Oral Treatments in Development for MS EMSP Information Day Brussels, 13 November 2008 Magnhild Sandberg-Wollheim

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

M Sandberg if you get MS… you are years old you are 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 if you get MS… At this time of your life, you do not want to hear 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 So, what is MS ? MS is an autoimmune disease MS is an autoimmune disease Our immune system is there to defend us against what is foreign Our immune system is there to defend us against what is foreign –for instance virus, bacteria but it must tolerate self but it must tolerate self –our own tissues and organs

M Sandberg CNS is under surveillance of the immune system Under normal circumstances white blood cells circulate through and survey tissues and organs Under normal circumstances white blood cells 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 Sometimes a white blood cell will mistakenly recognize a self molecule as foreign This will lead to an autoimmune reaction This will lead to an autoimmune reaction –in the CNS (brain and spinal cord) the result will be areas of inflammation -- MS

periphery Demyelination and axon loss Blood- brain- barrier transmigration CNS T T autoreactive T - cells Danger Signal or Trigger activation, differentiation, clonal expansion T T T T local reactivation T T APC adhesion T Release of cytokines Recruitment of M antibodies B M NO IFN- TNF- MS as an Autoimmune T-cell Mediated Process Courtesy sanofi-aventis

Why treat MS early with DMTs The disease is clinically episodic 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 Permanent damage (i.e. loss of axons and neurons) is an early and progressive event Fromann (1878), from the border of a cerebellar lesion Trapp et al, NEJM 1998;338;

M Sandberg From left to right From left to right –Normal axon –Demyelinated axon –Transected axon –Neuronal death MS Forum, 1999

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

M Sandberg DMTs today First line therapy First line therapy –Interferon β 1b subcutaneous injections once every other day subcutaneous injections once every other day –Interferon β 1a intramuscular injections once weekly intramuscular injections once weekly subcutaneous injections thrice weekly subcutaneous injections thrice weekly –Glatiramer acetate subcutaneous injections once daily subcutaneous injections once daily –Safety: no issues after years

IFN β and GA 2-year data Relapse rate / year p < (0.007*) *ANCOVA Reduces relapse frequency by ~30% T2 active lesions/patient/scan p <0.009 ? < Reduces MRI activity by up to 90%

M Sandberg DMTs today Second line therapy Second line therapy –natalizumab intravenous injections once monthly intravenous injections once monthly –safety issues encephalitis (PML) encephalitis (PML) liver damage liver damage

Reduces risk of progression by 42% (3 month sustained EDSS change) Placebo 29% TYSABRI 17% Proportion with Sustained Progression Polman CH, et al. N Engl J Med. 2006;354: HR=0.58 P<0.001 Natalizumab Efficacy Placebo n=315 TYSABRI n=627 Polman CH, et al. N Engl J Med. 2006;354: ; Data on file. Clinical study report. C–1808. Cambridge, MA: Biogen Idec, Inc.; Over 1 year P< Over 2 years Over 3 years Annualized relapse rate (95% CI) % P< % Reduces Relapse Rate by 68% 0.23

M Sandberg Oral therapies in development

Phase I BiosimilarsInjectablesOralsOther MLN3697 Millennium/sanofi- aventis CDP-323 Celltech Group Dronabinol Unimed Pharma AVE 9897 sanofi-aventis Alemtuzumab ILEX Pharma Laquinimod Teva BG-12 Fumapharm /Biogen BX-471 Berlex Biosciences/ Schering AG ZK Schering AG C-6448 Merck & Co GSK GSK CCI-779 Wyeth Interferon t, Pepgen Phase II Daclizumab, Biogen Idec NBI-5788 Neurocrine BioSci Inc. Abatacept Bristol-Myers ATL-1102 Antisense ABT-874 Abbots Lab ISIS Antisense MBP8298 Lilly/BioMS Cpn 10 Cbio Ltd EMZ 701 Transition CNTO1275 Centocor TV-5010 Teva Tovaxin, Opexa PharmaFrontiers IFN beta 1A Vakzine IFN beta 1A Synovex Teriflunomide sanofi aventis Cladribine Merck Serono Fingolimod Novartis/ Mitsubishi E-2007 Eisai Co. Ltd Fampridine Accorda/Elan Rituximab Biogen IFN beta 1A Biopartners Phase III Oral therapies in MS: the pipeline Courtesy Merck Serono

Immune targets of existing and future MS therapies TargetAgent Other indications Prevention of immune activation IFN beta – GA– MitoxantroneOncology BG-12 First-generation agents used in psoriasis Daclizumab Renal-transplant rejection Laquinimod– Lymphocyte trafficking Natalizumab– Fingolimod Failed Phase III studies for prevention of renal transplant rejection TolerizationMBP8298– Lymphocyte depletion CladribineHCL Teriflunomide (Lefluomide indicated in rheumatoid arthritis) AlemtuzumabCLL Rituximab Non-Hodgkin's lymphoma Courtesy Merck Serono

