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New Frontiers in Neurotherapy for Multiple Sclerosis Focus on the Foundation Role of Immunomodulation for Long-Term Efficacy, Safety, Neuronal Preservation,

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Presentation on theme: "New Frontiers in Neurotherapy for Multiple Sclerosis Focus on the Foundation Role of Immunomodulation for Long-Term Efficacy, Safety, Neuronal Preservation,"— Presentation transcript:

1 New Frontiers in Neurotherapy for Multiple Sclerosis Focus on the Foundation Role of Immunomodulation for Long-Term Efficacy, Safety, Neuronal Preservation, and Disability Mitigation Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California Investigations Innovation Clinical Application

2 Program Faculty BRUCE A. CREE, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California MARK J. TULLMAN, MD Assistant Professor of Neurology Director, Multiple Sclerosis Clinical Care Center Center The Neurological Institute of New York Columbia University Medical Center New York, New York ROHIT BAKSHI, MD, FAAN Associate Professor of Neurology & Radiology Radiology Director, Laboratory for Neuroimaging Research Research MS Center, Brigham & Womens Hospital Harvard Medical School Boston, MA GUY J. BUCKLE, MD, MPH Director of MS Clinical Care Partners Multiple Sclerosis Center Brigham and Womens Hospital Assistant Professor of Neurology Harvard Medical School Boston, Massachusetts

3 The Evidence for First Line Therapy with Immune-Modulating Agents From Mechanisms to TherapyLandmark Trials, Long-Term Safety Data and Clinical Experience Investigations Innovation Clinical Application Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California

4 Overview Mechanisms of action of first line therapies Mechanisms of action of first line therapies Outcome measures in clinical trials Outcome measures in clinical trials Comparison of landmark trials Comparison of landmark trials Longitudinal studies: what do they tell us? Longitudinal studies: what do they tell us?

5 Goals of Treatment Reduce frequency of relapse Reduce frequency of relapse Slow progression of disability Slow progression of disability Reduce MRI activity Reduce MRI activity Prevent morbidity from symptoms and provide palliative care Prevent morbidity from symptoms and provide palliative care Maintain adherence Maintain adherence Provide long-term efficacy and safety Provide long-term efficacy and safety

6 Treg Th2/ Th3 MO IL-4 IL-5 IL-6 IL-13 TGF B Histamine Proteases TNF NAA, ATP NO O 2 5-HT Mast Cell IL-12 APC Thp CD4 CD40LCD40 IL-4 & IL-10 CD4 APC Thp CD28 B7 Th2/ Th3 B7 CD40 Microglia CD40L CD28 Th1 Th17 B Glutamate T CD8 MMP- 2/9 VCAM-1ICAM-1 VCAM-1 IFN TNF IL-17 IL-10 TGF Ab+C 9neo CD8 Mast Cell T Granutocyte Complement Monocyte Pl Figure courtesy of Dhib-Jalbut S, 2008 Immunopathogenesis of the MS Lesion IFN TNF Th17 NO Oi TNFa MMP LFA-1 VLA-4 Th1 Th17 Oligo BBB MCP-1 MIP-1 P-10 RANTES Astrocyte IL-23 Treg CD4+CD25+ Myelin Ag Microbial Ag HLA Virus TCR

7 IFN- : Activity T H 1+ Resting T cell MMP Activated (+) T cells T H 1+ MMP BBBBloodCNS TNF-α IFN-γ IL-2 TH1TH1 APC IFN- β Myelin protein Antigen T H 1+ Adapted from Yong VW. Neurology. 2002;59:

8 Glatiramer Acetate: Activity Adapted from Ziemssen T et al. J Neurol Sci. 2005;233: BBB GA- specific T cell APC GA therapy TH1TH1TH2TH2 APC Microglia MHC CNS Ag TCR Macrophage PeripheryCNS TH2TH2 MHC GA TCR Neuroregeneration Bystander suppression effect Anti-inflammatory cytokines Neurotrophins + + TCR IL-4 IL-10 BDNF

9 Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (> 5 in 2 years) Weinhenker B et al. Brain. 1989;112:1422 Long-Term Disability Effect of Early Relapses

10 Number of Attacks, 1 st 2 years p <0.001 Interval Between 1 st 2 Attacks p <0.001 DSS at 2 years p < DSS at 5 years p < Development of Disability Effect of Early Clinical Course Clinical Characteristic Significance* * Controlled for age at onset, remitting at onset, cerebellar, cerebral Weinshenker B et al. Brain. 1991;114 ( Pt 2):

11 Relapses in MS Relapses are the most obvious evidence of inflammatory disease activity in RRMS Relapses are the most obvious evidence of inflammatory disease activity in RRMS Relapse frequency in typical untreated RRMS populations enables treatment effect to be rapidly assessable in a 12-month clinical study Relapse frequency in typical untreated RRMS populations enables treatment effect to be rapidly assessable in a 12-month clinical study Total number of relapses during the study period Total in-study person-years

12 Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study 35 % Reduction in relapse rates % 8 MIU qod IFN beta-1b P= % 4.4 MIU tiw IFN beta-1a P< % 8.8 MIU tiw IFN beta-1a P< % 20 mg qd glatiramer acetate P= MIU qw IFN beta-1a P= % N.B.: Results are from separate clinical trials Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert.

13 Is MS All About Relapses? Hypothesis: if relapses cause long-term disability then patients with frequent relapses should be at higher risk for disability Hypothesis: if relapses cause long-term disability then patients with frequent relapses should be at higher risk for disability From the London Ontario natural history studies patients with frequent attacks are at highest risk for future ambulatory disability From the London Ontario natural history studies patients with frequent attacks are at highest risk for future ambulatory disability Assumption: modifying the relapse rate will influence long-term disability Assumption: modifying the relapse rate will influence long-term disability Weinshenker et al Brain 112:1419

14 Proportion of Placebo Groups with Clinical Activity Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498. Relapses EDSS Progress IFNβ-1b (3 year) 86%39% IFNβ-1a (QW) (2 year) 77%35% IFNβ-1a (TIW) (2 year) 84%38% Glatiramer acetate (2 year) 73%25%

15 How is Sustained Progression Measured? Most clinical trials define progression by comparing the change in EDSS from baseline to study conclusion, and then confirm the change in EDSS at 3 or 6 months Most clinical trials define progression by comparing the change in EDSS from baseline to study conclusion, and then confirm the change in EDSS at 3 or 6 months Does this measure of confirmed progression reflect permanent disability? Does this measure of confirmed progression reflect permanent disability? If so, then confirmed changes in EDSS during the course of the trial should be sustained by the end of the study If so, then confirmed changes in EDSS during the course of the trial should be sustained by the end of the study

16 Does Sustained Disability Measure Permanent Disability? 50% of patients with a 1 point change, confirmed at 3 months will improve to a lower EDSS 50% of patients with a 1 point change, confirmed at 3 months will improve to a lower EDSS 33% of patients with a 1 point change, confirmed at 6 months, will improve to a lower EDSS 33% of patients with a 1 point change, confirmed at 6 months, will improve to a lower EDSS More stringent measures of change are harder to demonstrate in 2-year trials because relatively few MS patients will progress More stringent measures of change are harder to demonstrate in 2-year trials because relatively few MS patients will progress Conclusions: 6 months sustained EDSS change is more rigorous than a 3-month sustained change, but neither is a good predictor of long term disability Conclusions: 6 months sustained EDSS change is more rigorous than a 3-month sustained change, but neither is a good predictor of long term disability Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7.

17 * 1 EDSS point sustained for 6 months in 6 MIU qw phase III trial and for 3 months in all other phase III trials. Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655 IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277 Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701 PRISMS Study Group. Lancet. 1998;352:1498 Effect on Sustained Disability*: Summary of Phase III Trials 40 Reduction in sustained disability progression (%) 12% 22% 30% NS MIU tiw IFN beta-1a 4.4 MIU tiw IFN beta-1a 20 mg qd glatiramer acetate p<0.05 p=NS 37% 6 MIU qw IFN beta-1a p= % 8 MIU qod IFN beta-1b p=NS

18 Summary Relapses and disability progression represent different but complimentary aspects of MS natural history Relapses and disability progression represent different but complimentary aspects of MS natural history Relapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome measures in MS trials Relapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome measures in MS trials The generally accepted sustained change in EDSS measure is not a reliable marker of long term disability The generally accepted sustained change in EDSS measure is not a reliable marker of long term disability Phase III trials results showed: Phase III trials results showed: The interferons and glatiramer acetate modestly reduce the relapse rate The interferons and glatiramer acetate modestly reduce the relapse rate IFN beta-1a has a statistically significant impact on sustained disability progression over two years IFN beta-1a has a statistically significant impact on sustained disability progression over two years IFN beta-1a and glatiramer acetate have a statistically significant impact on the mean EDSS over two year IFN beta-1a and glatiramer acetate have a statistically significant impact on the mean EDSS over two year

19 Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons?

