The case for NEDA-4
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NEDA 4 Framing the Window of Opportunity in MS
Gavin Giovannoni
Barts and The London
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Disclosures
Over the last 15 years 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, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
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. He would also like to thank numerous colleagues for providing him with data and/or slides for this, and other, presentations.
Professor Giovannoni’s visit to Lebanon has been kindly sponsored by Novartis, therefore please interpret anything he says about fingolimod, Novartis’s product, in the correct context.
This presentation has been designed and prepared by Professor Giovannoni with no input from any other parties.
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Who thinks multiple sclerosis should be redefined as a dementia?
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Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.
• Normal activities of daily living
• Physical
• Mental
• Social
• Occupational
• Lasting more than six months
• Not present since birth
• Not associated with a loss or alteration of consciousness
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Consequences of increasing EDSS scores: loss of employment1
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
Pro
po
rtio
n o
f P
ati
en
ts ≤
65
Ye
ars
Old
Wo
rkin
g (
%)
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.
1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;
2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2
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Impact of MS: cognitive functioning in the CIS stage
Feuillet et al. MSJ 2007
CIS Patients n = 40
57%
7%
-20%
0%
20%
40%
60%
Healthy Controls n = 30
p < 0.0001
Deficits were found mainly in memory, speed of information
processing, attention and executive functioning Patients failing
≥ 2 cognitive tests
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163 patients with “benign” MS
(disease duration >15 years and EDSS <3.5):
45% cognitive impairment
49% fatigue
54% depression
What is benign MS?
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Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.
• Normal activities of daily living
• Physical
• Mental
• Social
• Occupational
• Lasting more than six months
• Not present since birth
• Not associated with a loss or alteration of consciousness
“Multiple sclerosis is a preventable dementia.”
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Control Multiple sclerosis
Slide courtesy of Dr Klaus Schmierer
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Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
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Association of MRI metrics and cognitive impairment in radiologically isolated syndromes
Amato et al. Neurology. 2012 Jan 31;78(5):309-14.
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AAN 2013
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AAN 2013
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11,000 to 1
Trapp, et al. NEJM 1998;338:278-85
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Kutzelnigg, et al. Brain 2005
Is MS a gray matter disease?
Female
Age 46y
SPMS for 16y
Mean ~ 13% GML SPMS ~ 0-69% PPMS ~ 0-39%
Mean ~ 24% WML (SP)
Mean ~ 7% WML (PP)
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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
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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.
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Reversal of pseudoatrophy
Baseline Year 1/2 Year 3
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No evidence of 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
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
Should we be adding a brain atrophy metric to our definition of NEDA?
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• Post-hoc analysis of a pivotal clinical trial of IFN β-1a IM1
• Treatment with IFN β-1a IM resulted in a 55% reduction in brain atrophy vs. placebo during the second year of a clinical trial (N = 140)
• Analysis of the MRI cohort of the European IFN β-1a IM dose comparison study2
• Derived from a double-dose study; all patients on-treatment; modelled from pre-treatment rate
IFN β-1a IM
BPF, brain parenchymal fraction; IFN β, beta-interferon; IM, intramuscular; MRI, magnetic resonance imaging; n.s., not significant. 1. Rudick RA, et al. Neurology 1999; 53:1698−1704; 2. Hardmeier M, et al. Neurology 2005; 64:236−240.
–1.06% per year
–0.33% per year
Treatment initiation
Month
0.795
0.800
0.805
0.810
0.815
0.820
0.825
0.830
–3 0 3 6 9 12 18 24 30 36 21 15 27 33
BP
F
p < 0.01
n.s.
Year 1
Year 2
Year 3
Month 4−12
Baseline− Month 4
p < 0.05
p < 0.01
n.s.
–1.6
–1.4
–1.2
–1.0
–0.8
–0.6
–0.4
0.0
–0.2
Annual MRI group (n = 368)
Frequent MRI subgroup (n = 138)
Re
lati
ve B
PF
chan
ge (
%)
–0.482% (+/ –0.58)
–0.228% (+/ –0.73)
–0.348% (+/ –0.61)
–0.393% (+/ –0.58)
–0.686% (+/-0.79)
–0.377% (+/-0.77)
–0.378% (+/-0.73)
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Teriflunomide
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TEMSO: 2-year, randomized, placebo-controlled Phase III trial of teriflunomide in patients with RMS (N = 1,088)
Change from baseline in white matter volume
Teriflunomide: white matter atrophy
RMS, relapsing MS. Wolinsky JS, et al. Mult Scler 2013; 19:1310−1319.