M Sandberg BG12

M Sandbergee BG12 Biogen Idec / Fumapharm Biogen Idec / Fumapharm Second generation oral fumarate Second generation oral fumarate –First generation used in psoriasis –50 years of experience in dermatology

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

BG12 Phase II study design Screening Placebo n=54 BG mg tid (360 mg/day) Blinded placebo-controlled treatment phase Blinded safety-extension phase 24 weeks BG mg qd (120 mg/day) BG mg tid (720 mg/day)* Randomization BG mg tid (720 mg/day) *Patients received 120 mg tid during the first week to determine tolerability qd=once daily; tid=three times daily n=59 n=257 n=56 n=54 Kappos L, et al. Lancet. 2008;372:

BG12 Phase II data: new Gd+ lesions (weeks 12 to 24) Gd+=gadolinium-enhancing; qd=once daily; tid=three times daily Placebo120 mg qd120 mg tid240 mg tid P < Treatment group n=54n=59n=56n=54 Mean number of new Gd+ lesions 69% reduction vs. placebo Pre-specified primary end point Kappos L, et al. Lancet. 2008;372:

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

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

M Sandberg Laquinimod

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

M Sandberg Laquinimod Potential mode of action 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 T and B cell numbers (mice) no effect on cytokine secretion (mice) no effect on cytokine secretion (mice) CIOHO O CH 3 CH 2 N N CH 3

M Sandberg Laquinimod May affect a pivotal pathway of inflammation May affect a pivotal pathway of inflammation –Rheumatoid arthritis (CIA) –Type I diabetes (NOD mice) –Guillain Barré 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

Effects of laquinimod on Gd-enhancing T1 lesions Mean ± SE Median % 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 Laquinimod: phase IIb safety Liver enzymes elevated (ALT) Liver enzymes elevated (ALT) –reversible –most normalized while on study drug –no sign of liver failure/damage Laboratory markers of inflammation Laboratory markers of inflammation –fibrinogen elevated in active treatment groups –all cases reversible while on study drug Mild reversible arthralgia, arthritis, oedema Mild reversible arthralgia, arthritis, oedema Single case of reversible Budd-Chiari syndrome Single case of reversible Budd-Chiari syndrome

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

M Sandberg Fingolimod (FTY720)

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

M Sandberg Fingolimod Potentional mode of action in MS 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 HO NH 2 FTY720

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

Total cumulative number of Gd+ lesions over 6 months primary end point nlesionnumbermeanSDlesionnumbermedianrangep placebo mg < mg vs placebo 5.0mg mg vs placebo p= mg vs 5.0mg ECTRIMS 2006

Mean annualized relapse rate months 0-6 n relapse rate p placebo mg mg vs placebo 5.0mg mg vs placebo ECTRIMS 2006

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

M Sandberg Fingolimod: development programme FREEDOMS I 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 FREEDOMS II –Phase III, Rzd, DB, PLC, 2 yrs, (0.5 mg, 1.25 mg, plc) –960 patients in USA –started June 2006 TRANSFORMS TRANSFORMS –Phase III, Rzd, Avonex ® -controlled, 12 months (0.5 mg, 1.25 mg, Avonex ® ) –1275 patients worldwide –started May 2006

M Sandberg Cladribine

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

M Sandberg Cladribine Mode of action Mode of action –preferential depletion of CD4+ rather than CD8+ T cells –relative sparing of other haematological and immune cells –reduction of pro-inflammatory chemokines CCL5 and CXCL8 Differs from other agents affecting purine metabolism Differs from other agents affecting purine metabolism –cytotoxic to both actively dividing and resting cells C 10 H 12 CIN 5 O 3 MWt =

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

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

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

M Sandberg Teriflunomide

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

M Sandberg Teriflunomide Potential mode of action in MS 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 Vital salvage pathways are preserved allowing for generalized immune surveillance NCCCN H C CH 3 HO O CF 3

Phase II study: Schematic design Screening (n=207) Observation (n=160) W - 4 W 0 W 36W 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) Treatment period Average # of unique active lesions Placebo (N=61) 7 mg (N=60) 14 mg (N=56) P=0.024 P=0.006 Courtesy sanofi-aventis

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

M Sandberg Teriflunomide: development programme TEMSO – Phase III, Rzd, DB, PLC, 2-yr study 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 TOWER – duplicates TEMSO but without MRI TOPIC – Phase III monotherapy in CIS TOPIC – Phase III monotherapy in CIS Phase II safety and efficacy trials in RRMS Phase II safety and efficacy trials in RRMS –in combination with IFNβ or GA

M Sandberg Conclusions

Treatment target Dosing regimen BG-12 BG-12 Prevention of T-cell activation Three times daily Laquinimod Laquinimod Prevention of T-cell activation Once daily Fingolimod Fingolimod Lymphocyte trafficking Once daily Cladribine Cladribine Preferential lymphocyte depletion Once daily for 5 days/month (2-4 consecutive months/year) Teriflunomide Teriflunomide Lymphocyte anti-proliferation Once daily Summary of oral therapies in development for MS Courtesy Merck Serono

M Sandberg End