Disease modifying treatments for multiple sclerosis have evolved significantly over time. Early treatments focused on interferon-beta, which showed moderate effectiveness in reducing relapses and disability progression. Newer monoclonal antibody treatments such as natalizumab provided greater reductions in disease activity but also carried increased safety risks. The latest oral therapies including fingolimod, teriflunomide, dimethyl fumarate, and laquinimod provide over 50% reductions in relapse rates compared to earlier treatments with generally improved safety profiles. Ongoing research continues to evaluate new mechanisms of action to more effectively treat multiple sclerosis.

1. Disease Modifying
Treatments:
Mediocrity and then some?
Dr Trevor Pickersgill
Consultant Neurologist
University Hospital of Wales
Royal Glamorgan Hospital
Hon Lecturer, Cardiff University

2. “Disease?”
 Advice
 Explanation
 Expertise
 Support
 Signposting
 Now ‘rationers’
 ‘prescribers’

4. “Modifying”

5. Theoretical model: treat early and
aggressively
Disability
Treatment
at diagnosis Intervention
at diagnosis
Time
Disease
Onset

7. Patients with a sustained (6 months) Expanded Disability Status Scale increase during the
first 3 years of treatment.
La Mantia L et al. J Neurol Neurosurg Psychiatry
doi:10.1136/jnnp-2012-303291
©2012 by BMJ Publishing Group Ltd

8. “Treatment?”
K Harding et al ENS 2012

10. ‘mild’ drugs?

11. The Pipeline

12. BIOGEN
Teva/Serono

13. Really…..?

18. Pts with >1 exacerbation

19. Pts with 2yr progression

21. The IFNB Multiple Sclerosis Study
Group. 1993 Neurology. 43: 655-
661
Jacobs LD et al. 1996 Annals of
Neurology. 39: 285-294
The PRISMS Study Group. 1998
Lancet. 352: 1498-1504
Jacobs LD et al. 2000 New
England Journal of Med
Medicine. 343: 898-904
European Study Group on
Interferon-1b in Secondary
Progressive MS. 1998 Lancet.
352: 1491-1497
Comi G et al. 2001 Lancet. 357:
1576-1582

23. The New Dawn:
monoclonals
 Alemtuzumab
 Natalizumab
 Daclizumab
 Ocrelizumab
 Rituximab

26. Immune attack on the central nervous system and the
mechanism of action of anti-VLA4 and anti-CD52.
Gold R , Hohlfeld R Pract Neurol 2006;6:248-251
©2006 by BMJ Publishing Grop Ltd

27. Natalizumab/Tysabri
 Monthly IVI
 £13K
 ‘twice’ as effective injectable DMT
 Reserved for ‘HARRMS’ (NICE)
 I.e. 2+attacks in 1 yr with active MRI
(significant increase in lesions or Gd+)
 25+ UHW.
 PML......

28. MOA of Natalizumab
1. Leukocyte migration
from blood to tissue
2. Leukocyte priming
and activation
3. Modulation of
leukocyte apoptosis
Cannella B et al. Ann Neurol. 1995;37:424-435.
TYSABRI SmPC; Yednock TA et al. Nature.
1992;356:63-66

29. TYSABRI Efficacy Summary
ITT Population
68% reduction in relapse rate vs placebo
over 2 years (p < 0.001)
54%
reduction in the risk of EDSS
progression, sustained for 24 weeks, as
assessed over 2 years (p < 0.001)
of patients free from all of the following
28%
measures of disease activity: relapses, Gd+
lesions, T1 weighted hypointense and T2
weighted hyperintense lesions and disability
progression at 2 years 2
TYSABRI SmPC; Polman CH, et al. NEJM 2006; 354(9):
899-910; 2. TY00-004, Data on file. Biogen Idec Ltd

30. Annualized Relapse Rate
1.0 0.81
Annualized Relapse Rate (95% CI)
0.9 0.73 0.67
P<0.001
0.8 P<0.001
P<0.001
0.7
0.6
66%
0.5 68% reduction 70%
reduction reduction
0.4 0.26
0.3 0.23 0.20
0.2
0.1
0.0
Years 0-2 Year 0-1 Year 1-2
Placebo n=315 Natalizumab n=627
Polman CH, et al. N Engl J Med. 2006;354:899-910; Polman C, et al. Presented at the 57th Annual Meeting of the
American Academy of Neurology; April 12, 2005; Miami, FL

32. Kaplan–Meier Plots of the Time to Sustained Progression of Disability among Patients Receiving
Natalizumab, as Compared with Placebo.
Polman CH et al. N Engl J Med 2006;354:899-910.