• Whole brain atrophy: − no significant effect
• Grey matter atrophy:
− no significant effect
Me
an ±
SE
chan
ge
fro
m b
ase
line
(m
l)
Week
Placebo Teriflunomide 7 mg Teriflunomide 14 mg
2.4
0.8
–0.8
–2.4
–4.0
–5.6
0 24 48 72 108
p = 0.0002
p = 0.0609
No. of patients
Placebo 358 329 309 270 256
7 mg 359 339 301 273 262
14 mg 355 328 293 273 260
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Dimethyl fumarate
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Dimethyl fumarate
DEFINE: 2-year, randomized, placebo-controlled study of DMF in patients with RRMS (N = 1,237)1
CONFIRM: 2-year, randomized, placebo-controlled active reference (GA) comparator study of DMF in patients with RRMS (N = 1,430)2
BID, twice daily; DMF, dimethyl fumarate; TID, three times daily. 1. Arnold DL, et al. AAN 2012. Abstract IN3-2.002; 2. Miller D, et al. ENS 2012. O259.
Week 24−Year 2
−30% vs. placebo (p = 0.02)
−17% vs. placebo (p = 0.2478)
• Significant reduction in brain volume loss vs. placebo with DMF BID but not TID
• No significant reduction in brain volume loss vs. placebo with both doses
−6% vs. placebo
(p = 0.831)
−3% vs. placebo
(p = 0.562)
−16% vs. placebo
(p = 0.706)
Week 24−Year 2
Me
dia
n c
han
ge
in w
ho
le b
rain
vo
lum
e (
%)
Me
dia
n c
han
ge
in w
ho
le b
rain
vo
lum
e (
%)
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Natalizumab
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-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
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Alemtuzumab
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Reduction in brain atrophy on alemtuzumab
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Fingolimod
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• In all three studies: PBVC assessed for all patients, prospectively, using the SIENA method • Fingolimod significantly reduced brain volume loss over 2 years vs. placebo
• These reductions were observed after 6 months (first post-baseline scan) • Fingolimod significantly reduced brain volume loss over 1 year vs. IFN β-1a IM
Atrophy data from three fingolimod trials
SIENA, Structural Image Evaluation, using Normalisation, of Atrophy. ITT population with evaluable MRI images at baseline and end of core study phase (Month 24). p values are for comparisons over Months 0–6, Months 0–12, Months 0–24. TRANSFORMS: *** p < 0.001 vs. IFN β-1a IM. Wilcoxon rank sum test; FREEDOMS/FREEDOMS II: * p < 0.05; ** p < 0.01; *** p < 0.001 vs. placebo. Rank ANCOVA adjusted for treatment, region and baseline normalized brain volume. 1. Cohen JA, et al. N Engl J Med 2010; 362:402–415; 2. Kappos L, et al. N Engl J Med 2010; 362:387–401; 3. Radue EW, et al. ECTRIMS 2012. P724.
Me
an P
BV
C f
rom
bas
elin
e
TRANSFORMS1
Time (months)
−32%
reduction
0.0
–0.4
–0.6
–1.4
–0.2
–0.8
–1.2
–1.0
0 24 12
*** n = 429
n = 431
0.0
–0.4
–0.6
–1.4
–0.2
–0.8
–1.2
–1.0
0 24 12 6
FREEDOMS2
Time (months)
−35%
reduction
*
**
***
n = 357
n = 331
0.0
–0.4
–0.6
–1.4
–0.2
–0.8
–1.2
–1.0
0 24 12 6
FREEDOMS II3
Time (months)
−33%
reduction
* ***
*** n = 358
n = 355
Placebo Fingolimod 0.5 mg IFN β-1a IM
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** **
***
***
*
FREEDOMS extension study: change in mean brain volume after switching to fingolimod
ITT population. * p < 0.05, ** p < 0.01, *** p <0.001 vs. placebo. Rank ANCOVA adjusted for treatment group, country and baseline normalized brain volume. †In the extension, these patients were initially re-randomized to fingolimod 0.5 or 1.25 mg, and then all transitioned to open-label fingolimod 0.5 mg. n, number of patients with non-missing value. Radue EW, et al. ENS 2012. O219.
