Kappos fingolimod moa-clin_results_vfinal_buenosaires1a

1. Fingolimod (Gilenya): Mode of Action and Clinical 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

3. Available therapies Oral Immuno-modulators Fumaric acid* Laquinimod* Teriflunomide* oral VLA4-antagonists Temsirolimus Mycophenolic acid Statins Others… Monoclonal Antibodies Alemtuzumab* Rituximab Ocrelizumab Ofetimumab (Atacicept) Daclizumab Cytotoxic agents Cladribine* Pixantrone Treosulfane Combination Therapy IFNB-based GA-based Novel agents Emerging Therapies and strategies Disease Modifying Treatments (DMT) in MS (Immunomodulation/-suppression) IFNB GA Ag-specific Therapies Altered peptide- Ligands MBP-, DNA- vaccination T-cell-, TCR- vaccination Patients with RR MS ? Natalizumab ? Mitoxantrone In yellow: agents in Phase III; *recently completed Phase III FTY 720

4. Fingolimod - a structural analogue of natural sphingosine 1 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 Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that plays a key role in inflammation and repair Both sphingosine and fingolimod are phosphorylated by ubiquitous intracellular sphingosine kinases to their active forms and act via S1P receptors 2 (G protein-coupled receptors, discovered in 1998 3 ) O H N H 2 O H Sphingosine O H O H N H 2 Fingolimod

5. Fingolimod-phosphate acts on four of five sphingosine 1-phosphate receptors 1 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 and von Andrian UH. N Engl J Med 2006 ; 8 . Kimura A et al. Stem Cells 2007; 9. Jaillard C et al. J Neurosci 2005 S1P 1 S1P 3 S1P 4 S1P 5 Effects Lymphocyte egress from lymph nodes 2 –4 Lymphocytes (low expression) CNS, oligodendrocytes, natural killer cells Lymphocytes, neural cells, EC, atrial myocytes, SMC Neural cells, EC, atrial myocytes, SMC Endothelial cell function, vasomotor tone and heart rate 5 –7 CNS cell function and migration 6,8 ,9

6. ( Mehling M et al, Neurology 2011)

7. T n , naive T cells; T CM , central memory T cell; T EM , 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 Fingolimod selectively modulates T cell recirculation through lymphoid organs TCM TEM CCR7 Mediates retention in the lymph node Lymph node ( 190 x 10 9 ) Tissue (290 x 10 9 ) S1P1 favors egress and overrides CCR7 Loss of CCR7 Fingolimod induces internalization of S1P 1 thereby favoring selective retention of CCR7+ Tnaive and TCM (incl. Th17) cells involved in MS pathology. 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. T activated CCR7- CCR7+ X T naive Fingolimod Blood (10x10 9 ) <2% of total lymphocytes

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

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

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

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

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

13. Proof of Concept in MS

14. 2006 ;355:1124-40 FTY- Phase II, POC study ( NEJM 2006;355:1124-40)

15. Fingolimod Phase II study: p atients free from Gd + lesions after 5 years *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 80 60 100 Patients free from Gd + lesions (%)* Time (months) Placebo Placebo / fingolimod Fingolimod 1.25 mg Fingolimod 5.0 mg / 1.25 mg 40 1 2 3 4 5 6 12 24 36 48 60 (n = 220) (n = 188) (n = 170) (n = 149) (n = 140) (n = 278) (n = 266) (n = 266) (n = 260) (n = 261) (n = 254) (n = 260) Placebo re-randomised to fingolimod 78.2% 76.7% 47.0% 88.7% 83.1% 79.2% 86.9% 81.0% 85.9% 89.3% 87.5% 89.7% 95.6% 98.1% 96.1% 93.0% 91.7% 91.1%

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

17. 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

18. 80 70 60 50 40 30 20 10 Fingolimod selectively inhibits naïve and central memory T cell egress but spares effector memory T cells Adapted from Mehling M et al . Neurology 2008 Percentage of CD4+ cells Untreated MS Fingolimod-treated MS Naïve (CCR7+CD45RA+ ) Central memory T cells (CCR7+CD45RA-) Effector memory T cells (CCR7-CD45RA- [TEM] and CCR7-CD45RA+ [TEMRA]) p<0.001 p<0.001 p<0.001 Selective retention: immunological effector functions are preserved

