Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty, Dpt. of...
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![Page 1: Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty, Dpt. of Neurology Praha, Czech Republic.](https://reader035.fdocuments.in/reader035/viewer/2022062516/56649e6a5503460f94b67481/html5/thumbnails/1.jpg)
Disease modifying drugs in MS
Eva Havrdová
Charles University, First Medical Faculty,Dpt. of Neurology
Praha, Czech Republic
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MS – what we want to treat
autoimmune inflammation in the CNSdriven by myelin antigens
myelin disintegrationaxonal loss
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Transsection of demyelinated axons by cytotoxic lymfocyte
Wekerle et al. (2000)
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Early diagnostics is the clue for early treatment
MRI, cerebrospinal fluid, evoked potentials
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cerebrospinal fluid: oligoclonal bands, plasma cells
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What we CAN treat? acute attacks (new or recurrent symptoms lasting > 24 hrs),
long term treatment to modify the natural course of the disease (to prevent inflammation and axonal loss) = moderate but only prevention of disease progression
symptomatic treatment in any disease stage to alleviate symptoms and improve QoL
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We have NO drugs to treat neither axonal loss nor to prevent it untill now
EXCEPT
EARLY suppression of CNS inflammation
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Treatment of acute attackTreatment of acute attack
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Treatment of acute attack
international consensus:
high-dose methylprednisolon (corticosteroids) 3-5g
with prevention of side-effects (protection of gut, antiosteoporotic treatment, etc)
Treatment of acute attack
international consensus:
high-dose methylprednisolon (corticosteroids) 3-5g
with prevention of side-effects (protection of gut, antiosteoporotic treatment, etc)
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Treatment of acute attackTreatment of acute attack
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Is it meaningful to treat all attacks with steroids?
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Influence of methylprednisolon on tissue integrity
B-CEL: lesions followed before Gd enhancement (n=15)S-CEL: lesions treated with steroids (n=15)
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Long term treatment with disease modifying drugs
(DMDs)
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permanentdisability
Axo
nal lo
ssA
xon
al loss
RR-MS SP-MS
treatment effect (1)
sile
ntc l
inic
al
t
treatment effect (2)
treatment effect (???)
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international consensus= early treatment initiation to
decrease relapse rate prevent disability progression
international consensus= early treatment initiation to
decrease relapse rate prevent disability progression
When to introduce this treatment?
disease activity (2 attacks / 2 years)
remittent disease stage
disability not too severe (chronic progression starts somewhere around Kurtzke EDSS 4-5)
compliance is guaranteed
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Long-term treatment to alter the natural course of MS:
first line treatment IFN-beta, glatiramer acetate
second-line treatment IVIG
third-line treatment azathioprin (older immunomodulators and immunosupressants)
Long-term treatment to alter the natural course of MS:
first line treatment IFN-beta, glatiramer acetate
second-line treatment IVIG
third-line treatment azathioprin (older immunomodulators and immunosupressants)
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1,75
1,2
1,5 1,451,36
1,27
0,9
1,28
0,84
1,26
0,84
0,61
0,86
0,590,52
0
0,5
1
1,5
2 before study placebo active medication
* high dose treatment groups
IFNß-1b*IFNß-MS Study
(n=227)
IFNß-1aMSCRG (n=172)
GlatiramerJohnson et al.
(n=215)
IVIGAIMS
(n=147)
IFNß-1a*PRISMS (n=371)
x axis: compared drugs: IFNB-1b=Betaferon, IFNB-1a=Avonex, IFNB-1a *=Rebif, Glatiramer= Copaxone, IVIG= intravenous immunoglobulins
y axis: relapse rate = number of attacks per year
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What to do when this treatment fails?
(relapses, progression of disability, MRI activity)
Therapy escalation
(Rieckmann 2004, Toyka 2008)
natalizumab (Tysabri)
pulses of cytostatics (mitoxantron, cyclophosphamide)
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Role for adhesion molecules(implications for MS therapy)
Reduced Leukocyte Infiltration and Brain Inflammation
Leukocyte Infiltration and Brain Inflammation
Leukocyte
Chemoattractant signal
441 (VLA-4)1 (VLA-4)
Blood Vessel Lumen
Endothelial Cells
Tissue VCAM-1VCAM-1
LeukocyteChemoattractant Signal
441 (VLA-4)1 (VLA-4)
Blood Vessel Lumen
Endothelial Cells
Tissue VCAM-1VCAM-1
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AFFIRM study: Relapse rate Primary Endpoint for Year 1
FDA per subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction)
P<0.0001
Placebo n=315Natalizumab n=627
P<0.0001P<0.0001
0.78
0.68 0.73
0.270.20
0.24
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Over 1 Year 1-2 Years Over 2 Years
An
nu
aliz
ed R
elap
se R
ate
(95%
CI)
66%71%
68%
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Mea
n N
o. o
f N
ew o
r E
nla
rgin
g T
2 L
esio
ns
0
2
4
6
8
10
12
6.1
1.2
4.9
0.7
11.0
1.9
P<0.0001Placebo n=315
Natalizumab n=627
83%
80%86%
Year 0–1 Year 1–2 Year 0–2
No of new and enlarging T2 lesions
P<0.0001
P<0.0001
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Number of Patients at RiskPlaceboNatalizumab
315 296 283 264 248 240 229 216 208 200627 601 582 567 546 525 517 503 490 478
Pro
po
rtio
n W
ith
Su
stai
ned
Pro
gre
ssio
nHazard Ratio (HR)=0.58 (95% CI: 0.43, 0.77)
P=0.0002 Placebo 29%
Natalizumab 17%
0.0
0.1
0.2
0.3
0.4
Weeks0 12 24 36 48 60 72 84 96 108 120
199473
Sustained Disability ProgressionSustained Disability Progression(Pre-specified Primary Endpoint)(Pre-specified Primary Endpoint)
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The more effective the therapy is,
the more risks you face
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SENTINEL – study combining natalizumabu with Avonex
After > 2 years of administration: 2 serious adverse events
Progressive multifocal leukoencephalopathy
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Registration in EU: August 2006 strictly for monotherapySafety measures: baseline MRI, normal lymphocyte count, no history of malignancy or severe immunosuppression, neurologists trained in PML diagnostics
June 2008: 2 cases of PML in monotherapy in EU
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Negotiations for reimbursement:
European Code of Good Practice National societies of professionals National patient organizations
Help: pharmacoeconomic data scientific data on early treatment (what is lost is not regained), placebo controlled randomized trials, international guidelines (included in the Code) PR strategies
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Never ever give up hope !