Paradigm Shifts in MS Therapy. John R. Corboy, MD Professor, University of Colorado School of Medicine Co-Director, RMMSC at AMC

Transcription

1 Paradigm Shifts in MS Therapy John R. Corboy, MD Professor, University of Colorado School of Medicine Co-Director, RMMSC at AMC

2 Disclosures Research support from, or consulting for NIH NMSS JDRF NIAID, Immune Tolerance Network Teva Neurosciences Novartis Lilly Peptimmune Genentech Celgene Therapeutics

3 MS Early Therapies BASED ON CONCEPT OF CAUSE OF MS Infection: Antimony, Fever Therapy Inflammation: Na Salicylate, X-Ray Therapy Vitamin Deficiency: Replace A, D, E, K, B1, B6, B12 Vascular: Coumadin, Caffeine (more recently CCSVI) Psychiatric: Hypnosis, Hydrotherapy Toxin: Remove Dental Fillings Physical: Dental/Tonsil Extraction, Electrical/Magnetic Stimulation, Pelvic/Rectal Massage, Repeated Lumbar Punctures

4 Modern Approach to MS Based on theory of autoimmunity Animal models of demyelination Numerous immunosuppressives, immunomodulators studied

5 1970 s - Early 1990 s Azathioprine Cyclophosphamide Cyclosporin A Methotrexate Plasma Exchange ACTH, Methylprednisolone, and Prednisone α and γ Interferon, Sulfasalazine, TNF-α Blockers Study Failures Likely due to Wide Variety of Patients Studied, Poor Blinding, Poor Controls, Drug Toxicities, and Drugs Just Didn t Work, or Made Things Worse (eg TNF antagonists)

6 Early Modern Era Interferon β-1b (Betaseron) Interferon β-1a (Avonex) Glatiramer Acetate (Copaxone) Mitoxantrone (Novantrone) Interferon β-1a (Rebif) Natalizumab (Tysabri) Fingolimod (Gilenya)? BG12, Teriflunomide, Alemtuzumab? Ocrelizumab, Laquinimod and others

7 Immunotherapy Phase I 1993: Interferon β-1b Lottery: Lasted a Few Months Slow Adoption, Conservative Approach to Therapy Late 1990 s to Early 2000 s Addition of Multiple Agents, All Injectible: ABC-R Switching between Medications Common Development of Interferon Antibody Test First Comparison Trials Medication Choice Based on Patient/MD Preference, Random Issues: Needle Size, # Injections

8 Immunotherapy Phase II Treat Early 2002: CHAMPS trial Treat with Multiple Drugs; Platform Drugs Avonex Combination Trial (ACT) Combi-Rx Treat to Selectively Remove Pieces of the Immune System Send in the Clones Natalizumab > Rituximab > Alemtuzumab, Ocrelizumab, Daclizumab, others Treat with More Tolerable Medications, eg Oral Treat to Reboot the Immune System Beginning of HDIT and Stem Cell Rescue

9 Immunotherapy Implementation Modern Therapy in 2012 First Line Therapy aka Platform Therapy ABC-R Medications Older Low Risk Modest Reward Poor Tolerance and Compliance Some Data in Combination with Others Lower Cost Second Line Therapy Rescue Approach Natalizumab, Fingolimod, and Off-Label (Rituximab, Cyclophosphamide, Mycophenylate, others) Newer Higher Risk Greater Reward Better Tolerance and Compliance Oral and IV Higher Cost

10 Institutionalization of Step Therapy MUST Use First Line Therapy at Outset Often Require Failure of Two or More First Line Therapies Private Insurers and Medicaid Requiring Based on Cost and? Safety

11 Logic for a New Paradigm Old Therapies are Partial at Best Old Therapies are All about the Same Efficacy The First Five Years Matter We Can Identify a Significant Number of Patients at High Short Term Risk of Disease Activity and Long Term Risk of Disability Most Newer Medications are Better We Need to be Identifying Responses to Medications Before Use, or During Early Use, not After the Fact

12 % Reduction in relapse rates Effect on Annual Relapse Rates: Summary of Phase III Trials %* P=0.002 P= % P= % P< % P< % NS P= % P= Avonex 30 mcg (30 mcg qw) Betaseron mcg (250 mcg qod) Rebif 66 mcg (22 mcg tiw) Rebif 132 mcg (44 mcg tiw) Copaxone 140 mg (20 mg qd) Weekly dose Note: Results shown are from separate clinical studies. *For patients who had been in the study for 2 years. Jacobs et al. Ann Neurol. 1996;39:285; Betaseron package insert; Johnson et al. Neurology. 1995;45:1268; PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert; Copaxone package insert.

