smart Devices
– End-organ damage
– Sustained improvement in disability
– Remyelination
– Neurorestoration
• Therapeutic time window
– Early or late
• Redefining progressive MS
– Asynchronous disease course
– Therapeutic lag
• Novel PoC trials
– OCT in acute optic neuritis
– CSF NF levels in SPMS
– VEPs and MTR in remyelination trials