Kappos fingolimod moa-clin_results_vfinal_buenosaires1a

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  • THIS IS AN ANIMATED SLIDE WITH 1 CLICK:fades in the orange text box on the right
  • THIS SLIDE CONTAINS A BUILD: The four trials feeding into the orange box appear first with the remainder appearing on click.At filing, fingolimod has the largest clinical trial programme.
  • Absolute lymphocyte count decreases within days of fingolimod administrationLymphocyte count returns to normal levels within weeks of treatment cessationLymphocytes are not destroyed and remain functional within the lymph nodes during fingolimod treatmentNo rebound effect; absolute lymphocyte count remains within normal range (approximately 1 to 4 x 109/L)Circulating lymphocytes in blood represent <2% of total number of lymphocytes Reported fingolimod-induced apoptosis of human lymphocytes in vitro (Suzuki S. et al. Immunology 1996) was at concentrations of 2 to 10 µM, significantly higher than the low nM concentrations at which in vivo activity has been observed.Source: ISS PTT 11.1-1Mean lymphocyte counts were returning to within the normal range in the first 45 days afterdiscontinuation. At the 3-month time point, the increase from study drug discontinuation wasmarked in FTY720 treatment groups. Only a minority of patients were followed for longer periods so thatthe information on the recovery beyond 3 months is limited.
  • Kappos fingolimod moa-clin_results_vfinal_buenosaires1a

    1. 1. Fingolimod (Gilenya):Mode of ActionandClinical Trial Results<br />Prof. Ludwig Kappos<br />Chair Neurology and Department of Biomedicine <br />University Hospital<br />CH-4031 Basel<br />
    2. 2. Disclosure<br />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<br />
    3. 3. Disease Modifying Treatments (DMT) in MS(Immunomodulation/-suppression)<br />GA<br />Patients<br />with RR MS<br />Available therapies<br />IFNB<br />?<br />?<br />FTY 720<br />Emerging Therapies and strategies<br />Natalizumab<br />Oral Immuno-modulators<br /><ul><li>Fumaric acid*
    4. 4. Laquinimod*
    5. 5. Teriflunomide*
    6. 6. oral VLA4-antagonists
    7. 7. Temsirolimus
    8. 8. Mycophenolic acid
    9. 9. Statins
    10. 10. Others…</li></ul>Mitoxantrone<br />Cytotoxic agents<br /><ul><li>Cladribine*
    11. 11. Pixantrone
    12. 12. Treosulfane</li></ul>Ag-specific<br />Therapies<br /><ul><li>Altered peptide- Ligands
    13. 13. MBP-, DNA- vaccination
    14. 14. T-cell-, TCR-</li></ul>vaccination<br />Combination Therapy<br /><ul><li>IFNB-based
    15. 15. GA-based
    16. 16. Novel agents</li></ul>Monoclonal Antibodies<br /><ul><li>Alemtuzumab*
    17. 17. Rituximab
    18. 18. Ocrelizumab
    19. 19. Ofetimumab
    20. 20. (Atacicept)
    21. 21. Daclizumab</li></ul>In yellow: agents in Phase III; *recently completed Phase III<br />
    22. 22. O<br />H<br />O<br />H<br />N<br />H<br />2<br />Fingolimod - a structural analogue of natural sphingosine1<br /><ul><li>Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that plays a key role in inflammation and repair
    23. 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)</li></ul>Sphingosine<br />O<br />H<br />H<br />O<br />Fingolimod<br />N<br />H<br />2<br />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<br />
    24. 24. S1P1<br />S1P3<br />S1P4<br />S1P5<br />Effects<br />Fingolimod-phosphate acts on four of five sphingosine 1-phosphate receptors1<br />Neural cells, EC, <br />atrial myocytes, SMC<br />Lymphocytes, neural cells, EC, atrial myocytes, SMC<br />CNS,oligodendrocytes,natural killer cells<br />Lymphocytes (low expression)<br />Endothelial cell function, vasomotor tone and heart rate5–7<br />Lymphocyte egress fromlymph nodes2–4<br />CNS cell function and migration6,8,9<br />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<br />
    25. 25. (Mehling M et al, Neurology 2011)<br />
    26. 26. Fingolimod selectively modulates T cell recirculation through lymphoid organs<br />Blood (10x109)<br /><2% of total lymphocytes<br />S1P1 <br />favors egress and overrides CCR7<br />CCR7<br />Mediates retention in the lymph node<br />Tissue<br />(290 x 109)<br />X<br />TEM<br />TCM<br />Loss of <br />CCR7<br />Lymph node<br />(190 x 109 )<br />T naive<br />T activated<br />CCR7-<br />CCR7+<br />Fingolimod<br /><ul><li>Fingolimod induces internalization of S1P1 thereby favoring selective retention of CCR7+ Tnaive and TCM (incl. Th17) cells involved in MS pathology.