19. Fingolimod reduces the proportion of Th17 cells in the circulation of people with MS * Pro-inflammatory Th17 cells reside mainly in the TCM pool and are enriched in the CSF and lesions of MS patients 1 –3 * 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 Fingolimod-treated MS 1.5 1.0 0.5 0.0 IL17+ T cells (%) in CD4+ T cells* Healthy donors Untreated MS IFN β-treated MS p<0.01 p<0.01 p<0.01 Fingolimod treatment Fingolimod reduces the proportion of circulating Th17 cells in people with MS

20. from POC to Clinical Practice

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

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

23. FREEDOMS: baseline characteristics 1272 patients in 22 countries across Europe, Canada, Australia, Israel, Russia and South Africa Fingolimod Placebo 0.5 mg 1.25 mg Randomised, N 418 425 429 Age (years), mean 37.2 36.6 37.4 Female, % 71 70 69 Duration of MS (years), mean 8.1 8.0 8.4 No. of relapses in last 2 years, mean 2.2 2.1 2.1 EDSS score, mean 2.5 2.3 2.4 Patients free from Gd + lesions, % 63 62 61 Treatment-naïve patients, % 60 57 60 ITT population Kappos L et al . N Engl J Med 2010

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

25. FREEDOMS: Effect on risk of disability progression confirmed after 3 or 6 months, at 2 years *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 . FREEDOMS 2-year results 1 30 Patients with EDSS progression confirmed after 3 months (%) 20 10 90 180 270 360 450 540 630 720 Placebo Fingolimod 0.5 mg p=0.02 for fingolimod vs placebo* 30 20 10 90 180 270 360 450 540 630 720 p=0.01 for fingolimod vs placebo* Patients with EDSS progression confirmed after 6 months (%) Time (days) 30% reduction in risk of progression (HR: 0.70 vs placebo) † 37% reduction in risk of progression (HR: 0.63 vs placebo) † 19.0% 12.5% 24.1% 17.7%

26. 12-month, randomised, double-blind, double-dummy, active-control, multicentre study Ongoing 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 IFN β -1a 30 µg IM and matching daily placebo capsule Randomisation Month 12 Month 6 MRI Clinical visit EDSS Extension study (fingolimod 0.5 mg) TRANSFORMS: Phase III study of fingolimod vs IFN β - 1a IM qw in RRMS (N = 1292) Cohen JA et al . N Engl J Med 2010

27. TRANSFORMS: baseline characteristics 1292 patients in 18 countries across Europe, Canada, Australia, Israel, Russia and South Africa Fingolimod IFN β -1a IM 0.5 mg 1.25 mg Randomised, n 435 431 426 Age (years), mean 36.0 36.7 35.8 Female, % 68 65 69 Duration of MS (years), mean 7.4 7.5 7.3 No. of relapses in last 2 years, mean 2.3 2.3 2.2 EDSS score, mean 2.2 2.2 2.2 Participants free from Gd + lesions, % 63 67 66 Treatment-naïve patients, % 44 45 42 Randomised population Cohen JA et al . N Engl J Med 2010

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

29. Phase III clinical outcome measures: Efficacy summary *p≤0.05; **p≤0.01; ***p≤0.001 MSFC, MS functional composite FREEDOMS at Month 24 vs placebo TRANSFORMS at Month 12 vs IFN β -1a Outcome 0.5 mg 1.25 mg 0.5 mg 1.25 mg ARR 54%*** 60%*** 52%*** 38%*** Time to relapse (HR) 52%*** 62%*** 48%*** 37%*** Proportion relapse-free 49%*** 58%*** 18%*** 15%*** Time to disability progression – 3 months (HR) 30%* 32%* 29% 15% Time to disability progression – 6 months (HR) 37%** 40%** - - MSFC mean difference (z-score) 0.09* 0.07* 0.07* 0.11***

