emerging therapies ms

8/3/2019 Emerging Therapies Ms

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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


Rebif

2010 2012

MLN1202

MLN1202

BG 12 Oral

Fumarate

BG 12 Oral

Fumarate

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



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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



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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



Rebif

2010 2012

MLN1202MLN1202

BG 12 Oral

Fumarate

BG 12 Oral

Fumarate



MBP 8298MBP 8298

Fil d

approvedIn phase II

I h III

SB683699SB683699

2013

Campath

emerging therapies ms

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