oral treatments in development for ms emsp information day brussels, 13 november 2008 magnhild...

Oral Treatments in Oral Treatments in Development for MSDevelopment for MS

EMSP Information DayEMSP Information Day

Brussels, 13 November 2008Brussels, 13 November 2008

Magnhild Sandberg-WollheimMagnhild Sandberg-Wollheim

M Sandberg 2008-11-13M Sandberg 2008-11-13

if you get MS…if you get MS…

you will have a chronic disease you will have a chronic disease withwith– unknown cause unknown cause – uncertain prognosisuncertain prognosis– unsatisfactory treatments unsatisfactory treatments

and you are one of and you are one of ~500,000 ~500,000 EuropeansEuropeans



you are 20 - 30 years old you are 20 - 30 years old – have started on your education…have started on your education…– have hopes of a spectacular have hopes of a spectacular

career… career… – have met the love of your life… have met the love of your life… – have begun to think of having a have begun to think of having a

family… family…



At this time of your life, you do At this time of your life, you do notnot want to hear want to hear – that you have a chronic diseasethat you have a chronic disease– that the treatment involves daily or that the treatment involves daily or

weekly injections weekly injections – and yetand yet, your future is uncertain, your future is uncertain


So, what is MS ?So, what is MS ?

MS is an MS is an autoimmuneautoimmune disease disease

Our immune system is there to Our immune system is there to defend us against what is ”foreign”defend us against what is ”foreign”– for instance virus, bacteriafor instance virus, bacteria

but it must tolerate ”self”but it must tolerate ”self”– our own tissues and organsour own tissues and organs


CNS is under surveillance CNS is under surveillance of the immune systemof the immune system Under Under normalnormal circumstances circumstances white bloodwhite blood

cellscells circulate through and survey tissues circulate through and survey tissues and organsand organs– if they do not encounter anything ”foreign”, they if they do not encounter anything ”foreign”, they

return to the circulation return to the circulation

SometimesSometimes a white blood cell will mistakenly a white blood cell will mistakenly recognize a ”self” molecule as foreign recognize a ”self” molecule as foreign

This will lead to an This will lead to an autoimmune reactionautoimmune reaction– in the CNS (brain and spinal cord) the result will be in the CNS (brain and spinal cord) the result will be

areas of inflammation -- MSareas of inflammation -- MS

periphery

Demyelination and axon loss

Blood-brain-barrier

transmigration

CNS

T

T

autoreactive T - cellsDanger Signal or Trigger

activation, differentiation,clonal expansion

T

T

T

T

local reactivationT

T

APC

APC

adhesion

T

Release of cytokinesRecruitment of M

antibodies

B

MNO

IFN-

TNF-

MS as an Autoimmune T-cell Mediated MS as an Autoimmune T-cell Mediated ProcessProcess

Courtesy sanofi-aventis

Why treat MS early with Why treat MS early with DMTsDMTs

The disease is clinically episodicThe disease is clinically episodic– BUT the BUT the disease processdisease process is ongoing is ongoing

and degenerative and degenerative Permanent damage (i.e. loss of Permanent damage (i.e. loss of

axons and neurons) is an early axons and neurons) is an early and progressive event and progressive event

Fromann (1878), from the border of a cerebellar lesion

Terminal axonal ovoids

Adapted with permission from Trapp BD et al. N Engl J Med. 1998; 338:278-285.

Nonphosphorylated neurofilaments

64 m 45 m

MS: A Disease which affects myelin and Axon

Trapp et al, NEJM 1998;338;278-285


From left to rightFrom left to right– Normal axonNormal axon– Demyelinated axonDemyelinated axon– Transected axonTransected axon– Neuronal deathNeuronal death

MS Forum, 1999


Slowing the early disease Slowing the early disease course may alter long-term course may alter long-term outcomeoutcome Long Term Follow UpLong Term Follow Up

– Natural history: Natural history: 50%50% of patients have progressive MS after 14 years of patients have progressive MS after 14 years

– PRISMS-study, IFNPRISMS-study, IFNββ 1a sc: 1a sc: <20%<20% have progressive MS after 14 years have progressive MS after 14 years

– BENEFIT-study, IFNBENEFIT-study, IFNββ 1b sc, 5-year follow up: 1b sc, 5-year follow up: treatment from first attack compared to up to 2 yrs treatment from first attack compared to up to 2 yrs

later delays accumulation of disability for 18 monthslater delays accumulation of disability for 18 months