30. 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors fingolimod Sex Female (n = 594) Male (n = 249) Age (years) ≤ 40 (n = 544) > 40 (n = 299) Previous treatment Untreated (n = 493) Treated (n = 350) FREEDOMS 2-year results 2 TRANSFORMS 1-year results 1 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors fingolimod Favors IFN b -1a IM Sex Female (n = 573) Male (n = 287) Age (years) ≤ 40 (n = 562) > 40 (n = 298) Previous treatment Untreated (n = 366) Treated (n = 494) Favors placebo 0.44 (0.32–0.62) 0.61 (0.37–1.01) 0.41 (0.28–0.58) 0.68 (0.42–1.10) 0.45 (0.27–0.75) 0.50 (0.36–0.70) 0.50 (0.39–0.64) 0.33 (0.22–0.50) 0.33 (0.25–0.43) 0.76 (0.54–1.09) 0.36 (0.27–0.49) 0.54 (0.39–0.73) Subgroup Analysis I: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Demographics 1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)

31. FREEDOMS 2-year results 2 High disease activity at baseline* Yes (n = 140) No (n = 701) Number of Gd-enhancing T1 lesions at baseline 0 (n = 525) ≥ 1 (n = 315) Number of relapses in year before study 0 or 1 (n = 528) > 1 (n = 315) Number of relapses in 2 years before study 1 (n = 256) 2 (n = 360) > 2 (n = 226) Subgroup Analysis II: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Activity *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) TRANSFORMS 1-year results 1 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors fingolimod Favors placebo 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors fingolimod Favors IFN b -1a IM High disease activity at baseline* Yes (n = 121) No (n = 734) Number of Gd-enhancing T1 lesions at baseline 0 (n = 556) ≥ 1 (n = 296) Number of relapses in year before study 0 or 1 (n = 535) > 1 (n = 325) Number of relapses in 2 years before study 1 (n = 239) 2 (n = 362) > 2 (n = 258) 0.48 (0.24–0.94) 0.51 (0.37–0.70) 0.56 (0.39–0.81) 0.44 (0.28–0.69) 0.53 (0.36–0.78) 0.43 (0.29–0.65) 0.50 (0.27–0.91) 0.49 (0.31–0.76) 0.50 (0.32–0.78) 0.37 (0.24–0.57) 0.46 (0.36–0.59) 0.48 (0.36–0.65) 0.40 (0.29–0.55) 0.52 (0.39–0.69) 0.37 (0.27–0.51) 0.37 (0.24–0.58) 0.45 (0.32–0.63) 0.50 (0.34–0.72)

32. Subgroup Analysis III: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Severity Baseline EDSS score 0.0–3.5 (n = 709) ≥ 4.0 (n = 134) Baseline T2 lesion volume (mm 3 ) ≤ 3300 (n = 418) > 3300 (n = 422) FREEDOMS 2-year results 2 1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster) TRANSFORMS 1-year results 1 Baseline EDSS score 0.0–3.5 (n = 733) ≥ 4.0 (n = 127) Baseline T2 lesion volume (mm 3 ) ≤ 3300 (n = 477) > 3300 (n = 376) 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors fingolimod 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors fingolimod Favors IFN b -1a IM Favors placebo 0.46 (0.33–0.63) 0.57 (0.31–1.08) 0.50 (0.33–0.74) 0.50 (0.34–0.75) 0.48 (0.38–0.60) 0.34 (0.20–0.58) 0.40 (0.29–0.57) 0.47 (0.36–0.63)

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

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

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

36. Effects on MRI Outcomes

37. Phase 3 MRI Outcome Measures – Mean Reductions Relative to Control *p<0.05; **p<0.01; ***p<0.001 FREEDOMS TRANSFORMS Outcome 0.5 mg 1.25 mg 0.5 mg 1.25 mg T2 count 74% *** 74% *** 35% ** 42% *** Gd + count 82% *** 82% *** 55% *** 73% *** Atrophy 35% *** 32% *** 31% *** 33% *** 38

38. Phase III MRI Outcome Measures – Mean Reductions Relative to Control *p<0.05; **p<0.01; ***p<0.001 FREEDOMS TRANSFORMS Outcome 0.5 mg 1.25 mg 0.5 mg 1.25 mg T2 count 74% *** 74% *** 35% ** 42% *** Gd + count 82% *** 82% *** 55% *** 73% *** Atrophy 35% *** 32% *** 31% *** 33% *** 39

