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The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis.

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The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis.

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Presentation on theme: "The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis."— Presentation transcript:

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2 The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis The Managed Care Pharmacy and Medical Directors Perspective Program Chairman Douglas R. Jeffery, MD, PhD Director, Multiple Sclerosis Center Advance Neurology Advance, NC

3 CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Supported by an independent educational grant from Teva Neuroscience, Inc. Faculty disclosures: Listed in program syllabus NOTE: Both trade and chemic names may be used in this program to establish clarity, and because many trials use acronyms that employ the brand name. The use of brand names should not be construed as endorsements for these products. Welcome and Program Overview

4 Program Faculty Program Chairman Douglas R. Jeffery, MD, PhD Director, Multiple Sclerosis Center Advance Neurology Advance, NC Norman Kachuck, MD Associate Professor of Neurology Chief, Neuroimmunology Division, Department of Neurology Director, Multiple Sclerosis Comprehensive Care Center and Research Group Vice-Chair, Health Sciences IRB University of Southern California Keck School of Medicine Los Angeles, California School of Medicine Los Angeles, California Ronald J. DeBellis, PharmD, FCCP Professor and Chairman Department of Pharmacy Practice-Vermont Campus Albany College of Pharmacy and Health Sciences Colchester, VT Jacquelyn Bainbridge, PharmD, FCCP Jacquelyn Bainbridge, PharmD, FCCP Associate Professor Department of Clinical Pharmacy/Department of Neurology University of Colorado Denver Aurora, CO

5 Program Agenda and Format 8:00 AM 8:20 AM Welcome and Introduction The Evolving and Complex Therapeutic Landscape for Multiple Sclerosis: Achieving the Ideal Balance Between Safety and Efficacy for Long-Term Treatment In the Managed Care Setting What Will Goals of MS Management in the Managed Care Setting Be? How Should MCO Pharmacists, Medical Directors, and Neurologists Respond? Program Chairman Douglas R. Jeffery, MD, PhD Director, Multiple Sclerosis Center Advance Neurology Advance, NC 8:20 AM 8:40 AM Group Discussion: Discuss Emerging Concerns, Challenges, and Strategic Needs for Optimizing MS Care in the Managed Care Environment

6 Program Agenda and Format 8:40 AM 9:05 AM Trial-Based Evidence for First Line Therapy with Immune- Modulating Agents (IMTs): From Mechanisms to TherapyLandmark Studies, Long-Term Safety Data, and Clinical Experience with IMTs in the Managed Care Environment Current Foundations of MS Care in the Managed Care Setting: What Has Worked? What Hasnt? Where Is the Room for Improvement? Program Chairman Douglas R. Jeffery, MD, PhD Director, Multiple Sclerosis Center Advance Neurology Advance, NC 9:05 AM 9:20 AM Group Discussion: Discuss Current Strategies and MS Treatment Paradigms Using IMT-Based Platforms for Initial Therapy for MS in the Managed Care Setting

7 Program Agenda and Format 9:20 AM 9:45 AM The Emergence of Oral Immunosuppressive and Other Agents for MS: What Do We Know (or Not Know) About Their Safety and Efficacy? Cautionary Notes for Managed Care Pharmacy and Medical Directors, and MS Treaters in Managed Care: How Do We Monitor Adverse Events, Risks for Infection, and Signals for Malignancy Over the Long Term? Norman Kachuck, MD Associate Professor of Neurology Chief, Neuroimmunology Division, Department of Neurology Director, Multiple Sclerosis Comprehensive Care Center and Research Group Vice-Chair, Health Sciences IRB University of Southern California Keck School of Medicine Los Angeles, California 9:45 AM 10:00 AM Group Discussion: Discuss Complexity of Evolving Agents for MS and Approaches to Making a Risk- Benefit Analysis

