Disease Modifying Therapies in Multiple Sclerosis

1
Disease Modifying Therapies in Multiple
Sclerosis

• ????? ?????
• ??????? ????? ????? - MRCP
• ???? ?????
• ???? ?????? ??????? ???? ?????

2
Introduction

• ???? ???????? ??????? ????? ???
• ????? ??? ?????
• ????? ??? ???????
• ????? ???? ?????

3
Introduction

• ??????? ??????? ?????
• Glatiramer acetate (Copaxone)
• Interferon beta 1b (Betaseron)
• Interferon beta 1a (Avonex)
• Interferon beta 1a (Rebif)
• Mitoxantrone (Novantrone)
• Natalizumab (Tysabri)

4
1- Glateramer acetat

• ?????? ??? ?????? ????
  (????? ??? ???? ??????? ??
  ????? T helper ?? ????? 1??? 2 ????? ???? BBB
  ????? ???? ???? ????????)
• ??????????? RRMS
• ?????? 20 mg\ sc\ q day
• ???????? ???????? ??? ??????
• ????????? ????????
• ???? ????? ? ??? ?????
• ???? ????? ????? ??? ???? ???? ???? ????
  ?? ????????? ??????
• ?????? ????? ???? ??? ???? ?? ????? ?? ????? ?
  ????? ?? ??? ???- ??? ???? ??? ? ????? ????
  ???????? ???? ??? ??? ??? ??? .
• ????????? ?? ????? ???? ??? ???????? B
  ??? ??? ?? ???? ?? ?????? ??
  ??????????? ?? ????? ? ??????? ??? ??????? ???
  ????? ????

5
Interferon beta

• ??????
• ???????? ???? ?? MS
• ????? ???? ????? ????????????? ???????
  ??????????? ??? I ??????? ?? ???? ???????
  ??????? (INF type 1 receptor )
• ??????? ?????? ??????? ?????
• ????? ?????? ??????? T ???????
• ???? ????? proinflammatory cytokine
• Down regulation of antigen presentation
• ????? ?????????? ??????? ?? ????
• Reduction of matrix metalloproteinase production

6
Interferon beta

• ???????? ????????
• LFT CBC ?? ????? ?? ?????? 1 ? 3 ?6
  ?? ?? 3- 6 ???? ??? ?????? ????????
• ????? ????? ??? ???? ??????? ?? ????? ?????
  ?????? ???? ?? 6 ????

7
Interferon beta

• ????????? ????????
• ?????? ????? ???? ????? (?????? ??????)
• ??? ???? ???? ????? (????)
• ????
• ?????? ???
• ????? ????? ??????? (??? ???? ????? ??????? -
  ??? ) ????? ??????? ???????(16)
• ???( ???????? ?????? ) ?????? LFT (?????
  ??????? ???????)
• ????? ?????? ??? ???? - ?????? ?????? ?????
  ???????? ???????? ???? ????? .

8
2- Interferon beta-1aAvonex

• ???????????
• ??????? ??????? ?? MS
• ??????? ?????? ?????? ?? ??????? ???????? ???????
  ?? MS
• ?????? 30 ??? / ????? / ??? ???????

9
3- Interferon beta-1aRebif

• ???????????
• ??????? ??????? ?? MS
• ??????
• 22 ?? 44 ??? / ??? ????? 3???? ???????

10
4- Interferon beta-1bBetaseron

• ???????????
• ??????? ???????
• CIS
• SPMS
• ??????
• 250 ??? / ??? ????? / qOD

11
Clinically Isolated syndromeCIS

• ???? ?? ????? ???? ???????? ???? ???? ?????
• ????? ??????
• ?????? ??????
• ??? ??????
• 85 ?? ????? MS ?????? ???? ?? CIS
• ?????? AAN ???? ???????? ??????????? ???? Level A
  Recomendation ?? ????? CIS
• US FDA ???? ??? ???? ?? ?? Avonex ? Betaseron
  ????????? ?? ??? ?????? .

