Disease modifying drugs in M Eva Havrdová Charles University, First Medical Faculty, Dpt. of Neurology Praha, Czech Republic
Dec 29, 2015
Disease modifying drugs in MS
Eva Havrdová
Charles University, First Medical Faculty,Dpt. of Neurology
Praha, Czech Republic
MS – what we want to treat
autoimmune inflammation in the CNSdriven by myelin antigens
myelin disintegrationaxonal loss
Transsection of demyelinated axons by cytotoxic lymfocyte
Wekerle et al. (2000)
Early diagnostics is the clue for early treatment
MRI, cerebrospinal fluid, evoked potentials
cerebrospinal fluid: oligoclonal bands, plasma cells
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
We have NO drugs to treat neither axonal loss nor to prevent it untill now
EXCEPT
EARLY suppression of CNS inflammation
Treatment of acute attackTreatment of acute attack
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)
Treatment of acute attackTreatment of acute attack
Is it meaningful to treat all attacks with steroids?
Influence of methylprednisolon on tissue integrity
B-CEL: lesions followed before Gd enhancement (n=15)S-CEL: lesions treated with steroids (n=15)
Long term treatment with disease modifying drugs
(DMDs)
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 (???)
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
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)
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
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)
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
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%
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
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)
The more effective the therapy is,
the more risks you face
SENTINEL – study combining natalizumabu with Avonex
After > 2 years of administration: 2 serious adverse events
Progressive multifocal leukoencephalopathy
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
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
Never ever give up hope !