    27. 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.</li></ul>Tn, naive T cells; TCM, central memory T cell; TEM, effector memory T cell<br />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<br />
    28. 28. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1<br />Vehicle-treated<br />3.5<br />3.0<br />2.5<br />2.0<br />Clinical score ± SEM<br />1.5<br />1.0<br />0.5<br />0.0<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />50<br />55<br />Days post-immunisation<br />EAE, experimental autoimmune encephalomyelitis <br />1. Foster CA et al. Brain Pathol 2009<br />
    29. 29. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1<br />Prophylactic Day 0-11<br />Vehicle-treated<br />Fingolimod† prophylactic<br />3.5<br />3.0<br />2.5<br />2.0<br />Clinical score ± SEM<br />1.5<br />1.0<br />0.5<br />***<br />0.0<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />50<br />55<br />Days post-immunisation<br />†Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis <br />1. Foster CA et al. Brain Pathol 2009<br />
    30. 30. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1<br />Prophylactic Day 0-11<br />Therapeutic Day 12-28<br />Vehicle-treated<br />Fingolimod† prophylactic<br />Fingolimod† therapeutic<br />3.5<br />3.0<br />2.5<br />2.0<br />Clinical score ± SEM<br />1.5<br />1.0<br />0.5<br />***<br />***<br />0.0<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />50<br />55<br />Days post-immunisation<br />†Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis <br />1. Foster CA et al. Brain Pathol 2009<br />
    31. 31. Fingolimod has prophylactic and therapeutic effects in EAE rat model of MS1<br />Prophylactic Day 0-11<br />Therapeutic Day 12-28<br />Rescue<br />Day 40-53<br />Vehicle-treated<br />Fingolimod† prophylactic<br />Fingolimod† therapeutic<br />Fingolimod† rescue<br />3.5<br />3.0<br />2.5<br />2.0<br />Clinical score ± SEM<br />***<br />1.5<br />1.0<br />0.5<br />***<br />***<br />0.0<br />0<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />50<br />55<br />Days post-immunisation<br />†Fingolimod dose 0.3 mg/kg; ***p≤0.001; EAE, experimental autoimmune encephalomyelitis <br />1. Foster CA et al. Brain Pathol 2009<br />
    32. 32. Fingolimod treatment restores nerve conduction in EAE<br />MOG-induced relapsing-remitting EAE in DA rats<br />Neuronal function determined by recording SEP<br />Treatment<br />SEP (electrical stimulation)<br />4.0<br />Fingolimod<br />Control<br />3.0<br />N2<br />EPrecording<br />2.0<br />Clinical score<br />SEP recordings Day 53<br />1.0<br />Naïve<br />Positive control<br />P1<br />0.0<br />Fingolimod<br />0<br />55<br />5<br />10<br />15<br />20<br />25<br />30<br />35<br />40<br />45<br />50<br />Days post-immunisation<br />Clinical score: 1, flaccid tail; 2, hind limb weakness or ataxia; 3, full paralysis of hind limbs<br />Fingolimod preserved and maintained electrophysiological nerve conduction in EAE<br />DA, dark agouti; EAE, experimental autoimmune encephalomyelitis; MOG, myelin-oligodendrocyte glycoprotein; SEP, somatosensory-evoked action potentials Balatoni B et al. Brain Res Bulletin 2007<br />
    33. 33. Proof of Concept in MS<br />
    34. 34. 2006;355:1124-40<br />FTY- Phase II, POC study <br />(NEJM 2006;355:1124-40)<br />
    35. 35. Fingolimod Phase II study: patients free from Gd+ lesions after 5 years<br />Placebo re-randomised <br />to fingolimod<br />100<br />95.6%<br />98.1%<br />93.0%<br />89.3%<br />80<br />96.1%<br />91.7%<br />87.5%<br />86.9%<br />91.1%<br />89.7%<br />88.7%<br />81.0%<br />83.1%<br />85.9%<br />Patients free from Gd+ lesions (%)*<br />79.2%<br />60<br />PlaceboPlacebo / fingolimodFingolimod 1.25 mgFingolimod 5.0 mg / 1.25 mg<br />78.2%<br />76.7%<br />40<br />47.0%<br />0<br />0<br />1<br />2<br />3<br />4<br />5<br />6<br />12<br />24<br />36<br />48<br />60<br />(n = 220)<br />(n = 188)<br />(n = 170)<br />(n = 149)<br />(n = 140)<br />(n = 266)<br />(n = 278)<br />(n = 261)<br />(n = 260)<br />(n = 266)<br />(n = 254)<br />(n = 260)<br />Time (months)<br />*Calculated at each time point using the number of patients with an available MRI scan as the denominator<br />Extension phase ITT population<br />Kappos L et al. ECTRIMS 2009, Montalban et al. MSJ 2011<br />
