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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.

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slide1
Disease modifying drugs in MS

Eva Havrdová

Charles University, First Medical Faculty,

Dpt. of Neurology

Praha, Czech Republic

slide2
MS – what we want to treat

autoimmune inflammation in the CNS

driven by myelin antigens

myelin disintegration

axonal loss

slide4
Early diagnostics is the clue for early treatment

MRI, cerebrospinal fluid, evoked potentials

slide6
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

slide7
We have NO drugs to treat neither axonal loss nor to prevent it untill now

EXCEPT

EARLY suppression of CNS inflammation

slide9
Treatment of acute attack

internationalconsensus:

 high-dose methylprednisolon (corticosteroids) 3-5g

with prevention of side-effects (protection of gut, antiosteoporotic treatment, etc)

slide12
Influence of methylprednisolon on tissue integrity

B-CEL: lesions followed before Gd enhancement (n=15)

S-CEL: lesions treated with steroids (n=15)

slide14
silent

clinical

RR-MS

SP-MS

permanent

disability

Axonal loss

treatment

effect (2)

treatment

effect (1)

treatment

effect (???)

t

slide15
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
slide16
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)

slide17
IFNß-1b*

IFNß-MS Study

(n=227)

IFNß-1a

MSCRG

(n=172)

IFNß-1a*

PRISMS

(n=371)

Glatiramer

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

slide18
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)

slide19
Leukocyte

Chemoattractant signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue

VCAM-1

Leukocyte

Chemoattractant Signal

a4b1 (VLA-4)

Blood Vessel Lumen

Endothelial Cells

Tissue

VCAM-1

Role for adhesion molecules(implications for MS therapy)

Leukocyte Infiltration and Brain Inflammation

Reduced Leukocyte Infiltration and Brain Inflammation

slide20
AFFIRM study: Relapse ratePrimary Endpoint for Year 1

0.78

1.0

0.73

0.68

0.9

0.8

0.7

0.6

Annualized Relapse Rate (95% CI)

0.5

0.4

0.27

0.24

0.20

0.3

0.2

0.1

0.0

Over 1 Year

1-2 Years

Over 2 Years

Placebo n=315

Natalizumab n=627

P<0.0001

P<0.0001

P<0.0001

66%

68%

71%

FDA per subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction)

slide21
No of new and enlarging T2 lesions

Placebo n=315

P<0.0001

Natalizumab n=627

12

11.0

10

P<0.0001

8

6.1

P<0.0001

83%

Mean No. of New or Enlarging T2 Lesions

6

4.9

4

80%

86%

1.9

2

1.2

0.7

0

Year 0–1

Year 1–2

Year 0–2

slide22
Sustained Disability 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

Proportion With Sustained Progression

Natalizumab 17%

0.1

0.0

0

12

24

36

48

60

72

84

96

108

120

Weeks

Number of Patients at Risk

Placebo

315

296

283

264

248

240

229

216

208

200

199

Natalizumab

627

601

582

567

546

525

517

503

490

478

473

slide24
SENTINEL – study combining natalizumabu with Avonex

After > 2 years of administration: 2 serious adverse events

Progressive multifocal leukoencephalopathy

slide25
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

slide26
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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