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Oral Treatments in Development for MS EMSP Information Day Brussels, 13 November 2008 Magnhild Sandberg-Wollheim if you get MS… you will have a chronic disease with unknown cause uncertain prognosis unsatisfactory treatments and you are one of ~500,000 Europeans if you get MS…

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oral treatments in development for ms

Oral Treatments in Development for MS

EMSP Information Day

Brussels, 13 November 2008

Magnhild Sandberg-Wollheim

if you get ms
if you get MS…
  • you will have a chronic disease with
    • unknown cause
    • uncertain prognosis
    • unsatisfactory treatments
  • and you are one of ~500,000 Europeans

M Sandberg 2008-11-13

if you get ms3
if you get MS…
  • you are 20 - 30 years old
    • have started on your education…
    • have hopes of a spectacular career…
    • have met the love of your life…
    • have begun to think of having a family…

M Sandberg 2008-11-13

if you get ms4
if you get MS…
  • At this time of your life, you do not want to hear
    • that you have a chronic disease
    • that the treatment involves daily or weekly injections
    • and yet, your future is uncertain

M Sandberg 2008-11-13

so what is ms
So, what is MS ?
  • MS is an autoimmune disease
  • Our immune system is there to defend us against what is ”foreign”
    • for instance virus, bacteria
  • but it must tolerate ”self”
    • our own tissues and organs

M Sandberg 2008-11-13

cns is under surveillance of the immune system
CNS is under surveillance of the immune system
  • Under normal circumstances white bloodcells circulate through and survey tissues and organs
    • if they do not encounter anything ”foreign”, they return to the circulation
  • Sometimes a white blood cell will mistakenly recognize a ”self” molecule as foreign
  • This will lead to an autoimmune reaction
    • in the CNS (brain and spinal cord) the result will be areas of inflammation -- MS

M Sandberg 2008-11-13

ms as an autoimmune t cell mediated process

Danger Signal or Trigger

T

T

activation, differentiation,clonal expansion

T

adhesion

T

transmigration

T

B

APC

T

IFN-

antibodies

local reactivation

APC

M

Release of cytokines

Recruitment of M

T

TNF-

NO

MS as an Autoimmune T-cell Mediated Process

autoreactive T - cells

T

T

periphery

Blood-brain-barrier

CNS

Demyelination and axon loss

Courtesy sanofi-aventis

why treat ms early with dmts
Why treat MS early with DMTs
  • The disease is clinically episodic
    • BUT the disease process is ongoing and degenerative
  • Permanent damage (i.e. loss of axons and neurons) is an early and progressive event

Trapp et al, NEJM

1998;338;278-285

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

slide10
From left to right
    • Normal axon
    • Demyelinated axon
    • Transected axon
    • Neuronal death

MS Forum, 1999

M Sandberg 2008-11-13

slowing the early disease course may alter long term outcome
Slowing the early disease course may alter long-term outcome
  • Long Term Follow Up
    • Natural history:
      • 50% of patients have progressive MS after 14 years
    • PRISMS-study, IFNβ 1a sc:
      • <20% have progressive MS after 14 years
    • BENEFIT-study, IFNβ 1b sc, 5-year follow up:
      • treatment from first attack compared to up to 2 yrs later delays accumulation of disability for 18 months

M Sandberg 2008-11-13

dmts today
DMTs today
  • First line therapy
    • Interferon β 1b
      • subcutaneous injections once every other day
    • Interferon β 1a
      • intramuscular injections once weekly
      • subcutaneous injections thrice weekly
    • Glatiramer acetate
      • subcutaneous injections once daily
    • Safety: no issues after 10-15 years

M Sandberg 2008-11-13

slide13

IFN β and GA2-year data

Relapse rate / year

T2 active lesions/patient/scan

p 0.0001 0.04 <0.0001 0.055 (0.007*)

*ANCOVA

Reduces relapse frequency by

~30%

p <0.009 ? <0.0001

Reduces MRI activity by

up to 90%

dmts today14
DMTs today
  • Second line therapy
    • natalizumab
      • intravenous injections once monthly
    • safety issues
      • encephalitis (PML)
      • liver damage

M Sandberg 2008-11-13

natalizumab efficacy

Placebo n=315

TYSABRI n=627

Over 3 years

Natalizumab Efficacy

Reduces risk of progression by 42%

(3 month sustained EDSS change)

Reduces Relapse Rate by 68%

P<0.001

1.0

P<0.001

HR=0.58 P<0.001

0.4

0.9

0.8

Placebo 29%

68%

0.3

68%

0.7

0.6

Proportion with Sustained Progression

0.5

0.81

0.73

0.2

Annualized relapse rate (95% CI)

0.4

0.3

0.1

TYSABRI 17%

0.2

0.27

0.23

0.23

0.1

0.0

0.0

0

12

24

36

48

60

72

84

96

108

120

0

12

24

36

48

60

72

84

96

108

120

Over 1 year

Over 2 years

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.