13 Comparison Trials First Line therapies Interferon β-1b 500mcg vs 250 mcg vs GA BEYOND trial Interferon β-1b 250 mcg vs GA BECOME trial Interferon β-1a 44mcg sq tiw vs GA REGARD trial Interferon β-1a 30 mcg im qw vs GA Combi-Rx trial

14 BECOME Trial No significant differences in these MRI outcomes or clinical outcomes, at months 1-12, or Two sites, total 75 patients However, Conversion of acute enhancing lesions to chronic black holes was less with interferon than GA (9.8% v 15.2%, p=0.02, not shown here) Cadavid, D. et al. Neurology 2009;72: Efficacy of treatment of MS with IFNβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study

15 REGARD Trial In β-1a vs GA, no difference in primary outcome of time to relapse, secondary clinical outcomes, and most MRI measures. There were less new enhancing lesions in the interferon group. Mikol et al. Lancet Neurol Oct;7(10): Epub 2008 Sep 11. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial.

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19 First Five Years Matter Relapses are most common shortly after onset of disease Relapses frequently produce disability MRI predicts relapse disease activity early Early brain atrophy, T1 holes, T2 lesions predict disability in near/long term

20 Relapse rate for men and women from onset and by current age (A) from onset (n = 2477), (B) by patient s current age (n = 2477). Tremlett H et al. J Neurol Neurosurg Psychiatry 2008;79: by BMJ Publishing Group Ltd

21 Figure 2. The net change in Expanded Disability Status Scale (EDSS) score from before an exacerbation to after. Lublin F D et al. Neurology 2003;61: by Lippincott Williams & Wilkins

22 Mean follow-up 5.2 years; mean time from RIS to CIS 2.3 years Lebrun et al. Association between clinical conversion to multiple sclerosis in radiologically isolated syndrome and magnetic resonance imaging, cerebrospinal fluid, and visual evoked potential: follow-up of 70 patients. Arch Neurol Jul;66(7):841-6.

23 MRI predictors of early conversion to clinically definite MS in the CHAMPS placebo group Neurology 2002 Oct 8;59(7): Table 3Risk of CDMS and combined CDMS/MRI outcomes according to T2 and Gd lesion N= 190 P= 0.01

24 Eur J Neurol Nov;16(11): Epub 2009 Jun 15. Oneyear MRI scan predicts clinical response to interferon beta in multiple sclerosis. Prosperini et al Poor clinical response was defined as the occurrence of a sustained disability progression of 1 point in the Expanded Disability Status Scale (EDSS) during the follow-up period of 4.8 years on average. Responders in white, poor responders in grey.

25 MRI Predictors of Progressive Disability on IFNβ Hazard rate for progressive disability at 5 yrs, based upon disease activity during first year of IFNβ therapy New MRI lesions are 5-20x more predictive of future disability than relapses and disability progression Prosperini L., et. al., Eur J. Neurol. 2009; 16:

26 Median T2 lesion volume (T2LV) (cm3) over time for patients groups. Fisniku L K et al. Brain 2008;131: Disability and T 2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis

27 Figure 1. Patients (n = 138) were categorized into quartiles based on the amount of atrophy during the phase III trial, i.e., change in brain parenchymal fraction (BPF) from baseline to year 2. (57 (44 reach EDSS 6.0) by year 8 Fisher E et al. Neurology 2002;59: by Lippincott Williams & Wilkins

28 Eight-year follow-up study of brain atrophy in patients with MS Fisher E et al. Neurology 2002;59:

29 Comparison Studies New Agents Newer Agents Generally Superior to Older TRANSFORMS: Fingolimod vs IFN β-1a 30 mcg im COMFIRM: BG12 vs Pb and vs GA MS CARE I and II: Alemtuzumab vs IFN β-1a 44 tiw Ocrelizumab vs Pb and vs IFN β-1a 30 mcg im TENERE: Teriflunomide equal efficacy to IFN β-1a 44 mcg tiw, but with less discontinuations and greater patient satisfaction DECIDE: Daclizumab vs IFN β-1a 44 mcg tiw (results pending)