DMTs todayDMTs today

First line therapyFirst line therapy– Interferon Interferon ββ 1b 1b

subcutaneous injections once every other subcutaneous injections once every other dayday

– Interferon Interferon ββ 1a 1a intramuscular injections once weeklyintramuscular injections once weekly subcutaneous injections thrice weekly subcutaneous injections thrice weekly

– Glatiramer acetateGlatiramer acetate subcutaneous injections once dailysubcutaneous injections once daily

– Safety: no issues after 10-15 years Safety: no issues after 10-15 years

IFN IFN ββ and GA and GA

2-year data2-year data

0

0,2

0,4

0,6

0,8

1

1,2

1,4

Betaferon Avonex Rebif 44 Copaxone

placeboactive

Relapse rate / year

p 0.0001 0.04 <0.0001 0.055 (0.007*)

*ANCOVA

Reduces relapse frequency by

~30%

0

0,5

1

1,5

2

2,5

3

Betaferon Avonex Rebif Copaxone

placeboactive

T2 active lesions/patient/scan

p <0.009 ? <0.0001

Reduces MRI activity by up to 90%


DMTs todayDMTs today

Second line therapy Second line therapy – natalizumab natalizumab

intravenous injections once monthly intravenous injections once monthly

– safety issues safety issues encephalitis (PML) encephalitis (PML) liver damageliver damage

Reduces risk of progression by 42%(3 month sustained EDSS change)

Placebo 29%

TYSABRI 17%

0.0

0.1

0.2

0.3

0.4

0 12 24 36 48 60 72 84 96 108 120

Pro

po

rtio

n w

ith S

ust

ain

ed

Pro

gre

ssio

n

0 12 24 36 48 60 72 84 96 108 120

Polman CH, et al. N Engl J Med. 2006;354:899-910.

HR=HR=0.58 0.58 PP<0.001<0.001

Natalizumab EfficacyNatalizumab Efficacy

Placebo n=315

TYSABRI n=627

Polman CH, et al. N Engl J Med. 2006;354:899-910; Data on file. Clinical study report. C–1808. Cambridge, MA: Biogen Idec, Inc.; 2006.

0.81

0.27

Over 1 year

P<0.001

0.73

0.23

Over 2 years Over 3 years

An

nu

aliz

ed

re

lap

se r

ate

(9

5%

CI)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

68%68%

P<0.001

68%68%

Reduces Relapse Rate by 68%

0.23


Oral therapies in development

Phase I

Biosimilars Injectables Orals Other

MLN3697 Millennium/sanofi-

aventis

CDP-323 Celltech Group

Dronabinol Unimed Pharma

AVE 9897sanofi-aventis

AlemtuzumabILEX Pharma

LaquinimodTeva

BG-12 Fumapharm

/Biogen

BX-471 Berlex Biosciences/ Schering AG

ZK-117137 Schering AG

C-6448 Merck & Co

GSK-683699GSK

CCI-779Wyeth

Interferon t,Pepgen

Phase II

Daclizumab, Biogen Idec

NBI-5788 Neurocrine BioSci Inc.

Abatacept Bristol-Myers

ATL-1102 Antisense

ABT-874 Abbots Lab

ISIS-107248 Antisense

MBP8298 Lilly/BioMS

Cpn 10 Cbio Ltd

EMZ 701 Transition

CNTO1275 Centocor

TV-5010 Teva

Tovaxin, OpexaPharmaFrontiers

IFN beta 1A Vakzine

IFN beta 1A Synovex

Teriflunomide sanofi aventis

Cladribine Merck Serono

Fingolimod Novartis/

Mitsubishi

E-2007Eisai Co. Ltd

Fampridine Accorda/Elan

Rituximab Biogen

IFN beta 1A Biopartners

Phase III

Oral therapies in MS: the pipeline Oral therapies in MS: the pipeline

Courtesy Merck Serono

Immune targets of Immune targets of existing and future MS existing and future MS

therapiestherapiesTargetTarget Agent Agent Other indications Other indications

Prevention of Prevention of immune immune activationactivation

IFN betaIFN beta ––

GAGA ––

MitoxantroneMitoxantrone Oncology Oncology

BG-12BG-12 First-generation agents used in psoriasis First-generation agents used in psoriasis

DaclizumabDaclizumab Renal-transplant rejection Renal-transplant rejection

LaquinimodLaquinimod ––

Lymphocyte Lymphocyte traffickingtrafficking

NatalizumabNatalizumab ––

FingolimodFingolimod Failed Phase III studies for prevention of renal Failed Phase III studies for prevention of renal transplant rejectiontransplant rejection