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

40. Green shaded area represents the estimated rate of brain volume loss in healthy individuals (0.2–0.4% per year) 3,4 *** Fingolimod Phase III Studies: Brain volume changes compared to Placebo, IFNB1a and healthy individuals -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 6 12 24 Time (months) Mean change from baseline (%) * ** ** *** *** *** 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 *** Placebo Fingolimod 1.25 mg Fingolimod 0.5 mg FREEDOMS 1 IFN β -1a Fingolimod 1.25 mg Fingolimod 0.5 mg TRANSFORMS 2

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

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

43. FREEDOMS: Effect on PBVC by baseline Gd-lesion status #O280, Kappos et al Brain volume decreased more rapidly in patients with Gd-enhancing lesions at baseline (A) than in patients without these lesions (B) , irrespective of treatment group Both fingolimod doses significantly reduced the rate of brain volume loss versus placebo, irrespective of baseline inflammatory lesion status A Time (months) Mean change from baseline(%) B Time (months) Mean change from baseline(%) Kappos L et al, ENS 2011

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

45. 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 0.1 0.2 0.3 0.4 0.5 0.6 IFN β -1a to fingolimod Continuous fingolimod 0.5 mg Continuous fingolimod 1.25 mg 12 (n=354) 12 (n=374) 12 (n=352) 24 (n=273) 24 (n=308) 24 (n=280) month Number of Gd-enhancing T1 lesions, mean (SD) 0.5 (1.86) 0.2 (0.87) 0.2 (0.97) 0.1 (0.43) 0.1 (0.58) 0.2 (0.94)

46. 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

47. Conclusions from brain volume measurements Over 2 years, fingolimod therapy significantly reduced the overall rate of brain volume loss, irrespective of inflammatory Gd-enhancing lesions at baseline. Brain volume loss occurred more quickly in patients with, than in those without, Gd-enhancing lesions at baseline, irrespective of treatment group. In patients without Gd-lesions at baseline the reduction in brain volume loss was apparent within the first 6 months and was sustained over the 2-year study In patients with Gd-lesions at baseline the reduction in brain volume loss was more apparent in the 2 nd year than the 1 st year Despite the anti-inflammatory effect of fingolimod on MRI lesions, which could result in initial pseudoatrophy in Gd+ patients, fingolimod did not lead to a greater rate of brain volume loss compared to placebo (suggestive of a superimposed neuroprotective effect?) #O280, Kappos et al

48. Adverse Event Profile and overall Safety

49. Fingolimod adverse event experience Phase III placebo-controlled (FREEDOMS) All studies + Placebo n = 418 Fingolimod Fingolimod 0.5 mg n = 425 1.25 mg n = 429 0.5 mg n = 1176 1.25 mg n = 1302 Event, N (%) At least one AE 387 (92.6) 401 (94.4) 404 (94.2) 1054 (89.6) 1203 (92.4) AE leading to study drug discontinuation * 32 (7.7) 32 (7.5) 61 (14.2) 92 (7.8) 186 (14.3) Any serious AE 56 (13.4) 43 (10.1) 51 (11.9) 111 (9.4) 170 (13.1) Deaths 2 (0.5) 1 (0.2) 5** (0.3) + 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)

50. Adverse events of special interest FREEDOMS All studies + Fingolimod Fingolimod Event, n (%) Placebo (n = 418) 0.5 mg (n = 425) 1.25 mg (n = 429) 0.5 mg (n = 1176) 1.25 mg (n = 1302) AV block, 1st degree, 6 hours post-dose 6 (1.5) n = 413 20 (4.8) n = 417 35 (8.3) n = 423 55 (4.8) n = 1156 113 (8.8) n = 1282 AV block, 2nd degree Mobitz I, 6 hours post-dose n = 413 1 (0.2) n = 417 2 (0.5) n = 423 2 (0.2) n = 1156 10 (0.8) n = 1282 Hypertension 16 (3.8) 26 (6.1) 27 (6.3) 74 (6.3) 100 (7.7) Macular oedema n = 413 n = 423 7 (1.7) n = 420 4 (0.3) n = 1167 14 (1.1) n = 1266 At least one infection 301 (72.0) 304 (71.5) 294 (68.5) 751 (63.9) 847 (65.1) Any serious infection 8 (1.9) 7 (1.6) 11 (2.6) 18 (1.5) 33 (2.5) Malignancies 10 (2.4) 4 (0.9) 4 (0.9) 17 (1.4) 14 (1.1) + 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

