emerging therapies ms
TRANSCRIPT
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Emerging Therapies for Multiple
Sclerosis
Horea Rus MD PhD
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Existing Therapies and
Emerging Therapies for MS2005 2011
Injectables
IV
Teriflunomide
Teriflunomide
Laquinimod
LaquinimodFTY 720
FTY 720
Oral
Cladribine
Oral
Cladribine
Daclizumab
DaclizumabGeneric
Mitoxantrone
(oncology) (MS)
Generic
Mitoxantrone
(oncology) (MS)
Orals
Tysabri
Tysabri
IV
2006 2007
Copaxone
Betaseron
Avonex
Novantrone
RituximabII - RRMS; III - PPMS
RituximabII - RRMS; III - PPMS
Rebif
2010 2012
MLN1202
MLN1202
BG 12 Oral
Fumarate
BG 12 Oral
Fumarate
Fampridineambulation indication?
Fampridineambulation indication?
MBP 8298
MBP 8298
Filed
approved
In phase IIIn phase III
SB683699
SB683699
2013
Campath
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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 switchedfrom placebo to fingoloimod
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Kappos L et al. N Engl J Med 2006;355:1124-1140
Proportions of Patients Who Were Free of Gadolinium-Enhanced Lesions on T1-Weighted MRI at 0to 6 Months (Panel A) and the Estimated Time to a First Confirmed Relapse (Panel B)
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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
Study Treatment Indication Duration
FREEDOMS II(2309)
Oral FTY7200.5 & 1.25 mgonce daily vsplacebo
RRMS 2
960
TRANSFORMS(2302)
Oral FTY7200.5 & 1.25 mgonce daily vsinterferon -1a(Avonex) onceweekly
RRMS 1 1275
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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 05.5 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 -1a (Avonex) once weekly
Treatment nave patients or patients alreadytreated with MS drugs can be screened.
18 - 55 years of age with a diagnosis of MS by2005 McDonald criteria
A relapsing-remitting course with at least 1
documented relapse during the previous year or 2documented relapses during the previous 2 years
Expanded Disability Status Scale (EDSS) scoreof 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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CladribinePhase 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 freesubjects 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 IIstudy: 235 patients were randomized to120, 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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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 -32%, NS
Cladribine (2.1 mg) -90%, P= .001 -51%, NS
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 improvingthe 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 2006;12, 171
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Chimeric and humanized
monoclonal antibody
From: The Neurologist 2006;12, 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 clinicallysignificant 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 2006;12, 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 (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 theannualized relapse rate compared to placebo (35%);
did not reach statistical significance.
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MBP8298 in secondary
progressive MSSynthetic 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 MS2005 2011
Injectables
IV
TeriflunomideTeriflunomide
LaquinimodLaquinimodFTY 720FTY 720
Oral
Cladribine
Oral
Cladribine
DaclizumabDaclizumabGeneric
Mitoxantrone
(oncology) (MS)
Generic
Mitoxantrone
(oncology) (MS)
Orals
TysabriTysabri
IV
2006 2007
Copaxone
Betaseron
Avonex
Novantrone
RituximabII - RRMS; III - PPMS
RituximabII - RRMS; III - PPMS
Rebif
2010 2012
MLN1202MLN1202
BG 12 Oral
Fumarate
BG 12 Oral
Fumarate
Fampridineambulation indication?
Fampridineambulation indication?
MBP 8298MBP 8298
Fil d
approvedIn phase II
I h III
SB683699SB683699
2013
Campath