33. Another magic bullet?
 Alemtuzumab
 Anti CD52
 Cell lysis
 Lymphocyte depleter
 Annual infusions x2
 Cheap.....
 .....but withdrawn
 autoimmunity

34. Haematological Effects of
CAMPATH-1H
Lymphocytes (x109/l)
Lymphocytes (x109/l)
2.5
4
2 Normal
3 Range
1.5
2
1
0.5 1
0 0
0 4 8 12 16 20 24
1 10 100 1000
Time post Campath Infusion (Hours) Days post CAMPATH-1H
95% reduction within 1hr. Unaffected by steroids
Moreau, T., A. Coles, et al. (1996).
Brain 119 (Pt 1): 225-37

35. Lymphocyte recovery after Alemtuzumab
Cossburn et al Neurology 2012(in press)

38. Campath rash

41. Cumulative number of relapses over time
Risk
Reduction
87% 72%
P <0.0001
Annualized Relapse Rate (95% C.I.)
Interferon-beta 1a Alemtuzumab Low- Alemtuzumab High-
0.35 (0.27, 0.44) Dose Dose
0.11 (0.07, 0.16) 0.05 (0.03, 0.09)
Coles et al. AAN 2007.

42. Relapse-free
100
Patients without Relapse (%)
95
90
85
80
78%
75
70
65
60 55% Risk Reduction
p<0.0001 59%
55
50
0 3 6 9 12 15 18 21 24
Follow-up Month
No. of Observations
SC IFNB-1a 187 175 156 137 127 118 116 109 101
Anti CD52 mAb 376 366 358 340 321 313 306 299 287
CARE-MS I

43. Mean EDSS Score Over Time
Alemtuzumab
v. IFNB1a
-0.57 (-0.30, -0.83)
-0.72 (-0.46, -0.98)
P<0.0001
Error bars = S.E.

44. The downside......
 30% thyroid
 3% ITP
 Goodpasture’s
 Lymphoma

45. Others
 Rituximab  Daclizumab
 1 small trial  IL2recA chain CD25
 Ocrelizumab
 ‘ritux-max’ CD20
 Phase 2 n=220
 6 montly infusion
 MRI

46. The Oral Explosion....

47. BG12/
Fingolimod Cladribine DMF
Laquinimod
Teriflunomide
“Aubagio”
Ponesimod ??

48. CLADRIBINE
 The ‘winner’ of the race to market
 CLARITY NEJM 2010
 N=1326
 Placebo v high v low dose
 0.33 v 0.15 relapse rate
 10 tumours (5 fibroids!)
 Withdrawn from market worldwide

49. Efficacy Outcome Measures Relating to Relapse and Progression of Disability during
the 96-Week Study Period (Intention-to-Treat Population).
Giovannoni G et al. N Engl J Med 2010;362:416-426.

50. FINGOLIMOD
 S1P receptor modulator
 TRANSFORMS v Avonex
 FREEDOMS v placebo
 EDSS 0-5.5 ARR=1
 N=1200 82% completion
 -54% RR
 MRI and disability
 Oral once daily

51. FINGOLIMOD
 First dose in hospital
 Cardiac SEs
 First dose brady
 1/2 deg HB
 Opthalmological - mac oedema
 Skin - 11 cancers (4 pl)
 £20,000

52. Gilenya prevents lymphocyte exit
from lymph nodes
Gilenya causes:
 Internalisation of
the S1P1 receptor
 Inhibition of
lymphocyte exit
along the S1P
gradient
Gilenya induces reversible retention of circulating lymphocytes in lymph nodes, reducing
peripheral lymphocyte counts and their recirculation to the CNS
CNS, central nervous system; S1P, sphingosine 1-phosphate
Model based on Brinkmann V et al. J Biol Chem 2002; Matloubian M et al. Nature 2004; Brinkmann V. Br J Pharmacol 2009

53. Annualized Relapse Rate at 12 Months and the Time to the First Relapse.
Cohen JA et al. N Engl J Med 2010;362:402-415.