51. Effects of Fingolimod on Lymphocytes

52. Lymphocyte count during treatment with fingolimod: FREEDOMS 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 ) Lymphocyte counts dropped rapidly, approaching steady state levels in 2- 4 weeks and remained stable on continued therapy.

53. LLN, lower limit of normal range; Population: all fingolimod-treated patients in MS trials who discontinued treatment. Francis et al ECTRIMS 2010 Rapid redistribution fingolimod reduces blood lymphocyte count within 4-6 hours (max after 1-2 weeks) lymphocytes are retained in the lymph nodes and are not destroyed Reversible effect lymphocyte function is maintained  Recovery to normal levels within 1-2 months Absolute lymphocyte count (10 9 /L) LLN Fingolimod leads to Selective and Reversible redistribution of lymphocytes, with no lymphocytotoxicity

54. Phase III placebo-controlled (D2301) All studies Placebo Fingolimod Fingolimod N=418 0.5 mg 1.25 mg 0.5 mg 1.25 mg N=425 N=429 N=1176 N=1302 At least one infection, n(%) 301 (72.0) 304 (71.5) 294 (68.5) 751 (63.9) 847 (65.1) Infections (events per 100 patient-years) 128.1 126.9 123.0 120.7 121.9 Any severe infection, n (%) 13 (3.1) 12 (2.8) 15 (3.5) 29 (2.5) 44 (3.4) Any serious infection, n (%) 8 (1.9) 7 (1.6) 11 (2.6) 18 (1.5) 33 (2.5) Infections of interest: LRTI and lung infections* 25 (6.0) 41 (9.6) 49 (11.4) 100 (8.5) 130 (10.0) Any Herpes infection 33 (7.9) 37 (8.7) 25 (5.8) 95 (8.1) 122 (9.4) Varicella-zoster 4 (1.0) 7 (1.6) 3 (0.7) 19 (1.9) 30 (2.6) Herpes Infection SAEs - 1 (0.2) 1 (0.2) 3 (0.3) 8 (0.6) 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)

55. Infections Similar incidence in all treatment groups Increased incidence in lower respiratory tract infections Phase III placebo-controlled (FREEDOMS) All completed studies Placebo Fingolimod Fingolimod N=418 0.5 mg 1.25 mg 0.5 mg 1.25 mg N=425 N=429 N=1176 N=1302 At least one infection, n(%) 301 (72.0) 304 (71.5) 294 (68.5) 751 (63.9) 847 (65.1) Infections (events per 100 patient-years) 128.1 126.9 123.0 120.7 121.9 Any severe infection, n (%) 13 (3.1) 12 (2.8) 15 (3.5) 29 (2.5) 44 (3.4) Any serious infection, n (%) 8 (1.9) 7 (1.6) 11 (2.6) 18 (1.5) 33 (2.5) Infections of interest: LRTI and lung infections* 25 (6.0) 41 (9.6) 49 (11.4) 100 (8.5) 130 (10.0) Any Herpes infection 33 (7.9) 37 (8.7) 25 (5.8) 95 (8.1) 122 (9.4) Varicella-zoster 4 (1.0) 7 (1.6) 3 (0.7) 19 (1.9) 30 (2.6) Herpes Infection SAEs - 1 (0.2) 1 (0.2) 3 (0.3) 8 (0.6) *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.