    36. 36. Annualize Relapse Rates in Different Epochs of the POC Study by Completion Status and Randomization<br />
    37. 37. Phase II Study – Key findings:<br />Pronounced antiinflammatory effect on MRI outcomes<br />Already after 6 mths significant ARR reduction by 50%<br />Identical effect with lower dose (1.25mg) that was thought not to be effective in preventing transplant rejection <br />No indication of decreasing efficacy over > 6 years, good tolerability<br />Valuable data about selective effects on immune cells<br />
    38. 38. Fingolimod selectively inhibits naïve and central memory T cell egress but spares effector memory T cells<br />p<0.001<br />p<0.001<br />80<br />Selective retention: immunological effector functions are preserved<br />70<br />60<br />p<0.001<br />50<br />Percentage of CD4+ cells<br />40<br />30<br />Untreated MS<br />Fingolimod-treated MS<br />20<br />10<br />0<br />Effector memory T cells(CCR7-CD45RA- [TEM] and CCR7-CD45RA+ [TEMRA]) <br />Naïve<br />(CCR7+CD45RA+)<br />Central memory T cells(CCR7+CD45RA-) <br />Adapted from Mehling M et al. Neurology 2008<br />
    39. 39. Fingolimod reduces the proportion of Th17 cells in the circulation of people with MS*<br />1.5<br />Pro-inflammatory Th17 cells reside mainly in the TCM pool and are enriched in the CSF and lesions of MS patients1–3<br />p<0.01<br />p<0.01<br />p<0.01<br />Fingolimodtreatment<br />1.0<br />IL17+ T cells (%) in CD4+ T cells*<br />0.5<br />Fingolimod reduces the proportion of circulating Th17 cells in people with MS<br />0.0<br />Fingolimod-treated MS<br />Healthy donors<br />Untreated MS<br />IFNβ-treated MS<br />* 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.<br />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<br />
    40. 40. from POC to Clinical Practice<br />
    41. 41. INFORMS<br />PPMS<br />n ~ 900<br />Japan<br />RRMS<br />n = 168<br />FREEDOMS II<br />(vs placebo)<br />in RRMS<br />n = 1083<br />> 5000 people with MS treated with fingolimod + 1079 (pharmacology)<br />Fingolimod Clinical Development<br />FREEDOMS (vs placebo)<br />in RRMS<br />n = 1272<br />TRANSFORMS (vs IFNB1a qw)<br />in RRMS<br />n = 1292<br />Phase II<br />POC Study (2201) in<br />RRMS(+SPMS)<br />n = 281<br />Pharmacology trials<br />n = 1079<br />Phase III<br />2845 patients with relapsing MS in completed clinical studies + 1079 in short term pharmacology trials<br />Ongoing<br />Ongoing<br />POC: proof of concept <br />
    42. 42.
    43. 43. FREEDOMS: Phase III study of fingolimod vs placebo in RRMS (N = 1272)<br />24-month, randomised, double-blind, placebo-controlled, parallel-group, multicentre study<br />Extension study<br />(fingolimod 0.5 mg)<br />MRI<br />Once-daily fingolimod 0.5 mg capsule<br />Visit<br />Once-daily fingolimod 1.25 mg capsule<br />Once-daily placebo capsule<br />Month 6<br />Month 12<br />Month 24<br />Randomisation<br />Kappos L et al. N Engl J Med 2010<br />
    44. 44. FREEDOMS: baseline characteristics<br />1272 patients in 22 countries across Europe, Canada, Australia, Israel, Russia and South Africa<br />ITT population<br />Kappos L et al. N Engl J Med 2010<br />
    45. 45. FREEDOMS: Effect on annualised relapse rate vs placebo<br />−54% vs placebo<br />p<0.001<br />−60% vs placebo<br />p<0.001<br />0.4<br />0.40<br />(0.34–0.47)<br />0.3<br />Annualised relapse rate (95% CI)<br />0.2<br />0.18<br />(0.15–0.22)<br />0.16<br />(0.13–0.19)<br />0.1<br />0.0<br />Placebo <br />(n = 418)<br />Fingolimod 0.5 mg<br />(n = 425)<br />Fingolimod 1.25 mg<br />(n = 429)<br />ITT population<br />Kappos L et al. N Engl J Med 2010<br />
