Biogen idec satellite symposium ectrims giovannoni gg7

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Biogen idec satellite symposium ectrims giovannoni gg7

  1. 1. Natalizumab: Early and Effective Use for the Right Patient Gavin Giovannoni
  2. 2. Disclosures I have received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Please note that the contents of Professor Giovannoni’s slides have been checked by Biogen-Idec to make sure they are compliant with legal requirements of the Danish authorities and that Professor Giovannoni has agreed to the necessary changes being made. Professor Giovannoni would like to acknowledge and thank Mark Hughes and Simon Whiteley, Infusion Communications, for editorial assistance with preparing these slides. Please note that the natalizumab data slides have been prepared by Biogen-Idec. Natalizumab should be used according to the SmPC
  3. 3. Why Would You Want to Silence the Disease from the Start? Clinical MRI Pathology MRI=magnetic resonance imaging. 3
  4. 4. Occup & Social Final year of school University Clinical Treatment 18 yr, 1st year university diagnosed with MS after having L optic neuritis 2000 Monitoring 17 yr female, diagnosed with CIS after presenting with myelitis 2001 2002 2003 2004 IFN-beta Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 CIS=clinically isolated syndrome; MS=multiple sclerosis; IFN=interferon. 4 Dec 2007 Jan 2008 Oct 2013
  5. 5. Occup & Social Splits from her partner Final year of school Clinical Treatment Monitoring 17 yr female, diagnosed with CIS after presenting with myelitis 18 yr, 1st year university diagnosed with MS after having L optic neuritis 2000 5 Graduate trainee marketing University 2001 depression, anxiety, and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction clumsy left hand pins & needles in legs R optic neuritis Brainstem syndrome; diplopia and ataxia 2002 2003 2004 Dec 2007 IFN-beta Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 Reduced mobility High lesion load with brain atrophy Jan 2008 Oct 2013
  6. 6. MS Is a Devastating Disease Cognitive Dysfunction • Prevalence: 43% to • Affects employment, activities of daily living, and social functioning2 65%1,2 Life Shortening • • • 5- to 11-year decrease in life expectancy3-7 2- to 7-fold increase in suicide risk5,8 50% MS patients die of disease-related causes5,6,8 QOL EDSS and utility* have shown a significant inverse relationship9 MS has a negative impact on… Mortality Mortality ratio of patients with MS exceeds CV disease,†,10 stroke,‡,11 and early breast cancer12 Employment 50% of patients with MS are unemployed as of EDSS 3.0 and/or after 10 years from diagnosis13 Healthcare costs Relationships Bulk of cost attributed to services (28.5%) and long-term sick leave and early retirement (30%)§,14 Compared with general population, patients with MS have a higher probability of separating/divorcing and doing so sooner13 *In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County, Minnesota; §MS patients with EDSS ≥6. EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular; EQ-5D=European Quality of Life-5 Dimensions. 1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994; 4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler. 2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196; 9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126; 14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85. 6
  7. 7. Consequences of Increasing EDSS Scores: Loss of Employment1 Proportion of Patients ≤65 Years Old Working (%) Work Capacity by Disability Level Austria Belgium Germany Italy Netherlands Spain Sweden Switzerland United Kingdom 90 80 70 60 50 40 30 ~10 yrs2 20 10 0 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0 EDSS Score The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger. 1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926; 2. Pfleger CC et al. Mult Scler. 2010;16:121-126. 7
  8. 8. Occup & Social Splits from her partner Final year of school Clinical Treatment Monitoring 17 yr female, diagnosed with CIS after presenting with myelitis 18 yr, 1st year university diagnosed with MS after having L optic neuritis 2000 8 Graduate trainee marketing University 2001 depression, anxiety, and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction clumsy left hand pins & needles in legs R optic neuritis Brainstem syndrome; diplopia and ataxia 2002 2003 2004 Dec 2007 Reduced mobility Jan 2008 IFN-beta ? glatiramer acetate Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Oct 2013