20 Cross Trial Comparisons Relative Efficacy (RR) IFNβ-1a 30 µg qw qw IFNβ-1b, 250 µg qod IFN β-1a 44 µg tiw GA 20 mg qd Relapse rate (annualized) -18%-34%-32%-29% Relapse-Free (2 years) +42%+95%+100%+36% Progression free -37%-29%-30%-12% New T2 Lesions -36%-83%-78%-38% Gd+ Lesions -42%--88%-33% BOD - 4% -17%-15%-8%

21 672 days (96 weeks) IFNβ-1a GA Time to first relapse (days) Hazard ratio (95% CI): (0.74, 1.21) p = Survival distribution function The REGARD Trial Time to First Relapse (1 o endpoint)

22 The BEYOND Trial Relapse Risk (1 o Endpoint) No significant difference in relapse risk between any group No significant difference in relapse risk between any group Interferon beta-1b 500 vs. Interferon beta-1b 250 Interferon beta-1b 500 vs. Glatiramer acetate Interferon beta-1b 250 vs. Glatiramer acetate Primary Analysis Sensitivity Analysis (no major protocol violations, 100% of doses, post-hoc) P-values(one-sided) P-values(one-sided) P=0.16P=0.73P=0.43 P=0.29P=0.30P=

23 What can be learned from long-term follow up studies?

24 Long-Term Follow Up Do long-term follow up studies adequately address medication safety? Do long-term follow up studies adequately address medication safety? Do long-term studies adequately address longitudinal efficacy? Do long-term studies adequately address longitudinal efficacy? Have methods of analysis for longitudinal studies been optimized? Have methods of analysis for longitudinal studies been optimized?

25 BiasImpactStrategy Ascertainment Modified therapeutic effect dependent on characteristics of participating patients. F/U must be as complete as possible Directly compare baseline and on- RCT characteristics of those patients in LTF to those not in LTF Informed Therapeutic Decisions Inflated estimate of therapeutic benefit because patients doing well continue therapy whereas failing patients switch or stop therapy. MPR: Use percent of total possible time on therapy instead of absolute time to assess exposure. Treatment Selection Modified therapeutic effect dependent on patient selection characteristics. Propensity Scoring: Adjust for the propensity (i.e., likelihood) that a particular treatment will be selected based on available patient characteristics Multiple Testing Increased risk of Type 1 error from the use of multiple predictor variables and weighting schemes Create a single model and apply adjustments to p-values according to the number of predictors tested in the model. Sources of Bias in LTFU Studies

26 Glatiramer Acetate 15 year LTFU Ford C et al. Mult Scler. 2010;16:

27 Glatiramer Acetate 15 year LTFU Ford C et al. Mult Scler. 2010;16:

28 Glatiramer Acetate 15 year LTFU In a small cohort of patients followed for 15 years, glatiramer acetate was safe and well tolerated In a small cohort of patients followed for 15 years, glatiramer acetate was safe and well tolerated 65% of continuously treated patients did not progress to SPMS 65% of continuously treated patients did not progress to SPMS 41% of patients withdrawing from the study did so because of disease progression 41% of patients withdrawing from the study did so because of disease progression Propensity scores were used to try to adjust for differences between ongoing and withdrawing patients Propensity scores were used to try to adjust for differences between ongoing and withdrawing patients EDSS at baseline predicts EDSS at 15 years EDSS at baseline predicts EDSS at 15 years

29 IFN β -1a (QW) LTFU Disposition Bermel R et al. Mult Scler Feb 18. [Epub ahead of print] Complete 2-year follow-up (n=172) Unascertained (n=36) Ascertained for ASSURANCE (n=136; 79%) Able to locate, Unable to contact (n=13) Unable to locate (n=23) Living (n=122; 90%) Deceased (n=14; 10%) ICF and question booklet completed LOCF

30 IFN β -1a QW LTFU Outcomes Bermel R et al. Mult Scler Feb 18. [Epub ahead of print] Currently receiving IM IFN ß-1a (n=56) Not currently receiving IM IFN ß-1a (n=66) Patients, % P=0.062 EDSS Milestone P=0.326 P=0.114 P=0.006

31 IFN β -1a QW LTFU Conclusions 79% of eligible patients were located for the 15 year follow up 79% of eligible patients were located for the 15 year follow up At 15 years, patients currently on IFN β-1a had less progression in EDSS scores than patients not on IFN β- 1a At 15 years, patients currently on IFN β-1a had less progression in EDSS scores than patients not on IFN β- 1a However, patients not currently on IFN β-1a had higher baseline EDSS scores suggesting more severe baseline MS However, patients not currently on IFN β-1a had higher baseline EDSS scores suggesting more severe baseline MS Propensity scores were used to adjust for these differences Propensity scores were used to adjust for these differences Inferences with regard to association with lower EDSS and ongoing treatment were not made Inferences with regard to association with lower EDSS and ongoing treatment were not made Bermel R et al. Mult Scler Feb 18. [Epub ahead of print]

32 IFNβ-1b 250 µg IFNβ-1b 50 µg Placebo Pivotal Study (n=372) LTF 2005 Cross-sectional investigation of: - clinical outcomes (disability, relapse rate) - imaging (brain and spinal MRI) - cognition and mood - QoL, resource use - lab parameter including NAb's and PgX Patients under regular medical care - no trial 1990 IFN β-1b LTFU Design Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

33 Event Rates and Long-Term Efficacy Clinical and Radiological Endpoints 1.Need to demonstrate that the short-term event-rates are correlated with long-term outcome. 2.Need to demonstrate that the short-term event-rates contribute independently to predicting outcome. 3.Need to demonstrate that therapies which reduce the event-rates, are also associated with improved long-term outcome. Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

34 IFN β -1b LTFU Adjusted OUtcome Any Variable + Any Exposure Weighting – Any Negative Outcome EDSS p< Exposure p< High Low Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

35 Event Rates and Long-Term Efficacy Conclusions 1.The LTF study demonstrates that the short-term event- rate is correlated with long-term outcome. 2.The LTF study also demonstrates that the short-term event-rate contributes independently to predicting long- term outcome. 3.The LTF study provides convincing evidence that early initiation and sustained use of IFNβ-1b has a beneficial impact on long-term outcome in MS. 4.The analysis strategy employed provides a methodological framework for mitigating bias in assessing long-term efficacy in other clinical trials having similar non-randomized data.

36 Disease modifying therapy seems favorably effect the long-term course of MSDisease modifying therapy seems favorably effect the long-term course of MS Propensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, unblinded studies are important statistical advances for interpreting these studiesPropensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, unblinded studies are important statistical advances for interpreting these studies Once the MS community agrees on the relevant covariates, these methods can be used to sort out some of these issues without the cost (and ethical dilemmas) posed by long-term placebo-controlled trials.Once the MS community agrees on the relevant covariates, these methods can be used to sort out some of these issues without the cost (and ethical dilemmas) posed by long-term placebo-controlled trials. Conclusions

37 The Emergence of Immunosuppressive Agents for MS Safety, Efficacy, and Cautionary Notes Patient Monitoring, Risks for Infection, and Mechanisms of Action Mark J. Tullman, MD Assistant Professor of Neurology Director, Multiple Sclerosis Clinical Care Center The Neurological Institute of New York Columbia University Medical Center New York, New York Investigations Innovation Clinical Application

38 Existing and Emerging MS Therapies Injectables IV Generic Mitoxantrone (oncology) (MS) Generic Mitoxantrone (oncology) (MS) Tysabri Rebif Filed Approved In phase II In phase III Cladribine Ampyra BG12 Teriflunomide Laquinimod Ocrelizumab IV Alemtuzumab Oral Extavia Rebif Betaseron Copaxone Avonex Novantrone Ampyra Extavia Tysabri BG12 Caldribine Fingolimod Ocrelizumab Teriflunomide Laquinimod Alemtuzumab Generic Mitoxantrone (oncology) MS

