1) Fingolimod is a sphingosine 1-phosphate receptor modulator approved for relapsing forms of multiple sclerosis. It works by retaining lymphocytes in lymph nodes, reducing their migration into the central nervous system. 2) Phase II clinical trial results showed fingolimod significantly reduced relapse rates and brain lesion activity compared to placebo over 5 years of follow up. It selectively retained naive and central memory T cells while sparing effector memory T cells. 3) Phase III FREEDOMS trial of over 1200 patients found fingolimod 0.5mg reduced annualized relapse rates by 54% and risk of disability progression by 30% compared to placebo over 2 years. It established

1. Fingolimod (Gilenya):Mode of ActionandClinical Trial Results Prof. Ludwig Kappos Chair Neurology and Department of Biomedicine University Hospital CH-4031 Basel

2. Disclosure L.K. is the Principal Investigator for the FTY 720 Phase II and FREEDOMS studies and has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Sereno, Medicinova, Novartis, Novo Nordisk, Peptimmune, Sanofi-Aventis, Santhera, Roche, Teva, UCB and Wyeth

4. Laquinimod*

5. Teriflunomide*

6. oral VLA4-antagonists

7. Temsirolimus

8. Mycophenolic acid

9. Statins

11. Pixantrone

13. MBP-, DNA- vaccination

15. GA-based

17. Rituximab

18. Ocrelizumab

19. Ofetimumab

20. (Atacicept)

21. DaclizumabIn yellow: agents in Phase III; *recently completed Phase III

23. Both sphingosine and fingolimod are phosphorylated by ubiquitous intracellular sphingosine kinases to their active forms and act via S1P receptors2 (G protein-coupled receptors, discovered in 19983)Sphingosine O H H O Fingolimod N H 2 1. Brinkmann V and Lynch KR. Curr Opin Immunol 2002; 2. Anliker B and Chun J. J Biol Chem 2004; 3. Lee MJ et al. Science 1998

24. S1P1 S1P3 S1P4 S1P5 Effects Fingolimod-phosphate acts on four of five sphingosine 1-phosphate receptors1 Neural cells, EC, atrial myocytes, SMC Lymphocytes, neural cells, EC, atrial myocytes, SMC CNS,oligodendrocytes,natural killer cells Lymphocytes (low expression) Endothelial cell function, vasomotor tone and heart rate5–7 Lymphocyte egress fromlymph nodes2–4 CNS cell function and migration6,8,9 EC, endothelial cells; SMC, smooth muscle cells; S1P, sphingosine 1-phosphate 1. Chun J and Hartung HP. Clin Neuropharmacol 2010; 2. Mandala S et al. Science 2002; 3. Baumruker T et al. Expert Opin Investig Drugs 2007; 4. Matloubian M et al. Nature 2004; 5. Brinkmann V. Pharmacol Ther 2007; 6. Mizugishi K et al. Mol Cell Biol 2005; 7. Massberg S andvon Andrian UH. N Engl J Med 2006; 8. Kimura A et al. Stem Cells 2007; 9. Jaillard C et al. J Neurosci 2005

25. (Mehling M et al, Neurology 2011)

27. TEM, which are important for immune surveillance and maintenance of protective immunity, lack the homing and retention-promoting receptor CCR7, and are therefore largely spared by fingolimod.Tn, naive T cells; TCM, central memory T cell; TEM, effector memory T cell Sallusto et al, Nature 1999; Mackay Nature 1999; Sallusto et al., Annu Rev Immunol 2004; Lanzavecchia et al Science 2000; Appay et al, Cytometry 2008; Westermann J and Pabst R. Clin Investig 1992; Pham et al, Immunity 2008

28. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1 Vehicle-treated 3.5 3.0 2.5 2.0 Clinical score ± SEM 1.5 1.0 0.5 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Days post-immunisation EAE, experimental autoimmune encephalomyelitis 1. Foster CA et al. Brain Pathol 2009

29. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1 Prophylactic Day 0-11 Vehicle-treated Fingolimod† prophylactic 3.5 3.0 2.5 2.0 Clinical score ± SEM 1.5 1.0 0.5 *** 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Days post-immunisation †Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis 1. Foster CA et al. Brain Pathol 2009

30. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1 Prophylactic Day 0-11 Therapeutic Day 12-28 Vehicle-treated Fingolimod† prophylactic Fingolimod† therapeutic 3.5 3.0 2.5 2.0 Clinical score ± SEM 1.5 1.0 0.5 *** *** 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Days post-immunisation †Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis 1. Foster CA et al. Brain Pathol 2009

31. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1 Prophylactic Day 0-11 Therapeutic Day 12-28 Rescue Day 40-53 Vehicle-treated Fingolimod† prophylactic Fingolimod† therapeutic Fingolimod† rescue 3.5 3.0 2.5 2.0 Clinical score ± SEM *** 1.5 1.0 0.5 *** *** 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Days post-immunisation †Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis 1. Foster CA et al. Brain Pathol 2009

32. Fingolimod treatment restores nerve conduction in EAE MOG-induced relapsing-remitting EAE in DA rats Neuronal function determined by recording SEP Treatment SEP (electrical stimulation) 4.0 Fingolimod Control 3.0 N2 EPrecording 2.0 Clinical score SEP recordings Day 53 1.0 Naïve Positive control P1 0.0 Fingolimod 0 55 5 10 15 20 25 30 35 40 45 50 Days post-immunisation Clinical score: 1, flaccid tail; 2, hind limb weakness or ataxia; 3, full paralysis of hind limbs Fingolimod preserved and maintained electrophysiological nerve conduction in EAE DA, dark agouti; EAE, experimental autoimmune encephalomyelitis; MOG, myelin-oligodendrocyte glycoprotein; SEP, somatosensory-evoked action potentials Balatoni B et al. Brain Res Bulletin 2007

33. Proof of Concept in MS

34. 2006;355:1124-40 FTY- Phase II, POC study (NEJM 2006;355:1124-40)

35. Fingolimod Phase II study: patients free from Gd+ lesions after 5 years Placebo re-randomised to fingolimod 100 95.6% 98.1% 93.0% 89.3% 80 96.1% 91.7% 87.5% 86.9% 91.1% 89.7% 88.7% 81.0% 83.1% 85.9% Patients free from Gd+ lesions (%)* 79.2% 60 PlaceboPlacebo / fingolimodFingolimod 1.25 mgFingolimod 5.0 mg / 1.25 mg 78.2% 76.7% 40 47.0% 0 0 1 2 3 4 5 6 12 24 36 48 60 (n = 220) (n = 188) (n = 170) (n = 149) (n = 140) (n = 266) (n = 278) (n = 261) (n = 260) (n = 266) (n = 254) (n = 260) Time (months) *Calculated at each time point using the number of patients with an available MRI scan as the denominator Extension phase ITT population Kappos L et al. ECTRIMS 2009, Montalban et al. MSJ 2011

36. Annualize Relapse Rates in Different Epochs of the POC Study by Completion Status and Randomization

37. Phase II Study – Key findings: Pronounced antiinflammatory effect on MRI outcomes Already after 6 mths significant ARR reduction by 50% Identical effect with lower dose (1.25mg) that was thought not to be effective in preventing transplant rejection No indication of decreasing efficacy over > 6 years, good tolerability Valuable data about selective effects on immune cells

38. Fingolimod selectively inhibits naïve and central memory T cell egress but spares effector memory T cells p<0.001 p<0.001 80 Selective retention: immunological effector functions are preserved 70 60 p<0.001 50 Percentage of CD4+ cells 40 30 Untreated MS Fingolimod-treated MS 20 10 0 Effector memory T cells(CCR7-CD45RA- [TEM] and CCR7-CD45RA+ [TEMRA]) Naïve (CCR7+CD45RA+) Central memory T cells(CCR7+CD45RA-) Adapted from Mehling M et al. Neurology 2008

39. Fingolimod reduces the proportion of Th17 cells in the circulation of people with MS* 1.5 Pro-inflammatory Th17 cells reside mainly in the TCM pool and are enriched in the CSF and lesions of MS patients1–3 p<0.01 p<0.01 p<0.01 Fingolimodtreatment 1.0 IL17+ T cells (%) in CD4+ T cells* 0.5 Fingolimod reduces the proportion of circulating Th17 cells in people with MS 0.0 Fingolimod-treated MS Healthy donors Untreated MS IFNβ-treated MS * Mehling M et al. Neurology 2010; Purified blood T cells from patients with MS treated with fingolimod during the Phase II study and controls. Flow cytometry analysis of IL-17 producing CD4+ T cells. 1. Tzartos JS et al. Am J Pathol 2008; 2. Kébir et al. Ann Neurol 2009; 3.Brucklacher-Waldert et al. Brain 2009. TCM, central memory T cell