30 TRANSFORMS Trial Fingolimod vs interferonβ1a 44 mcg tiw sq Annualized Relapse Rate at 12 Months is lower, % of relapse-free patients greater, and the Time to the First Relapse is longer with both doses of Fingolimod vs interferon-β1a 2010; /NEJMoa Cohen et al. NEJM Jan 28, Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis patients J Med 2010; /NEJMoa

31 CONFIRM Study CONFIRM : 2 year study followed the DEFINE Pb-Controlled Trial BG mg BID and TID versus placebo Active reference comparator arm with subcutaneous glatiramer acetate 20 mg/day 1417 patients received treatment Baseline demographic and clinical characteristics were similar across treatment groups Primary endpoint was ARR at 2 years Secondary clinical endpoints included proportion of patients who relapsed and disability progression as measured by EDSS at 2 years Secondary MRI endpoints included number of new/enlarging T2-hyperintense lesions and new T1-hypointense lesions Fox R, et al. Abstract S Miller D, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

32 CONFIRM: Clinical and MRI Results Outcome BG mg BID* BG mg TID* Glatiramer Acetate* Annualized relapse rate 1 44% (p<0.0001) 51% (p<0.0001) 29% (p<0.02) Proportion of patients with relapses 1 34% (p<0.003) 45% (p<0.0001) 29% (p<0.01) 12-week confirmed EDSS progression 1 21% (NS) 24% (NS) 7% (NS) Mean # of new/enlarging T2 lesions 2 71% (p<0.0001) 73% (p<0.0001) 54% (p<0.0001) Mean # of new T1-hypointense lesions 2 57% (p<0.0001) 65% (p<0.0001) 41% (p<0.0001) *Compared with placebo. 1. Fox R, et al. Abstract S01.003; 2. Miller D, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

33 Alemtuzumab Monoclonal antibody to CD52 Alters circulating lymphocyte pool Prolonged T and B lymphocyte depletion IV infusion annually Phase II (CAMMS223) results vs SC INFB-1a at 3 years: ARR reduced by 74% (P<0.001) Risk of sustained accumulation of disability reduced by 71% (P<0.001) Patients free of clinical disease activity (absence of both relapses and sustained disability) significantly higher for alemtuzumab vs IFNB-1a Side effects: auto-immune diseases (thyroid, ITP, Goodpasture s), infusion reactions CAMMS223 Trial Investigators. NEJM 2008;359:

34 CARE-MS I: Treatment-Naive Alemtuzumab Vs. IFNB-1a Phase 3 pivotal study; 2-year, randomized activecomparator trial in active 581 patients from 98 centers in 16 countries Mean age was 33; mean EDSS was 2; mean time since first episode was 2 years Study drugs: Alemtuzumab: 12 mg/day iv for 5 days at study start and 3 days 1 year later IFNB-1a: 44 mcg SC 3-times weekly for 24 months Primary efficacy endpoints: relapse rate and time to 6-month sustained accumulation of disability (SAD) Coles A, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

35 CARE-MS I: Annualized Relapse Rate 55%; P< Coles A, et al. Presented at ECTRIMS/ACTRIMS 2011; Amsterdam, Netherlands. Coles A, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012;

36 CARE-MS I: Other Relapse Outcomes Proportion relapse-free (P<0.0001): Alemtuzumab: 77.6% (95% CI: 72.9, 81.6) IFNB-1a: 58.7% (95% CI: 51.1, 65.5) Number needed to treat with alemtuzumab to prevent 1 relapse: 2.3 (95% CI: 1.47, 5.65) Relapse reduction was 53% in first year of study (P<0.0001): Alemtuzumab: 0.22 IFNB-1a: 0.46 Further increased in second year of study Treatment effects favoring alemtuzumab: Risk of severe relapses (64% reduction, P=0.0035) Steroid-treated relapses (59% reduction, P<0.0001) Fox E, et al. Abstract PD Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New

37 CARE-MS I: Sustained Accumulation of Disability Hazard ratio=0.70 Coles A, et al. Presented at ECTRIMS/ACTRIMS 2011; Amsterdam, Netherlands. Coles A, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Or