39 Efficacy in Recent Studies Annualized relapse rate over 2 years Annualized relapse rate over 2 years 58-61% relapse-free over 2 years 58-61% relapse-free over 2 years 79-81% without disability progression over 2 years 79-81% without disability progression over 2 years 88.3% without disability progression over 96 weeks 88.3% without disability progression over 96 weeks 91.3% without disability progression over 96 weeks 91.3% without disability progression over 96 weeks 74% without disability progression over 3 years 74% without disability progression over 3 years 75% without EDSS progression 5 years after CIS onset 75% without EDSS progression 5 years after CIS onset 13.3% reduction in MRI T2 lesion load over 3 years 13.3% reduction in MRI T2 lesion load over 3 years All in placebo, interferon, or glatiramer acetate- treated patients All in placebo, interferon, or glatiramer acetate- treated patients Kappos L, et al. Lancet Neurol 2009; 8: 987–97; Giovannoni G, et al. N Engl J Med. 2010;362: ; CAMMS223 Trial Investigators. NEJM 2008;359: ; Kappos L et al. N Engl J Med. 2006;355: ; Mikol et al. Lancet Neurol 2008; 7: 903–14

40 Prognostic Signs Favorable Outcome Favorable Outcome Female Female Younger age at onset Younger age at onset Little disability 5 years after onset Little disability 5 years after onset Optic neuritis as 1 st attack Optic neuritis as 1 st attack Worse Outcome Worse Outcome Male Male Older age at onset Older age at onset Frequent attacks Frequent attacks Short interval between 1 st 2 attacks Short interval between 1 st 2 attacks Incomplete recovery from 1 st attack Incomplete recovery from 1 st attack Cerebellar involvement as 1 st symptom Cerebellar involvement as 1 st symptom Rapidly accumulating disability Rapidly accumulating disability Progressive disease from onset Progressive disease from onset

41 Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:

42 Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:

43 Disease Free State Proportion Free of Clinical and MRI Activity p < Hardova E, et al. Lancet Neurol 2009;8: Natalizumab Placebo

44 Alemtuzumab Monoclonal humanized antibody directed against CD52 antigen Monoclonal humanized antibody directed against CD52 antigen CD52 antigen is a cell surface glycoprotein that is present on >95% of T lymphocytes, B lymphocytes, monocytes, and eosinophils CD52 antigen is a cell surface glycoprotein that is present on >95% of T lymphocytes, B lymphocytes, monocytes, and eosinophils Results in prolonged depletion of B cells, T cells, and monocytes Results in prolonged depletion of B cells, T cells, and monocytes Within an hour following a single 5- to 10-mg dose, lymphocytes and monocytes are no longer detectable in circulation Within an hour following a single 5- to 10-mg dose, lymphocytes and monocytes are no longer detectable in circulation FDA-approved for B-CLL FDA-approved for B-CLL Muraro P, et al. Neurotherapeutics. 2007;4: Coles A, et al. J Neurol. 2006;253:

45 CAMMS223 Trial Investigators. NEJM 2008;359: Month 0 Month 12 Month 24 Month 36 Month 0 Month 12 Month 24 Month IFNβ-1a 44 mcg thw SC Alemtuzumab 12 mg daily IV Alemtuzumab 24 mg daily IV

46 Alemtuzumab CAMMS223: Co-Primary Endpoints (36 months) CAMMS223 Trial Investigators. NEJM 2008;359:

47 Alemtuzumab CAMMS223: MRI Outcomes CAMMS223 Trial Investigators. N Engl J Med. 2008;359: P0.03 for both doses of alemtuzumab vs. IFN at m 0-12 and P=NS at m 0-36 Months n=91 n=96 n=100 n=75 n=96 n=91 n=60 n=80 n=87 P=0.16 P=0.04 P=0.03 Months

48 Alemtuzumab CAMMS223: Safety Principal AEs associated with alemtuzumab included: Principal AEs associated with alemtuzumab included: Infusion reactions Infusion reactions Mild-to-moderate infections Mild-to-moderate infections Autoimmunity Autoimmunity Immune thrombocytopenia in 6 of 216 patients (2.8%) including one death Immune thrombocytopenia in 6 of 216 patients (2.8%) including one death Thyroid disorders (28% vs. 3% for IFNβ-1a) Thyroid disorders (28% vs. 3% for IFNβ-1a) 1 case of Goodpastures syndrome 1 case of Goodpastures syndrome CAMMS223 Trial Investigators. N Engl J Med. 2008;359: CAMMS223 Trial Investigators. N Engl J Med. 2008;359:

49 Alemtuzumab CAMMS223: Safety Infections, % IFN ß-1a (n=107) Alem 12 mg (n=108) Alem 24 mg (n=108) Upper resp. infection* Lower resp. infection* Herpes simplex Herpes zoster Meningitis**001.8 * P<0.001 alemtuzumab vs. IFN ** Listeria or viral meningitis CAMMS223 Trial Investigators. N Engl J Med. 2008;359: CAMMS223 Trial Investigators. N Engl J Med. 2008;359:

50 Alemtuzumab: Effects on the Immune System B cells returned to normal within 3-6 months B cells returned to normal within 3-6 months Median recovery time for CD4+ T cells > 100 cells/µL = 3 months Median recovery time for CD4+ T cells > 100 cells/µL = 3 months 6-9 months for CD4+ T cells > 200 cells/µL 6-9 months for CD4+ T cells > 200 cells/µL Median recovery time to baseline levels of CD4+ T cells = 61 months Median recovery time to baseline levels of CD4+ T cells = 61 months Thompson S, et al. J Clin Immunol 2010;30:99–105. Coles A, et al. J Neurol. 2006;253:

51 Cladribine Synthetic purine nucleoside analogue prodrug Synthetic purine nucleoside analogue prodrug Accumulates and is incorporated into the DNA of lymphocytes as a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase activity Accumulates and is incorporated into the DNA of lymphocytes as a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase activity Selectively induces apoptosis in dividing and non-dividing lymphocytes Selectively induces apoptosis in dividing and non-dividing lymphocytes Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells and B cells Sustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells and B cells Relatively transient effects on other immune cells such as neutrophils and monocytes Relatively transient effects on other immune cells such as neutrophils and monocytes Reduces levels of pro-inflammatory chemokines Reduces levels of pro-inflammatory chemokines Crosses the blood brain barrier - CSF concentration = 25% of plasma (patients with no BBB compromise) Crosses the blood brain barrier - CSF concentration = 25% of plasma (patients with no BBB compromise) FDA-approved for hairy cell leukemia FDA-approved for hairy cell leukemia Carson et al. Blood 1983;62:737–43; 2Beutler et al. Proc Natl Acad Sci USA 1996;93:1716–20. Rice et al.Neurology 2000;54:1145–55. Szczucinski et al. Acta Neurol Scand 2007;115:137–46Bartosik-Psujek et al. Acta Neurol Scand 2004;109:390–2. Liliemark.ClinPharmacokinet1997;32:120–3.