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

oral therapies in development

Oral therapies in development

M Sandberg 2008-11-13

slide17

CDP-323

Celltech Group

MLN3697 Millennium/sanofi-aventis

Dronabinol

Unimed Pharma

AVE 9897

sanofi-aventis

Oral therapies in MS: the pipeline

Laquinimod

Teva

Cladribine

Merck Serono

GSK-683699

GSK

NBI-5788

Neurocrine

BioSci Inc.

BG-12

Fumapharm

/Biogen

ZK-117137

Schering AG

IFN beta 1A Biopartners

Cpn 10

Cbio Ltd

Rituximab

Biogen

ATL-1102 Antisense

Daclizumab, Biogen Idec

ISIS-107248 Antisense

Teriflunomide

sanofi aventis

Abatacept

Bristol-Myers

ABT-874

Abbots Lab

IFN beta 1A Synovex

IFN beta 1A Vakzine

Phase III

TV-5010

Teva

MBP8298

Lilly/BioMS

Phase II

Interferon t,

Pepgen

C-6448

Merck & Co

Fampridine

Accorda/Elan

BX-471 Berlex Biosciences/ Schering AG

EMZ 701 Transition

E-2007

Eisai Co. Ltd

Fingolimod

Novartis/

Mitsubishi

CNTO1275 Centocor

CCI-779

Wyeth

Tovaxin, Opexa

PharmaFrontiers

Alemtuzumab

ILEX Pharma

Phase I

Biosimilars

Injectables

Orals

Other

Courtesy Merck Serono

slide19

BG12

M Sandberg 2008-11-13

slide20
BG12
  • Biogen Idec / Fumapharm
  • Second generation oral fumarate
    • First generation used in psoriasis
    • 50 years of experience in dermatology

M Sandbergee 2008-11-13

slide21
BG12
  • Potential mode of action in MS
    • promotes T-cell apoptosis
      • programmed cell death
    • promotes Th1  Th2 shift
      • shift from pro-inflammatory to suppressive
    • activates Nrf2 regulatory pathway
      • essential for immune homeostasis
      • regulates myelin maintenance in CNS, implicated as a potential neuroprotective mechanism

M Sandberg 2008-11-13

bg12 phase ii study design
BG12 Phase II study design

Blinded placebo-controlled treatment phase

Blinded safety-extension phase

Screening

BG00012 240 mg tid (720 mg/day)

Placebon=54

BG00012 120 mg qd (120 mg/day)

n=59

Randomization

BG00012 120 mg tid (360 mg/day)

n=56

n=257

BG00012 240 mg tid (720 mg/day)*

n=54

4

8

12

16

20

24

24 weeks

24 weeks

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

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

qd=once daily; tid=three times daily

bg12 phase ii data new gd lesions weeks 12 to 24
BG12 Phase II data: new Gd+ lesions (weeks 12 to 24)

Pre-specified primary end point

6

5

4

69%reduction

vs. placebo

Mean number of new Gd+ lesions

3

P < 0.001

2

1

n=54

n=59

n=56

n=54

0

Placebo

120 mg qd

120 mg tid

240 mg tid

Treatment group

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

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

bg12 phase ii safety
BG12: phase II safety
  • Common Adverse Events
    • headache, GI symptoms, flushing
    • most AEs decreased over time
  • Serious Adverse Events
    • similar proportions of patients with SAEs in placebo and BG12 groups
  • Renal functions/urinalysis tests
    • no clinically significant findings
  • Similar low incidence of infections across groups

M Sandberg 2008-11-13

bg12 development programme
BG12:Development programme
  • DEFINE study
    • Phase III, Rzd, DB, PLC, 2-yr
    • PEP: Proportion relapsing patients at 2 yrs
    • started January 2007
  • CONFIRM study
    • Phase III, Rzd, DB/rater blinded for GA, 2 yrs
    • PEP: Relapse rate at 2 yrs
    • started June 2007