  9. 9. MRI – High Lesion Load 9
  10. 10. Occup & Social Splits from her partner Final year of school Clinical Treatment Monitoring 17 yr female, diagnosed with CIS after presenting with myelitis 18 yr, 1st year university diagnosed with MS after having L optic neuritis 2000 10 Graduate trainee marketing University 2001 depression, anxiety, and fatigue clumsy left hand pins & needles in legs 2002 2003 Full time employment Off work ~3 months of the year Bladder dysfunction Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 IFN-beta ? glatiramer acetate Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Oct 2013
  11. 11. MRI – Acute Cervical Cord Lesion Jan 2008 11
  12. 12. How Can We Optimise Natalizumab Patient Management? In EU, natalizumab is indicated for use as a single disease-modifying therapy in highly active RRMS for the following adult patient groups: High disease activity despite a full and adequate course with IFNβ or GA (normally ≥1 year of treatment) ≥1 relapse in the last year while on therapy, ≥9 T2-hyperintense lesions, or ≥1 Gd+ lesion or a “nonresponder”, defined as patient with unchanged or increased relapse rate or ongoing severe relapses, compared with the previous year Rapidly evolving severe RRMS ≥2 disabling relapses in 1 year, ≥1 Gd+ lesion or significant increase in T2 lesion load EU=European Union; RRMS=relapsing-remitting MS; IFNβ=interferon beta; GA=glatiramer acetate; Gd+=gadolinium-enhancing. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf. Accessed September 7, 2013. 12
  13. 13. Occup & Social Splits from her partner Final year of school Clinical Treatment Monitoring 17 yr female, diagnosed with CIS after presenting with myelitis 18 yr, 1st year university diagnosed with MS after having L optic neuritis 2000 13 Graduate trainee marketing University 2001 depression, anxiety, and fatigue clumsy left hand pins & needles in legs 2002 2003 Full time employment Off work ~3 months of the year Bladder dysfunction Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 IFN-beta ? glatiramer acetate natalizumab Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Oct 2013
  14. 14. Treat-2-Target Proposed NEDA Treatment Algorithm for Relapsing MS High Efficacy Intermediate Efficacy Moderate Efficacy E A D 14 M B C NEDA=no evidence of disease activity. X N Y
  15. 15. Early Treatment Choice and Management Has the Potential to Delay MS Disease Progression Disability Optimal window of opportunity Later treatment Natural course of MS Later treatment Earlier treatment Early treatment AND earlier management Time Symptom Onset Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11. 15 15
  16. 16. Natalizumab Reduces Both Clinical and MRI Measures of Disease AFFIRM Overall Patients: Natalizumab vs Placebo Primary Outcomes Secondary Outcomes Exploratory Outcomes 42% to 54% 68% reduction of disability progression reduction in relapse rate 92% reduction in Gd+ lesions 30% vs 19% with sustained improvement in function† 83% reduction in T2-hyperintense lesions* 37% vs 7% Freedom from disease activity/disease activity free‡ *Decrease in new or newly enlarging hyperintense lesions; †baseline EDSS >2.0, with 1.0-point decrease in EDSS sustained for >12 weeks; ‡Post hoc analysis of patients with no relapse, no 12-week sustained EDSS progression, no new or enlarging T2-hyperintense lesions, and no Gd+ lesions. AFFIRM: a 2-year, randomised, multicenter, double-blind, placebo-controlled study of 942 patients that evaluated the effect of natalizumab on annualised relapse rate and disability progression; all differences were statistically significant (P<0.05). Polman C et al. N Engl J Med. 2006;354:899-910; Havrdová E et al. Lancet Neurol. 2009;8:254-260; Phillips JT et al. Mult Scler. 2011;17:970-979. 16
  17. 17. Natalizumab and Freedom from Disease Activity/Disease Activity Free (AFFIRM) Freedom from Disease Activity/Disease Activity Free: Post hoc analysis of patients with no relapses, no sustained (12-week) disability progression, no Gd+ lesions, no new or enlarging T2-hyperintense lesions Placebo P<0.0001 80 60 Natalizumab P<0.0001 70 51 40 20 0 18 n=248 15 n=458 Year 0–1 n=228 n=407 Year 1–2 100 Percentage of Patients (%) Percentage of Patients (%) 100 P<0.0001 P<0.0001 80 65 60 34 40 20 4 3 0 n=59 n=146 Year 0–1 n=56 n=137 Year 1–2 Non-Highly Active Disease Highly Active Disease <2 relapses in past 12 months or no Gd+ lesions at study entry ≥2 relapses in past 12 months and ≥1 Gd+ lesion at study entry Havrdová E. et al. Lancet Neurol. 2009;8:254-226. 17