52 Dosing: 4-5 day courses at month 1 and 2 (3.50 mg/kg) or months 1-4 (5.25 mg/kg) and 2 additional monthly courses beginning at week patients Placebo (n = 437) Cladribine 3.50 mg/kg total dose; 4 courses (n = 433) Cladribine 5.25 mg/kg total dose; 6 courses (n = 456) 4896 Time (weeks) MRI Neurological examination –4 X X 9516 X X X 4452 X Giovannoni G, et al. N Engl J Med. 2010;362:

53 CLARITY: Clinical Outcomes * P < ( ) 0.14* ( ) 0.15* ( ) 57.6% 54.5% Annualized relapse rate (95% CI) * 78.9* Odds Ratio (95% CI) 2.43 ( ) Odds Ratio (95% CI) 2.53 ( ) Percent of relapse-free patients at 98 weeks Placebo (n = 437) Cladribine 3.50 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) Giovannoni G, et al. N Engl J Med. 2010;362:

54 CLARITY: Clinical Outcomes Placebo mg mg Placebo Cladribine 3.50 mg/kg 0.67 ( ); P = 0.02 Cladribine 5.25 mg/kg 0.69 ( ); P = HR vs Placebo (95% CI) Weeks Proportion with confirmed 3-month EDSS progression (%) Time to Confirmed EDSS Progression Giovannoni G, et al. N Engl J Med. 2010;362:

55 CLARITY: MRI Outcomes All P < % mean ± SE lesions/patient/scan % T1 Gadolinium- Enhancing Lesions Active T2-Weighted Lesions % 76.9% % 77.9% Combined Unique Lesions Placebo (n = 437) Cladribine 3.50 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) Giovannoni G, et al. N Engl J Med. 2010;362:

56 CLARITY: Safety and Tolerability Preferred term, n (%) patients Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cladribine 5.25 mg/kg (n = 454) Cladribine overall (n = 884) Herpes zoster08 (1.9)11 (2.4)19 (2.1) Herpes zoster oticus001 (0.2)1 (0.1) Varicella1 (0.2) 2 (0.2) Any infection or infestation188 (42.5)205 (47.7)222 (48.9)427 (48.3) Deaths2 (0.5) 2 (0.4)4 (0.5) 20 patients had 21 zoster events in the cladribine groups 20 patients had 21 zoster events in the cladribine groups All 21 cases were self-limiting and dermatomal; no cases were disseminated All 21 cases were self-limiting and dermatomal; no cases were disseminated 3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study developed zoster versus 1.8% of those that did not 3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study developed zoster versus 1.8% of those that did not 70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia at the approximate time zoster developed 70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia at the approximate time zoster developed Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrest Deaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrest Giovannoni G, et al. N Engl J Med. 2010;362:

57 CLARITY: Safety and Tolerability Preferred term, n (%) Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cladribine 5.25 mg/kg (n = 454) Cladribine overall (n = 884) During Study Melanoma Melanoma01(0.2)01(0.2) Ovarian Ovarian01(0.2)0 1 (0.1) Pancreatic Pancreatic0 1 (0.2) 0 1 (0.1) Cervix Cervix001(0.2)1(0.2) During post-study surveillance Choriocarcinoma Choriocarcinoma001(0.2)1(0.2) Malignancies Giovannoni G, et al. N Engl J Med. 2010;362:

58 CLARITY: Effects on Lymphocyte Subsets Maximum Effects on CD4 and CD 19 Counts* Weeks 0-48 Weeks Weeks 0-48 Weeks mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg CD4 (week) Cells/µL Cells/µL CD19 (week) Cells/µL Cells/µL Add Reference *Median values Rieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, Poster #816.

59 Fingolimod (FTY720) 1. Brown B, et al. Ann Pharmacother. 2007;41: Kappos L, et al. N Engl J Med. 2006;355: Mullershausen F, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 4. Miron VE, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. 5. Barske C, et al. Presented at: ECTRIMS; October 11-14, 2007; Prague, Czech Republic. Sphingosine-1-phosphate (S1P) receptor modulator Sphingosine-1-phosphate (S1P) receptor modulator Sequesters circulating lymphocytes into secondary lymphoid organs Sequesters circulating lymphocytes into secondary lymphoid organs Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells), CD45RO+ (memory T cells) and CD19+ cells Peripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells), CD45RO+ (memory T cells) and CD19+ cells No effect on lymphocyte induction, proliferation, or memory function No effect on lymphocyte induction, proliferation, or memory function May inhibit the production of IL-17 May inhibit the production of IL-17 S1P receptors located within the CNS S1P receptors located within the CNS Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE

60 1272 patients (1:1:1) Clinic visits Oral fingolimod 0.50 mg once daily (n = 425) MRI Oral fingolimod 1.25 mg once daily (n = 429) Placebo once daily (n = 418) Randomization Month 6 Month 12 Month 24 Kappos L, et al. N Engl J Med. 2010;362:

61 FREEDOMS: Primary Efficacy Endpoint Annualized Relapse Rate at 24 months β Placebo (n = 431) Fingolimod 0.5 mg (n = 429) Fingolimod 1.25 mg (n = 420) -54% vs Placebo p < % vs Placebo p < Kappos L, et al. N Engl J Med. 2010;362:

62 FREEDOMS: Disability Data Number at Risk FTY mg FTY mg Placebo FTY mg (17%) Days on study Placebo (24%) FTY mg (18%)* Percent with 3-month confirmed EDSS progression FTY mg vs placebo HR 0.70 P = 0.02 in time to disability Progression FTY mg vs placebo HR 0.68 P = 0.02 in time to disability Progression * P = 0.03 vs placebo P = 0.01 vs placebo Kappos L, et al. N Engl J Med. 2010;362:

63 FREEDOMS: MRI Endpoints T2 and Gadolinium-Enhancing Lesions at 24 Months -82% P< % P<0.001 Kappos L, et al. N Engl J Med. 2010;362:

64 FREEDOMS: Brain Volume P0.03 for both doses of fingolimod vs. placebo at all time points Kappos L, et al. N Engl J Med. 2010;362:

65 RandomizationMonth 6Month 12Ongoing Oral fingolimod 0.5 mg once daily and matching weekly placebo injection IM Optional extension phase Oral fingolimod 1.25 mg once daily and matching weekly placebo injection IM IFNβ-1a 30 µg IM once weekly and matching daily oral placebo capsule Assessments MRI EDSS Clinical visit Cohen J, et al. N Engl J Med. 2010;362:

66 TRANSFORMS: Primary Efficacy Endpoint Annualized Relapse Rate at 12 months β IFNβ-1a 30 µg IM once weekly (n = 431) Oral fingolimod 0.5 mg (n = 429) Oral fingolimod 1.25 mg (n = 420) -52% vs IFNβ-1a, p < % vs IFNβ-1a, p < Cohen J, et al. N Engl J Med. 2010;362:

67 TRANSFORMS: MRI Endpoints T2 and Gadolinium-Enhancing Lesions at 12 Months Cohen J, et al. N Engl J Med. 2010;362: % vs. IFNß-1a P< % vs. IFNß-1a P= % vs. IFNß-1a P< % vs. IFNß-1a P<0.001

68 TRANSFORMS: Brain Volume P < Cohen J, et al. N Engl J Med. 2010;362:

69 Fingolimod: Safety Transient reduction in heart rate on initiation of treatment Transient reduction in heart rate on initiation of treatment Elevated blood pressure Elevated blood pressure mean systolic BP (1.9 and 3.6 mm Hg for 0.5 mg and 1.25 mg, respectively) and diastolic BP (0.7 and 2.1 mm HG for 0.5 and 1.25 mg, respectively) mean systolic BP (1.9 and 3.6 mm Hg for 0.5 mg and 1.25 mg, respectively) and diastolic BP (0.7 and 2.1 mm HG for 0.5 and 1.25 mg, respectively) Elevated liver enzymes Elevated liver enzymes LFTs 3 x ULN 8% for FTY mg, 10% for FTY mg, 1.2% for placebo, 2% for IFNß-1a LFTs 3 x ULN 8% for FTY mg, 10% for FTY mg, 1.2% for placebo, 2% for IFNß-1a Macular edema Macular edema FREEDOMS - 7 cases in the 1.25 mg dose group (1.6%) and none in the 0.5 mg dose group FREEDOMS - 7 cases in the 1.25 mg dose group (1.6%) and none in the 0.5 mg dose group TRANSFORMS – 6 cases (4 in the 1.25 mg dose group (1%) and 2 in the 0.5 mg dose group (0.5%)) TRANSFORMS – 6 cases (4 in the 1.25 mg dose group (1%) and 2 in the 0.5 mg dose group (0.5%)) Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:

70 Fingolimod: Safety AE, n (%) FTY mg (n = 854) FTY mg (n = 849) Placebo (n = 418) IFNß-1a (n = 431) Skin Cancers Basal cell carcinoma7(0.8)3(0.4)3(0.7)1(0.2) Melanoma3(0.4)1(0.1)1(0.2)0 Bowens Disease 1 (0.1) 000 Infections Herpes infections46(5.4)48(5.7)33(7.9)12(2.8) Malignancies and Herpes Infections Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:

