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Emerging Therapies for Multiple Sclerosis. Horea Rus MD PhD. approved. In phase II. Filed. In phase III. Existing Therapies and Emerging Therapies for MS. 2005. 2006. 2007. 2010. 2011. 2012. 2013. Orals. Injectables. BG 12 Oral Fumarate. Oral Cladribine. Rebif. Teriflunomide.

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slide2

approved

In phase II

Filed

In phase III

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

SB683699

Fampridine

ambulation indication?

Avonex

IV

Novantrone

IV

Campath

Tysabri

Rituximab

II - RRMS; III - PPMS

Generic Mitoxantrone

(oncology) (MS)

Daclizumab

MLN1202

MBP 8298

fingolimod fty720

Fingolimod (FTY720)

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

fingolimod fty7201
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
slide6

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 2006;355:1124-1140

fingolimod
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
freedoms ii inclusion criteria
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
transforms inclusion criteria
TRANSFORMS: Inclusion Criteria
  • Oral FTY720 0.5 & 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.
  • 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
cladribine
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
cladribine1
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
laquinimod
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.
fumaric acid derivate bg00012
Fumaric acid derivate BG00012
  • Medication is used in treatment of psoriasis
  • Cytoprotective and anti-inflammatory effects
  • Phase IIstudy: 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
fumaric acid derivate bg000121
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
teriflunomide
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
teriflunomide1
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.
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

-32%, NS

Cladribine (2.1 mg)

-90%, P = .001

-51%, NS

Phase II Studies of New Oral Multiple Sclerosis Therapies
conclusions oral therapies
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.
monoclonal antibody production
Monoclonal antibody production.

From: The Neurologist 2006;12, 171

slide22

Chimeric and humanized

monoclonal antibody

From: The Neurologist 2006;12, 171

alemtuzumab
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
slide24

Alemtuzumab in multiple sclerosis

Humanized monoclonal antibody against CD 52

From: The Neurologist 2006;12, 171

alemtuzumab1
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
rituximab in ms
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

rituximab in ms1
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
daclizumab in ms
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.
mbp8298 in secondary progressive ms
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
slide31

approved

In phase II

Filed

In phase III

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

SB683699

Fampridine

ambulation indication?

Avonex

IV

Novantrone

IV

Campath

Tysabri

Rituximab

II - RRMS; III - PPMS

Generic Mitoxantrone

(oncology) (MS)

Daclizumab

MLN1202

MBP 8298