54. Fingolimod significantly reduced annualized
relapse rates versus IFNβ-1a IM and placebo
TRANSFORMS 1-year results11
TRANSFORMS 1-year results FREEDOMS 2-year results22
FREEDOMS 2-year results
p < 0.001 for fingolimod versus IFNβ-1a IM p < 0.001 for fingolimod versus placebo
0.4
0.4
0.40
Annualized relapse rate
0.3
Annualized relapse rate
0.33 0.17 or 52% 0.3 0.22 or 54%
reduction reduction
0.2
0.2
0.18
0.1 0.16
0.1
0
0
IFNβ-1a IM Fingolimod 0.5 mg Placebo Fingolimod 0.5 mg
(n = 431) (n = 429) (n = 418) (n = 425)
Annualized Relapse Rate estimate and p value are calculated using negative binomial regression model adjusted
for treatment group, country, number of relapses in previous 2 years and baseline EDSS score.
EDSS, Expanded Disability Status Scale; IM, intramuscular 1. Table 2 page 8 FDA Advisory Committee presentation (10 June 2010).
2. Cohen JA et al. N Engl J Med 2010;362:402–15.
Data refers to study group broader than the CHMP licensed indication. Fingolimod is indicated in patients with highly active and rapidly evolving severe
RRMS. A consistent treatment effect was demonstrated in the licensed highly active subgroups.”

55. TERIFLUNOMIDE
 Selective and reversible inhibitior DHODH dihydro-orotate
dehydrogensae
 Mitoch enzyme
 Inhibits proliferation B/T cells
 Approved FDA 2012
 2 phase 3 trials
 TEMSO
 N=1088
 ARR 31%
 SAD 30% (27-31%)

56. Annualized Relapse Rate and
Sustained Disability
Progression.
TEMSO
O'Connor P et al. N Engl J Med
2011;365:1293-1303.

57. TOWER
 2nd phase 3 trial terif
 Alopecia 13%
 1+relapse 1yr 2+ 2yrs
 TENERE: no superiority
Rebif
 48wks n=1169
 TOPIC - CIS
 70% completed study
 ARR -22.3% -36.3%
 Effective, well tolerated,
 Free relapses 55.4% v
more long term safety data
37.7%
needed
 SAD 22/21% v 15.8%  2M pt-yrs in RA

60. BG12
 Anti inflamm antioxidative stress
 ?cytoprotective
 DEFINE v pl /CONFIRM v pl v GLA
 Fox NEJM 2012
 50% RR
 SAD 33%
 Decreased brain atrophy

61.  BG-12/DMF
 Risk relapse 2yrs 43%
 New/enlarging T2 75%
 N=2307 120 v 240 v pl v GLA (n=360)
 At least 1 relapse 12m
 -83% Gd+
 Flushing/GI SEs

62. Clinical Outcomes at 2
Years in the Intention-to-
Treat Population.
Fox RJ et al. N Engl J Med
2012;367:1087-1097.

63. LAQUNIMOD
 ALLEGRO 23% RR 36% SAD
 BRAVO
 More
pronounced effect on disability than
RR??

64. Clinical Outcomes and MRI Measures
of Efficacy According to Study
Group.
ALLEGRO
Comi G et al. N Engl J Med
2012;366:1000-1009.

68. Treatment Map
CIS RRMS HARRMS
NEW
ABCR ORALS
NAT
Monoclonals
FING
ALEM

69. Acknowledgements
 Slideshare - Prof G Giovannoni
 Helen Durham Centre:
 Dr Katharine Harding
 Dr Mark Cossburn
 Prof Neil Robertson
 Dr Sebastian Luppe
 Dr Claire Hurst