71 Fingolimod: Safety Two fatal infections in patients treated with FTY mg Two fatal infections in patients treated with FTY mg Herpes encephalitis Herpes encephalitis primary disseminated varicella primary disseminated varicella Hemorrhagic encephalitis in a patient treated with FTY mg Hemorrhagic encephalitis in a patient treated with FTY mg Posterior reversible encephalopathy syndrome in a patient treated with 5 mg in the phase 2 study Posterior reversible encephalopathy syndrome in a patient treated with 5 mg in the phase 2 study Cohen J, et al. N Engl J Med. 2010;362: ; Kappos L et al. N Engl J Med. 2006;355: ; Leypoldt F, et al. LK. Neurology 2009;72:

72 Normal range Treatment duration (yrs), mean ± SEM 1.9 ± Lymphocyte count (x 10 9 /L), mean ± SEM 0.4 ± CD4 T cell count (cells/µL), mean ± SEM 78 ± CD8 T cell count (cells/µL), mean ± SEM 149 ± FTY mg (n = 16) Mehling M, et al. Neurology 2008;71:1261–1267

73 [PD5.006] Prolonged Reduction in Circulating Lymphocytes after Discontinuation of FTY720 (Fingolimod): Possible Relationship to Duration of Therapy Mark R. Keezer, Yves Lapierre, Igor Shames, David Haegert, Amit Bar-Or, Jack Antel, Montreal, QC, Canada CONCLUSIONS/RELEVANCE: Peripheral lymphocyte counts remained depressed beyond the currently expected time period in 2 patients following cessation of long-term FTY720 therapy. Regional lymph node architecture was preserved in the one available patient. Exploration of larger datasets will determine the true incidence of prolonged lymphopenia and whether time to recovery of circulating lymphocytes may provide a potential biomarker for guiding continued therapy. Category - MS and Related Diseases - Clinical Science Presented at the AAN Annual Meeting 2010.

74 Emerging Therapies: Trading Efficacy for Safety ? Impaired immune surveillance and opportunistic infections ? Impaired immune surveillance and opportunistic infections Viral and other infections Viral and other infections ? Malignancies ? Malignancies Long-lasting effects Long-lasting effects Autoimmunity Autoimmunity Teratogenicity Teratogenicity Rare, but serious infusion reactions Rare, but serious infusion reactions The Unknown The Unknown

75 Natalizumab and the Risk of PML

76 Humanized monoclonal antibody directed against CD11a affecting T-lymphocyte activation, migration, and reactivation Humanized monoclonal antibody directed against CD11a affecting T-lymphocyte activation, migration, and reactivation Evaluated in 4 randomized, double-blind, placebo- controlled trials Evaluated in 4 randomized, double-blind, placebo- controlled trials FDA-approved for psoriasis in 2003 FDA-approved for psoriasis in 2003 At the time of approval, 2764 patients had been treated At the time of approval, 2764 patients had been treated 218 treated for 1 year 218 treated for 1 year Nijsten T, et al. Arch Dermatol 2009;145:

77 October 2008: Label update to include PML October 2008: Label update to include PML February 2009: February 2009: FDA issued a Public Health Advisory and changed the label to include a black box warning for PML FDA issued a Public Health Advisory and changed the label to include a black box warning for PML –At the time, 48,000 patients treated with efalizumab, but only 14,000 for > 1 year, 5,100 for > 2 years, and 1,900 for > 3 years EMEA recommends suspension of marketing EMEA recommends suspension of marketing Health Canada suspends marketing Health Canada suspends marketing April 2009: Genentech announced plans for a voluntary withdrawal from the U.S. market April 2009: Genentech announced plans for a voluntary withdrawal from the U.S. market Nijsten T, et al. Arch Dermatol 2009;145:

78 Meaningful impact Disease Course MRI ? Better than ABCR ? Window of opportunity Convenience Benefits Risks Benefits Risks Treatment Decisions: Considering Benefits and Risks Short-term safety Long-term safety Pharmacovigilance Post-approval studies Pregnancy issues

79 The Long Haul: Optimizing Long-Term Functional Status and Financial Outcomes in RRMS with Immunomodulation Therapy What Do The Trials Teach Us? What Do The Trials Teach Us? New Frontiers in Neurotherapy Guy J. Buckle, MD, MPH Director of MS Clinical Care Partners Multiple Sclerosis Center Brigham and Womens Hospital Assistant Professor of Neurology Harvard Medical School Boston, Massachusetts

80 CNS = central nervous system. Compston A, et al. Lancet. 2002;359(9313): Frohman EM. Med Clin N Am. 2003;87(4): Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9): National Multiple Sclerosis Society. Who gets MS? Accessed January 8, Lage MJ, et al. Work. 2006;27(2): Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9): National Multiple Sclerosis Society. Who gets MS? Accessed January 8, Lage MJ, et al. Work. 2006;27(2): Epidemiology of MS The most common chronic disease affecting the CNS in young adults The most common chronic disease affecting the CNS in young adults Approximately 400,000 cases in the United States Approximately 400,000 cases in the United States Estimates range from 250,000 to 500,000 Estimates range from 250,000 to 500,000 The chances of developing MS are 1:1000 in the general population The chances of developing MS are 1:1000 in the general population Estimated 2.5 million cases worldwide Estimated 2.5 million cases worldwide Highest incidence in Caucasians Highest incidence in Caucasians Higher incidence in women (approximately 3:1) Higher incidence in women (approximately 3:1) MS strikes individuals between the ages 20-50, normally a time of peak productivity MS strikes individuals between the ages 20-50, normally a time of peak productivity

81 Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B): Potential Triggers for MS Environmental Factors Infectious Agent Genetic Predisposition MS Abnormal Immunologic Response

82 National Multiple Sclerosis Society. about-ms/symptoms/index.aspx. Accessed February 21, Clinical Manifestations Fatigue Fatigue Pain Pain Depression Depression Numbness/paresthesias Numbness/paresthesias Cognitive dysfunction Cognitive dysfunction Weakness Weakness Spasticity Spasticity Optic neuritis Optic neuritis Bladder dysfunction Bladder dysfunction Bowel dysfunction Bowel dysfunction Cerebellar dysfunction Cerebellar dysfunction Sexual dysfunction Sexual dysfunction Gait abnormalities Gait abnormalities Partial/complete paralysis Partial/complete paralysis

83 Age of Onset of MS Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B): Years Patients (%) Distribution of Patients According to the Decade of Life of MS Symptoms Onset

84 EDSS = Expanded Disability Status Scale. Kurtzke JF. Neurology. 1983;33: Progression of Disability: EDSS 8.0–8.5 = Confined to bed or chair 7.0–7.5 = Confined to wheelchair 6.0–6.5 = Walking assistance is needed 5.0–5.5 = Increasing limitation in ability to walk 4.0–4.5 = Disability is moderate 3.0–3.5 = Disability is mild to moderate 2.0–2.5 = Disability is minimal 1.0–1.5 = No disability 0 = Normal neurologic exam Increasing disease burden 10.0 = Death due to MS 9.0–9.5 = Completely dependent

85 Natural History of MS and Cost of MS *Curve is based on an estimation of the decrease in cost for early treatment of about 40% at each range of EDSS Burks J. J Manag Care Med. 2008;12(1): [Exhibit 8]. Comi G. Neurol Sci. 2006;27:S8-S12. Kobelt G, et al. Neurology. 2006;66(11): CISRRMSSPMS Pre-clinical Predicted Cost Early Intervention* MRI lesion activity Clinical Threshold Atrophy and Axonal Degradation US$ per Year

86 Weinshenker BG, et al. Brain. 1989;112: Early Relapses Affect Long-term Disability Time from Onset of MS (years) Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (5 in 2 years) Patients (%) Actuarial analysis of disabilitypercentage of patients not having reached EDSS 6: difference between the groups is significant (P <.0001).