TolerizationTolerization MBP8298MBP8298 ––

Lymphocyte Lymphocyte depletiondepletion

CladribineCladribine HCLHCL

TeriflunomideTeriflunomide (Lefluomide indicated in rheumatoid arthritis) (Lefluomide indicated in rheumatoid arthritis)

AlemtuzumabAlemtuzumab CLL CLL

Rituximab Rituximab Non-Hodgkin's lymphoma Non-Hodgkin's lymphoma



BG12BG12

M Sandbergee 2008-11-13M Sandbergee 2008-11-13

BG12BG12

Biogen Idec / FumapharmBiogen Idec / Fumapharm Second generation oral fumarateSecond generation oral fumarate

– First generation used in psoriasisFirst generation used in psoriasis– 50 years of experience in 50 years of experience in

dermatologydermatology


BG12BG12

Potential mode of action in MSPotential mode of action in MS– promotes T-cell promotes T-cell apoptosisapoptosis

programmed cell deathprogrammed cell death

– promotes Th1 promotes Th1 Th2 shiftTh2 shift shift from pro-inflammatory to suppressiveshift from pro-inflammatory to suppressive

– activates Nrf2 regulatory pathwayactivates Nrf2 regulatory pathway essential for immune homeostasisessential for immune homeostasis regulates myelin maintenance in CNS, regulates myelin maintenance in CNS,

implicated as a potential implicated as a potential neuroprotectiveneuroprotective mechanism mechanism

BG12 Phase II BG12 Phase II study study designdesign

Screening

Placebo n=54

BG00012 120 mg tid (360 mg/day)

Blinded placebo-controlled treatment phase

Blinded safety-extension phase

24 weeks 24 weeks

BG00012 120 mg qd (120 mg/day)

BG00012 240 mg tid (720 mg/day)*

Randomization

BG00012 240 mg tid (720 mg/day)

*Patients received 120 mg tid during the first week to determine tolerability

4 8 12 16 20 24

qd=once daily; tid=three times daily

n=59

n=257n=56

n=54

Kappos L, et al. Lancet. 2008;372:1463-72.

BG12 Phase II data: BG12 Phase II data: new Gd+ lesions (weeks 12 to 24)new Gd+ lesions (weeks 12 to 24)

Gd+=gadolinium-enhancing; qd=once daily; tid=three times daily

0

1

2

3

4

5

6

Placebo 120 mg qd 120 mg tid 240 mg tid

P < 0.001

Treatment group

n=54 n=59 n=56 n=54

Mea

n n

um

ber

of

new

Gd

+ l

esio

ns

69%reduction

vs. placebo

Pre-specified primary end point

Kappos L, et al. Lancet. 2008;372:1463-72.


BG12: phase II safetyBG12: phase II safety

Common Adverse Events Common Adverse Events – headache, GI symptoms, flushingheadache, GI symptoms, flushing– most AEs decreased over timemost AEs decreased over time

Serious Adverse EventsSerious Adverse Events– similar proportions of patients with SAEs in placebo similar proportions of patients with SAEs in placebo

and BG12 groupsand BG12 groups

Renal functions/urinalysis testsRenal functions/urinalysis tests– no clinically significant findings no clinically significant findings

Similar low incidence of infections across Similar low incidence of infections across groups groups


BG12:BG12:Development Development programmeprogramme DEFINE studyDEFINE study

– Phase III, Rzd, DB, PLC, 2-yrPhase III, Rzd, DB, PLC, 2-yr– PEP: PEP: Proportion relapsingProportion relapsing patients at 2 yrs patients at 2 yrs– started January 2007started January 2007

CONFIRM studyCONFIRM study– Phase III, Rzd, DB/rater blinded for Phase III, Rzd, DB/rater blinded for GAGA, 2 yrs, 2 yrs– PEP: PEP: Relapse rateRelapse rate at 2 yrs at 2 yrs– started June 2007started June 2007


LaquinimodLaquinimod



Active Biotech / TEVAActive Biotech / TEVA

Laquinimod has been tested in Laquinimod has been tested in two phase II studies two phase II studies