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

57. Incidence of overall infections per patient-year categorised by mean lymphocyte count, over 2 years (FREEDOMS) Data are for the FREEDOMS core study group Francis G et al . Presentation S30.001 at AAN 2011 0.0 1.2 1.6 2.0 Incidence rate per patient-year of any infection 0.8 0.4 <0.2 (n = 23) Mean lymphocyte count (x10 9 / L) 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) Fingolimod Infections by lymphocyte count (all treatment groups) Overall infections

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

59. 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 Seroprotected patients (%) Days Anti-influenza A IgG Seroprotected patients (%) Days Anti-influenza B IgG 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

60. 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 atropine Presentation FDA-Advisory Committee Meeting June 10, 2010 FREEDOMS All studies + Placebo Fingolimod Fingolimod Event, n (%) n = 418 0.5 mg n = 425 1.25 mg n = 429 0.5 mg n = 1176 1.25 mg n = 1302 <35 bpm - - - - 3 (0.2) 35-39 bpm - - 6 (1.4) 1* (0.1) 8 (0.6) 40-44 bpm 1 (0.2) 7 (1.6) 10 (2.3) 15 (1.3) 30 (2.3) 45-54 bpm 26 (6.2) 62 (14.6) 124 (28.9) 196 (16.7) 363 (27.9) 55-64 bpm 156 (37.3) 212 (49.9) 213 (49.7) 589 (50.1) 654 (50.2) >65 bpm 235 (56.2) 141 (33.1) 76 (17.7) 372 (31.6) 242 (18.6)

61. First dose effects of fingolimod on heart rate

62. Fingolimod : cardiac electrophysiological activity Fingolimod, via S1PRs, activates a G-protein-activated inwardly rectifying K (GIRK) channel The resulting current, I KACh, causes sinus slowing and increased AV nodal conduction and refractoriness 1 Electrophysiological effects are transient due to receptor internalization/desensitization despite continued exposure with higher plasma drug concentrations 1 Koyrakh L et al. Am J Transplant 2005;5:529–36 ACh, acetylcholine; AV, atrioventricular; K, potassium; M2, muscarinic acetylcholine receptor 2

63. Transient effect of fingolimod on heart rate Mild symptomatic bradycardia observed in 0.5% of patients receiving fingolimod 0.5 mg The HR changes attenuated with continued therapy and returned to baseline levels by month 1 Pooled FREEDOMS and TRANSFORMS safety population. Data are mean ± SD. AV, atrioventricular DiMarco JP et al . Poster P830 at ECTRIMS 2010

64. Transient dose-dependent slowing of AV conduction after first fingolimod dose Placebo Interferon beta-1a IM Fingolimod 0.5 mg Fingolimod 1.25 mg Patients, n 418 431 854 849 ECG recordings, n 413 422 837 840 First-degree AV block 6 (1.5) 12 (2.8) 39 (4.7) 82 (9.8) Wenckebach (Mobitz Type I) second-degree AV block 2 (0.2) 6 (0.7) 2:1 second-degree AV block 2 (0.2) 1 month ECG, n 407 414 835 824 First degree AV block 3 (0.7) 16 (3.9) 16 (1.9) 16 (1.9) Second degree AV block Mobitz I 2:1 AV block Third degree AV block FREEDOMS 2- year /TRANSFORMS 1-year safety population AV conduction changes attenuated with continued therapy and no effect on conduction system observed by month 1 .

65. Systolic & Diastolic Blood Pressure over Time: Safety population (FREEDOMS :D2301) 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 Presentation FDA-Advisory Committee Meeting June 10, 2010

66. Ophthalmic Effects of Fingolimod

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

68. Hepatic effects of Fingolimod

69. ALT / Bilirubin Phase III placebo-controlled (D2301) All studies Placebo Fingolimod Fingolimod N=414 0.5 mg 1.25 mg 0.5 mg 1.25 mg ALT N=424 N=425 N=1172 N=1287 ≥3 x ULN 7 (1.7) 36 (8.5) 53 (12.5) 94 (8.0) 150 (11.7) ≥5 x ULN 4 (1.0) 8 (1.9) 13 (3.1) 18 (1.5) 34 (2.6) ≥10 x ULN - 1 (0.2) - 2 (0.2) 4 (0.3) Bilirubin > 1 x ULN 39 (9.4) 47 (11.1) 42 (9.9) 119 (10.2) 126 (9.8) FREEDOMS 2 year safety population ALT: Alanine transaminase; ULN: Upper limit of normal

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

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

72. 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)