8 Program Agenda and Format 10:00 AM 10:20 AM The Changing MS Therapeutic Landscape: Perspectives of an MS-Focused Pharmacist How Will We Need to Adapt to and Analyze the New Generation of MS Therapies? How Will Pharmacy and Medical/Neurology Program Directors Come Together to Make Decisions About Long-Term Therapy for MS in the Managed Care Setting? Ronald J. DeBellis, PharmD, FCCP Professor and Chairman Professor and Chairman Department of Pharmacy Practice-Vermont Campus Department of Pharmacy Practice-Vermont Campus Albany College of Pharmacy and Health Sciences Albany College of Pharmacy and Health Sciences Colchester, VT 10:20 AM 10:40 AM Group Discussion: The Near Future of MS Care

9 Program Agenda and Format 10:40 AM 11:00 AM The Role of Comparative Effectiveness Guidelines, Long Term Safety Considerations, and Monitoring Costs for Evaluating Therapies for MS Impact on Managed Care-Based Management for Improving Health Outcomes and Providing Value for their Health PlansThe Managed Care Medical and Pharmacy Directors Perspective Jacquelyn Bainbridge, PharmD, FCCP Associate Professor Department of Clinical Pharmacy/ Department of Neurology University of Colorado Denver Aurora, CO 11:00 AM 11:30 AM Group Discussion: The Complexities, Challenges and Solutions for Making Sense and Adapting to the Emerging Landscapeand New Risk/Benefit Equationsof Oral Agents for MS. Will Patient Registries Be Required?

10 Format: We Want a Dialogue PROGRAM FORMAT PROGRAM FORMAT Following each didactic presentation, we will call upon the regional and local leaders in the managed care community pharmacy, medical and department of neurology directors who are seated at the faculty tableto respond, analyze and discuss how they and their colleague are responding to these new challenges and dilemmas. We thank them for coming and participating as adjunct faculty members and educational leaders for this program. The Group Discussions are key to helping us complete the journey form challenges to real world solutions.

11 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 Multiple Sclerosis 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

12 Age of Onset of Multiple Sclerosis 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

13 National Multiple Sclerosis Society. about-ms/symptoms/index.aspx. Accessed February 21, Clinical Manifestations of MS 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

14 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

15 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

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

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

18 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

19 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

20 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

21 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 Cladribine Fingolimod Ocrelizumab Teriflunomide Laquinimod Alemtuzumab Generic Mitoxantrone (oncology) MS

22 The Evolving Landscape of MS Therapy New generation of multiple sclerosis therapies is currently emerging New generation of multiple sclerosis therapies is currently emerging Among them are four oral agents: dalfampridine, laquinimod, cladribine, and fingolimod, that have been or likely will be approved for managing patients with MS Among them are four oral agents: dalfampridine, laquinimod, cladribine, and fingolimod, that have been or likely will be approved for managing patients with MS Efficacy data for these new oral agents are impressive and demonstrate that they have the potential to replace or complement injectable treatment options for MS Efficacy data for these new oral agents are impressive and demonstrate that they have the potential to replace or complement injectable treatment options for MS

23 The Evolving Landscape of MS Therapy However, there are concerns relating to safety and cost, especially for the immunosuppressive agents However, there are concerns relating to safety and cost, especially for the immunosuppressive agents In addition, patients with MS have poor treatment adherence to the current available therapies and it is uncertain if the introduction of oral agents will increase patient adherence In addition, patients with MS have poor treatment adherence to the current available therapies and it is uncertain if the introduction of oral agents will increase patient adherence

24 Analyzing Risk-to-Benefit Equation for Established and Emerging Agents

25 Questions We Will Address Today 1.How has your organization decided to provide and make decisions about MS care? 2.Who makes these decisions? A formulary committee? Department of Pharmacy? Neurologists and MS Specialists? A consensus among many stakeholders? 3.Are all MS drugs available in your managed care organization? Or have you made restrictions and/or prioritized agents? And if so, how and why?

26 The Evolving Landscape of MS Therapy 4.Do you employ a formalized pathway for MS care in your MCO? For first-line treatment? Second line treatment? Or are these decisions left to the treating physicians? 5.What is the patient's role in determining the initial MS therapy offered to them? Is it a dialogue? If so, what is the shape of the dialogue? If not, how is the decision made?