    46. 46. FREEDOMS:Effect on risk of disability progression confirmed after 3 or 6 months, at 2 years<br />30% reductionin risk of progression<br />(HR: 0.70 vs placebo)†<br />37% reductionin risk of progression<br />(HR: 0.63 vs placebo)†<br />PlaceboFingolimod 0.5 mg<br />FREEDOMS 2-year results1<br />30<br />24.1%<br />p=0.02 for fingolimod vs placebo*<br />Patients with EDSS progression confirmed after 3 months (%)<br />20<br />17.7%<br />10<br />0<br />0<br />90<br />180<br />270<br />360<br />450<br />540<br />630<br />720<br />30<br />Patients with EDSS progression confirmed after 6 months (%)<br />19.0%<br />20<br />p=0.01 for fingolimod vs placebo*<br />10<br />12.5%<br />0<br />0<br />90<br />180<br />270<br />360<br />450<br />540<br />630<br />720<br />Time (days)<br />*Log-rank test comparing the survival distributions between treatment groups; †Cox’s proportional hazard model adjusted for treatment, country, baseline EDSS and age<br />1. Kappos L et al. N Engl J Med 2010; 362: 387-401. <br />
    47. 47. MRI<br />EDSS<br />Clinical visit<br />TRANSFORMS: Phase III study of fingolimod vs IFNβ-1a IM qw in RRMS (N = 1292)<br />12-month, randomised, double-blind, double-dummy, active-control, multicentre study<br />Extension study<br />(fingolimod 0.5 mg)<br />Once-daily fingolimod 0.5 mg capsule<br />and matching weekly placebo IM<br />Once-daily fingolimod 1.25 mg capsule<br />and matching weekly placebo IM<br />Once-weekly IFNβ-1a 30 µg IM<br />and matching daily placebo capsule<br />Ongoing<br />Randomisation<br />Month 12<br />Month 6<br />Cohen JA et al. N Engl J Med 2010<br />
    48. 48. TRANSFORMS: baseline characteristics<br />1292 patients in 18 countries across Europe, Canada, Australia, Israel, Russia and South Africa<br />Randomised population<br />Cohen JA et al. N Engl J Med 2010<br />
    49. 49. TRANSFORMS: Annualised relapse rate vs IFNβ-1a IM<br />−52% vs IFNβ-1a<br />p<0.001<br />−38% vs IFNβ-1a<br />p<0.001<br />(0.26–0.42)<br />Annualised relapse rate (95% CI)<br />(0.16–0.26)<br />(0.12–0.21)<br />IFNβ-1a IM(n = 431)<br />Fingolimod 0.5 mg(n = 429)<br />Fingolimod 1.25 mg(n = 420)<br />ITT population<br />Cohen JA et al. N Engl J Med 2010<br />
    50. 50. Phase III clinical outcome measures: Efficacy summary<br />*p≤0.05; **p≤0.01; ***p≤0.001MSFC, MS functional composite<br />
    51. 51. Subgroup Analysis I: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Demographics<br />FREEDOMS 2-year results2<br />TRANSFORMS 1-year results1<br />Favors fingolimod<br />Favors fingolimod<br />Favors IFNb-1a IM<br />Favors placebo<br />Sex<br />Sex<br />0.50 (0.39–0.64)<br />0.44 (0.32–0.62)<br />Female (n = 594)<br />Female (n = 573)<br />0.61 (0.37–1.01)<br />0.33 (0.22–0.50)<br />Male (n = 249)<br />Male (n = 287)<br />Age (years)<br />Age (years)<br />0.41 (0.28–0.58)<br />0.33 (0.25–0.43)<br />≤ 40 (n = 544)<br />≤ 40 (n = 562)<br />0.76 (0.54–1.09)<br />0.68 (0.42–1.10)<br />> 40 (n = 299)<br />> 40 (n = 298)<br />Previous treatment<br />Previous treatment<br />0.45 (0.27–0.75)<br />0.36 (0.27–0.49)<br />Untreated (n = 493)<br />Untreated (n = 366)<br />0.50 (0.36–0.70)<br />0.54 (0.39–0.73)<br />Treated (n = 350)<br />Treated (n = 494)<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.4<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.4<br />1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)<br />
    52. 52. Subgroup Analysis II: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Activity<br />FREEDOMS 2-year results2<br />TRANSFORMS 1-year results1<br />Favors fingolimod<br />Favors placebo<br />Favors fingolimod<br />Favors IFNb-1a IM<br />High disease activity at baseline*<br />High disease activity at baseline*<br />0.48 (0.24–0.94)<br />0.37 (0.24–0.57)<br />Yes (n = 140)<br />Yes (n = 121)<br />0.51 (0.37–0.70)<br />0.46 (0.36–0.59)<br />No (n = 701)<br />No (n = 734)<br />Number of Gd-enhancing T1 lesions at baseline<br />Number of Gd-enhancing T1 lesions at baseline<br />0.56 (0.39–0.81)<br />0.48 (0.36–0.65)<br />0 (n = 525)<br />0 (n = 556)<br />0.44 (0.28–0.69)<br />0.40 (0.29–0.55)<br />≥ 1 (n = 315)<br />≥ 1 (n = 296)<br />Number of relapses in year before study<br />Number of relapses in year before study<br />0.53 (0.36–0.78)<br />0.52 (0.39–0.69)<br />0 or 1 (n = 528)<br />0 or 1 (n = 535)<br />0.43 (0.29–0.65)<br />0.37 (0.27–0.51)<br />> 1 (n = 315)<br />> 1 (n = 325)<br />Number of relapses in 2 years before study<br />Number of relapses in 2 years before study<br />0.50 (0.27–0.91)<br />0.37 (0.24–0.58)<br />1 (n = 256)<br />1 (n = 239)<br />0.49 (0.31–0.76)<br />0.45 (0.32–0.63)<br />2 (n = 360)<br />2 (n = 362)<br />0.50 (0.32–0.78)<br />0.50 (0.34–0.72)<br />> 2 (n = 226)<br />> 2 (n = 258)<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.4<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.4<br />*High disease activity was defined as ≥1 Gd-enhancing lesion at baseline and ≥2 relapses in the year prior to the study<br />1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)<br />
    53. 53. Subgroup Analysis III: ARR Ratios for Fingolimod versus Comparator (95% Confidence Intervals) by Baseline Disease Severity<br />FREEDOMS 2-year results2<br />TRANSFORMS 1-year results1<br />Favors fingolimod<br />Favors fingolimod<br />Favors IFNb-1a IM<br />Favors placebo<br />Baseline EDSS score<br />Baseline EDSS score<br />0.46 (0.33–0.63)<br />0.48 (0.38–0.60)<br />0.0–3.5 (n = 709)<br />0.0–3.5 (n = 733)<br />0.57 (0.31–1.08)<br />0.34 (0.20–0.58)<br />≥ 4.0 (n = 134)<br />≥ 4.0(n = 127)<br />Baseline T2 lesion volume (mm3)<br />Baseline T2 lesion volume (mm3)<br />0.50 (0.33–0.74)<br />0.40 (0.29–0.57)<br />≤ 3300 (n = 418)<br />≤ 3300 (n = 477)<br />0.47 (0.36–0.63)<br />0.50 (0.34–0.75)<br />> 3300 (n = 422)<br />> 3300 (n = 376)<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.4<br />0.2<br />0.4<br />0.6<br />0.8<br />1.0<br />1.2<br />1.4<br />1., 2. :Cohen J et al NEJM 2010; Kappos L et al NEJM 2010; von Rosenstiel P et al. ECTRIMS 2010 (poster)<br />
    54. 54. FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group<br />KM, Kaplan Meier; SE, Standard Error<br />
    55. 55. FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group<br />Havrdova E et al ENS 2011<br />
    56. 56. FREEDOMS: 3-Month Confirmed Disability ProgressionKM (SE) estimates by sub-group<br />Havrdova E et al ENS 2011<br />
    57. 57. Effects on MRI Outcomes<br />
    58. 58. Phase 3 MRI Outcome Measures – Mean Reductions Relative to Control<br />*p<0.05; **p<0.01; ***p<0.001<br />38<br />
    59. 59. Phase III MRI Outcome Measures –Mean Reductions Relative to Control<br />*p<0.05; **p<0.01; ***p<0.001<br />39<br />
    60. 60. 12<br />6<br />24<br />0<br />0<br />**<br />-0.2<br />**<br />***<br />-0.4<br />*<br />-0.6<br />***<br />***<br />-0.8<br />***<br />***<br />-1.0<br />-1.2<br />-1.4<br />Fingolimod Phase III Studies:Brain volume changes compared to Placebo, IFNB1a and healthy individuals<br />Time (months) <br />TRANSFORMSOverall rate of brain atrophy reduced by 31-33% with fingolimod over 1 year vs IFNb-1a<br />FREEDOMSOverall rate of brain atrophy reduced by 32-36% with fingolimod over 2 years vs placebo<br />Mean change from baseline (%)<br />FREEDOMS1<br />TRANSFORMS2<br />Fingolimod 1.25 mg <br />Fingolimod 1.25 mg <br />Fingolimod 0.5 mg <br />Fingolimod 0.5 mg <br />Placebo<br />IFNβ-1a<br />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<br />
    61. 61. 12<br />6<br />24<br />0<br />0<br />**<br />-0.2<br />**<br />***<br />-0.4<br />*<br />-0.6<br />***<br />***<br />-0.8<br />***<br />***<br />-1.0<br />-1.2<br />-1.4<br />Fingolimod Phase III Studies:Brain volume changes compared to Placebo, IFNB1a and healthy individuals<br />Time (months) <br />Mean change from baseline (%)<br />FREEDOMS1<br />TRANSFORMS2<br />Fingolimod 1.25 mg <br />Fingolimod 1.25 mg <br />Fingolimod 0.5 mg <br />Fingolimod 0.5 mg <br />Placebo<br />IFNβ-1a<br />Green shaded area represents the estimated rate of brain volume loss in healthy individuals (0.2–0.4% per year)3,4<br />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<br />
    62. 62. #O280, Kappos et al<br />Change in brain volume in FREEDOMS<br />FREEDOMS 12- and 24-month data<br />Fingolimod 0.5 mg<br />(n = 357)†<br />Fingolimod 1.25 mg<br />(n = 334)†<br />Placebo<br />(n = 331)†<br />0.0<br />-0.2<br />-0.44**<br />-0.50*<br />-0.4<br />-0.65<br />-0.6<br />Mean brain volume change (%)<br />-0.34<br />-0.45<br />-0.8<br />P <0.001<br />P <0.001<br />-1.0<br />-1.2<br />-0.66<br />-1.4<br />Month 0-12<br />Month 12-24<br /> *p=0.03 vs placebo at Month 12; **p=0.001 vs placebo at Month 12; †evaluable patients at Month 24.<br />Kappos L et al, ENS 2011<br />