12
Clinically Isolated syndromeCIS

• CHAMPS
• Avonex vs placebo
• Randomized, double blind,383 patients with CIS
  and at least 2 MRI lesions
• Probability of developing CDMS lower in Avonex
  group Vs placebo (35 Vs 50 )
• Significantly fewer new or enlarging T2 or T1
  enhancing lesions on MRI .
• Open label extension of CHAMPS placebo group
  offered Avonex and the probability of developing
  CDMS within 5 years was significantly reduced in
  the initially treated group.

13
Clinically Isolated syndromeCIS

• ETOMS
• 309 patients- randomized to receive either
  placebo or 22mcg INF beta-1a once q week for 2
  years
• Allowed patients with multifocal demyelination
  and 4 or more T2 lesions on MRI (Vs CHAMPS)
• Fewer subjects in INF group developed CDMS
  than placebo group
• Significantly fewer new T2 lesions developed in
  the INF group than placebo
• Note that the dose of INF in this study is far
  lower than that was used in trials of RRMS

14
Clinically Isolated syndromeCIS

• BENEFIT
• in 487 CIS patients with at least 2 clinically
  silent MRI lesions
• Interferon beta-1b 250 mcg\sc every other day Vs
  placebo for 24 month or until CDMS was diagnosed
• INF group developed lower numbers of cumulative
  CELs Vs placebo
• Significant delay in time to diagnosis of CDMS in
  INF group (28) Vs placebo (45)

15
Clinically Isolated syndromeCIS

• ????? ???????? ??? ??????????? ???? ??????? ??
  ????? ?????? ????????? ??? ???? CIS
• ????? ??? ?? ???? ?????? ?????? ??????
• ???? ?? ???? ???? ????? ????? ??? ???????
• Level A Recomendation
• ?????? ?????? ?????? ???? ???????? ?????? ??????
  ????? ?????? ?????? ??? ????? ???? ??? ???? ???
  ???? ?????? ??? ??? ???? CIS .

16
Glatiramer AcetateCIS

• No results assessing Glateramer
  acetates impact on CIS have been published to
  date.

17
Relapsing-Remitting MSRRMS

• ???? ??????? ??????? ??? ???? ? ?????? ????????
  ??????? ????? ?? ???? ????? ??????- ??????
• ????? ????????? ???????? ????????? ???? ???????
  ???????? ??? ????????????????.
• ????? ??????? ???? ?? ???? ??? ??? ????? RRMS .

18
RRMS - GA

• Pilot trial ????? ?????????
• Double-blind ,randomized , placebo-controlled ,48
  patients, 2years.
• Proportion of exacerbation-free patients
  significantly higher in GA group (56)Vs
  placebo group (26)

19
RRMS - GA

• Pivotal phase 3 trial
• 251subjects randomized to receive SC placebo or
  20mg GA every day 2years
• 29 reduction in relapse rate in GA group Vs
  placebo.
• More profound effect in subjects with lower EDSS
  score
• No significant difference between the 2 groups in
  sustained disability progression
• MRI end points were not obtained in this study.

20
RRMS - GA

• Extension of phase 3 trial (1-11 months)
• GA showed sustained effect reducin relapses rate
  by 32
• Beneficial impact on progression of disability
  was seen in GA group Vs placebo.
• Extension an open-label phase, 8years
  data
• Early initiation of GA therapy is efficacious in
  slowing disease progression

21
RRMS - GA

• European /Canadian GA Study Group
• 239 patients with RRMS, Randomized , placebo
  controlled , 9 months.
• GA group
• significant reduction in CELs
• Lower numbers of new CELs and T2 lesions
• 33 reduction in relapse rate

22
RRMS Interferon beta

• INF-Beta Multiple Sclerosis Study Group
• Randomized, Multicenter , Double-blind ,
  placebo-controlled .
• 372 RRMS patients, 2years , 3groups
• INF-beta 1b 1.6 mIU
• INF-beta 1b 8 mIU
• Placebo
• Both INF groups had significantly lower relapse
  rate Vs placebo
• Dose related effect in the relapse rate
• No significant difference in EDSS score VS
  placebo
• Significant reduction(80) in new MRI lesions

23
RRMS Interferon beta

• Multiple Sclerosis Collaborative Research Group
• Double-blind , multicenter.
• INF beta-1a , weekly IM,
• Slowed progression of disability
• Fewer exacerbations
• Lower number and volume of CELs on MRI

24
RRMS Interferon beta

• PRISMS Study Group (1998)
• Double-blind , placebo-controlled, 2 years,
  3groups
• INF beta -1a 22 mcg 3 times a week
• INF beta-1a 44 mcg 3 times a week
• Placebo 3 times a week
• Dose related effect in reducing relapses and MRI
  activity.