27 The Evolving Landscape of MS Therapy MISSION STATEMENT MISSION STATEMENT The purpose of this Challenges and Solutions Workshop is to discuss possible approaches for evaluating the risk- benefit-cost profiles of these new oral agents; to compare them against established IMTs and each other; to evaluate the implications for long-term safety monitoring and pharmacovigilance that will be required, especially for immunosuppressive agents; how placement of these oral agents on managed care organization (MCO) formularies may also influence and/or modify use of established IMTs; and what impact this landscape change might have on clinical outcomes of MS patients managed in MCOs. The purpose of this Challenges and Solutions Workshop is to discuss possible approaches for evaluating the risk- benefit-cost profiles of these new oral agents; to compare them against established IMTs and each other; to evaluate the implications for long-term safety monitoring and pharmacovigilance that will be required, especially for immunosuppressive agents; how placement of these oral agents on managed care organization (MCO) formularies may also influence and/or modify use of established IMTs; and what impact this landscape change might have on clinical outcomes of MS patients managed in MCOs.

28 The Evidence for First Line Therapy with Immune-Modulating Agents Landmark Trials, Perils and Pitfalls of Cross- Trial Comparisons, and What can be Learned from Long Term Studies Investigations Innovation Clinical Application Program Chairman Douglas R. Jeffery, MD, PhD Director, Multiple Sclerosis Center Advance Neurology Advance, NC

29 Overview of Presentation Mechanisms of action of IMTs Mechanisms of action of IMTs 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? Price of MS versus cost of treatment Price of MS versus cost of treatment

30 Mechanisms of Action Mechanisms of Action The Evolving Landscape of MS Therapy

31 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:

32 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

33 Fingolimod: modulates S1P1 receptors T cell FTY720-P S1P receptor FTY720 results in internalisation of the S1P1 receptor This blocks lymphocyte egress from lymph nodes while sparing immune surveillance by circulating memory T cells Prevents T cell invasion of CNS LN FTY720 traps circulating lymphocytes in peripheral lymph nodes

34 Laquinimod Induced Immunomodulation on the Molecular Level Overexpression/downregulation

35 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

36 Relapses in Multiple Sclerosis 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

37 ITT population Negative binomial regression model adjusted for treatment group, country, number of relapses in previous two years and baseline Expanded Disability Status Scale ARR, annualized relapse rate; DMT, disease-modifying therapy Annualized relapse rate Placebo (n=418) Fingolimod 0.5 mg (n=425) Fingolimod 1.25 mg (n=429) ARR was consistently reduced in both treatment-naïve patients and patients previously treated with DMT (p<0.01 for all comparisons) p< % reduction 60% reduction FREEDOMS Primary Endpoint: Annualized Relapse Rate

38 Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study % Reduction in relapse rates 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. Kappos et al. N Engl J Med 2010;362: ; Gilenya package insert. 31% 18% 29% 32% 60% P=.0001 P=.04 P<.001 P<.0001 P=.055 P<.0001

39 *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

40 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

41 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

42 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

43 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% Fingolimod (2 year)54%24%

44 How is Sustained Progression Measured? Most clinical trials define progression by demonstrating a 1 point change in the EDSS, and then confirming the change in 3 or 6 months Most clinical trials define progression by demonstrating a 1 point change in the EDSS, and then confirming the change in 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

45 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.

46 Effect on Sustained Disability*: Summary of Phase III Trials * 1 EDSS point sustained for 3 months in IFN β-1b, IFN β-1a tiw, GA trials and fingolimod phase III trials. 1 EDSS point sustained for 6 months in IFN β-a qw and fingolimod 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 Kappos et al. N Engl J Med 2010;362: ; Gilenya package insert. Reduction in sustained disability progression (%) 29% 37% 22% 30% 12% 30% P=NS P=.02 P<.05 P=NS P=.02

47 Summary Disability progression in clinical trials with RRMS patients is for the primarily related to disability from relapses Disability progression in clinical trials with RRMS patients is for the primarily related to disability from relapses 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, glatiramer acetate and fingolimod reduce the relapse rate The interferons, glatiramer acetate and fingolimod reduce the relapse rate IFN beta-1a and fingolimod have statistically significant effects on sustained change in EDSS measure over two years IFN beta-1a and fingolimod have statistically significant effects on sustained change in EDSS measure over two years IFN beta-1a, glatiramer acetate and fingolimod have statistically significant impacts on the mean change in EDSS over two years IFN beta-1a, glatiramer acetate and fingolimod have statistically significant impacts on the mean change in EDSS over two years