40. from POC to Clinical Practice

41. INFORMS PPMS n ~ 900 Japan RRMS n = 168 FREEDOMS II (vs placebo) in RRMS n = 1083 > 5000 people with MS treated with fingolimod + 1079 (pharmacology) Fingolimod Clinical Development FREEDOMS (vs placebo) in RRMS n = 1272 TRANSFORMS (vs IFNB1a qw) in RRMS n = 1292 Phase II POC Study (2201) in RRMS(+SPMS) n = 281 Pharmacology trials n = 1079 Phase III 2845 patients with relapsing MS in completed clinical studies + 1079 in short term pharmacology trials Ongoing Ongoing POC: proof of concept

43. FREEDOMS: Phase III study of fingolimod vs placebo in RRMS (N = 1272) 24-month, randomised, double-blind, placebo-controlled, parallel-group, multicentre study Extension study (fingolimod 0.5 mg) MRI Once-daily fingolimod 0.5 mg capsule Visit Once-daily fingolimod 1.25 mg capsule Once-daily placebo capsule Month 6 Month 12 Month 24 Randomisation Kappos L et al. N Engl J Med 2010

44. FREEDOMS: baseline characteristics 1272 patients in 22 countries across Europe, Canada, Australia, Israel, Russia and South Africa ITT population Kappos L et al. N Engl J Med 2010

45. FREEDOMS: Effect on annualised relapse rate vs placebo −54% vs placebo p<0.001 −60% vs placebo p<0.001 0.4 0.40 (0.34–0.47) 0.3 Annualised relapse rate (95% CI) 0.2 0.18 (0.15–0.22) 0.16 (0.13–0.19) 0.1 0.0 Placebo (n = 418) Fingolimod 0.5 mg (n = 425) Fingolimod 1.25 mg (n = 429) ITT population Kappos L et al. N Engl J Med 2010

46. FREEDOMS:Effect on risk of disability progression confirmed after 3 or 6 months, at 2 years 30% reductionin risk of progression (HR: 0.70 vs placebo)† 37% reductionin risk of progression (HR: 0.63 vs placebo)† PlaceboFingolimod 0.5 mg FREEDOMS 2-year results1 30 24.1% p=0.02 for fingolimod vs placebo* Patients with EDSS progression confirmed after 3 months (%) 20 17.7% 10 0 0 90 180 270 360 450 540 630 720 30 Patients with EDSS progression confirmed after 6 months (%) 19.0% 20 p=0.01 for fingolimod vs placebo* 10 12.5% 0 0 90 180 270 360 450 540 630 720 Time (days) *Log-rank test comparing the survival distributions between treatment groups; †Cox’s proportional hazard model adjusted for treatment, country, baseline EDSS and age 1. Kappos L et al. N Engl J Med 2010; 362: 387-401.

47. MRI EDSS Clinical visit TRANSFORMS: Phase III study of fingolimod vs IFNβ-1a IM qw in RRMS (N = 1292) 12-month, randomised, double-blind, double-dummy, active-control, multicentre study Extension study (fingolimod 0.5 mg) Once-daily fingolimod 0.5 mg capsule and matching weekly placebo IM Once-daily fingolimod 1.25 mg capsule and matching weekly placebo IM Once-weekly IFNβ-1a 30 µg IM and matching daily placebo capsule Ongoing Randomisation Month 12 Month 6 Cohen JA et al. N Engl J Med 2010

48. TRANSFORMS: baseline characteristics 1292 patients in 18 countries across Europe, Canada, Australia, Israel, Russia and South Africa Randomised population Cohen JA et al. N Engl J Med 2010

49. TRANSFORMS: Annualised relapse rate vs IFNβ-1a IM −52% vs IFNβ-1a p<0.001 −38% vs IFNβ-1a p<0.001 (0.26–0.42) Annualised relapse rate (95% CI) (0.16–0.26) (0.12–0.21) IFNβ-1a IM(n = 431) Fingolimod 0.5 mg(n = 429) Fingolimod 1.25 mg(n = 420) ITT population Cohen JA et al. N Engl J Med 2010