  18. 18. Natalizumab and Quality of Life AFFIRM1 Short Form-36 (SF-36) Placebo IMSE Swedish registry2 Multiple Sclerosis Impact Scale (MSIS-29) Natalizumab Month 24 2.5 1.5 0.5 -0.5 -1.5 -2.5 P<0.05 MCS P<0.01 PCS Week 104 Mean Percent Change From Baseline in MSIS-29 Score Mean Percent Change From Baseline in SF-36 Score IMPROVEMENT -1 -3 -5 -7 -9 -11 -13 -15 WORSENING MCS=mental component summary. 1. Rudick RA et al. Ann Neurol. 2007;62:335-346; 2. Holmén C et al. Mult Scler. 2011;17:708-719. 18 P<0.05 Physical P<0.05 Psychological IMPROVEMENT
  19. 19. Escalation to Natalizumab Is More Effective Than Switching Between IFN/GA Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161 Over 24 months* % Patients 100 P<0.0001 75 P=0.0003 P<0.0001 83 77 50 P<0.0045 67 51 59 51 36 25 21 0 No Relapses No EDSS Progression No MRI Activity Disease Activity Free Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. Prosperini L et al. Mult Scler. 2012;18:64-71. 19
  20. 20. Escalation to Natalizumab Is More Effective Than Switching Between IFN/GA Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161 Over 24 months* % Patients 100 P<0.0001 75 P=0.0003 P<0.0001 83 77 50 P<0.0045 67 51 59 × 25 0 No Relapses No EDSS Progression 51 36 21 No MRI Activity  Disease Activity Free Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. Prosperini L et al. Mult Scler. 2012;18:64-71. 20
  21. 21. Occup & Social Final year of school Clinical Treatment Monitoring Graduate trainee marketing University 17 yr female, diagnosed with CIS after presenting with myelitis 18 yr, 1st year university diagnosed with MS after having L optic neuritis 2000 21 New partner Splits from her partner 2001 depression, anxiety, and fatigue clumsy left hand pins & needles in legs 2002 2003 Full time employment Off work ~3 months of the year Bladder dysfunction Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Residual deficits: Normal walking 300 m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 Oct 2013 IFN-beta ? glatiramer acetate natalizumab Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy New job junior management position Gd-enhancing lesion of upper cervical cord Annual MRI monitoring
  22. 22. Natalizumab and Functional Benefit – Double-blind, Placebocontrolled Study (AFFIRM) Compared with placebo, Natalizumab showed sustained improvement in • EDSS1 • Upper limb2 • Walking2 • Vision3 and reduced the risk of progression of cognitive deficit4 Favours natalizumab 4.2 0.5 0.5 3.7 3.2 Favours placebo 2.7 2.2 1.7 1.2 0.7 0.2 -0.3 1.0 Favours placebo Cognitive deficit – PASAT-3 (P=0.013) Favours natalizumab Vision – 1.25% low contrast acuity (P=0.014) Vision - 2.5% low contrast acuity (P=0.012) Timed 25-foot walk (P=0.028) 9-hole peg test (P=0.044) EDSS (P=0.006) 1.5 2.0 3.0 Hazard Ratio (95% Confidence Interval) 4.0 5.0 5 1. Phillips JT et al., Mult Scler 2011;17:970-979; 2. Munschauer F et al., ECTRIMS Meeting September 9–12, 2009, Dusseldorf, Germany, P434; 3. Balcer LJ et al., J Neurol Sci 2012;318:119-24; 4. Weinstock-Guttmanen B et al., J Neurol 2012;259:898–905. 22 Natalizumab should be used according to the SmPC
  23. 23. Natalizumab and Functional Improvement – Post-approval Studies 0 -1 Mean FMSC score Mean change from baseline Treatment with natalizumab has also been shown to improve Bladder function (TRUST)1 and Fatigue (TYNERGY)2 P<0.0001 for time effect -2 -3 -4 -5 -6 P<0.0001 for time effect -7 -8 0 4 8 12 16 Time (Weeks) 20 Urogenital Distress Impact Questionnaire 24 75 70 65 60 55 50 45 40 35 30 25 Change from baseline at Month 12 P<0.0001 P<0.0001 P<0.0001 Baseline Month 3 Month 6 Month 9 Month 12 Total Score Motor Score Cognitive Score Incontinence Impact Questionnaire Confirmation of improvements in: Walking 6-minute (TYNERGY2) and 100 meter (TIMER3) tests Cognition Improvement in single digit modalities test (IMSE Swedish registry4) 1. Khatri B et al. ECTRIMS Meeting October 19–22, 2011; Amsterdam, The Netherlands, P1040; 2. Svenningsson A et al. PLoS One 2013;8:e58643; 3. Nehrych T et al. ENS Meeting June 8-11, 2013, Barcelona, Spain, P369; 4. Holmén C et al. Mult Scler 2011;17:708-719. 23 Natalizumab should be used according to the SmPC