Crosses bloodCrosses blood–brain barrier–brain barrier



Potential mode of actionPotential mode of action– a quinoline-3-carboxamide derivativea quinoline-3-carboxamide derivative– immunomodulatory immunomodulatory by changing by changing

dendritic cell responsedendritic cell response– promotes promotes shift towards Th2shift towards Th2 immunity immunity– not immunosuppressive not immunosuppressive

no effect on T and B cell numbers (mice)no effect on T and B cell numbers (mice) no effect on cytokine secretion (mice)no effect on cytokine secretion (mice)

CI OH O

OCH3

CH2

N

N

CH3



May affect May affect a pivotal pathway of inflammationa pivotal pathway of inflammation – Rheumatoid arthritis (CIA)Rheumatoid arthritis (CIA)– Type I diabetes (NOD mice)Type I diabetes (NOD mice)– GuillainGuillain Barré Syndrome (EAN) Barré Syndrome (EAN) – Inflammatory bInflammatory bowel diseaseowel disease (DSS) (DSS) – Lupus (NZB/W)Lupus (NZB/W)

– Modulates Th1/Th2Modulates Th1/Th2 disease specific pro- disease specific pro-inflammatory immune responses inflammatory immune responses

– Does not affect the ability to mount cellular and Does not affect the ability to mount cellular and humoral immune responseshumoral immune responses

Effects of laquinimod on Gd-enhancing T1 Effects of laquinimod on Gd-enhancing T1 lesionslesions

0

10

20

30

40

Mean ± SE Median

0

10

20

30

40

51% reduction in mean total number of Gd-T1 lesions (12-36wks; p<0.0001)

60% reduction in median total number of Gd-T1 lesions (12–36 wks)


Laquinimod: phase IIb Laquinimod: phase IIb safetysafety

Liver enzymes elevated (ALT)Liver enzymes elevated (ALT)– reversiblereversible– most normalized while on study drugmost normalized while on study drug– no sign of liver failure/damageno sign of liver failure/damage

Laboratory markers of inflammationLaboratory markers of inflammation– fibrinogen elevated in active treatment groupsfibrinogen elevated in active treatment groups– all cases reversible while on study drugall cases reversible while on study drug

Mild reversible arthralgia, arthritis, oedemaMild reversible arthralgia, arthritis, oedema Single case of reversible Budd-Chiari syndrome Single case of reversible Budd-Chiari syndrome


Laquinimod: Laquinimod: development development programmeprogramme ALLEGRO studyALLEGRO study

– Phase III, Rzd, DB, PLC, 2-yrPhase III, Rzd, DB, PLC, 2-yr– 1,0001,000 RRMS patients worldwide RRMS patients worldwide– started September 2007started September 2007

BRAVO study BRAVO study – Phase III, Rzd, DB/rater blinded, 2-yr, Phase III, Rzd, DB/rater blinded, 2-yr,

against Avonexagainst Avonex®®

– 1,2001,200 RRMS patients worldwide RRMS patients worldwide– started April 2008 started April 2008


Fingolimod (FTY720)Fingolimod (FTY720)


Fingolimod / FTY720Fingolimod / FTY720

Novartis Novartis S1P (sphingosine-1-phosphate) S1P (sphingosine-1-phosphate)

receptor agonistreceptor agonist Original indication Original indication

– renal allograft rejectionrenal allograft rejection Crosses blood–brain barrierCrosses blood–brain barrier


FingolimodFingolimod

Potentional mode of action in MS Potentional mode of action in MS – blocks lymphocyte egressblocks lymphocyte egress from secondary from secondary

lymphoid organs lymphoid organs – has no effect on innate immunity (NK cells, has no effect on innate immunity (NK cells,

monocytes) monocytes) – is vasoprotective is vasoprotective – enhances myelinationenhances myelination and and axonal axonal

protectionprotection, increases oligodendrocyte , increases oligodendrocyte numbers, activates S1P receptors on numbers, activates S1P receptors on astrocytes, stimulates astrocyte migrationastrocytes, stimulates astrocyte migration

HONH2

FTY720


Fingolimod: phase II Fingolimod: phase II studystudy Phase II, Rzd, DB, PLC, 6-month Phase II, Rzd, DB, PLC, 6-month

trial trial – placebo, 1.25 mg, 5 mgplacebo, 1.25 mg, 5 mg

At 6 mths, plc group was At 6 mths, plc group was randomized randomized – to 1.25 mg or 5 mg to 1.25 mg or 5 mg – and followed for 24 mthsand followed for 24 mths