48 Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons? The Evolving Landscape of MS Therapy

49 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 Fingolimod 0.5 mg qd Relapse rate (annualized)-18%-34%-32%-29%-60% Relapse-Free (2 years)+42%+95%+100%+36%+52% Progression free-37%-29%-30%-12% -30% / -37% New T2 Lesions-36%-83%-78%-38%-75% Gd+ Lesions-42%--88%-33%-82% Predict: IFNβ-1a tiw will be superior to GA for relapse free outcome

50 672 days (96 weeks) IFNβ-1a tiw 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)

51 Head to Head Studies and Cross Trial Comparisons Head to head studies of glatiramer acetate and interferon β underscore the problem with cross trial comparisons Head to head studies of glatiramer acetate and interferon β underscore the problem with cross trial comparisons Differences in patients enrolled in different studies heavily influence disease activity observed during trials Differences in patients enrolled in different studies heavily influence disease activity observed during trials Differences in definitions of relapses (confirmed versus non-confirmed) and disability measures (3 month versus 6 month sustained change versus mean change in EDSS) may be different between studies further complicating cross trial comparisons Differences in definitions of relapses (confirmed versus non-confirmed) and disability measures (3 month versus 6 month sustained change versus mean change in EDSS) may be different between studies further complicating cross trial comparisons Relative efficacy is best measured by well-designed head to head trials Relative efficacy is best measured by well-designed head to head trials

52 What can be learned from long-term follow up studies? The Evolving Landscape of MS Therapy

53 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?

54 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

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

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

57 Glatiramer Acetate 15 year LTFU In a small cohort of patients (N=100) followed for 15 years, glatiramer acetate was safe and well tolerated In a small cohort of patients (N=100) 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

58 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

59 IFN β -1b LTFU Adjusted Outcome Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3 LTFU of IFN β-1b showed that patients with a baseline EDSS score 2 were more likely to have lower disability at 15 year follow up than patients with baseline EDSS scores > 2 regardless of treatment LTFU of IFN β-1b showed that patients with a baseline EDSS score 2 were more likely to have lower disability at 15 year follow up than patients with baseline EDSS scores > 2 regardless of treatment For patients with baseline EDSS score > 2, the duration of exposure to treatment with IFN β-1b influenced the long term outcome. For patients with baseline EDSS score > 2, the duration of exposure to treatment with IFN β-1b influenced the long term outcome. Patients with longer duration of treatment had less disability than patients with shorter duration of treatment Patients with longer duration of treatment had less disability than patients with shorter duration of treatment Any Variable + Any Exposure Weighting – Any Negative Outcome EDSS p< Exposure p< High Low

60 Disease modifying therapy seems to favorably effect the long-term course of MSDisease modifying therapy seems to favorably effect the long-term course of MS Propensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, open label studies are important statistical advances for interpreting these studiesPropensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, open label studies are important statistical advances for interpreting these studies These methods can provide complimentary information about the long term effects of treatment without the cost (and ethical dilemmas) posed by long-term placebo- controlled trialsThese methods can provide complimentary information about the long term effects of treatment without the cost (and ethical dilemmas) posed by long-term placebo- controlled trials Conclusions

61 Price of MS versus Cost of Care. Is Treatment Worth It? The Evolving Landscape of MS Therapy

62 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%)

63 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

64 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 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 Fingolimod 0.5 mg PO daily $131.51$48,000

65 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.

66 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

67 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

68 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

69 Questions to Consider 1.How do you anticipate responding to the new MS treatment landscape that will include high cost, oral therapies that require monitoring measures? 2.How, depending on the risk-to- benefit ratio, will managed care pharmacy and medical directors respond to a new landscape for MS as oral agents with potentially less favorable side effect profiles become available?