  24. 24. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Monitoring Treatment IFN-beta 24 ? glatiramer acetate natalizumab Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 New job junior management position High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring
  25. 25. Natalizumab and Clinical Recovery from Relapses Patients with complete recovery (%) AFFIRM: Probability of 12-week confirmed complete recovery from relapses 100 90 80 70 60 50 40 30 20 10 0 Placebo Placebo(N=86) Natalizumab (N=70) Natalizumab Adjusted HR for natalizumab vs placebo=1.673 (95% CI:1.046–2.678); 67% increase; P=0.0319* First Relapse 76.0% 43.1% 3 6 9 12 15 18 21 24 27 Months Since Relapse Overall population : Subjects with an increase of EDSS ≥ 1.0 point at relapse *Based on Cox Proportional Hazards model adjusted for baseline EDSS, age, gender, relapses in year prior to enrollment, disease duration, baseline Gd-enhancing lesions and baseline T2 lesion volume. Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524. 25 Natalizumab should be used according to the SmPC 30
  26. 26. Natalizumab and Clinical Recovery from Relapses Disabling Magnitude of Relapses in AFFIRM EDSS change from pre-relapse to at relapse Placebo At least 0.5 point EDSS increase Proportion of patients (%) **P=0.0088 100% 80% **P=0.0019 At least 1.0 point EDSS increase P=0.8259 91% 84% 74% 71% 70% 68% 60% 40% 20% 0% *P=0.0349 Proportion of patients (%) Natalizumab **P=0.0048 P=0.5976 100% 80% 71% 61% 60% 49% 50% 43% 48% 40% 20% 0% Overall population Baseline EDSS<3.0 Baseline EDSS≥3.0 Overall population Baseline EDSS<3.0 Baseline EDSS≥3.0 n=140 n=143 n=93 n=47 n=140 n=143 n=93 n=80 n=47 n=80 n=63 Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524. 26 Natalizumab should be used according to the SmPC n=63
  27. 27. Early Treatment Choice and Management Has the Potential to Delay MS Disease Progression Disability Optimal window of opportunity Later treatment Natural course of MS Later treatment Earlier treatment Early treatment AND earlier management Time Symptom Onset Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11. 27 27
  28. 28. Patient Management Using the Anti-JCV Antibody Assay Anti-JCV Antibody Status Negative* Positive 0.1/1000 Using this assay, anti-JCV antibodies were detected in 172 of 174 (99%) natalizumab-treated patients assessed more than 6 months prior to PML diagnosis. JCV=JC virus; PML=progressive multifocal leukoencephalopathy; IS=immunosuppressant; CI=confidence interval. *Medical information website. Boston, MA, USA: Biogen Idec Inc. https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. 28 Natalizumab should be used according to the SmPC
  29. 29. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Monitoring Treatment IFN-beta 29 ? glatiramer acetate natalizumab JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring
  30. 30. Patient Management Using the Anti-JCV Antibody Assay Anti-JCV Antibody Status 1 in 189 Negative Positive* No Prior IS Use Natalizumab Exposure 1–24 months 25–48 months 49–72 months PML Risk 0.7/1000 5.3/1000 6.1/1000 Risk of PML is ≤1/1000 for all patients with no prior IS use in the first 2 years *https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior immunosuppressant use is 1.8/1000 for natalizumab exposure of 1–24 months and 11.2/1000 for exposure of 25–48 months. 30 Natalizumab should be used according to the SmPC
  31. 31. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate natalizumab Monitoring ? fingolimod 31 JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring
  32. 32. Recent Report of Higher Anti-JCV Antibody Levels in AntiJCV Positive Patients Who Developed PML P=0.0178 nOD450 • Higher normalised optical densities (Gen1) were observed in the patients who developed PML (n=9) as compared with those who did not develop PML (n=2253) 1.5 1 0.5 0 Pre-PML nOD450=normalised optical density. Trampe AK et al. Neurology 2012;78:1736–174. 32 Natalizumab should be used according to the SmPC Non-PML (seropositive)