50. Phase III clinical outcome measures: Efficacy summary *p≤0.05; **p≤0.01; ***p≤0.001MSFC, MS functional composite

51. Subgroup Analysis I: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Demographics FREEDOMS 2-year results2 TRANSFORMS 1-year results1 Favors fingolimod Favors fingolimod Favors IFNb-1a IM Favors placebo Sex Sex 0.50 (0.39–0.64) 0.44 (0.32–0.62) Female (n = 594) Female (n = 573) 0.61 (0.37–1.01) 0.33 (0.22–0.50) Male (n = 249) Male (n = 287) Age (years) Age (years) 0.41 (0.28–0.58) 0.33 (0.25–0.43) ≤ 40 (n = 544) ≤ 40 (n = 562) 0.76 (0.54–1.09) 0.68 (0.42–1.10) > 40 (n = 299) > 40 (n = 298) Previous treatment Previous treatment 0.45 (0.27–0.75) 0.36 (0.27–0.49) Untreated (n = 493) Untreated (n = 366) 0.50 (0.36–0.70) 0.54 (0.39–0.73) Treated (n = 350) Treated (n = 494) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

52. Subgroup Analysis II: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Activity FREEDOMS 2-year results2 TRANSFORMS 1-year results1 Favors fingolimod Favors placebo Favors fingolimod Favors IFNb-1a IM High disease activity at baseline* High disease activity at baseline* 0.48 (0.24–0.94) 0.37 (0.24–0.57) Yes (n = 140) Yes (n = 121) 0.51 (0.37–0.70) 0.46 (0.36–0.59) No (n = 701) No (n = 734) Number of Gd-enhancing T1 lesions at baseline Number of Gd-enhancing T1 lesions at baseline 0.56 (0.39–0.81) 0.48 (0.36–0.65) 0 (n = 525) 0 (n = 556) 0.44 (0.28–0.69) 0.40 (0.29–0.55) ≥ 1 (n = 315) ≥ 1 (n = 296) Number of relapses in year before study Number of relapses in year before study 0.53 (0.36–0.78) 0.52 (0.39–0.69) 0 or 1 (n = 528) 0 or 1 (n = 535) 0.43 (0.29–0.65) 0.37 (0.27–0.51) > 1 (n = 315) > 1 (n = 325) Number of relapses in 2 years before study Number of relapses in 2 years before study 0.50 (0.27–0.91) 0.37 (0.24–0.58) 1 (n = 256) 1 (n = 239) 0.49 (0.31–0.76) 0.45 (0.32–0.63) 2 (n = 360) 2 (n = 362) 0.50 (0.32–0.78) 0.50 (0.34–0.72) > 2 (n = 226) > 2 (n = 258) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 0.2 0.4 0.6 0.8 1.0 1.2 1.4 *High disease activity was defined as ≥1 Gd-enhancing lesion at baseline and ≥2 relapses in the year prior to the study 1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

53. Subgroup Analysis III: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Severity FREEDOMS 2-year results2 TRANSFORMS 1-year results1 Favors fingolimod Favors fingolimod Favors IFNb-1a IM Favors placebo Baseline EDSS score Baseline EDSS score 0.46 (0.33–0.63) 0.48 (0.38–0.60) 0.0–3.5 (n = 709) 0.0–3.5 (n = 733) 0.57 (0.31–1.08) 0.34 (0.20–0.58) ≥ 4.0 (n = 134) ≥ 4.0(n = 127) Baseline T2 lesion volume (mm3) Baseline T2 lesion volume (mm3) 0.50 (0.33–0.74) 0.40 (0.29–0.57) ≤ 3300 (n = 418) ≤ 3300 (n = 477) 0.47 (0.36–0.63) 0.50 (0.34–0.75) > 3300 (n = 422) > 3300 (n = 376) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

54. FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group KM, Kaplan Meier; SE, Standard Error

55. FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group Havrdova E et al ENS 2011

56. FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group Havrdova E et al ENS 2011

57. Effects on MRI Outcomes

58. Phase 3 MRI Outcome Measures – Mean Reductions Relative to Control *p<0.05; **p<0.01; ***p<0.001 38

59. Phase III MRI Outcome Measures –Mean Reductions Relative to Control *p<0.05; **p<0.01; ***p<0.001 39

60. 12 6 24 0 0 ** -0.2 ** *** -0.4 * -0.6 *** *** -0.8 *** *** -1.0 -1.2 -1.4 Fingolimod Phase III Studies:Brain volume changes compared to Placebo, IFNB1a and healthy individuals Time (months) TRANSFORMSOverall rate of brain atrophy reduced by 31-33% with fingolimod over 1 year vs IFNb-1a FREEDOMSOverall rate of brain atrophy reduced by 32-36% with fingolimod over 2 years vs placebo Mean change from baseline (%) FREEDOMS1 TRANSFORMS2 Fingolimod 1.25 mg Fingolimod 1.25 mg Fingolimod 0.5 mg Fingolimod 0.5 mg Placebo IFNβ-1a Evaluable ITT population. *p<0.05 for fingolimod vs placebo; **p<0.01 for fingolimod vs placebo; ***p≤0.001 for fingolimod vs placebo / IFNβ-1a 1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010

61. 12 6 24 0 0 ** -0.2 ** *** -0.4 * -0.6 *** *** -0.8 *** *** -1.0 -1.2 -1.4 Fingolimod Phase III Studies:Brain volume changes compared to Placebo, IFNB1a and healthy individuals Time (months) Mean change from baseline (%) FREEDOMS1 TRANSFORMS2 Fingolimod 1.25 mg Fingolimod 1.25 mg Fingolimod 0.5 mg Fingolimod 0.5 mg Placebo IFNβ-1a Green shaded area represents the estimated rate of brain volume loss in healthy individuals (0.2–0.4% per year)3,4 Evaluable ITT population. *p<0.05 for fingolimod vs placebo; **p<0.01 for fingolimod vs placebo; ***p≤0.001 for fingolimod vs placebo / IFNβ-1a 1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010; 3. Fotenos AF et al. Arch Neurol 2008; 4. Simon JH. Mult Scler 2006

62. #O280, Kappos et al Change in brain volume in FREEDOMS FREEDOMS 12- and 24-month data Fingolimod 0.5 mg (n = 357)† Fingolimod 1.25 mg (n = 334)† Placebo (n = 331)† 0.0 -0.2 -0.44** -0.50* -0.4 -0.65 -0.6 Mean brain volume change (%) -0.34 -0.45 -0.8 P <0.001 P <0.001 -1.0 -1.2 -0.66 -1.4 Month 0-12 Month 12-24 *p=0.03 vs placebo at Month 12; **p=0.001 vs placebo at Month 12; †evaluable patients at Month 24. Kappos L et al, ENS 2011

63. Effects of Fingolimod on Brain Volumein FREEDOMS / TRANSFORMS FREEDOMS1 – 24 M data TRANSFORMS2 – 12 M data Fingolimod 0.5 mg (n = 357)† Fingolimod 1.25 mg (n = 334)† Fingolimod 0.5 mg (n = 368) Fingolimod 1.25 mg (n = 345) Placebo (n = 331)† IFNβ-1a IM (n = 359) 0.0 0.0 -0.30 -0.2 -0.31 -0.2 -0.45 -0.44** -0.50* -0.4 -0.4 -0.65 -0.6 -0.6 Mean Change in Brain Volume at 12 M as compared to Baseline (%) Mean Change in Brain Volume at 12 and 24 M as compared to Baseline (%) -0.34 -0.45 -0.8 -0.8 -1.0 -1.0 p<0.001 vs Placebo at M 24 p<0.001 vs Placebo at M 24 p<0.001 vs IFNβ-1a at M 12 p<0.001 vs IFNβ-1a At M 12 -1.2 -1.2 -0.66 -1.4 -1.4 Months 0-12 Months 12-24 Evaluable ITT population. FREEDOMS: *p=0.03 vs Placebo at M 12; **p=0.001 vs Placebo at M 12; †Evaluable patients at M 24 1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010

65. Both fingolimod doses significantly reduced the rate of brain volume loss versus placebo, irrespective of baseline inflammatory lesion statusKappos L et al, ENS 2011

