1. Emerging Therapies for Multiple Sclerosis
Horea Rus MD PhD

2. Existing Therapies and Emerging Therapies for MS
2005
2006
2007
2010
2011
2012
2013
Orals
Injectables
BG 12 Oral Fumarate
Oral Cladribine
Rebif
Teriflunomide
Betaseron
FTY 720
Laquinimod
Copaxone
Fampridine
ambulation indication?
SB683699
Avonex IV
Novantrone IV
Campath
Tysabri
Rituximab
II - RRMS; III - PPMS
Generic Mitoxantrone
(oncology) (MS)
Daclizumab
MBP 8298
MLN1202
Filed
approved
In phase II
In phase III

3. New Oral Therapies

4. Fingolimod (FTY720)
A sphingosine -1-phosphate inhibitor that reversibly sequester lymphocytes to lymph nodes

5. Fingolimod (FTY720)
Phase II studies:
281 patients received FTY or 5 mg or placebo
once daily
Primary end point : number of gadolinium enhancing lesions
Reduced the number of gadolinium enhancing lesions
detected on the brain MRI and clinical disease activity
Both measures decreased in patients who switched
from placebo to fingoloimod

6. Proportions of Patients Who Were Free of Gadolinium-Enhanced Lesions on T1-Weighted MRI at 0 to 6 Months (Panel A) and the Estimated Time to a First Confirmed Relapse (Panel B)
Figure 2. Proportions of Patients Who Were Free of Gadolinium-Enhanced Lesions on T1-Weighted MRI at 0 to 6 Months (Panel A) and the Estimated Time to a First Confirmed Relapse (Panel B). P values are for each fingolimod dose as compared with placebo.
Kappos L et al. N Engl J Med 2006;355:

7. Fingolimod Clinically asymptomatic elevations of liver enzymes
Side effects:
Clinically asymptomatic elevations of liver enzymes
Initial reduction of the heart rate
Modest decrease of forced expiratory volume
No serious infections reported

8. Fingolimod (FTY720) Phase III Studies have begun and patients can be referred
Study
Treatment
Indication
Duration
FREEDOMS II (2309)
Oral FTY & 1.25 mg once daily vs placebo
RRMS 2
960
TRANSFORMS (2302)
Oral FTY & 1.25 mg once daily vs interferon β-1a (Avonex®) once weekly 1
1275
Novartis has two large-scale, randomised global Phase III studies underway: FREEDOMS and TRANSFORMS. Another study, 2309, has started in the US and is similar in design to FREEDOMS.
The purpose of these studies are to evaluate the efficacy and safety of FTY720 in RRMS and permit successful registration and marketing approval throughout the world.

9. FREEDOMS II: Inclusion Criteria
Oral FTY & 1.25 mg once daily vs. placebo
Male and Females18 through 55 years of age with a diagnosis of multiple sclerosis by 2005 McDonald criteria
EDSS score 0−5.5 inclusive
One documented relapse in the last year or two documented relapses in the last 2 years
From the protocol: Inclusion criteria: Patients who explicitly decline initiation or continuation of treatment with available disease modifying drugs for multiple sclerosis, for whatever reason, after having been informed about their respective benefits and possible adverse events by the investigator.

10. TRANSFORMS: Inclusion Criteria
Oral FTY & 1.25 mg once daily vs. i.m. interferon β-1a (Avonex®) once weekly
Treatment naïve patients or patients already treated with MS drugs can be screened.
years of age with a diagnosis of MS by 2005 McDonald criteria
A relapsing-remitting course with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years
Expanded Disability Status Scale (EDSS) score of inclusive

11. Cladribine It disrupts cellular metabolism, induces DNA damage
Purine nucleoside with lymphocyte depleting properties
It disrupts cellular metabolism, induces DNA damage
and subsequent cell death.
Was shown to suppress Gd-enhancing lesions in patients
which received iv Cladribine for 12 months
Reduced the frequency of relapses

12. Cladribine 1290 patients recruited; 10 mg Cladribine vs. placebo for
Phase III study with oral Cladribine is ongoing.
1290 patients recruited;
10 mg Cladribine vs. placebo for
5 days a month, 2-4 cycles a year.
End points: Relapse rate, EDSS, MRI activity
Side effects:
Lymphopenia , but risk of opportunistic infections is low,
limited to segmental Herpes Zoster, one case of fulminant hepatitis B
Long term safety of tablets use not established

13. Laquinimod Phase II - 306 patients randomized to either Laquinimod
Oral immunomodulator
Phase II patients randomized to either Laquinimod
0.3 or 0.6 mg/day or placebo;
Significant reduction in cumulative number of enhancing
lesions on brain MRI for 36 weeks with 0.6 mg/day;
Positive trends on annual relapse rates, relapse free
subjects and time to first relapse;
Phase III trials to begin soon.

