Transcript Prezentace aplikace PowerPoint

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 CNS
driven by myelin antigens
myelin disintegration
axonal 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 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
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)
Axonal loss
RR-MS
SP-MS
permanent
disability
treatment
effect (2)
treatment
effect (1)
treatment
effect (???)
t
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)
before study
2
placebo
active medication
1,75
1,5
1
1,5
1,27
1,36
1,28
1,2
0,9
0,84
1,45
0,86
0,61
1,26
0,84
0,59
0,52
0,5
0
IFNß-1b*
IFNß-1a
IFNß-MS Study
(n=227)
MSCRG
(n=172)
IFNß-1a* Glatiramer
PRISMS
(n=371)
Johnson et al.
(n=215)
IVIG
AIMS
(n=147)
* high dose treatment groups
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)
Leukocyte
Chemoattractant signal
a4b1 (VLA-4)
Blood Vessel Lumen
Leukocyte
Infiltration
and Brain
Inflammation
Endothelial Cells
Tissue
VCAM-1
Leukocyte
Chemoattractant Signal
a4b1 (VLA-4)
Blood Vessel Lumen
Endothelial Cells
Tissue
VCAM-1
Reduced
Leukocyte
Infiltration
and Brain
Inflammation
Annualized Relapse Rate (95% CI)
AFFIRM study: Relapse rate
Primary Endpoint for Year 1
1.0
0.9
Placebo n=315
Natalizumab n=627
0.78
0.73
0.68
P<0.0001
0.8
P<0.0001
P<0.0001
0.7
0.6
66%
0.5
0.4
0.27
0.20
0.3
68%
71%
0.24
0.2
0.1
0.0
Over 1 Year
1-2 Years
Over 2 Years
FDA per subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction)
No of new and enlarging T2 lesions
Mean No. of New or Enlarging T2 Lesions
Placebo n=315
12
P<0.0001
Natalizumab n=627
11.0
10
8
P<0.0001
6.1
P<0.0001
6
83%
4.9
4
80%
86%
2
1.2
1.9
0.7
0
Year 0–1
Year 1–2
Year 0–2
Sustained Disability Progression
Proportion With Sustained Progression
(Pre-specified Primary Endpoint)
0.4
Hazard Ratio (HR)=0.58 (95% CI: 0.43, 0.77)
P=0.0002
Placebo 29%
0.3
0.2
Natalizumab 17%
0.1
0.0
0
Placebo
Natalizumab
12
24 36
48
60 72
Weeks
84
96 108 120
Number of Patients at Risk
315 296 283 264 248 240 229 216 208 200 199
627 601 582 567 546 525 517 503 490 478 473
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
monotherapy
Safety 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 !