25
RRMS Interferon beta

• PRISMS Study Group (2001)
• Extension for 4 years and the placebo group
  offered INF beta-1a in 2 dose groups (22,44 mcg
  3times a week)
• Both INF treated groups from the outset had lower
  numbers of relapses Vs patients on placebo
• Cross over group had 50 reduction in relapse
  rate during years 3,4 Vs years 1,2
• The high dose group had fewer EDSS changes and
  significantly fewer T2 lesions over 4 years
• 8years follow-up(2006) confirmed the results

26
Comparision of INF Beta

• INCOMIN study
• Compared
• INF beta- 1b (250 mcg /other day)
• INF beta- 1a ( 30 mcg / week)
• Higher doses given more frequently reduced
  relapses and new MRI lesions.

27
Comparision of INF Beta

• EVIDENCE trial
• Compared
• INF beta-1a (44 mcg - 3times/week) Rebif
• INF beta-1a (30 mcg once a week) Avonex
• In RRMS for 48 weeks
• Higher dose and higher frequency group had a
  greater proportion of relapse-free patients.

28
Comparision of INF Beta

• Extension of EVIDENCE trial
• Patienst who were on 30mcg INF Beta-1a switched
  to 44 mcg INF Beta-1a 3/week
• Those patients demonstrated 50 relative
  Reduction in relapse rate

29
Case

• ???? 43 ????????? RRMS ??? 5 ????? ? ??????
  ?????? ??? INF Beta-1b ?? ????? ???? ???
• ???? ????? ??????? ???? ?? ?????? ? ??? ???????
  ???????????? ? ?? ???? ??? INF Beta-1a ????? 44
  ??? 3???? ??????? ?? ??????? ?????????.
• ??? ??? ???? ??? ????? ???? ????? ????? ???? ????
  ??????? ?????? ??????? ??????? ???????
  ??????????? ????? 35 nU/ml

30
Neutralizing antibody

• ????? ???? ??????? ?????? ?????? ? ???????
  ??????????? ???????? ??? ????? ????? ?????????
  ?????? ??? ?????? ???????
• ??? ???????? ?????????
• ??? ?????? ????? ??????????? ??? 12- 24 ??? Level
  A
• ?? ???? ?????? ?????? ??? ???? ????? ??? ??? ???
  ??? ???? ?????? ????? .
• ??? ????? ???????? ??? 3-6 ???? ??? ???????
  ?????????? ???? ??? ?????? ????? ????? ?????
  ?????? ??? ??? ????

31
Neutralizing antibody

• ?AAN ?? ?????? ????? ????? ????? ???? ??????
  ????? ???
• ??? ????? ???????
• ???? ???? ??????? ????????? ??? ??????
• ??? ?????? ?????? ???????
• LEVEL U

32
????? ????? ??????

• ?? ???? ??? ??????? ?????? ???????????? ?
  ?????????
• ????? ??? ???????
• ????? ??? ?????? ????? ??????? ??? T2 ? \ ??
  ?????? ??????? ????? ??? T1
• ???????? ???? ?????? ???? ? ????? ??????????? ??
  ???????? ??? ?????? ???? ?? ???????? ??????? .

33
Mitoxantrone

• ??????
• ?????? ?? DNA ????? ?????? ??????? ?? ???? ???
  ?????
• ????? ???? ?????? ??????? T
• ????? ??????? ???????
• ???????????
• (FDA ) ????? ??????? ??????? ? ??????? ?????????
  ?? ????? ?????? ??????.
• ??????
• 12???/?2 ?? 3 ???? ? ?????? ?????? ??? ??????
  ?? 140???/?2 ???? ?????? ???????