66. Effects of Fingolimod on Brain Volumein FREEDOMS / TRANSFORMS FREEDOMS1 – 24 M data TRANSFORMS2 – 12 M data Fingolimod 0.5 mg (n = 357)† Fingolimod 1.25 mg (n = 334)† Fingolimod 0.5 mg (n = 368) Fingolimod 1.25 mg (n = 345) Placebo (n = 331)† IFNβ-1a IM (n = 359) 0.0 0.0 -0.30 -0.2 -0.31 -0.2 -0.45 -0.44** -0.50* -0.4 -0.4 -0.65 -0.6 -0.6 Mean Change in Brain Volume at 12 M as compared to Baseline (%) Mean Change in Brain Volume at 12 and 24 M as compared to Baseline (%) -0.34 -0.45 -0.8 -0.8 -1.0 -1.0 p<0.001 vs Placebo at M 24 p<0.001 vs Placebo at M 24 p<0.001 vs IFNβ-1a at M 12 p<0.001 vs IFNβ-1a At M 12 -1.2 -1.2 -0.66 -1.4 -1.4 Months 0-12 Months 12-24 Evaluable ITT population. FREEDOMS: *p=0.03 vs Placebo at M 12; **p=0.001 vs Placebo at M 12; †Evaluable patients at M 24 1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010

67. 0.6 0.5 (1.86) 0.5 0.4 Number of Gd-enhancing T1 lesions, mean (SD) 0.3 0.2 (0.87) 0.2 (0.97) 0.2 (0.94) 0.2 0.1 (0.43) 0.1 (0.58) 0.1 0 12 (n=354) 12 (n=374) 12 (n=352) 24 (n=273) 24 (n=308) 24 (n=280) month Continuous fingolimod 0.5 mg Continuous fingolimod 1.25 mg IFNβ-1a to fingolimod TRANSFORMS-24 Mth follow-up: Sustained fingolimod 0.5 mg or 1.25 mg treatment compared with switching to fingolimod after 12 months treatment with IFNβ-1a: Number of Gd-enhancing lesions at months 12 and 24

68. TRANSFORMS-24 Mth follow-up: Sustained fingolimod 0.5 mg or 1.25 mg treatment compared with switching to fingolimod after 12 months treatment with IFNβ-1a: % change of normalized brain volume Khatri B et al, Lancet Neurology 2011

70. Brain volume loss occurred more quickly in patients with, than in those without, Gd-enhancing lesions at baseline, irrespective of treatment group.

71. In patients withoutGd-lesions at baseline the reduction in brain volume loss was apparent within the first 6 months and was sustained over the 2-year study

72. In patients withGd-lesions at baseline the reduction in brain volume loss was more apparent in the 2nd year than the 1st year

74. Fingolimod adverse event experience +Includes all available data from Phase II and Phase III core and extension studies with treatment durations varying between 1 to 6 years – data cut-off from 120 day safety update; *Includes events occurring in patients whose primary or secondary reason for discontinuing the study drug was an AE (including abnormal laboratory findings) **Includes 1 fatal disseminated varicella infection and 1 fatal Herpes simplex Encephalitis (TRANSFORMS)

75. Adverse events of special interest +Includes all available data from Phase II and Phase III core and extension studies with treatment durations varying between 1 to 6 years – data cut-off from 120 day safety update AV, atrioventricular

76. Effects of Fingolimod on Lymphocytes

77. Lymphocyte count during treatment with fingolimod: FREEDOMS Lymphocyte counts dropped rapidly, approaching steady state levels in 2- 4 weeks and remained stable on continued therapy. Values represent the mean; error bars are the standard deviation. Francis G et al.AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)

79. fingolimod reduces blood lymphocyte count within 4-6 hours (max after 1-2 weeks)

80. lymphocytes are retained in the lymph nodes and are not destroyed

81. Reversible effect

82. lymphocyte function is maintainedRecovery to normal levels within 1-2 months LLN LLN, lower limit of normal range; Population: all fingolimod-treated patients in MS trials who discontinued treatment. Francis et al ECTRIMS 2010

83. Infections *LTRI = Lower respiratory tract infections. Only type of infection with higher incidence (>1% difference vs placebo) in the 1.25 mg group in Phase III. Bronchitis was the most frequently reported LRTI. Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)

84. InfectionsSimilar incidence in all treatment groupsIncreased incidence in lower respiratory tract infections *LTRI = Lower respiratory tract infections. Only type of infection with higher incidence (>1% difference vs. placebo) in the 1.25 mg group in Phase III. Bronchitis was the most frequently reported LRTI.