38 CARE-MS I: MRI Outcomes for Alemtuzumab Vs. IFNB-1a % of Patients with Gd-Enhancing Lesions % of Patients with New/Enlarging T2 Lesions -44% P= % P=0.035 Coles A, et al. Presented at ECTRIMS/ACTRIMS 2011; Amsterdam, Netherlands. Arnold D, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Or

39 CARE-MS I: MRI Outcomes for Alemtuzumab Vs. IFNB-1a Change in Brain Parenchymal Fraction P = P < P < Coles A, et al. Presented at ECTRIMS/ACTRIMS 2011; Amsterdam, Netherlands.

40 CARE-MS II: Patients Who Relapsed on Prior Therapy CARE-MS II is a 2-year rater-blinded trial with RRMS patients who have relapsed during prior therapy 840 patients from 180 centers in 23 countries Baseline characteristics (mean): Age: 35 years Disease duration: 3.9 years EDSS: and 2.7 relapses in 1 and 2 years, respectively Most common prior MS therapies: Interferon- beta (78.6%) Glatiramer acetate (32.5%) Other (<5%) Cohen J, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

41 CARE-MS II: Key Relapse Data Relapse-free at 2 years: Alemtuzumab: 65% IFNB-1a: 47% 47% percent risk reduction (P<0.0001) 49% reduction in relapse rate vs IFNB-1a 44 mcg sc tiw (P<0.0001) Cohen J, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

42 CARE-MS II: Key Disability Data Mean change in EDSS score (P<0.0001): Alemtuzumab: IFNB-1a: month sustained reduction in disability (P=0.0002): Alemtuzumab: 29% IFNB-1a: 13% 42% reduction in sustained accumulation of disability with alemtuzumab vs. IFN (P<0.0084) Cohen J, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

43 CARE-MS II: MRI End Points End Point Alemtuzumab Interferon P Value New or enlarging T2-hyperintense lesions (%) < New gadolinium-enhancing lesions (%) < Brain parenchymal fraction (median % change from baseline) Cohen J, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

44 Ocrelizumab: Phase II Results, 24 Weeks 89 96%, P< for both ocrelizumab doses vs placebo Primary endpoint At Weeks 24, 48, and 72, all patients received openlabel ocrelizumab Kappos L, et al. Lancet. 2011;378:

45 Ocrelizumab: Phase II Long-Term Efficacy(96 Weeks) N=18 3 Group C Group A Group B Group D Weeks 0-24 Placebo OCR 600 mg OCR 2000 mg IFNB-1a 30 mcg IM Weeks OCR 600 mg OCR 600 mg OCR 1000 mg OCR 600 mg Weeks OCR 600 mg OCR 600 mg OCR 1000 mg OCR 600 mg Weeks OCR 600 mg Hauser S, et OCR al. 600 Abstract mg S Presented OCR 600 mg OCR 600 mg at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012;

46 Outcomes: Weeks 0 96 Annualized relapse rate Group A 0.18 (95% CI: ) Group B 0.22 (95% CI: ) Relapse-free 78.2% 80.0% Free of clinical disease activity* 67.3% 76.4% Group A Group B Weeks 0-24 OCR 600 mg OCR 2000 mg Weeks OCR 600 mg OCR 1000 mg Weeks OCR 600 mg OCR 1000 mg Weeks OCR 600 mg OCR 600 mg * No relapses or confirmed EDSS progression. Hauser S, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

47 ARR in Groups Switched at Week 24 Group C Switched from PBO Group D Switched from IFN Week 24 Week 96 Week 24 Week 96 Annualized relapse rate (95% CI: ) (95% CI: ) Group C Group D Weeks 0-24 Placebo IFNB-1a 30 mcg IM Weeks OCR 600 mg OCR 600 mg Weeks OCR 600 mg OCR 600 mg Weeks OCR 600 mg OCR 600 mg Hauser S, et al. Abstract S Presented at the American Academy of Neurology 64th Annual Meeting; May 22-28, 2012; New Orleans.