34
Mitoxantrone

• ????????? ????????
• ????? ??? ?????
• ????
• ???? ???? ?????? ? ?????
• ??? WBC (????? ??????? )
• ???? ?????? ???????
• ?????? ?????? ???? ????? ??????? ( ?? ???? MS
  ???? ??????? ?????? ???????)

35
Mitoxantrone

• ???????? ????? ??????
• ????? ?????? ?????? ??? ????? ? ??? ?? ????
• ????? ???? ????? ????? ? ??????
• ??? ????? ?????? ?????? ???? ???? ???????
  ????????? Level A recommendation

36
Natalizumab

• ??????
• ????? ????? ??????? ?????? humanized ????
  ????????? ???? ??? ?? MS .
• ????? ?? ??? ????? ?????? ?? ??????? ???????
  ????? ?????? ???BBB .
• ?????? 300 ??? q 4wk ???? ?? 100 ?? 0.9 NaCl
  ????? ???? ????
• ????????? ???? ???? ?? ??????? ??????? ?? MS
  (US FDA )

37
Natalizumab

• ????????? ????????
• ?? ??? 2005 ??? ?? ????????? ????? ???? ???? 3
  ????? PML (2 ?? ????? SENTINEL ????? ??? ???????
  ????? ??? ????)
• ?? ??? 2006 ???? ??????? ?????? ??? ???? ??????
  ??? ?? ??? ????? (TOUCH ) ?????? ?????? 5716
  ???? ??? ??? ??????(??? 2007) ?? ???? ?? ???? PML
  ??? ????? ??????? .

38
Natalizumab

• AFFIRM Trial
• Natalizumab group had lower annual relapse
  rate(0.26) Vs placebo(0.81) (1 year)
• 83 reduction of mean number of new or enlarging
  T2 lesions (2 years)

39
Natalizumab

• SENTINEL Trial
• Combination therapy of natalizumab and INF
  Beta-1a(Avonex) was more effective in reducing
  annualized relapse rate over 2 years Vs placebo
• Reduction in of disability progression at 2 years
• reduction of mean number of new or enlarging T2
  lesions (2 years)

40
????? ???????

• ?? ????? ???????? ??? ????? ?????????? ???? ??
  ??? ????? ???????
• ????? ???? ?????? ????? ??? ???? ?????
• ??????? ????????? ????? ??? ???? ??????? ??????
  ???????

41
????? ??????? ??????

• ?? ?????? ??????? ??????? ????? ???? ????? ?????
  ?????? ?? ??? ????? ?? ????? ???? ????? ?????? ??
  ???? ?? ???? ???? ????????? ???? ??????

42
??????? ????? ??????

• ?????? ??????? ?????? ??? ?????? ????? ?? ???????
  ??????? ???? ????? ???? ????????? ????????.
• Azathioprine
• ???? ????? ???????? ??? ???? ?? ??????? ??????
• Methotrexate
• ???? ?????????????? ???????
• Cladribine
• ???? ???????? ???? ?????????? ????????
• ????? ????? ?????? ??????????.

43
??????? ????? ??????

• ( IVIG) ????? ?? RR
• ??? ????? ?? ????? ???????
• ??????????????? ??? ???????? ????? ????? ??????
  ?????? ??????? ??????? ??? ???????? ?? ????
  ??????
• ??? ??????? ??????? ??????? ??????? ??? ?????
  ????? ????? ??? ?????? ??? ???????? ???? ?????? .

44
???? ???????

• ?????? ????? ????? ?? ????? ???????? ???????
  ??????? ?????? ??????? ????? ????? ?? 24???? ???
  ????? ????? ??????? ?? ??????? ??????? ??????
  ???? ?? ???? ??? ????? ?????? ??????? .
• ????????????
• ?? ?????? ?????? ????????? ????????? ???????
  ???????? ?? ????.
• ???? ???? ???? ??????????? 500??? _ 1000???\???
  ?? 3-5???? ???????? ????? ??????????? ????
  10-14???
• ?? ???????? ??1250??? ??????????? ???? ?1? ????
  ??????????? ????? ???????.