85. Incidence of overall infections/per year categorized by mean lymphocyte counts: FREEDOMS core study group Infections by Lymphocyte Count Infections Overall 2 1.8 1.6 1.4 1.2 Incidence rate per patient-year of any infections 1 0.8 0.6 0.4 0.2 0 <0.2 (n=23) 0.2-0.3 0.3-0.4 0.4-0.5 0.5-0.7 >0.7 Placebo Fingolimod Fingolimod (n=169) (n=194) (n=169) (n=150) (n=102) (n=414) 0.5 mg 1.25 mg (n=422) (n=423) Mean lymphocyte count (x10^9 / L) Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)

86. Incidence of overall infectionsper patient-year categorised by mean lymphocyte count, over 2 years (FREEDOMS) Infections by lymphocyte count(all treatment groups) Overall infections 2.0 1.6 1.2 Incidence rate per patient-year of any infection 0.8 0.4 0.0 <0.2(n = 23) 0.2-0.3(n = 169) 0.3-0.4(n = 194) 0.4-0.5(n = 169) 0.5 -0.7(n = 150) >0.7(n = 102) Placebo(n = 414) 0.5 mg(n = 422) 1.25 mg*(n = 423) Mean lymphocyte count (x109 / L) Fingolimod Data are for the FREEDOMS core study group Francis G et al. Presentation S30.001 at AAN 2011

87. Fingolimod preserved immune response to novel antigens in healthy volunteers Increase in anti-KLH IgG levels from pre-immunisation Increase in anti-PPV-23 IgG levels from pre-immunisation Placebo (n = 22) Fingolimod 0.5 mg (n = 22) Fingolimod 1.25 mg* (n = 22) Responder rate (%) Responder rate (%) Ability to increase T cell-dependent and T cell-independent antibody response in response to novel antigens was retained KLH, keyhole limpet haemocyanin; PPV, pneumococcal polysaccharides vaccine Schmouder R et al. Poster P412 presented at ECTRIMS 2010

88. Fingolimod preserved immune response to influenza vaccination in patients with MS After vaccination, in patients with MS treated with fingolimod vaccine-triggered T cells in blood were similar to healthy controls increases in anti-influenza A / B IgM and IgG similar to those in healthy controls Anti-influenza A IgG Anti-influenza B IgG Seroprotected patients (%) Seroprotected patients (%) Days Days Healthy controls (n = 18) MS fingolimod (n = 14*) *Six patients received fingolimod 0.5 mg and eight patients received fingolimod 1.25 mg; Mehling M et al. Ann Neurol 2011

89. Effect of fingolimod on heart rate: lowest heart rate >45 bpm in >97% of patients +Includes all available data from Phase II and Phase III core and extension studies with treatment durations varying between 1 to 6 years – data cut-off from 120 day safety update*Lowest HR of 36 bpm 3 hours post-dose, asymptomatic, treated with atropinePresentation FDA-Advisory Committee Meeting June 10, 2010

90. First dose effects of fingolimod on heart rate

92. The resulting current, IKACh, causes sinus slowing and increased AV nodal conduction and refractoriness1

93. Electrophysiological effects are transient due to receptor internalization/desensitization despite continued exposure with higher plasma drug concentrations1Koyrakh L et al. Am J Transplant 2005;5:529–36ACh, acetylcholine; AV, atrioventricular; K, potassium; M2, muscarinic acetylcholine receptor 2

95. The HR changes attenuated with continued therapy and returned to baseline levels by month 1Pooled FREEDOMS and TRANSFORMS safety population. Data are mean ± SD. AV, atrioventricular DiMarco JP et al. Poster P830 at ECTRIMS 2010

96. Transient dose-dependent slowing of AV conduction after first fingolimod dose AV conduction changes attenuated with continued therapy and no effect on conduction system observed by month 1 . FREEDOMS 2-year/TRANSFORMS 1-year safety population