Total cumulative number of Gd+ lesions over 6 Total cumulative number of Gd+ lesions over 6 monthsmonths

primary end pointprimary end point

nnlesionlesion

number number

meanmeanSDSD

lesionlesion

numbernumber

medianmedianrangerange pp

placeboplacebo 8181 14.814.8 22.522.5 55 0-1140-114

1.25mg1.25mg 8383 8.48.4 23.723.7 11 0-1820-182

<0.001<0.001

1.25mg 1.25mg vs vs

placeboplacebo

5.0mg5.0mg 7777 5.75.7 11.611.6 33 0-910-91

0.0060.006

5.0mg vs 5.0mg vs placeboplacebo

p=0.212 1.25mg vs 5.0mg ECTRIMS 2006

Mean annualized relapse rateMean annualized relapse rate months 0-6months 0-6

nn relapse raterelapse rate pp

placeboplacebo 9292 0.770.77

1.25mg1.25mg 9393 0.350.350.0090.009


5.0mg5.0mg 9292 0.360.360.0140.014


ECTRIMS 2006


Fingolimod: safetyFingolimod: safety

In In phase IIphase II most common side effects most common side effects – nasopharyngitis, dyspnoea, headache, diarrhoea, nasopharyngitis, dyspnoea, headache, diarrhoea,

nauseanausea Other side effects Other side effects

– bradycardia, deteriorating lung functionbradycardia, deteriorating lung function– retinopathy, macular oedemaretinopathy, macular oedema– skin cancerskin cancer

In In phase IIIphase III: two fatal infections: two fatal infections– one case of Herpes simplex encephalitisone case of Herpes simplex encephalitis– one case of disseminated Varicella zosterone case of disseminated Varicella zoster


Fingolimod: Fingolimod: development development programmeprogramme FREEDOMS I FREEDOMS I

– Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg,1.25 mg, plc)Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg,1.25 mg, plc)– 12501250 patients worldwide (not USA) patients worldwide (not USA)– started January 2006started January 2006

FREEDOMS IIFREEDOMS II– Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg, 1.25 mg, plc)Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg, 1.25 mg, plc)– 960960 patients in USA patients in USA – started June 2006started June 2006

TRANSFORMSTRANSFORMS– Phase III, Rzd, AvonexPhase III, Rzd, Avonex®®-controlled, 12 months -controlled, 12 months

(0.5 mg, 1.25 mg, Avonex(0.5 mg, 1.25 mg, Avonex®®))– 12751275 patients worldwide patients worldwide– started May 2006started May 2006


CladribineCladribine



Merck SeronoMerck Serono Synthetic purine nucleoside Synthetic purine nucleoside

analogue analogue – 2-chloro-2’-deoxyadenosine (2-CdA)2-chloro-2’-deoxyadenosine (2-CdA)

Original indication Original indication – lymphocyte malignancies lymphocyte malignancies

Crosses the blood–brain barrierCrosses the blood–brain barrier



Mode of action Mode of action – preferential depletion of CD4+preferential depletion of CD4+ rather than CD8+ T rather than CD8+ T

cellscells– relative sparing of other haematological and relative sparing of other haematological and

immune cellsimmune cells– reduction of pro-inflammatory chemokinesreduction of pro-inflammatory chemokines CCL5 CCL5

and CXCL8and CXCL8

Differs from other agents affecting purine Differs from other agents affecting purine metabolism metabolism – cytotoxic to both actively dividing and resting cellscytotoxic to both actively dividing and resting cells

C10H12CIN5O3

MWt = 285.69


Cladribine: trialsCladribine: trials

Early studies in MS: parenteralEarly studies in MS: parenteral– few patientsfew patients– relatively short trialsrelatively short trials

Ongoing studies in MS: oralOngoing studies in MS: oral– many patientsmany patients– longer trialslonger trials

Registry for long-term follow up in placeRegistry for long-term follow up in place


Cladribine: safetyCladribine: safety

Ongoing studies – no safety signals to Ongoing studies – no safety signals to date date

Possible risks Possible risks – severe infections severe infections

due to lymphocyte depletion due to lymphocyte depletion

– malignanciesmalignancies due to agent being mutagenic due to agent being mutagenic

– myelodysplasiamyelodysplasia due to effect on haematologic parameters due to effect on haematologic parameters


Cladribine: Cladribine: development development programmeprogramme CLARITY studyCLARITY study

– Phase III, Rzd, DB, PLC, 2-yr, monotherapy Phase III, Rzd, DB, PLC, 2-yr, monotherapy in RRMS, in RRMS, 1327 patients1327 patients

LastPatientLastVisit in November 2008LastPatientLastVisit in November 2008 extension study is underwayextension study is underway