    63. 63. Effects of Fingolimod on Brain Volumein FREEDOMS / TRANSFORMS<br />FREEDOMS1 – 24 M data <br />TRANSFORMS2 – 12 M data<br />Fingolimod 0.5 mg<br />(n = 357)†<br />Fingolimod 1.25 mg<br />(n = 334)†<br />Fingolimod 0.5 mg<br />(n = 368)<br />Fingolimod 1.25 mg<br />(n = 345)<br />Placebo<br />(n = 331)†<br />IFNβ-1a IM<br />(n = 359)<br />0.0<br />0.0<br />-0.30<br />-0.2<br />-0.31<br />-0.2<br />-0.45<br />-0.44**<br />-0.50*<br />-0.4<br />-0.4<br />-0.65<br />-0.6<br />-0.6<br />Mean Change in Brain Volume at 12 M<br />as compared to Baseline (%)<br />Mean Change in Brain Volume at 12 and 24 M <br />as compared to Baseline (%)<br />-0.34<br />-0.45<br />-0.8<br />-0.8<br />-1.0<br />-1.0<br />p<0.001<br />vs Placebo at M 24<br />p<0.001<br />vs Placebo at M 24<br />p<0.001<br />vs IFNβ-1a<br />at M 12<br />p<0.001<br />vs IFNβ-1a<br />At M 12<br />-1.2<br />-1.2<br />-0.66<br />-1.4<br />-1.4<br />Months 0-12<br />Months 12-24<br />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 <br />1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010<br />
    64. 64. FREEDOMS: Effect on PBVC by baseline Gd-lesion status<br />#O280, Kappos et al<br />A<br />Time (months)<br />B<br />Time (months)<br />Mean change from baseline(%)<br />Mean change from baseline(%)<br /><ul><li>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
    65. 65. Both fingolimod doses significantly reduced the rate of brain volume loss versus placebo, irrespective of baseline inflammatory lesion status</li></ul>Kappos L et al, ENS 2011<br />
    66. 66. Effects of Fingolimod on Brain Volumein FREEDOMS / TRANSFORMS<br />FREEDOMS1 – 24 M data <br />TRANSFORMS2 – 12 M data<br />Fingolimod 0.5 mg<br />(n = 357)†<br />Fingolimod 1.25 mg<br />(n = 334)†<br />Fingolimod 0.5 mg<br />(n = 368)<br />Fingolimod 1.25 mg<br />(n = 345)<br />Placebo<br />(n = 331)†<br />IFNβ-1a IM<br />(n = 359)<br />0.0<br />0.0<br />-0.30<br />-0.2<br />-0.31<br />-0.2<br />-0.45<br />-0.44**<br />-0.50*<br />-0.4<br />-0.4<br />-0.65<br />-0.6<br />-0.6<br />Mean Change in Brain Volume at 12 M<br />as compared to Baseline (%)<br />Mean Change in Brain Volume at 12 and 24 M <br />as compared to Baseline (%)<br />-0.34<br />-0.45<br />-0.8<br />-0.8<br />-1.0<br />-1.0<br />p<0.001<br />vs Placebo at M 24<br />p<0.001<br />vs Placebo at M 24<br />p<0.001<br />vs IFNβ-1a<br />at M 12<br />p<0.001<br />vs IFNβ-1a<br />At M 12<br />-1.2<br />-1.2<br />-0.66<br />-1.4<br />-1.4<br />Months 0-12<br />Months 12-24<br />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 <br />1. Kappos L et al. N Engl J Med 2010; 2. Cohen JA et al. N Engl J Med 2010<br />
    67. 67. 0.6<br />0.5<br />(1.86)<br />0.5<br />0.4<br />Number of Gd-enhancing T1 lesions,<br /> mean (SD)<br />0.3<br />0.2<br />(0.87)<br />0.2<br />(0.97)<br />0.2<br />(0.94)<br />0.2<br />0.1<br />(0.43)<br />0.1<br />(0.58)<br />0.1<br />0<br />12<br />(n=354)<br />12<br />(n=374)<br />12<br />(n=352)<br />24<br />(n=273)<br />24<br />(n=308)<br />24<br />(n=280)<br />month<br />Continuous fingolimod<br />0.5 mg<br />Continuous fingolimod<br />1.25 mg<br />IFNβ-1a to fingolimod<br />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: <br />Number of Gd-enhancing lesions at months 12 and 24<br />
    68. 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<br />Khatri B et al, Lancet Neurology 2011<br />
    69. 69. #O280, Kappos et al<br />Conclusions from brain volume measurements<br /><ul><li>Over 2 years, fingolimod therapy significantly reduced the overall rate of brain volume loss, irrespective of inflammatory Gd-enhancing lesions at baseline.
    70. 70. Brain volume loss occurred more quickly in patients with, than in those without, Gd-enhancing lesions at baseline, irrespective of treatment group.
