Emerging Therapies for Multiple Sclerosis

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Emerging Therapies for Multiple Sclerosis

• Horea Rus MD PhD

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Existing Therapies and Emerging Therapies for MS
2005
2011
2006
2007
2010
2012
2013
Orals
Injectables
BG 12 Oral Fumarate
Oral Cladribine
Rebif
Teriflunomide
Betaseron
FTY 720
Laquinimod
Copaxone
SB683699
Fampridine ambulation indication?
Avonex
IV
Novantrone
IV
Campath
Tysabri
Rituximab II - RRMS III - PPMS
Generic Mitoxantrone (oncology)
(MS)
Daclizumab
MLN1202
MBP 8298
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New Oral Therapies
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Fingolimod (FTY720)

• A sphingosine -1-phosphate inhibitor that
  reversibly sequester lymphocytes to lymph nodes

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Fingolimod (FTY720)

• Phase II studies
• 281 patients received FTY 720 1.25 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

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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)
Kappos L et al. N Engl J Med 20063551124-1140
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Fingolimod

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

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Fingolimod (FTY720) Phase III Studies have begun
and patients can be referred
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FREEDOMS II Inclusion Criteria

• Oral FTY720 0.5 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

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TRANSFORMS Inclusion Criteria

• Oral FTY720 0.5 1.25 mg once daily vs. i.m.
  interferon ß-1a (Avonex) once weekly
• Treatment naïve patients or patients already
  treated with MS drugs can be screened.
• 18 - 55 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
  0-5.5 inclusive

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Cladribine

• 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

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Cladribine

• 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

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Laquinimod

• Oral immunomodulator
• Phase II - 306 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.

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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

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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

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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

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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.

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Phase II Studies of New Oral Multiple Sclerosis
Therapies
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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.

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MONOCLONAL ANTIBODIES
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Monoclonal antibody production.
From The Neurologist 200612, 171
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Chimeric and humanized monoclonal antibody
From The Neurologist 200612, 171
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Alemtuzumab

• 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

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Alemtuzumab in multiple sclerosis
Humanized monoclonal antibody against CD 52
From The Neurologist 200612, 171
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Alemtuzumab

• Side effects
• 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

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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
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T. Ito, H. Rus 2007
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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

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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 (p0.004).
• 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.

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MBP8298 in secondary progressive MS

• Synthetic peptide aa 82-98 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

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