87 *In 224 placebo patients from the NMSS task force on clinical outcome assessment. EDSS = Expanded Disability Status Scale; NMSS = National Multiple Sclerosis Society. Lublin FD, et al. Neurology. 2003;61: Relapses Can Result in Residual Long-Term Disability Net Change in EDSS Score from before a Relapse to after a Relapse* % of patients had a residual deficit 0.5 point 42% of patients had a residual deficit 0.5 point 28% had a residual deficit 1.0 point 42.4% increase 0.5 or more 28.1% increase 1 or more Number of Subjects

88 Long-term Study Design in RRMS Copaxone ® (glatiramer acetate injection) 20,21 N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter open-label extension, and 1 patient received 1 dose of COPAXONE ® and never returned for evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort included 108 patients at 10 years and 100 patients at 15 years. Avonex ® (IFNβ-1a) 9,23 Avonex ® : N=301; 158 Avonex ®, 143 placebo; subset (85 Avonex ®, 87 placebo) followed for 2 years. 15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year 15. Betaseron ® (IFNβ-1b) 24,25 Betaseron ® : N=372; 125 Betaseron ® 1.6 MIU, 124 Betaseron ® 8 MIU, 123 placebo. 16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but included in the study as identified patients). LTFU data were obtained in an observational study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients were not taking Betaseron ®. Rebif ® (IFNβ-1a) 26 N=560; 184 Rebif ® 44 mcg, 189 Rebif ® 22 mcg, 187 placebo; at end of year 2, 172 placebo patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was continued to year 4. LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8 years after enrollment. Tysabri ® (natalizumab) 27 N=942; Tysabri ® 300 mg (n=627) or placebo (n=315). Up to 15 years 2 yrs 15 years 5 yrs 16 years 4 yrs 7-8 years 3 yrs Key Prospective study design Retrospective follow-up 9. Jacobs LD, et al. Ann Neurol. 1996;39: Ford C, et al. WCTRIMS Abstract P Ford CC, et al. Mult Scler. 2006;12: Bermel RA, et al. WCTRIMS Abstract P IFNβ Study Group. Neurology. 1995;45: Ebers G, et al. AAN P Kappos L, et al. Neurology. 2006;67: OConnor PW, et al. AAN P

89 Ryan M, et al. J Manag Care Pharm. 2009;15(1)(Suppl S-b):S1-S17. Data Supporting Long-Term Use of DMT Disease Duration (Years) Percentage Reaching EDSS 4 Percentage Reaching EDSS 6 GA 15-year LTFU >18.538%18% High-dose IFN -1a PRISMS 8 ~1326.8%20% IFN -1b 16 Year(> 80) ~20 Not reported ~45% Low-dose IFN -1a 15-year14.364%32%

90 Scope of QoL Three important domains in life Three important domains in life Physical functioning Physical functioning Psychosocial functioning Psychosocial functioning Symptom-related phenomenon Symptom-related phenomenon

91 The Two Faces of Multiple Sclerosis MS Relapse Progression MRI Symptoms Mobility Employment Depression Fatigue Cognition

92 HRQOL = Health-related quality of life. Petajan JH, et al. Ann Neurol. 1996;39(4): Motl R,W et al. Psychol Health Med. 2009;14(1) Mobility and HRQOL Improvement in strength and mobility can lead to improved social interaction and emotional behavior Improvement in strength and mobility can lead to improved social interaction and emotional behavior Improved fitness in MS is associated with improved HRQOL Improved fitness in MS is associated with improved HRQOL Physical activity is indirectly associated with improved depression, fatigue, pain, in individuals with MS Physical activity is indirectly associated with improved depression, fatigue, pain, in individuals with MS

93 Heesen C, et al. Mult Scler. 2008;14(7): Multiple Sclerosis Walking Power and Coordination of Hands Normal Skin Sensations Lack of Pain Bladder Control Bowel Control Visual Function Awakefulness and Alertness Thinking and Memory First Rank (%) Speech Swallowing Mood sexuality MS >15 Years MS <5 Years

94 Walking Impairment and Quality of Life 64% of patients report difficulty walking 64% of patients report difficulty walking Impairment worsens with increasing EDSS severity Impairment worsens with increasing EDSS severity Percent Among Patients who Reported Walking Impairment Johanesson et al. J Neurol. 2007;254:

95 Trends Across MS Clinical Trials Annualized Relapse Rate (ARR) Johnson 1995 Polman 2006 REGARD 2007 BECOME 2007 Kappos TRANSFORMS Jacobs 1996 β IFN β -1b study group,1993 PRISMS BEYOND 2007 CAMMS years HERMES weeks FORTE year CLARITY 2009

96 Cost of MS Relapse Reducing relapses is key to reducing costs Reducing relapses is key to reducing costs The number of relapses is a significant predictor of total cost The number of relapses is a significant predictor of total cost Cost of treating a relapse is difficult to calculate Cost of treating a relapse is difficult to calculate Includes initial care, acute treatment costs, post-discharge services, daily cost of outpatient medications Includes initial care, acute treatment costs, post-discharge services, daily cost of outpatient medications In one study, using 2002 dollars, costs ranged from $243 to $12,870, depending on level of management needed In one study, using 2002 dollars, costs ranged from $243 to $12,870, depending on level of management needed Cost estimates do not differentiate between the different forms of MS Cost estimates do not differentiate between the different forms of MS Morrow TJ. J Neurol Sci. 2007;256(supp 1):S39-S44. Grudzinski AN, et al. J Manag Care Pharm. 2000;6: OBrien JA, et al. BMC Health Serv Res. 2003;3:17-29.

97 Medical Costs Per Relapse ED = emergency department; IV = intravenous. OBrien J, et al. BMC Health Serv Res. 2003;3(1): Therapists Consults Follow-Up Office Visits Symptom-Related Medications Follow-Up Office Visits Hospital readmissions Nursing home Skilled nursing Home healthcare Rehabilitation Outpatient follow-up Home administration Post Discharge Services Hospital day case Hospital Admission IV Methylprednisolone Symptom-Related Medications EDED Usual care physician Initial Contact High-Intensity Episode Moderate-Intensity Episode Low-Intensity Episode $12,870$1847$243

98 Whetton-Goldstein K, et al. Mult Scler. 1998;4(5): Pope GC, et al. Neurology. 2002;58(1): Kobelt G, et al. Neurology. 2006;66(11): Patwardhan MB, et al. Mult Scler. 2005;11(2): OBrien JA, et al. J Neurosurg Psychiatry. 2006;77: Economic Implications Annual cost of MS in the United States is estimated at approximately $13.6 billion (in 1994 dollars) Annual cost of MS in the United States is estimated at approximately $13.6 billion (in 1994 dollars) Total lifetime direct and indirect costs per patient are estimated at approximately $2.4 million (in 1994 dollars) Total lifetime direct and indirect costs per patient are estimated at approximately $2.4 million (in 1994 dollars) Mean annual direct and indirect costs per patient total an estimated $47,215 (in 2004 dollars) Mean annual direct and indirect costs per patient total an estimated $47,215 (in 2004 dollars) Mean direct healthcare costs incurred by insured patients with MS are 2 to 3 times higher than those without MS Mean direct healthcare costs incurred by insured patients with MS are 2 to 3 times higher than those without MS Direct correlation between cost (direct and indirect) and severity of disease has been well-established Direct correlation between cost (direct and indirect) and severity of disease has been well-established Therapeutics that modify MS activity and severity can result in both clinical and economic benefits Therapeutics that modify MS activity and severity can result in both clinical and economic benefits

99 DMT = disease-modifying therapy. Kobelt G, et al. Neurology. 2006;66(11): MS Cost Drivers Sick Leave/Reduced Working Time (10%) Early Retirement (34%) Hospital Inpatient Care (3%) Ambulatory Care (4%) Tests (2%) Other Drugs (6%) Services (2%) Adaptations (5%) DMTs (22%) Informal Care (12%)

100 DMTs = disease-modifying therapies. Kobelt G, et al. Neurology. 2006;66(11): Costs of MS by Disease Severity 70,000 60,000 50,000 40,000 30,000 20, ,000 Mild EDSS <4.0 Moderate EDSS Severe EDSS >6.0AllPatients Indirect Costs Direct Costs Informal Care Other Drugs DMTs Cost ($)

101 Cost of Care Cost and functionality Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702. * 2004 US Dollars Non-Drug Costs EDSS Score Approximate Mean Annual Cost* Medical Unpaid Caregiver Time Lost Work Time Total Mild EDSS $3,106$932$9,938$13,976 Moderate EDSS $5,100$3,188$22,950$31,238 Severe EDSS $12,524$12,524$21,291$46,339