M Sandberg 2008-11-13

laquinimod

Laquinimod

M Sandberg 2008-11-13

laquinimod27
Laquinimod
  • Active Biotech / TEVA
  • Laquinimod has been tested in two phase II studies
  • Crosses blood–brain barrier

M Sandberg 2008-11-13

laquinimod28

CI

OH

O

N

CH2

O

N

CH3

CH3

Laquinimod
  • Potential mode of action
    • a quinoline-3-carboxamide derivative
    • immunomodulatory by changing dendritic cell response
    • promotes shift towards Th2 immunity
    • not immunosuppressive
      • no effect on T and B cell numbers (mice)
      • no effect on cytokine secretion (mice)

M Sandberg 2008-11-13

laquinimod29
Laquinimod
  • May affect a pivotal pathway of inflammation
    • Rheumatoid arthritis (CIA)
    • Type I diabetes (NOD mice)
    • GuillainBarré Syndrome (EAN)
    • Inflammatory bowel disease (DSS)
    • Lupus (NZB/W)
    • Modulates Th1/Th2 disease specific pro-inflammatory immune responses
    • Does not affect the ability to mount cellular and humoral immune responses

M Sandberg 2008-11-13

effects of laquinimod on gd enhancing t1 lesions
Effects of laquinimod on Gd-enhancing T1 lesions

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

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

40

40

30

30

20

20

10

10

0

0

Mean ± SE

Median

laquinimod phase iib safety
Laquinimod: phase IIb safety
  • Liver enzymes elevated (ALT)
    • reversible
    • most normalized while on study drug
    • no sign of liver failure/damage
  • Laboratory markers of inflammation
    • fibrinogen elevated in active treatment groups
    • all cases reversible while on study drug
  • Mild reversible arthralgia, arthritis, oedema
  • Single case of reversible Budd-Chiari syndrome

M Sandberg 2008-11-13

laquinimod development programme
Laquinimod: development programme
  • ALLEGRO study
    • Phase III, Rzd, DB, PLC, 2-yr
    • 1,000 RRMS patients worldwide
    • started September 2007
  • BRAVO study
    • Phase III, Rzd, DB/rater blinded, 2-yr, against Avonex®
    • 1,200 RRMS patients worldwide
    • started April 2008

M Sandberg 2008-11-13

fingolimod fty720

Fingolimod (FTY720)

M Sandberg 2008-11-13

fingolimod fty72034
Fingolimod / FTY720
  • Novartis
  • S1P (sphingosine-1-phosphate) receptor agonist
  • Original indication
    • renal allograft rejection
  • Crosses blood–brain barrier

M Sandberg 2008-11-13

fingolimod

HO

FTY720

NH2

Fingolimod
  • Potentional mode of action in MS
    • blocks lymphocyte egress from secondary lymphoid organs
    • has no effect on innate immunity (NK cells, monocytes)
    • is vasoprotective
    • enhances myelination and axonal protection, increases oligodendrocyte numbers, activates S1P receptors on astrocytes, stimulates astrocyte migration

M Sandberg 2008-11-13

fingolimod phase ii study
Fingolimod: phase II study
  • Phase II, Rzd, DB, PLC, 6-month trial
    • placebo, 1.25 mg, 5 mg
  • At 6 mths, plc group was randomized
    • to 1.25 mg or 5 mg
    • and followed for 24 mths

M Sandberg 2008-11-13

total cumulative number of gd lesions over 6 months primary end point
Total cumulative number of Gd+ lesions over 6 monthsprimary end point

p=0.212 1.25mg vs 5.0mg

ECTRIMS 2006

fingolimod safety
Fingolimod: safety
  • In phase II most common side effects
    • nasopharyngitis, dyspnoea, headache, diarrhoea, nausea
  • Other side effects
    • bradycardia, deteriorating lung function
    • retinopathy, macular oedema
    • skin cancer
  • In phase III: two fatal infections
    • one case of Herpes simplex encephalitis
    • one case of disseminated Varicella zoster

M Sandberg 2008-11-13

fingolimod development programme
Fingolimod: development programme
  • FREEDOMS I
    • Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg,1.25 mg, plc)
    • 1250 patients worldwide (not USA)
    • started January 2006
  • FREEDOMS II
    • Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg, 1.25 mg, plc)
    • 960 patients in USA
    • started June 2006
  • TRANSFORMS
    • Phase III, Rzd, Avonex®-controlled, 12 months (0.5 mg, 1.25 mg, Avonex®)
    • 1275 patients worldwide
    • started May 2006