    71. 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. 72. In patients withGd-lesions at baseline the reduction in brain volume loss was more apparent in the 2nd year than the 1st year
    73. 73. 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?)</li></li></ul><li>Adverse Event Profile and overall Safety<br />
    74. 74. Fingolimod adverse event experience<br />+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)<br />
    75. 75. Adverse events of special interest<br />+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 <br />AV, atrioventricular<br />
    76. 76. Effects of Fingolimod on Lymphocytes<br />
    77. 77. Lymphocyte count during treatment with fingolimod: FREEDOMS<br />Lymphocyte counts dropped rapidly, approaching steady state levels in 2- 4 weeks and remained stable on continued therapy.<br />Values represent the mean; error bars are the standard deviation.<br />Francis G et al.AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)<br />
    78. 78. Fingolimod leads to Selective and Reversible redistribution of lymphocytes, with no lymphocytotoxicity<br />Absolute lymphocyte count (109/L)<br /><ul><li>Rapid redistribution
    79. 79. fingolimod reduces blood lymphocyte count within 4-6 hours (max after 1-2 weeks)
    80. 80. lymphocytes are retained in the lymph nodes and are not destroyed
    81. 81. Reversible effect
    82. 82. lymphocyte function is maintained</li></ul>Recovery to normal levels within 1-2 months<br />LLN<br />LLN, lower limit of normal range; Population: all fingolimod-treated patients in MS trials who discontinued treatment. Francis et al ECTRIMS 2010<br />
    83. 83. Infections<br />*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. <br />Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)<br />
    84. 84. InfectionsSimilar incidence in all treatment groupsIncreased incidence in lower respiratory tract infections<br />*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. <br />
    85. 85. Incidence of overall infections/per year categorized by mean lymphocyte counts: FREEDOMS core study group<br />Infections by Lymphocyte Count<br />Infections Overall<br />2<br />1.8<br />1.6<br />1.4<br />1.2<br />Incidence rate per patient-year<br />of any infections<br />1<br />0.8<br />0.6<br />0.4<br />0.2<br />0<br /><0.2<br />(n=23)<br />0.2-0.3<br />0.3-0.4<br />0.4-0.5<br />0.5-0.7<br />>0.7<br />Placebo<br />Fingolimod<br />Fingolimod<br />(n=169)<br />(n=194)<br />(n=169)<br />(n=150)<br />(n=102)<br />(n=414)<br />0.5 mg<br />1.25 mg<br />(n=422)<br />(n=423)<br />Mean lymphocyte count (x10^9 / L)<br />Francis G et al. AAN April 2011; Lymphocytes and Fingolimod Temporal pattern and relationship with Infections (S30.001)<br />
    86. 86. Incidence of overall infectionsper patient-year categorised by mean lymphocyte count, over 2 years (FREEDOMS)<br />Infections by lymphocyte count(all treatment groups)<br />Overall infections<br />2.0<br />1.6<br />1.2<br />Incidence rate per patient-year of any infection<br />0.8<br />0.4<br />0.0<br /><0.2(n = 23)<br />0.2-0.3(n = 169)<br />0.3-0.4(n = 194)<br />0.4-0.5(n = 169)<br />0.5 -0.7(n = 150)<br />>0.7(n = 102)<br />Placebo(n = 414)<br />0.5 mg(n = 422)<br />1.25 mg*(n = 423)<br />Mean lymphocyte count (x109 / L)<br />Fingolimod<br />Data are for the FREEDOMS core study group<br />Francis G et al. Presentation S30.001 at AAN 2011<br />
    87. 87. Fingolimod preserved immune response to novel antigens in healthy volunteers<br />Increase in anti-KLH IgG levels from pre-immunisation<br />Increase in anti-PPV-23 IgG levels from pre-immunisation<br />Placebo (n = 22)<br />Fingolimod 0.5 mg (n = 22)<br />Fingolimod 1.25 mg* (n = 22)<br />Responder rate (%)<br />Responder rate (%)<br />Ability to increase T cell-dependent and T cell-independent antibody response in response to novel antigens was retained<br />KLH, keyhole limpet haemocyanin; PPV, pneumococcal polysaccharides vaccine<br />Schmouder R et al. Poster P412 presented at ECTRIMS 2010<br />
    88. 88. Fingolimod preserved immune response to influenza vaccination in patients with MS<br />After vaccination, in patients with MS treated with fingolimod<br />vaccine-triggered T cells in blood were similar to healthy controls<br />increases in anti-influenza A / B IgM and IgG similar to those in healthy controls<br />Anti-influenza A IgG<br />Anti-influenza B IgG<br />Seroprotected patients (%)<br />Seroprotected patients (%)<br />Days<br />Days<br />Healthy controls (n = 18)<br />MS fingolimod (n = 14*)<br />*Six patients received fingolimod 0.5 mg and eight patients received fingolimod 1.25 mg; Mehling M et al. Ann Neurol 2011<br />
    89. 89. Effect of fingolimod on heart rate: lowest heart rate >45 bpm in >97% of patients<br />+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<br />
    90. 90. First dose effects of fingolimod on heart rate <br />
    91. 91. Fingolimod : cardiac electrophysiological activity<br /><ul><li>Fingolimod, via S1PRs, activates a G-protein-activated inwardly rectifying K (GIRK) channel
    92. 92. The resulting current, IKACh, causes sinus slowing and increased AV nodal conduction and refractoriness1
    93. 93. Electrophysiological effects are transient due to receptor internalization/desensitization despite continued exposure with higher plasma drug concentrations</li></ul>1Koyrakh L et al. Am J Transplant 2005;5:529–36ACh, acetylcholine; AV, atrioventricular; K, potassium; M2, muscarinic acetylcholine receptor 2<br />