102 AWP = average wholesale price. Prescott JD, et al. J Manag Care Pharm. 2007;13(1): CuraScript 2008 Specialty Drug Trend Report. April Red Book Update. Vol. 30(1). January DMT-Associated Costs Approximately 65% of annual direct per patient healthcare costs in MS are attributable to drug therapy Approximately 65% of annual direct per patient healthcare costs in MS are attributable to drug therapy MS drugs represent 20.2% of specialty drug expenditures within managed care plans MS drugs represent 20.2% of specialty drug expenditures within managed care plans National trend in MS drug expenditures was +18.3% in 2008 National trend in MS drug expenditures was +18.3% in % increase in manufacturer pricing was primary driver of trend 23.5% increase in manufacturer pricing was primary driver of trend Comparative AWPs of DMT options: Comparative AWPs of DMT options: AgentDosageAWP/dayAWP/year Interferon beta-1b 0.25 mg SC every other day $105.41$38,475 Interferon beta-1a IM 30 mcg IM once weekly $98.66$36,010 Interferon beta-1a SC 44 mcg SC 3 times weekly $106.20$38,761 Glatiramer acetate 20 mg SC daily $110.10$40,187

103 National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus Statement Accessed February 10, MS Consensus Guidelines National MS Society Expert Consensus Statement (2007): National MS Society Expert Consensus Statement (2007): Initiate therapy as soon as possible following diagnosis of active- relapsing disease with an interferon beta agent or glatiramer acetate Initiate therapy as soon as possible following diagnosis of active- relapsing disease with an interferon beta agent or glatiramer acetate Drug therapy should also be considered in patients with first attack at high risk of MS Drug therapy should also be considered in patients with first attack at high risk of MS Access to medications should not be limited by age, level of disability, or frequency of relapses Access to medications should not be limited by age, level of disability, or frequency of relapses Continue treatment indefinitely unless lack of benefit, intolerant adverse effects, or better treatment becomes available Continue treatment indefinitely unless lack of benefit, intolerant adverse effects, or better treatment becomes available Ensure adequate accessibility of all FDA-approved drugs for MS Ensure adequate accessibility of all FDA-approved drugs for MS Change treatments only for medically appropriate reasons Change treatments only for medically appropriate reasons

104 No One Available to Give *P<.05 P<.01. Treadaway K, et al. J Neurol. 2009;256(4): Factors Influencing Adherence with DMT in MS Total Dosing Inconvenient Pregnant or Planning Other Tired of Shots Not Sure of Benefits Didnt Refill Didnt Feel Like It Headache Fatigue Weakness Flu-Like* Depression Inj Site Forgot to Take* Financial Skin Reaction Injection Anxiety**

105 Promoting Adherence to Therapeutic Regimens in MS Starting Therapy Starting Therapy Educate Educate Make a plan with the patient Make a plan with the patient Reconfirm goals Reconfirm goals Schedule proper follow-up Schedule proper follow-up Treat relapses appropriately Treat relapses appropriately Treat comorbid conditions Treat comorbid conditions Keep channels of communication open Keep channels of communication open Brandes DW, et al. Curr Med Res Opin. 2009;25(1): Figure 2. Establishing a therapeutic relationship Educating patient and family Managing patient expectations Addressing patient concerns Managing adverse events Increased adherence to treatment

106 Treadaway K, et al. J Neurol. 2009;256(4): Optimizing Treatment Outcomes in MS Patients Understanding disease Understanding disease Clinical implications Clinical implications Rationale for treatment Rationale for treatment Reviewing treatment options Reviewing treatment options Setting realistic goals/expectations Setting realistic goals/expectations Potential adverse effects Potential adverse effects Ways to minimize and manage adverse effects Ways to minimize and manage adverse effects Minimizing fear and anxiety Minimizing fear and anxiety Proper injection training Proper injection training Recognizing relapses Recognizing relapses Tracking and reporting symptoms/relapses/adverse effects Tracking and reporting symptoms/relapses/adverse effects Emphasizing importance of adherence to therapy Emphasizing importance of adherence to therapy Patient Education Is Essential

107 Rio J, et al. Mult Scler. 2005;11: Twork et al. Curr Med Res Opin. 2007;23(6): ORourke KE, et al. Mult Scler. 2005;11(1): Ross AP. Neurology. 2008;71(Suppl 3):S1-S2. DiMatteo MR, et al. Arch Intern Med. 2000;160: Challenges to Adherence Cognition and physical limitations negatively impact adherence Cognition and physical limitations negatively impact adherence Up to half of patients reportedly discontinue because of an AE or a lack of efficacy Up to half of patients reportedly discontinue because of an AE or a lack of efficacy Association of depression carried a 3-fold risk of nonadherence Association of depression carried a 3-fold risk of nonadherence Third-party reimbursement challenges Third-party reimbursement challenges Formulary status Formulary status Copays Copays Adherence tends to decrease over time due to a variety of factors, such as treatment fatigue, loss of motivation, and complacency Adherence tends to decrease over time due to a variety of factors, such as treatment fatigue, loss of motivation, and complacency

108 Recent Analyses of the Economic Impact of MS Treatment In an analysis of an employer medical, drug and disability claims database: In an analysis of an employer medical, drug and disability claims database: Baseline MS-related medical costs were higher for treated vs untreated employees ($2520 vs $1012,P < ) Baseline MS-related medical costs were higher for treated vs untreated employees ($2520 vs $1012,P < ) Risk-adjusted total annual medical costs ($4,393 vs $6,187) and indirect costs ($2,252 vs $3,053) were significantly lower (P < ) for treated vs untreated employees with MS Risk-adjusted total annual medical costs ($4,393 vs $6,187) and indirect costs ($2,252 vs $3,053) were significantly lower (P < ) for treated vs untreated employees with MS Study limitation: lack of clinical detail on MS severity Study limitation: lack of clinical detail on MS severity Early use of DMTs in patients with CIS that delayed conversion to CDMS provided a positive incremental cost-effectiveness ratio (ICER) per patient-year compared with no treatment (Euros 2,574.94) Early use of DMTs in patients with CIS that delayed conversion to CDMS provided a positive incremental cost-effectiveness ratio (ICER) per patient-year compared with no treatment (Euros 2,574.94) Birnbaum HG, et al. Curr Med Res Opin. 2009;25(4): Lazzaro C, et al. Neurol Sci. 2009;30:21-31.

109 *Proportion of individuals unemployed during the study who had been employed at some time during his or her lives. Dennett SL, et al. Value Health (3): Rates of Unemployment in Individuals with MS StudyCountry Duration of MS Since Onset (Years) Unemployment Rate Busche et al., 2003 Canada 14.8 (median) (range 1-47) Baseline: 49.9% 2.5 years later: 59.4% Jackson and Quaal, 1991 Canada > 5 in 80% of patients 76%* Gronning et al., 1990 Norway 10 (mean) (range 1-33 years) 72% of those with definite MS OConnor et al., 2005 U.K. Employed: 10 (mean) Unemployed: 15 (mean) 64% Beatty et al., 1995 U.S (mean) 60-66% Kornblith et al., 1986 U.S. 13 (mean) 80%* LaRocca et al., 1982 U.S. 13 (mean) 77%

110 Lage MJ, et al. Work. 2006;27(2): Effect of IMT and Other Factors on Employment Loss Time Focus: factors that influence time missed from work among individuals with MS (N = 284) Focus: factors that influence time missed from work among individuals with MS (N = 284) Records were examined for details of medical claims Records were examined for details of medical claims Multivariate regressions were performed, controlling for demographic characteristics, type of immunomodulatory medication, and overall severity of illness Multivariate regressions were performed, controlling for demographic characteristics, type of immunomodulatory medication, and overall severity of illness Looked at total number of days missed from work for any reason and specifically due to absenteeism, short-term disability, or workers compensation Looked at total number of days missed from work for any reason and specifically due to absenteeism, short-term disability, or workers compensation Results indicate that lost work time is affected by severity of illness and type of IMT Results indicate that lost work time is affected by severity of illness and type of IMT

111 Fewer days absent from work from 1999–2002 for individuals with MS treated with GA (n = 28), INF - 1a (n = 74), or INF -1b (n = 16) compared to untreated individuals with MS (n = 166) Lage MJ, et al. Work. 2006;27(2): Effect of Immunomodulatory Therapy on Employment Loss Time Short-term Disability Workers Comp Any Reason Fewer Days Absent (P =.003) (P =.71) (P =.09) (P =.04) (P =.18) (P =.47) (P =.03) (P =.33) (P =.39) INFbeta-1a INFbeta-1b GA

