Emerging Therapies for Multiple Sclerosis

Horea Rus MD PhD

Existing Therapies and Emerging Therapies for MS

2005 2011

Injectables

IV

TeriflunomideTeriflunomide

LaquinimodLaquinimodFTY 720FTY 720

Oral CladribineOral 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 FumarateBG 12 Oral Fumarate

Fampridineambulation indication?

Fampridineambulation indication?

MBP 8298MBP 8298

Filed

approved In phase II

In phase III

SB683699SB683699

2013

Campath

New Oral Therapies

Fingolimod (FTY720)

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

nodes

Fingolimod (FTY720)

• Phase II studies: •281 patients received FTY 720 1.25 or 5 mg or placeboonce 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

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 0 to 6 Months (Panel A) and the Estimated Time to a First Confirmed Relapse (Panel B)

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

Fingolimod (FTY720) Phase III Studies have begun and patients can be referredStudy Treatment Indication Duration

FREEDOMS II (2309)

Oral FTY720 0.5 & 1.25 mg once daily vs placebo

RRMS 2

960

TRANSFORMS (2302)

Oral FTY720 0.5 & 1.25 mg once daily vs interferon β-1a (Avonex®) once weekly

RRMS 1 1275

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

• 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

• 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

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

• 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• 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

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

•Analogue of Leflunomide used in the therapy of Rheumatoid Arthritis• Inhibits a mitochondrial enzyme and proliferation of T and BCells

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

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.

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

• 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 ANTIBODIES

Monoclonal antibody production.

From: The Neurologist 2006;12, 171

Chimeric and humanized monoclonal antibody

From: The Neurologist 2006;12, 171

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

Alemtuzumab in multiple sclerosis

Humanized monoclonal antibody against CD 52

From: The Neurologist 2006;12, 171

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 MSChimeric Monoclonal antibody anti CD20

Stem Pro-B Pre-B Immature Transitional Activated Memory Plasma Cell

CD20

T. Ito, H. Rus 2007

T. Ito, H. Rus 2007

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 MSPhase 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

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

Existing Therapies and Emerging Therapies for MS

2005 2011

Injectables

IV

TeriflunomideTeriflunomide

LaquinimodLaquinimodFTY 720FTY 720

Oral CladribineOral 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 FumarateBG 12 Oral Fumarate

Fampridineambulation indication?

Fampridineambulation indication?

MBP 8298MBP 8298

Filed

approved In phase II

In phase III

SB683699SB683699

2013

Campath