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 !