45
???? ???????

• ONTT ????? ?????? ?????? ????? ??????
• ??????? ??????? ???? ??? 6 ???? ?? ??? ??????
  ??????? ??????? ??????? ???? ??? ???? ?? ?????
  ?????? ???????
• ??????? ?????? ???? ?????
• ??? ????????

46
????? ???? ??????? ?? ?????

• ???????? A ??????? ???? ???? ???????? ????????
  ?? ????? ??????? ??????? ???? ????? ????? ????? ?
  ??????? ??????? ????? ???? ????
• ???????? B ??????? ???? ????? ???????? ????????
  ???? ?? ???? ????? ??? ???? ????????? ?? ????
  ???? ??? ??????? ? ???? ?? ??? ????? ?????? ?????
  ??? ???? ????? ?? ?? ???? ???????? ???? ????
  ?????? ??? ???? ?????????
• ???????? C ??????? ????? ?????? ??? ????????? ?
  ????? ?? ???? ??? ???? ???? ??????? ???? ??? ????
  ????????? ? ????? ??? ?????? ??????? ????? ?????
  .
• ???????? D ??????? ???? ??? ???? ???? ??????
  ?????? ???? ???? ????????? ???????? ??????? ?
  ???????? (???? ????? ?? ????? ??????)
• ???????? X ??????? ???? ??? ???? ????? ?? ????
  ??? ??? ????????? ? ????? ??? ?????? ???? ???
  ??????? ????? ?? ???? ????????? ??? ?????? ? ??
  ?????? ????????? ??? ?????? ???? ???? ????? ?????

47
????? ????

• ????? \ ???????
• ?? ??????? ????? ??????? ????? ??? ?????
  ????????? ???? ????? ????? ???? ??????? ????????
  ?????? ?????? ?????? ??? ????? .
• GA ???? B
• ?????????? ???? ???? C
• ?????????????? ?????????????? D
• ???? ????? ???????????? ??? ????? ????? ?? ?????
  ?????? ????? ????? ?? ???? ????? IVIG?? ?? ?????
  ?????? ?????? ???????????? ?? ????? ??????

48
????? ????

• ?????? ????? ?????? ??????? ( ??? ?????)
• ?? ???? ?????? .. ???? ?????? ?????? ??????
• ????? ????? ???? ????? ??? ???????? ???? IgG
  ??? ?? ?????? ????? ?????? ??????? ????? ??
  aquaporin-4 ??? ???? ??????? ???? ????? ?????? ??
  ?????
• ???? ?????? ??????????? ?? 5-7????
• ?? ??? ??????
• ?? IVIG

49
?????? ????? ?????? ?????????? ?????

• RITUXIMAB ???? ?????? ????? ??????? CD-20 ????
  ???? ??????? ??????? ???????? ?? ???? ?? ????? .
• ????? ????? ???????????? 12???\?2 ?????? ?? ???
  ????? ? ??? ???????? ??? ???????.
• AZATHIOPRINE ?????????? ????? ????? ?? ??? ????
  ????? ?? 18 ??? ( ????? ??? ???? )

50
????????? ??????????

• ???????? ???????? ?????????? ???? ???? Glatiramer
  ???? ???? ???? ????? ???????? ??? ?????
• ?????? ???? ?????
• 1- ????????? ???? (1A ) 30 ?????????
• 2- Glatiramer 20 ?? \ SC ?? ???
• 3-?????? ???????
• ?????? ??????? ??? 2010

51
????????? ??????????

• ?- Daclizumab (Zenapax)
• ??? ?? ??????? ???????? ( Humanized) ?????
  ??????? ????? ????? ?? CD25 ? ????? ????
  ????????? ???????????2 ??? ???? ??? ????? ?????
  ??????? ??????? ??????? . ?????? ???? ?? GVHD ???
  ???? ????? ??????
• ???? ????? ????? ??? ???????? ??? ????? ?? ?????
  ?????? ??????? ?????? ?????? .

52
????????? ??????????