70 Questions to Consider 3.Given these considerations, in the absence of long- term data, how do you get to the bottom of a benefit-risk-cost decision for new MS therapies in the managed care setting? How will that play out? 4.What incentives are there, if any, for altering the current approach to initial therapy for MS, in which IMTs have demonstrated long-term safety and efficacy? 5.How will Obamacare influence MS treatment decisions?

71 The Next Generation of Immune-Modulating Therapies for MS What do we know (and not know) about their safety and efficacy How will their usefulness be established? Investigations Innovation Clinical Application Norman Kachuck, MD Associate Professor of Neurology Chief, Neuroimmunology Division, Department of Neurology Director, Multiple Sclerosis Comprehensive Care Center and Research Group Vice-Chair, Health Sciences IRB University of Southern California Keck School of Medicine Los Angeles, California

72 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 Cladribine Fingolimod Ocrelizumab Teriflunomide Laquinimod Alemtuzumab Generic Mitoxantrone (oncology) MS

73 What We Do Not Know What initiates MS? What initiates MS? Can we identify the different pathogenetic mechanisms in different individuals? Can we identify the different pathogenetic mechanisms in different individuals? Which occurs first: Myelin breakdown or oligodendrocyte destruction? Which occurs first: Myelin breakdown or oligodendrocyte destruction? What are the mechanisms of axonal injury/loss? What are the mechanisms of axonal injury/loss? What mediates regeneration of axons/myelinating elements What mediates regeneration of axons/myelinating elements Why does repair ultimately fail? Why does repair ultimately fail?

74 Implications of the Paradigm Shift Homogeneity of lesion type in an individual Homogeneity of lesion type in an individual Heterogeneity in the phenotype of disease across individuals Heterogeneity in the phenotype of disease across individuals Variable response to a given intervention due to this heterogeneity Variable response to a given intervention due to this heterogeneity Likely need to create combinations of therapies based on an individuals disease Likely need to create combinations of therapies based on an individuals disease Biomarkers and noninvasive metrics are critical to evaluate, target, and follow disease and its injury and repair response to treatment Biomarkers and noninvasive metrics are critical to evaluate, target, and follow disease and its injury and repair response to treatment Bielekova B, Martin R. Brain. 2004;127;

75 What We Do Not Know How can we optimize therapy for a given patient using this information? How can we optimize therapy for a given patient using this information? How do we optimize therapy for a heterogeneous MS population under managed care, using this information How do we optimize therapy for a heterogeneous MS population under managed care, using this information How do we keep such decisions rational, evidence-based, AND ETHICAL? How do we keep such decisions rational, evidence-based, AND ETHICAL? And when we cant know with certainty, how do we communicate and act on that uncertainty? And when we cant know with certainty, how do we communicate and act on that uncertainty?

76 Therapies Reviewed Today Alemtuzumab (Campath®) Alemtuzumab (Campath®) Cladribine (Leustatin®, Movecto®) Cladribine (Leustatin®, Movecto®) Fingolimod (Gilenya®) Fingolimod (Gilenya®)

77 Alemtuzumab (Campath®) 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:

78 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

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

80 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

81 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:

82 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:

83 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:

84 Alemtuzumab long term efficacy at 5 years – ECTRIMS % Alem in follow-up 68% Alem in follow-up ARR ARR months 0-60 = 0.11 months 0-60 = 0.11 Months = 0.14 Months = = =.13 Mean EDSS Mean EDSS % IFNB-1a follow-up 42% IFNB-1a follow-up ARR ARR Months 0-60 =.35 Months 0-60 =.35 Months 36-60=.28 Months 36-60= = =.38 Mean EDSS Mean EDSS ARR=annualized relapse rate; SAD-sustained accumulation of disability

