Disease modifying drugs in MS
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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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Disease modifying drugs in ms eva havrdov charles university first medical faculty

Disease modifying drugs in MS

Eva Havrdová

Charles University, First Medical Faculty,

Dpt. of Neurology

Praha, Czech Republic


Disease modifying drugs in ms eva havrdov charles university first medical faculty

MS – what we want to treat

autoimmune inflammation in the CNS

driven by myelin antigens

myelin disintegration

axonal loss


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Transsection of demyelinated axons by cytotoxic lymfocyte

Wekerle et al.(2000)


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Early diagnostics is the clue for early treatment

MRI, cerebrospinal fluid, evoked potentials


Disease modifying drugs in ms eva havrdov charles university first medical faculty

cerebrospinal fluid: oligoclonal bands, plasma cells


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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

EXCEPT

EARLY suppression of CNS inflammation


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Treatment of acute attack


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Treatment of acute attack

internationalconsensus:

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

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Treatment of acute attack


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Is it meaningful to treat all attacks with steroids?


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Influence of methylprednisolon on tissue integrity

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

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Long term treatment with disease modifying drugs (DMDs)


Disease modifying drugs in ms eva havrdov charles university first medical faculty

silent

clinical

RR-MS

SP-MS

permanent

disability

Axonal loss

treatment

effect (2)

treatment

effect (1)

treatment

effect (???)

t


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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)


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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)


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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)


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

The more effective the therapy is,

the more risks you face


Disease modifying drugs in ms eva havrdov charles university first medical faculty

SENTINEL – study combining natalizumabu with Avonex

After > 2 years of administration: 2 serious adverse events

Progressive multifocal leukoencephalopathy


Disease modifying drugs in ms eva havrdov charles university first medical faculty

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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

  • 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


Disease modifying drugs in ms eva havrdov charles university first medical faculty

Never ever give up hope !


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