M Sandberg 2008-11-13

cladribine

Cladribine

M Sandberg 2008-11-13

cladribine42
Cladribine
  • Merck Serono
  • Synthetic purine nucleoside analogue
    • 2-chloro-2’-deoxyadenosine (2-CdA)
  • Original indication
    • lymphocyte malignancies
  • Crosses the blood–brain barrier

M Sandberg 2008-11-13

cladribine43
Cladribine

C10H12CIN5O3

MWt = 285.69

  • Mode of action
    • preferential depletion of CD4+ rather than CD8+ T cells
    • relative sparing of other haematological and immune cells
    • reduction of pro-inflammatory chemokinesCCL5 and CXCL8
  • Differs from other agents affecting purine metabolism
    • cytotoxic to both actively dividing and resting cells

M Sandberg 2008-11-13

cladribine trials
Cladribine: trials
  • Early studies in MS: parenteral
    • few patients
    • relatively short trials
  • Ongoing studies in MS: oral
    • many patients
    • longer trials
  • Registry for long-term follow up in place

M Sandberg 2008-11-13

cladribine safety
Cladribine: safety
  • Ongoing studies – no safety signals to date
  • Possible risks
    • severe infections
      • due to lymphocyte depletion
    • malignancies
      • due to agent being mutagenic
    • myelodysplasia
      • due to effect on haematologic parameters

M Sandberg 2008-11-13

cladribine development programme
Cladribine: development programme
  • CLARITY study
    • Phase III, Rzd, DB, PLC, 2-yr, monotherapy in RRMS, 1327 patients
      • LastPatientLastVisit in November 2008
      • extension study is underway
  • ONWARD study
    • Phase IIb, Rzd, DB, 2-yr, cladribine add-on in ‘active’ RRMS
  • ORACLE study
    • Phase III, Rzd, DB, 2-yr, disease modification study in CIS
    • approx 650 patients

M Sandberg 2008-11-13

teriflunomide

Teriflunomide

M Sandberg 2008-11-13

teriflunomide48
Teriflunomide
  • sanofi aventis
  • Active metabolite of leflunomide (ARAVA)
    • ARAVA indicated for rheumatoid arthritis since 1998

M Sandberg 2008-11-13

teriflunomide49

O

CF3

N

C

C

C

N

H

C

HO

CH3

Teriflunomide
  • Potential mode of action in MS
    • inhibits DHODH, a key enzyme needed for de novo pyrimidine synthesis
    • mediates a cytostatic effect on B and T cells, but B cells are more sensitive than T cells
    • both anti-proliferative and anti-inflammatory
  • Vital salvage pathways are preserved allowing for generalized immune surveillance

M Sandberg 2008-11-13

phase ii study schematic design

(n=61)

Placebo

Teriflunomide 7 mg

(n=61)

Teriflunomide 14 mg

(n=57)

W - 4

Phase II study: Schematic design

Randomization

(n=179)

Screening

Observation

(n=207)

(n=160)

W 0

W 36

W 42

*

*

*

*

*

*

*

*

*

*

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

Courtesy sanofi-aventis

unique active lesions primary endpoint
Unique active lesions (primary endpoint)

Average number of unique active lesions per MRI scan*

(Adjusted raw means ± SEM)

3.5

Placebo (N=61)

3.0

7 mg (N=60)

14 mg (N=56)

2.5

2.69

2.0

Average # of unique active lesions

P=0.024

P=0.006

1.5

1.0

1.06

0.98

0.5

0.0

Treatment period

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

Courtesy sanofi-aventis

teriflunomide phase ii safety
Teriflunomide: phase II safety
  • Most AEs were considered unrelated to study drug
  • More common with active study drug
    • alopecia
    • nausea
    • paraesthesia
  • Leflunomide
    • has risk of teratogenicity
    • has been associated with vasculitis and peripheral neuropathy in RA

M Sandberg 2008-11-13

teriflunomide development programme
Teriflunomide: development programme
  • TEMSO – Phase III, Rzd, DB, PLC, 2-yr study
    • RRMS with / without progression of disability
    • 1080 patients in three arms
    • placebo, 7 mg, 14 mg
    • long-term extension
  • TOWER – duplicates TEMSO but without MRI
  • TOPIC – Phase III monotherapy in CIS
  • Phase II safety and efficacy trials in RRMS
    • in combination with IFNβ or GA

M Sandberg 2008-11-13

conclusions

Conclusions

M Sandberg 2008-11-13

slide56

End

M Sandberg 2008-11-13