• ?? - Alemtuzumab ( Campath-1H)
• ?? ???? ??????? ????? ????? ?? ????? CD52 ?????
  ?? ????? ??????? ???????? ??????? ????????
  ???????? ??????? ???? ?????? CLL ??????? ???
  ??????????
• ?????? ?? ????? ?????? ?? MS ????? ???? ??? ?????
  ????? 75 ? ???? ??? EDSS
• ?? ???????? ???????? ?????? ????? ???????
  ?????? ? ??? ???????? ???????

53
????????? ??????????

• ? - Rituximab
• ?? ???? ??????? Chimeric ????? ?? CD20 ?????????
  ??? ????? ??????? ??????? ???????? ???????
  ??????? ???? ??? ??????? ?????????.
• ???? ?? NHL ??????? ?? ????? ?????? ? RA ???????
  ? ?????? ????? ????????
• ???? ????? ????? ??? ?????? ?? ?????? ???????
  ??????? ?????? ????? ?????? PML ??? ???? ????
  ?????? ???????
• ??? ???? ??? ?? ???? ????????? ???????? ????
  ????? ??? ????.

54
????????? ??????????

• ?? - Fingolimod
• ???? ??????? ???? ???? ???? ?????????? ??? ????
  CNS ????? ??????? ???????? ?????? ?? ?????
  ??????? ???????? ??? ???? ??? ?????????? ?????
  ???????.
• ???? ???????? (1.25 5 ??? ) ???? ????? ? CELs
• ?? ???????? ???????? ?????? ??????? ?????? ?
  ?????? ? ?????? LFT? ?????? ?????? ??????
  ?????? .

55
??? ???? ?????? ?????? ??????

• ??? ????? ??? ?? ??? ?????? ?????? ?????
• ?????? ?? CIS ????? ????? ????? ????? ???? ?????
  ???? ???? ??? ??? ????? ???? ?????? ??? ???????
• ???? ?????? ETOMS \ CHAMPS \BENEFIT ??? ??
  ??? ?????? ?? ????? CIS ???? ?????? ??? ????
  ????? ???? ??????.
• ?? ???? ????? ?????? ?? 2 ??? ??????? ???????
  ????? ?? ?????
• ?? ??? ??????? ?? ?? ??????? ??????? ??? ???????
  ?????? ????? ??? ???, ????? ????? ???????? ???
  ??????? ??????? .

56
??? ???? ?????? ?????? ??????

• CIS ?? ???? ?????? ??? ??????? ?RRMS ?????? ??
  ??? ?? ??????????? (????? A )
• ??????? GA ?? CIS ??? ??????? ????? ???? ????
  ???????? ??? ??? ???? ??????? ???????? ??????????
  ????
• ???????????? ??????????? ?????? ?? ????? ??????
  ??????? ?????? ?????? ??? ????? ?? ???????
  ??????? ?????? ??????? ????? ??? ????? ??? ???
  ????????
• ?? ????? SPMS \ RRMS ??????? ???? ???????
  ????????????
• ?? ????? ?? ???? ???? ???? ????? ??????? ??????.

57
Rating of Therapeutic Article
58
Rating of Therapeutic Article
59
Rating of Therapeutic Article
60
Rating of Therapeutic Article
61
Translation of evidence torecommendations
62
Translation of evidence torecommendations
63
Rating of recommendation
64
Rating of recommendation
65
Report ofThe Therapeutics and Technology
Assessment Subcommitteeof the American Academy
of NeurologyandThe MS Council for Clinical
Practice Guidelines
66
An evidence based summaryGlucocorticoids
67
An evidence based summary Glucocorticoids
68
An evidence based summaryINF Beta
69
An evidence based summary INF Beta
70
An evidence based summary INF Beta
71
An evidence based summary INF Beta
72
An evidence based summaryGlateramer acetate
73
An evidence based summaryMitoxantrone
74
An evidence based summaryCyclophosphamide
75
An evidence based summaryMethotrexate
76
An evidence based summaryAzathioprine
77
An evidence based summaryCladribine
78
An evidence based summaryCyclosporine
79
An evidence based summaryIv Ig
80
An evidence based summaryPlasma Exchange
81
An evidence based summarySulfasalazine
82
(No Transcript)