  33. 33. Anti-JCV Antibody Index Values May Differentiate PML Risk For Those With No Prior IS Use PML risk estimates (95% CI) per 1000 patients with no prior IS use Index 1−24 months 25−48 months 49−72 months ≤0.9 0.1 0.3 0.4 (0, 0.41) (0.04, 1.13) (0.01, 2.15) 0.1 0.7 0.7 (0, 0.34) (0.21, 1.53) (0.08, 2.34) 0.1 1.0 1.2 (0.01, 0.39) (0.48, 1.98) (0.31, 2.94) 0.1 1.2 1.3 (0.03, 0.42) (0.64, 2.15) (0.41, 2.96) 1.0 8.1 8.5 (0.64, 1.41) (6.64, 9.80) (6.22, 11.38) ≤1.1 ≤1.3 ≤1.5 >1.5  Further evaluation of this new hypothesis correlating anti-JCV antibody index and PML risk assessment is ongoing PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (September 2012) and predicted probabilities (using data from patients with no prior IS use: 2242 non-PML patients and 51 patients who developed PML using all available anti-JCV antibody index data at least 6 months prior to PML diagnosis) for the population at or below that particular index (0.9−1.5) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates. Plavina T et al. Poster DX51, CMSC May 29–June 1 2013, Orlando, USA; Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228. 33 33 Natalizumab should be used according to the SmPC
  34. 34. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Monitoring Treatment IFN-beta 34 ? glatiramer acetate natalizumab JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive
  35. 35. Patient Management Using the Anti-JCV Antibody Assay Anti-JCV Antibody Status > 1 in 189 Negative Positive* No Prior IS Use Natalizumab Exposure 1–24 months 25–48 months 49–72 months PML Risk 0.7/1000 5.3/1000 6.1/1000 Risk of PML is ≤1/1000 for all patients with no prior IS use in the first 2 years Use of anti-JC virus antibody index may further define risk of PML in antiJCV antibody positive natalizumab-treated patients with MS. Plavina T et al. Presented at CMSC, May 29 – June 1 2013, Orlando, USA DX51. Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228. The earlier, the smaller, the better for natalizumab-associated PML: in MRI vigilance veritas? Phan-Ba R. et al. Neurology 2012;79:1067-1069. *https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior immunosuppressant use is 1.8/1000 for natalizumab exposure of 1–24 months and 11.2/1000 for exposure of 25–48 months. 35 Natalizumab should be used according to the SmPC
  36. 36. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate natalizumab Monitoring ? fingolimod 36 JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive 3-monthly MRI monitoring
  37. 37. Early Detection of PML and Clinical Outcome Months From PML Diagnosis  Detection of PML on routine MRI (confirmed by CSF analysis) has been demonstrated in asymptomatic patients1–5 – Asymptomatic PML patients have improved survival and less functional disability compared with symptomatic patients6 MRI=magnetic resonance imaging; CSF=cerebrospinal fluid; FLAIR=fluid-attenuated inversion recovery. 1. Vermersch P et al. Neurology. 2011;76:1697-1704. 2. Phan-Ba R et al. Neurology. 2012;79:1067-1069; 3. Blair NF et al. Neurology. 2012;78:507-508; 4. Ayzenberg I et al. J Neurol. 2012;259:1732-1733; 5. Yousry TA et al. Ann Neurol. 2012;72:779-787; 6. Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271. Natalizumab should be used according to the SmPC 37
  38. 38. When is the Right Time to Start Natalizumab ? 38 Natalizumab should be used according to the SmPC
  39. 39. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate natalizumab Early or late? Monitoring ? fingolimod 39 JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive 3-monthly MRI monitoring
  40. 40. STRATA: Patients Had Stable EDSS Scores for Up to 5 Years Cessation/ Treatment Gap* Original Placebo Original Natalizumab 4.0 Original Placebo – Now on Natalizumab Mean EDSS Score 3.5 3.13 2.90 3.0 2.69 2.54 2.72 2.69 2.36 2.38 2.36 381 707 280 552 3.21 2.84 3.15 2.85 2.79 2.39 n = 380 707 2.5 3.24 3.22 3.07 2.0 1.5 1.0 0.5 0.0 Feeder Study Baseline 40 Feeder Study End Safety Study End 385 709 STRATA Baseline 274 569 230 479 205 462 194 427 174 393 STRATA STRATA STRATA STRATA STRATA 48 Weeks 96 Weeks 144 Weeks 192 Weeks 240 Weeks 1 Year 2 Years *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. Natalizumab should be used according to the SmPC 3 Years 4 Years 5 Years
  41. 41. TOP: Earlier Natalizumab Treatment Favours Annualised Relapse Rate Outcomes 41 P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor of interest. Error bars represent 95% CIs. DMT=disease-modifying therapy; CI=confidence interval. Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372. Natalizumab should be used according to the SmPC