14. Fumaric acid derivate BG00012
Medication is used in treatment of psoriasis
Cytoprotective and anti-inflammatory effects
Phase II study: 235 patients were randomized to
120, 360 or 720 mg/ day
Reduced the number of new gadolinium –enhancing
lesions by 69% versus placebo
Relapse rate in all treatment groups decreased
as compared with placebo

15. Fumaric acid derivate BG00012
When patients on placebo were switched to BG00012
720 mg/day for the extension phase the relapse rate
was reduced by 52%
Side effects:
Favorable safety profile
Reported: flushing,increased liver enzymes,
no infections
Phase III in progress

16. TERIFLUNOMIDE
Analogue of Leflunomide used in the therapy of Rheumatoid
Arthritis
Inhibits a mitochondrial enzyme and proliferation of T and B
Cells
Phase II study: Two different regimens: 7 and 14 mg/day vs.
Placebo for 36 weeks in 179 patients.
Patients on Teriflunomide when compared with placebo had :
Significantly reduced number of active and new lesions
On the brain MRI
A lower annualized relapse rate

17. TERIFLUNOMIDE Side effects: Generally well tolerated
Most common side effects: upper respiratory tract infections
and headache
In RA patients- toxic liver necrosis and pancytopenia have
been described.

18. Phase II Studies of New Oral Multiple Sclerosis Therapies
Cumulative Number
of Gd-Positive Lesions
Annualized Relapse Rate
Fingolimod (1.25 mg)
-43%, P < .001
-55%, P = .009
Teriflunomide (7 mg)
-61%, P < .03
-32%, NS
Laquinimod (0.3 mg)
-44%, P = .05
No difference
BG00012 (720 mg)
-69%, P < .001
Cladribine (2.1 mg)
-90%, P = .001
-51%, NS

19. Conclusions – Oral therapies
Potential benefits of oral treatments for modifying the course
of RRMS are significant.
They will expand the options available while improving
the ease of administration
Will reduce the cost of therapy (?).
Might facilitate new combinations of agents
Could lead to increase adherence.

20. MONOCLONAL ANTIBODIES

21. Monoclonal antibody production.
From: The Neurologist 2006;12, 171

22. Chimeric and humanized
monoclonal antibody
From: The Neurologist 2006;12, 171

23. Alemtuzumab -334 patients, -3 year data were reported at ECTRIMS 2007
Phase II study:
-334 patients,
-3 year data were reported at ECTRIMS 2007
73% reduction in the risk for relapse after 3 years
follow-up when compared to patients treated with
interferon beta 1a
70% reduction in the risk for progression of clinically
significant disability when compared to patients treated with
Interferon beta 1a

24. Alemtuzumab in multiple sclerosis
Humanized monoclonal antibody against CD 52
From: The Neurologist 2006;12, 171

25. Alemtuzumab Six patients developed ITP Infusion related side effects
Severe Infections were infrequent
Thyroid related events were less then expected
Two phase III studies to start:
CARE-MS I - Alemtuzumab as a first line therapy
CARE-MS II – Alemtuzumab in patients which
continued to experience relapses

26. RITUXIMAB IN MS Chimeric Monoclonal antibody anti CD20
Stem
Pro-B
Pre-B
Immature
Transitional
Activated
Memory
Plasma Cell
CD20
T. Ito, H. Rus 2007

27. T. Ito, H. Rus 2007

28. RITUXIMAB IN MS Phase II Study: 104 patients 1000 mg iv x 2
91% relative reduction in number of cumulative number
of Gd-enhancing lesions
58% Reduction in clinical relapses
Decision on starting phase III trial is pending

29. DACLIZUMAB IN MS Phase II CHOICE study:
At 24 weeks, 75 patients in the 2 mg/kg group experienced
72% fewer new or enlarged Gd+ on average compared to the
77 patients who received a placebo (p=0.004).
The 78 patients in the 1 mg/kg group experienced a 25%
reduction in new or enlarged lesions: did not achieve
statistical significance.
Both daclizumab regimens revealed a trend in reducing the
annualized relapse rate compared to placebo (35%);
did not reach statistical significance.

30. MBP8298 in secondary progressive MS
Synthetic peptide aa of myelin basic protein
Immunodominant target for both B- and T-cells in MS
patients with HLA haplotype DR2.
Administration of the peptide results in long term suppression
of anti-MBP autoantibodies;
Phase II study:
32 patients, followed for 24 months
500mg of MBP8298 every 6 months.
the HLADR2 positive responder group showed a median time to
progression of 78 months as compared with 18 months for placebo
Phase III study - recruiting patients

31. Existing Therapies and Emerging Therapies for MS
2005
2006
2007
2010
2011
2012
2013
Orals
Injectables
BG 12 Oral Fumarate
Oral Cladribine
Rebif
Teriflunomide
Betaseron
FTY 720
Laquinimod
Copaxone
Fampridine
ambulation indication?
SB683699
Avonex IV
Novantrone IV
Campath
Tysabri
Rituximab
II - RRMS; III - PPMS
Generic Mitoxantrone
(oncology) (MS)
Daclizumab
MBP 8298
MLN1202
Filed
approved
In phase II
In phase III