48 Natalizumab Comparisons?? No Head-to Head Comparison Trials Comparisons BETWEEN Studies Favor Natalizumab Anecdotal Data Arguing It is Better than ABC-R Significant Recurrence/Rebound Activity after Drug Discontinuation Numerous Studies Showing QOL and Related Symptom Checklists with IMPROVEMENT

49 Time to Flip the Approach? Treat with Most Aggressive Therapy at Time the Disease is Most Active, ie Early Transition to Safer Therapies when Risk of Disease Itself is Similarly Lower, ie Later Approaches Stratify by Disease Severity, Risk, Futility of Therapy, Predicting Response to Therapy, Actual Response to Therapy

50 Biomarkers and the Advent of Personalized Medicine Disease Severity, Now Use Clinical/MRI Criteria Risk of Therapy, eg JCV Antibodies (Natalizumab, Rituximab, Ocrelizumab,? Others), Cytokines (IL-7, IL-21 and CCL21 in Alemtuzumab); Prior Chemo (Natalizumab) Futility of Therapy, eg Interferon Ab, Natalizumab Ab, HACAS (Human AntiChimeric AntibodieS) Predicting Response to Therapy, eg, Microarray Analysis of Super-Responders with GA;?IL-7/17 with IFN; Interferon Response Genes; CSF-Specific IgM Bands and IFN Response Monitoring Response to Therapy, eg MRIs, CD56 bright

51 MS Prognostic Factors UNFAVORABLE Older age at onset, African-American, male, high relapse rate, short interval to second relapse, early cerebellar or motor involvement, early disability, cognitive impairment, high T2 lesion load on first brain MRI, atrophy and T1 holes on MRI, PPMS, smoker FAVORABLE Young at onset, Caucasian, female, low relapse rate, longer time to second relapse, mostly sensory symptoms, no early disability, normal brain MRI at presentation, non-smoker PEDIATRIC MS under age 18 onset, about 5% of new Acts like RRMS, with much earlier onset and disability

52 Disease Severity MRI Accumulation of T2 Burden/Volume in First five Years Atrophy T1 Lesion Burden/Volume Lipid-Specific IgM Bands

53 Fig. 1. Kaplan Meier estimates of the time from first relapse to the second relapse, according to the presence of oligoclonal IgG bands and lipid-specific oligoclonal IgM bands. Risk of Second Attack Bands vs No Bands IgG vs non IgG/IgM vs non IgG/IgM vs IgG 9.3x inc 39.6x inc 4.4x inc The risk of relapse after a clinically isolated syndrome is related to the pattern of oligoclonal bands. Bosca et al. J Neuroimmunol 2010 Sep 14;226(1-2): Epub 2010 Jun 9. in 192 patients

54 Increased T2 Lesion Volume in patients with IgM and IgG bands vs just IgG and vs no OCBs Magraner et al. Brain atrophy and lesion load are related to CSF lipid-specific IgM oligoclonal bands in clinically isolated syndromes. Neuroradiology 012 Jan;54(1):5-12. Epub 2011 Feb 16.

55 Figure 1A significant correlation between intrathecal IgM synthesis (IgM index) at the onset of disease and disease progression (EDSS) after a mean disease duration of 14.4 (SD 2.1) years) was found in 80 patients with MS Perini et al. Intrathecal IgM production at clinical onset correlates with a more severe disease course in multiple sclerosis. JNNP 2006 Aug;77(8): Epub 2006 Mar 30.

56 Risk of Therapy Natalizumab and PML JCV Status Duration of Use Prior Chemotherapy/Immunosuppression Autoimmunity with Alemtuzumab IL-7, IL-21, CCL21 Levels Predictive of Risk Remains to be verified

57 Estimated Incidence of Natalizumab-Associated PML Stratified by Risk Factors Anti-JCV Antibody Status Negative Positive No Prior IS Use Yes 0.11/ % CI: (based on 1 hypothetical anti-jcv antibody negative PML case) Natalizumab exposure No Prior IS Use Prior IS Use 1 24 mo mo 0.35/ % CI: / % CI: / % CI: / % CI: IS = immunosuppressant Bloomgren G, et al. Presented at ECTRIMS / ACTRIMS 2011; Amsterdam, Netherlands. [P995]

58 Prevalence of JCV Ab: STRATIFY-1 Numbers at lower end of each bar indicate number of patients; error bars represent 95% CI. Bozic C, et al. Abstract P Presented at the American Academy of Neurology 63rd Annual Meeting; April 9-16, 2011; Honolulu.