  42. 42. TOP: Natalizumab Stabilises EDSS Scores in Patients with Either a High or Low Starting EDSS Score at Baseline 5.0 Median EDSS Score 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 Baseline EDSS Score >3.0 (n=1840) Baseline EDSS Score ≤3.0 (n=1591) 0.5 0.0 0 6 12 18 24 30 Time (months) Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261. 42 Natalizumab should be used according to the SmPC 36 42 48
  43. 43. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate Early or late? natalizumab Monitoring ? fingolimod 43 JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Natalizumab should be used according to the SmPC Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive 3-monthly MRI monitoring
  44. 44. Early Treatment Choice and Management Has the Potential to Delay MS Disease Progression Disability Optimal window of opportunity Later treatment Natural course of MS Later treatment Earlier treatment Early treatment AND earlier management Time Symptom Onset Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11. 44 Natalizumab should be used according to the SmPC 44
  45. 45. Treatment Objectives in Relapsing MS Treat Early Freedom from disease activity/disease activity free Reduced ongoing damage 45 T2T - NEDA Zero Tolerance Natalizumab should be used according to the SmPC
  46. 46. Treatment Objectives in Relapsing MS Improved Quality of Life Treat Early Freedom from disease activity/disease activity free CNS Repair Reduced ongoing damage 46 Functional T2T - NEDA Improvement Zero Maintain reserve capacity Tolerance Healthy ageing Natalizumab should be used according to the SmPC
  47. 47. clinical Occup. & social What does the future hold? Splits from her partner Final year of school 17yr female, diagnosed with CIS after presenting with myelitis Graduate trainee marketing University 18yr, 1st year university diagnosed with MS after having L optic neuritis 2000 depression , anxiety and fatigue Full time employment clumsy left hand pins & needles in legs R optic neuritis 2001 2001 Off work ~3 months of the year Bladder dysfunction 2003 2004 Brainstem syndrome; diplopia and ataxia Dec 2007 Pregnancy New partner New job junior management position Occupational health assessment Reduced mobility Cervical cord relapse weak L arm with pain Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Jan 2008 treatment IFN-beta ? glatiramer acetate natalizumab monitoring ? fingolimod JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy 47 Gd-enhancing lesion of upper cervical cord Annual MRI monitoring Natalizumab should be used according to the SmPC JCV high positive 3-monthly MRI monitoring Old Age
  48. 48. Optimizing Use of Natalizumab • Freedom from disease activity* was achieved in 65% to 70% patients during the second year of treatment in AFFIRM1 • Natalizumab in AFFIRM reduced the rate of brain atrophy in the second year2 and also significantly reduced the rate of conversion of new Gd+ lesions to T1 hypointense lesions over 12 months3 • Risk of PML is very low (1 in 10,000) in in anti-JCV antibody–negative patients4 • In anti-JCV antibody-positive patients without prior IS use, risk of PML in first 2 years is low (≤1 in 1000)3; use of natalizumab for > 2 years is based on a caseby-case decision • In clinical practice, when used mostly in patients on an injectable DMT with uncontrolled disease: • A stable EDSS score is observed in most patients especially when used earlier in the disease course5,6 • Improvements in fatigue, cognition, bladder function, and QoL are seen following switch to natalizumab7-9 *Post hoc analysis of patients with no relapses, no sustained (12-week) disability progression, no Gd+ lesions, no new or enlarging T2-hyperintense lesions. 1. Havrdová E. et al. Lancet Neurol. 2009;8:254-226; 2. Miller DH et al. Neurology. 2007;68:1390-1401; 3. Dalton CM et al. J Neurol. 2004;251:407-413; 4. Bloomgren G et al. N Engl J Med. 2012;366:1870-1880; 5. Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261; 6. Kallweit U et al. Clin Neuropharmacol. 2012;35:77-80; 7. Svenningsson A et al. PLoS One. 2013;8:e58643; 8. Khatri B et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. P1040; 9. Holmen C et al. Mult Scler. 2011;17:708-719. 48 Natalizumab should be used according to the SmPC

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