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

2. M Sandberg 2008-11-13 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

3. M Sandberg 2008-11-13 if you get MS… you are 20 - 30 years old 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…

4. M Sandberg 2008-11-13 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

5. M Sandberg 2008-11-13 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

6. M Sandberg 2008-11-13 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

7. 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

9. 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;278-285

10. M Sandberg 2008-11-13 From left to right From left to right –Normal axon –Demyelinated axon –Transected axon –Neuronal death MS Forum, 1999

11. M Sandberg 2008-11-13 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

12. M Sandberg 2008-11-13 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 10-15 years

13. IFN β and GA 2-year data Relapse rate / year p 0.0001 0.04 <0.0001 0.055 (0.007*) *ANCOVA Reduces relapse frequency by ~30% T2 active lesions/patient/scan p <0.009 ? <0.0001 Reduces MRI activity by up to 90%

14. M Sandberg 2008-11-13 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

15. 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 01224364860728496108120 Proportion with Sustained Progression 01224364860728496108120 Polman CH, et al. N Engl J Med. 2006;354:899-910. HR=0.58 P<0.001 Natalizumab 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 Annualized relapse rate (95% CI) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 68% P<0.001 68% Reduces Relapse Rate by 68% 0.23

16. M Sandberg 2008-11-13 Oral therapies in development

17. 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-117137 Schering AG C-6448 Merck & Co GSK-683699 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-107248 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

18. 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

19. M Sandberg 2008-11-13 BG12

20. M Sandbergee 2008-11-13 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

21. M Sandberg 2008-11-13 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

22. BG12 Phase II study design Screening Placebo n=54 BG00012 120 mg tid (360 mg/day) Blinded placebo-controlled treatment phase Blinded safety-extension phase 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 4812162024 qd=once daily; tid=three times daily n=59 n=257 n=56 n=54 Kappos L, et al. Lancet. 2008;372:1463-72.

23. BG12 Phase II data: new Gd+ lesions (weeks 12 to 24) Gd+=gadolinium-enhancing; qd=once daily; tid=three times daily 0 1 2 3 4 5 6 Placebo120 mg qd120 mg tid240 mg tid P < 0.001 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;372:1463-72.

24. M Sandberg 2008-11-13 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

25. M Sandberg 2008-11-13 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

26. M Sandberg 2008-11-13 Laquinimod

27. 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

28. M Sandberg 2008-11-13 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

29. M Sandberg 2008-11-13 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

30. Effects of laquinimod on Gd-enhancing T1 lesions 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)

31. M Sandberg 2008-11-13 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

32. M Sandberg 2008-11-13 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

33. M Sandberg 2008-11-13 Fingolimod (FTY720)

34. M Sandberg 2008-11-13 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

35. M Sandberg 2008-11-13 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

36. M Sandberg 2008-11-13 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

37. Total cumulative number of Gd+ lesions over 6 months primary end point nlesionnumbermeanSDlesionnumbermedianrangep placebo8114.822.550-114 1.25mg838.423.710-182<0.001 1.25mg vs placebo 5.0mg775.711.630-910.006 5.0mg vs placebo p=0.212 1.25mg vs 5.0mg ECTRIMS 2006

38. Mean annualized relapse rate months 0-6 n relapse rate p placebo920.77 1.25mg930.350.009 1.25mg vs placebo 5.0mg920.360.014 5.0mg vs placebo ECTRIMS 2006

39. M Sandberg 2008-11-13 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

40. M Sandberg 2008-11-13 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

41. M Sandberg 2008-11-13 Cladribine

42. 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

43. M Sandberg 2008-11-13 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 = 285.69

44. M Sandberg 2008-11-13 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

45. M Sandberg 2008-11-13 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

46. M Sandberg 2008-11-13 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

47. M Sandberg 2008-11-13 Teriflunomide

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

49. M Sandberg 2008-11-13 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

50. 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

51. 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 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

52. M Sandberg 2008-11-13 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

53. M Sandberg 2008-11-13 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

54. M Sandberg 2008-11-13 Conclusions

55. 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

56. M Sandberg 2008-11-13 End