59 Futility of Therapy Interferon Antibodies More Clinical Activity More MRI Activity Natalizumab Antibodies Associated with Infusion Reactions More Clinical/MRI Activity

60 Figure 3 Kaplan Meier estimates: cumulative probability of sustained disability progression, using EDSS scores, by antibody status over the 2-year AFFIRM Trial Calabresi P A et al. Neurology 2007;69: by Lippincott Williams & Wilkins

61 The incidence and significance of anti-natalizumab antibodies Results from AFFIRM and SENTINEL Calabresi P A et al. Neurology 2007;69:

62 Figure 6 Adjusted annualized relapse rates (95% CI) by antibody status over 2 years of natalizumab treatment. Calabresi P A et al. Neurology 2007;69: by Lippincott Williams & Wilkins

63 Predicting Response to Therapy Interferons RNA Expression of IFN Response Genes High IFIT1, ISG15, IF16 Predict Nonresponders (Charbit H, et al. Predictive markers to interferon-beta therapy in multiple sclerosis patients. ECTRIMS and ACTRIMS: October 19-22, 2011; Amsterdam, The Netherlands. Abstract 538.) Single Nucleotide Polymorphisms? CSG Lipid-Specific IgM Bands. Those with IgM bands taking interferon (102 patients) had higher risk of relapse, ARR at three years, less likely to be relapse-free and more with increased EDSS (Bosca et al. Response to interferon in multiple sclerosis is related to lipid-specific oligoclonal IgM bands. Multiple Sclerosis (2010 Jul;16(7): Epub 2010 Jun 10) IL-7 Levels? High Levels Predict Responsiveness IL-10 Levels? Low Levels Predict Responsiveness

64 Fig. 1 High serum IL-7 is a strong predictor of clinical response to IFN-β. Lee L et al. Sci Transl Med 2011;3:93ra68-93ra68 Published by AAAS

65 The interleukin-10 levels as a potential indicator of positive response to interferon beta treatment of multiple sclerosis patients Halina Bartosik-Psujek,, Zbigniew Stelmasiak. Clin Neurol and Neurosurg 2006 Oct;108(7): responders and 10 nonresponders at 2 years

66 Copaxone Single Nucleotide Polymorphisms A group of 81 may predict a subset of hyperresponders

67 New Paradigms/Algorithms Assumes Approval of Multiple Medications Assumes Confirmation of Test Utility Assumes Availability of Screening Tests Assumes Insurance Company Compliance Will Change as We Gain More Information, Especially with Comparison Trials Following are Three Possible Approaches, with Qualitative Conclusions; There Are Others

68 More Severity Less Neg Natalizumab Rituximab/ Ocrelizumab Do Well JCV status Pos IL-7, IL-21, CCL21 Autoimmune Risk Low Alemtuzumab Do Poorly High Low Risk Medications GA responder Pregnancy GA Do Poorly Fingolimod, BG12 Teriflunomide /Combo Laquinimod/Combo Rituximab/Ocrelizumab Daclizumab IFN responder Interferon Continue Indefinitely CD56bright HI LOW

69 OR

70 More Severity Less Neg JCV status Pos Low Risk Medications Natalizumab Rituximab/ Ocrelizumab IL-7, IL-21, CCL21 Autoimmune Risk Low Alemtuzumab High Fingolimod? BG12 Teriflunomide /Combo Laquinimod/Combo Daclizumab? Do Well Continue Indefinitely Poorly Rituximab/Ocrelizumab Natalizumab x mos If JCV+ If Fail Multiple Agents GA responder Pregnancy GA IFN responder Interferon

71 OR

72 Negative Natalizumab Rituximab/Ocrelizumab Do Well If Need Alternative Ongoing Activity Side effects New Dx?JCV? Pregnancy Glatiramer Positive Fingolimod BG12 Teriflunomide /Combo Laquinimod/Combo Daclizumab Rituximab/Ocrelizumab Natalizumab x mo If Need Alternative Continue Indefinitely Low IL-7, IL-21, CCL21 Autoimmune Risk High GA responder Pregnancy IFN responder Alemtuzumab GA or Interferon GA Interferon

73 THANK YOU