    94. 94. Transienteffect of fingolimod on heart rate<br /><ul><li> Mild symptomatic bradycardiaobserved in 0.5% of patients receiving fingolimod 0.5 mg
    95. 95. The HR changes attenuated with continued therapy and returned to baseline levels by month 1</li></ul>Pooled FREEDOMS and TRANSFORMS safety population. Data are mean ± SD. AV, atrioventricular<br />DiMarco JP et al. Poster P830 at ECTRIMS 2010<br />
    96. 96. Transient dose-dependent slowing of AV conduction after first fingolimod dose<br />AV conduction changes attenuated with continued therapy and no effect on conduction system observed by month 1 .<br />FREEDOMS 2-year/TRANSFORMS 1-year safety population<br />
    97. 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<br />Systolic & Diastolic Blood Pressure over Time: Safety population (FREEDOMS :D2301)<br />Presentation FDA-Advisory Committee Meeting June 10, 2010<br />
    98. 98. Ophthalmic Effects of Fingolimod<br />
    99. 99. Clinical Characteristics of 16 Macular oedema (ME) Patients in MS Clinical Studies<br />Total no of patients studied n= 2615<br />Zarbin M et al.AAN Aprill 2011; Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in Multiple Sclerosis (MS) (Poster 208)<br />
    100. 100. Hepatic effects of Fingolimod<br />
    101. 101. ALT / Bilirubin<br />FREEDOMS 2 year safety population<br />ALT: Alanine transaminase; ULN: Upper limit of normal<br />
    102. 102. Adverse events: fingolimod compared with placebo<br />Higher with placebo<br />Higher with fingolimod 0.5 mg<br />Overall AEs<br />Hepatic enzyme increased<br />Leukopenia<br />Lymphopenia<br />Gamma-glutamyltransferase increased<br />Tinea versicolour<br />Migraine<br />Alanine aminotransferase increased<br />Vision blurred<br />Bronchitis<br />Back pain<br />Hypertension<br />Diarrhoea<br />Dyspnoea<br />Urinary tract infection<br />Micturition urgency<br />Musculoskeletal stiffness<br />Somnolence<br />0.016<br />0.002<br />0.125<br />1<br />8<br />64<br />512<br />Fingolimod 0.5 mg (N = 425)<br />Placebo (N = 418)<br />Relative risk with 95% CI<br />Safety population<br />Presentation FDA-Advisory Committee Meeting June 10, 2010; Collins AW et al. Poster P843 at ECTRIMS 2010<br />
    103. 103. Adverse events: fingolimod compared with IFNβ-1a IM<br />Higher with IFNβ-1a IM<br />Higher with fingolimod 0.5 mg<br />Overall AEs<br />Gamma-glutamyltransferase increased<br />Hepatic enzyme increased<br />Alanine aminotransferase increased<br />Hypertension<br />Bronchitis<br />Depression<br />Arthralgia<br />Myalgia<br />Pyrexia<br />Infusion-related reaction<br />Influenza-like illness<br />Chills<br />0.004<br />0.016<br />0.063<br />1<br />4<br />0.250<br />16<br />64<br />256<br />Fingolimod 0.5 mg (N = 429)<br />IFNβ-1a IM (N = 431)<br />Relative risk with 95% CI<br />Safety population<br />Presentation FDA-Advisory Committee Meeting June 10, 2010<br />
    104. 104. Safety conclusions<br />Based on > 4,500 patient-years in > 2,600 MS patients with comprehensive multi-organ safety assessments in all studies<br />Overall incidence of SAEs and AEs leading to drug discontinuation similar between 0.5 mg dose and comparator (placebo & IFNβ-1a IM)<br />Similar incidence for overall (with the exception of LRTIs) and serious/severe infections in fingolimod and comparator arms (IFNβ-1a IM, or placebo)<br />No clear relationship between lymphocyte count, mean or nadir, and infection<br />No signal for malignancy, but long-term risk including lymphomas must be closely followed as part of a Risk Management Plan<br />Data in pregnancy is limited – strict contraception recommended in females of childbearing potential<br />Fingolimod database has >90% power to detect serious events occurring more frequently than 1/3000 patient-years (1/1500 patients)<br />
    105. 105. Safety conclusions<br />Related to specific mode of action<br />Transient Bradyarrhythmias on treatment initiation <br />symptomatic in <0.5% for fingolimod 0.5mg<br />ECG changes: mainly transient 1st and 2nd degree type 1 AV block (Wenckebach) on Day 1 of treatment; <br />Macular oedema <br />Fingolimod 0.5mg is associated with low incidence (0.2%)<br />Most ME cases diagnosed within 3-4 months of treatment initiation and resolved after study drug discontinuation<br />Elevation of liver enzymes<br />Asymptomatic dose-dependent elevations of liver enzymes (8% had 3-fold increase in 0.5 mg group)<br />No patient developed liver failure<br />
    106. 106. Where Might Fingolimod Fit in the Treatment Algorithm?<br />Natalizumab<br />Immuno-suppressive<br />Therapies<br />Fingolimod<br />Efficacy<br />?<br />IFNβGA<br />Burden of Therapy<br />Factors affecting burden of therapy include convenience, tolerability, shortterm and longterm safety. <br />GA=glatiramer acetate.<br />75<br />
    107. 107. Where Might Fingolimod Fit in the Treatment Algorithm?<br />Natalizumab<br />Immuno-suppressive<br />Therapies<br />Fingolimod<br />Efficacy<br />IFNβGA<br />Burden of Therapy<br />Factors affecting burden of therapy include convenience, tolerability, shortterm and longterm safety. <br />GA=glatiramer acetate.<br />76<br />
    108. 108. Interdisciplinary Team of the MS-Center in Basel<br />
    109. 109. Thank you for <br />your attention !<br />

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