ONWARD studyONWARD study– Phase IIb, Rzd, DB, 2-yr, cPhase IIb, Rzd, DB, 2-yr, cladribine ladribine add-on in add-on in

‘active’ RRMS ‘active’ RRMS

ORACLE studyORACLE study– Phase III, Rzd, DB, 2-yr, disease modification study Phase III, Rzd, DB, 2-yr, disease modification study

in CISin CIS– approx approx 650 patients650 patients


TeriflunomideTeriflunomide



sanofi aventissanofi aventis Active metabolite of leflunomide Active metabolite of leflunomide

(ARAVA)(ARAVA)– ARAVA indicated for rheumatoid ARAVA indicated for rheumatoid

arthritis since 1998arthritis since 1998



Potential mode of action in MSPotential mode of action in MS– inhibits DHODH, a key enzyme needed for inhibits DHODH, a key enzyme needed for

de novode novo pyrimidine synthesis pyrimidine synthesis – mediates a cytostatic effect on mediates a cytostatic effect on B and T cellsB and T cells, ,

but but B cells are more sensitive than T cellsB cells are more sensitive than T cells – both both anti-proliferativeanti-proliferative and and anti-inflammatoryanti-inflammatory

Vital salvage pathways are preserved Vital salvage pathways are preserved allowing for generalized immune allowing for generalized immune surveillance surveillance

N C C C N

HC

CH3HO

O

CF3

Phase II study: Phase II study: Schematic designSchematic design

Screening (n=207)

Observation (n=160)

W - 4 W 0 W 36 W 42

* * * * * ****

Placebo (n=61)

Teriflunomide 7 mg (n=61)

Teriflunomide 14 mg (n=57)

*

Randomization

(n=179)

*MRI scans were performed at screening (x2), every 6 weeks throughout treatment and at follow-up


Unique active lesions (primary endpoint)

•Adjusted for study site, disease severity, and baseline activity

Average number of unique active lesions per MRI scan* (Adjusted raw means ± SEM)

2.69

1.06 0.98

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Treatment period

Ave

rag

e #

of

un

iqu

e ac

tive

les

ion

s

Placebo (N=61)7 mg (N=60)14 mg (N=56)

P=0.024P=0.006



Teriflunomide: phase II Teriflunomide: phase II safetysafety

Most AEs were considered unrelated to Most AEs were considered unrelated to study drugstudy drug

More common with active study drug More common with active study drug – alopeciaalopecia– nauseanausea– paraesthesiaparaesthesia

Leflunomide Leflunomide – has risk of teratogenicityhas risk of teratogenicity– has been associated with vasculitis and has been associated with vasculitis and

peripheral neuropathy in RAperipheral neuropathy in RA


Teriflunomide: Teriflunomide: development development programmeprogramme TEMSO – Phase III, Rzd, DB, PLC, 2-yr studyTEMSO – Phase III, Rzd, DB, PLC, 2-yr study

– RRMS with / without progression of disabilityRRMS with / without progression of disability– 1080 patients1080 patients in three arms in three arms– placebo, 7 mg, 14 mgplacebo, 7 mg, 14 mg– long-term extensionlong-term extension

TOWER – duplicates TEMSO but without MRITOWER – duplicates TEMSO but without MRI

TOPIC – Phase III monotherapy in CIS TOPIC – Phase III monotherapy in CIS

Phase II safety and efficacy trials in RRMSPhase II safety and efficacy trials in RRMS– in combination with IFNin combination with IFNββ or GA or GA


ConclusionsConclusions

Treatment targetTreatment target Dosing regimenDosing regimen

BG-12BG-12 Prevention of T-cell activation Prevention of T-cell activation Three times dailyThree times daily

LaquinimodLaquinimod Prevention of T-cell activation Prevention of T-cell activation Once dailyOnce daily

FingolimodFingolimod Lymphocyte trafficking Lymphocyte trafficking Once dailyOnce daily

CladribineCladribine Preferential lymphocyte Preferential lymphocyte depletiondepletion

Once daily for 5 days/monthOnce daily for 5 days/month

(2-4 consecutive (2-4 consecutive months/year)months/year)

TeriflunomideTeriflunomide Lymphocyte anti-proliferationLymphocyte anti-proliferationOnce dailyOnce daily

Summary of oral Summary of oral therapies in therapies in

development for MSdevelopment for MS



EndEnd

oral treatments in development for ms emsp information day brussels, 13 november 2008 magnhild...

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