Disease modifying drugs in MS
Sponsored Links
This presentation is the property of its rightful owner.
1 / 27

Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty, PowerPoint PPT Presentation


  • 75 Views
  • Uploaded on
  • Presentation posted in: General

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.

Download Presentation

Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty,

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

internationalconsensus:

 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)


silent

clinical

RR-MS

SP-MS

permanent

disability

Axonal loss

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)


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


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)


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


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)


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


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


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 !


  • Login