112 Specialty Pharmacy Overview Key Disease States Managed by a Specialty Pharmacy Key Disease States Managed by a Specialty Pharmacy MS, RA, Hep C, hGH, Oral Oncolytics MS, RA, Hep C, hGH, Oral Oncolytics The number of patients utilizing Specialty Pharmacies continues to increase The number of patients utilizing Specialty Pharmacies continues to increase Currently estimated to be 40% - 50% of MS patients Currently estimated to be 40% - 50% of MS patients

113 SP Value Proposition Compliance & Adherence Compliance & Adherence Typically 15% - 20% higher than retail* Typically 15% - 20% higher than retail* Patient Education Patient Education Specially trained on rare diseases and therapies Specially trained on rare diseases and therapies Collaborate with manufacturers and MS Specialists to assist with training Collaborate with manufacturers and MS Specialists to assist with training Patient Monitoring Patient Monitoring Efficacy Efficacy Side effects Side effects Co-Morbid Conditions Co-Morbid Conditions *2008 IMS Report

114 SP Value Proposition Data Tracking and Monitoring Data Tracking and Monitoring Compliance/Adherence Compliance/Adherence Efficacy Efficacy Baseline Baseline Relapses Relapses EDSS EDSS Side Effects Side Effects Flu like symptoms Flu like symptoms Injection site reactions Injection site reactions Co-Morbidities Co-Morbidities Asthma, Hypertension, diabetes Asthma, Hypertension, diabetes Symptom Management Symptom Management Fatigue, Fatigue, Bladder Bladder Depression Depression Appropriate and timely interventions Appropriate and timely interventions

115 Therapy OPtimization in MS (TOP MS) An Outcomes Study of disease management (DM) for MS based in Specialty Pharmacies who have demonstrated commitment to DM: An Outcomes Study of disease management (DM) for MS based in Specialty Pharmacies who have demonstrated commitment to DM: Therapy Adherence and Compliance Therapy Adherence and Compliance Disease Characteristics Disease Characteristics Relapses Relapses Disability Progression Disability Progression Quality of Life Quality of Life Work / Usual Activity Productivity Work / Usual Activity Productivity

116 Therapy OPtimization in MS (TOP MS) Brief Outline: Brief Outline: 3 Specialty Pharmacies 3 Specialty Pharmacies ~3,000 patients followed for 2 years ~3,000 patients followed for 2 years Patient-specific clinical reports to physicians Patient-specific clinical reports to physicians De-identified data collected in a research-quality database will be available to address outcomes research questions De-identified data collected in a research-quality database will be available to address outcomes research questions

117 Study Population Subjects who are treated with glatiramer acetate or interferon (IFN)-β and receive their therapy from a Specialty Pharmacy: Subjects who are treated with glatiramer acetate or interferon (IFN)-β and receive their therapy from a Specialty Pharmacy: Copaxone® Copaxone® Avonex® Avonex® Betaseron® Betaseron® Rebif® Rebif® Extavia® Extavia®

118 Study Objective To demonstrate the benefits of compliance and adherence to MS therapy with patient outcomes: To demonstrate the benefits of compliance and adherence to MS therapy with patient outcomes: Relapses Relapses Disability progression Disability progression Quality of life Quality of life Work and usual activities productivity Work and usual activities productivity

119 Advocacy Assist patients with resources and support Assist patients with resources and support Assist patients with navigation of health care system and insurance coverage Assist patients with navigation of health care system and insurance coverage Speak with third-party payors to advocate for coverage for all DMTs Speak with third-party payors to advocate for coverage for all DMTs Become involved with advocacy organizations Become involved with advocacy organizations IOMSN IOMSN CMSC CMSC NMSS NMSS MSAA MSAA MSF MSF Educational activities for professionals and patients Development of written materials Working at organizational level for FDA approvals, third-party reimbursement IOMSN = International Organization of MS Nurses; CMSC = Consortium of MS Centers; NMSS = National MS Society; MSAA = MS Association of America.

120 Conclusion MS is a chronic, debilitating, and progressive disease MS is a chronic, debilitating, and progressive disease Economic implications are significant and appear directly correlated with disease severity Economic implications are significant and appear directly correlated with disease severity Although costly, long-term data and expert consensus support the primary role of DMT in managing disease progression Although costly, long-term data and expert consensus support the primary role of DMT in managing disease progression Optimal therapeutic benefit with DMT hinges strongly on multidimensional support from the healthcare system Optimal therapeutic benefit with DMT hinges strongly on multidimensional support from the healthcare system Patient education and careful monitoring are key factors driving success in MS therapy Patient education and careful monitoring are key factors driving success in MS therapy

121 Challenging Cases in the Management of Multiple Sclerosis Case Studies

122 24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusual 24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusual Back in Houston another ophthalmologist called it some type of optic nerve inflammation and gave her 5 days of oral steroids Back in Houston another ophthalmologist called it some type of optic nerve inflammation and gave her 5 days of oral steroids 2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia and oscillopsia 2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia and oscillopsia Multiple Sclerosis Case #1

123 UPIN /06/08

124 UPIN /06/08

125 4 days later continued double vision on looking to the right 4 days later continued double vision on looking to the right Extensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoning Extensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoning Nystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normal Nystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normal CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBs CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBs Intravenous methylprednisolone course started Intravenous methylprednisolone course started Multiple Sclerosis Case #1

126 UPIN /02/08

127 UPIN /02/08

128 The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this?The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this? When you have CIS and cant diagnose more than suspect MS by McDonalds or Swantons, do you just treat, use Frohman?When you have CIS and cant diagnose more than suspect MS by McDonalds or Swantons, do you just treat, use Frohman? When asked about the familial risk of MS in the company of the patients twin sister, what is the best course?When asked about the familial risk of MS in the company of the patients twin sister, what is the best course? Multiple Sclerosis Case #1 The Issues

129 30-year-old Caucasian female presented initially with right optic neuritis. 30-year-old Caucasian female presented initially with right optic neuritis. Vision improved after high dose intravenous methylprednisolone treatment Vision improved after high dose intravenous methylprednisolone treatment T2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and subcortical white matter. T2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and subcortical white matter. No disease modifying therapy was started at that time. No disease modifying therapy was started at that time. Multiple Sclerosis Case #2

130 1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days. 1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days. MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1. MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1. MRI brain- one new periventricular white matter lesion without enhancement in comparison to last years. MRI brain- one new periventricular white matter lesion without enhancement in comparison to last years. Motor symptoms improved with high dose corticosteroid therapy Motor symptoms improved with high dose corticosteroid therapy Residual numbness in the feet and bladder control difficulties. Residual numbness in the feet and bladder control difficulties. Multiple Sclerosis Case #2

131 Given diagnosis of MS and therapy with once weekly IM interferon beta was begun. Given diagnosis of MS and therapy with once weekly IM interferon beta was begun. 6 months later she complained of markedly increased fatigue and fuzzy thinking. 6 months later she complained of markedly increased fatigue and fuzzy thinking. Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new enhancing lesions around the corpus callosum. Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new enhancing lesions around the corpus callosum. Disease modifying therapy was changed to a high dose subcutaneous interferon beta. Disease modifying therapy was changed to a high dose subcutaneous interferon beta. Multiple Sclerosis Case #2

132 Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan. Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan. After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue. After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue. MRI scan showed additional Gd+ enhancing lesions. MRI scan showed additional Gd+ enhancing lesions. A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100. A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100. Multiple Sclerosis Case #2

133 The same interferon treatment was continued but after several months she complained of ongoing problems with memory. The same interferon treatment was continued but after several months she complained of ongoing problems with memory. Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged. Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged. Multiple Sclerosis Case #2

134 Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst. Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst. 18 months later, follow-up MRI shows unchanged cyst but single periventricular non- enhancing white matter lesion. 18 months later, follow-up MRI shows unchanged cyst but single periventricular non- enhancing white matter lesion. Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities. Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities. Multiple Sclerosis Case #3

135 While hiking with physician husband on hot afternoon, she notes numbness in left foot. While hiking with physician husband on hot afternoon, she notes numbness in left foot. Spinal cord MRI shows enhancing lesion at T17. Spinal cord MRI shows enhancing lesion at T17. Is it MS? Is it MS? Treatment recommendations? Treatment recommendations? Is it Multiple Sclerosis?


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