97. An average increase of blood pressure of 2 mmHg systolic and 1 mmHg diastolic was seen with fingolimod after 2 months which stabilized by 6 months Systolic & Diastolic Blood Pressure over Time: Safety population (FREEDOMS :D2301) Presentation FDA-Advisory Committee Meeting June 10, 2010

98. Ophthalmic Effects of Fingolimod

99. Clinical Characteristics of 16 Macular oedema (ME) Patients in MS Clinical Studies Total no of patients studied n= 2615 Zarbin M et al.AAN Aprill 2011; Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in Multiple Sclerosis (MS) (Poster 208)

100. Hepatic effects of Fingolimod

101. ALT / Bilirubin FREEDOMS 2 year safety population ALT: Alanine transaminase; ULN: Upper limit of normal

102. Adverse events: fingolimod compared with placebo Higher with placebo Higher with fingolimod 0.5 mg Overall AEs Hepatic enzyme increased Leukopenia Lymphopenia Gamma-glutamyltransferase increased Tinea versicolour Migraine Alanine aminotransferase increased Vision blurred Bronchitis Back pain Hypertension Diarrhoea Dyspnoea Urinary tract infection Micturition urgency Musculoskeletal stiffness Somnolence 0.016 0.002 0.125 1 8 64 512 Fingolimod 0.5 mg (N = 425) Placebo (N = 418) Relative risk with 95% CI Safety population Presentation FDA-Advisory Committee Meeting June 10, 2010; Collins AW et al. Poster P843 at ECTRIMS 2010

103. Adverse events: fingolimod compared with IFNβ-1a IM Higher with IFNβ-1a IM Higher with fingolimod 0.5 mg Overall AEs Gamma-glutamyltransferase increased Hepatic enzyme increased Alanine aminotransferase increased Hypertension Bronchitis Depression Arthralgia Myalgia Pyrexia Infusion-related reaction Influenza-like illness Chills 0.004 0.016 0.063 1 4 0.250 16 64 256 Fingolimod 0.5 mg (N = 429) IFNβ-1a IM (N = 431) Relative risk with 95% CI Safety population Presentation FDA-Advisory Committee Meeting June 10, 2010

104. Safety conclusions Based on > 4,500 patient-years in > 2,600 MS patients with comprehensive multi-organ safety assessments in all studies Overall incidence of SAEs and AEs leading to drug discontinuation similar between 0.5 mg dose and comparator (placebo & IFNβ-1a IM) Similar incidence for overall (with the exception of LRTIs) and serious/severe infections in fingolimod and comparator arms (IFNβ-1a IM, or placebo) No clear relationship between lymphocyte count, mean or nadir, and infection No signal for malignancy, but long-term risk including lymphomas must be closely followed as part of a Risk Management Plan Data in pregnancy is limited – strict contraception recommended in females of childbearing potential Fingolimod database has >90% power to detect serious events occurring more frequently than 1/3000 patient-years (1/1500 patients)

105. Safety conclusions Related to specific mode of action Transient Bradyarrhythmias on treatment initiation symptomatic in <0.5% for fingolimod 0.5mg ECG changes: mainly transient 1st and 2nd degree type 1 AV block (Wenckebach) on Day 1 of treatment; Macular oedema Fingolimod 0.5mg is associated with low incidence (0.2%) Most ME cases diagnosed within 3-4 months of treatment initiation and resolved after study drug discontinuation Elevation of liver enzymes Asymptomatic dose-dependent elevations of liver enzymes (8% had 3-fold increase in 0.5 mg group) No patient developed liver failure

106. Where Might Fingolimod Fit in the Treatment Algorithm? Natalizumab Immuno-suppressive Therapies Fingolimod Efficacy ? IFNβGA Burden of Therapy Factors affecting burden of therapy include convenience, tolerability, shortterm and longterm safety. GA=glatiramer acetate. 75

107. Where Might Fingolimod Fit in the Treatment Algorithm? Natalizumab Immuno-suppressive Therapies Fingolimod Efficacy IFNβGA Burden of Therapy Factors affecting burden of therapy include convenience, tolerability, shortterm and longterm safety. GA=glatiramer acetate. 76

108. Interdisciplinary Team of the MS-Center in Basel

109. Thank you for your attention !