27.6%
reduction
p < 0.05
0.5 mg vs.
placebo
Month
Placebo–fingolimod†
Fingolimod 0.5 mg
Me
an p
erc
en
t ch
ange
in b
rain
vo
lum
e f
rom
bas
elin
e
n = 395
n = 383
383
358 357
331
290
254 115
93
Point of switch placebo–fingolimod
Fingolimod delayed brain
volume loss vs. placebo
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• For all annual BVL thresholds, significantly more NEDA-4 patients were in the fingolimod-treated group than in the placebo group
Results: NEDA-4 by Annual BVL Thresholds
aORs were derived from logistic regression of freedom from disease activity on treatment.
Kappos et al. ACTRIMS/ECTRIMS 2014. FC1.5
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Residual deficits: • Walking distance >500m
• Unable to run
• Exercise induces intermittent
sensory symptoms in L arm
• Mild urinary frequency
17-yr girl, myelitis
Jun-2000
1st-yr University
L-optic neuritis
Feb-2001
clumsy
left hand
Jan -2002
pins & needles
in legs
Oct-2003
R optic neuritis
Mar-2004
Brainstem
syndrome;
diplopia and
ataxia
Dec 2007
Cervical cord
relapse
weak L arm
with pain
Jan 2008
Bladder
dysfunction
depression,
anxiety and
fatigue
Reduced
mobility
Mild urinary frequency
No depression ,anxiety
or fatigue
Fully mobile
NEDA (no evident disease activity)
Feb-2008 to May-2014
IFN-beta
Feb-2001
Natalizumab
Jan-2008
ED
SS
IFN-beta Natalizumab Jun-2000 May-2014
6.0
3.5 3.5
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MRI – progressive brain atrophy
Dec 2007 Jul 2010 Jul 2013
Is this patient in long-term remission?
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Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
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Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
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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
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38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London
Glatiramer acetate treatment for 3 years (good adherence and tolerance)
Relapse with a mild left sensory loss
Referred to me for a second opinion
Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk)
Mild persistent flu-like side effects and lymphopenia
12/12’s neutralizing antibodies screen negative
Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol
Teacher
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38-year-old teacher with relapsing–remitting MS As a result of fatigue and cognitive problems she is forced to take
early retirement Although fully functional she develops depression and anxiety In her spare time she spends a lot of time on the web and becomes
an expert patient Widely read
Net savvy; regular follower of www.ms-res.org
Teacher X
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Rheumatoid arthritis End-stage joint disease
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Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases
Sandborn et al. Journal of Crohn's and Colitis 2014(8):927–935
X
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Overview DMTs and BVL
IV, intravenous.
Therapy Administration Reduction in PBVC
IFN β/GA SC IM
IFN β-1a IM: positive effect Year 2
Teriflunomide Oral Not significant
DMF Oral −30% (for BID in DEFINE); not significant for TID Not significant for both doses in CONFIRM
Fingolimod Oral –35% (FREEDOMS); –33% (FREEDOMS II); –32% (TRANSFORMS)
Natalizumab IV Significant in year 2
Alemtuzumab IV –42% (naive vs. IFN); –24% (previously treated vs. IFN)
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Conclusions
• MS is a bad disease
• Mortality, disability, unemployment, divorce, suicide cognitive impairment, etc.
• MS is as much a gray matter disease as it is a white matter disease
• Brain volume loss or atrophy
• Present from the earliest stages of the disease
• Occurs at a constant rate (>2x normal)
• Predicts long-term disability
• Associated with cognitive impairment
• Should MS be reclassified as a dementia?
• Or at least a preventable dementia?
• Being accepted as a preventable dementia will help drive adoption of early effective treatment and zero tolerance (T2T-NEDA-ZeTo)
• Should we include brain atrophy as part of our treatment target?
• NEDA-4
• Brain atrophy occurs very early in the course of the disease (RIS/CIS)
• Can brain atrophy be normalised in MS with early treatment?