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Transcript of 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
M Sandberg 2008-11-13M Sandberg 2008-11-13
if you get MS…if you get MS…
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…
M Sandberg 2008-11-13M Sandberg 2008-11-13
if you get MS…if you get MS…
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
From left to rightFrom left to right– Normal axonNormal axon– Demyelinated axonDemyelinated axon– Transected axonTransected axon– Neuronal deathNeuronal death
MS Forum, 1999
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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%
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
Courtesy Merck Serono
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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.
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
LaquinimodLaquinimod
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
LaquinimodLaquinimod
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
LaquinimodLaquinimod
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)
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
Fingolimod (FTY720)Fingolimod (FTY720)
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
1.25mg vs 1.25mg vs placeboplacebo
5.0mg5.0mg 9292 0.360.360.0140.014
5.0mg vs 5.0mg vs placeboplacebo
ECTRIMS 2006
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
CladribineCladribine
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
CladribineCladribine
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
TeriflunomideTeriflunomide
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
TeriflunomideTeriflunomide
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
Courtesy sanofi-aventis
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
Courtesy sanofi-aventis
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
M Sandberg 2008-11-13M Sandberg 2008-11-13
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
Courtesy Merck Serono
M Sandberg 2008-11-13M Sandberg 2008-11-13
EndEnd