85 Alemtuzumab – Current Status (CARE-MS I/II) Phase III Studies in Progress CAMMS323 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One CAMMS323 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One CAMMS323 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One CAMMS323 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study One Randomized, Rater- and Dose- Blinded Study Comparing 2 Annual Cycles of IV 12 mg and 24 mg Alemtuzumab to 3x Weekly SC Interferon Beta-1a (Rebif®) in Relapsing-Remitting Multiple Sclerosis Patients Who Have Relapsed on Therapy Randomized, Rater- and Dose- Blinded Study Comparing 2 Annual Cycles of IV 12 mg and 24 mg Alemtuzumab to 3x Weekly SC Interferon Beta-1a (Rebif®) in Relapsing-Remitting Multiple Sclerosis Patients Who Have Relapsed on Therapy Enrollment: 840 Study Start Date: October 2007 Estimated Study Completion Date: September 2011 Enrollment: 840 Study Start Date: October 2007 Estimated Study Completion Date: September 2011 CAMMS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two CAMMS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two CAMMS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two CAMMS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study Two Randomized, Rater-Blinded Study Comparing Two Annual Cycles of Intravenous Alemtuzumab to Three-Times Weekly Subcutaneous Interferon Beta-1a (Rebif®) in Treatment- Naïve Patients With Relapsing- Remitting Multiple Sclerosis Randomized, Rater-Blinded Study Comparing Two Annual Cycles of Intravenous Alemtuzumab to Three-Times Weekly Subcutaneous Interferon Beta-1a (Rebif®) in Treatment- Naïve Patients With Relapsing- Remitting Multiple Sclerosis Enrollment: 581 Study Start Date: September 2007 Estimated Study Completion Date: May 2011 Enrollment: 581 Study Start Date: September 2007 Estimated Study Completion Date: May 2011 Source: Clinicaltrials.gov

86 Cladribine (Leustatin) 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.

87 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:

88 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:

89 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:

90 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:

91 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:

92 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:

93 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.

94 Cladribine – Current Status Approved in Australia and Russia (Movectro®) Approved in Australia and Russia (Movectro®) Applications pending elsewhere Applications pending elsewhere 9/24/2010 Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) says no FDA application granted Priority Review

95 Fingolimod (FTY720) (Gilenya®) 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 (S1PR1 and 5 > 2,3,4) Sphingosine-1-phosphate (S1P) receptor modulator (S1PR1 and 5 > 2,3,4) 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 Crosses BBB, and S1P receptors shown to function within the CNS, but unknown clinical relevance Crosses BBB, and S1P receptors shown to function within the CNS, but unknown clinical relevance Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE and can stimulate OPC maturation Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE and can stimulate OPC maturation

96 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:

97 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:

98 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:

99 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:

100 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:

101 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:

102 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:

103 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

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

105 Gilenya®: 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:

106 Fingolimod (Gilenya®): 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:

107 Fingolimod (Gilenya®): 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:

108 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

109 Gilenya®: Current Status Sept 22, 2010 FDA approval, indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Sept 22, 2010 FDA approval, indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Recommended dose: 0.5 mg orally once daily, with or without food Recommended dose: 0.5 mg orally once daily, with or without food REMS includes outreach letters, with recommendations for 6 hour initiation observation period, monitoring for infections, ophthalmologic, dermatologic and hepatic toxicity; NO REGISTRY or restricted distribution process REMS includes outreach letters, with recommendations for 6 hour initiation observation period, monitoring for infections, ophthalmologic, dermatologic and hepatic toxicity; NO REGISTRY or restricted distribution process

110 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

111 Natalizumab and the Risk of PML

112 112 Changing therapy options MS treatment side effects. 6. Company news; F.D.A. approves a multiple sclerosis drug. 7. Biotechnology medications move closer to the market. 8. Serono's rebif(R) receives FDA approval. 9. Immunex gets FDA OK. 10. Multiple sclerosis (relapsing-remitting): emerging therapies that offer improved convenience will not unseat current drugs. Decision Base Giovannoni G, et al ECTRIMS. Abstract P Cohen J, et al ECTRIMS. Abstract P Study results: multiple sclerosis patients have significant and sustained reduction in disability and risk of relapse on alemtuzumab versus approved therapy. 14. Clinicaltrials.gov Web site. ALLEGRO study. 15. Clinicaltrials.gov Web site. BRAVO study. 16. Biogen Idec showcases more than 70 data presentations at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis [news release]. 17. Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with multiple sclerosis (TEMSO). 18. Novantrone ® (mitoxantrone). National Multiple Sclerosis Society Web site. 19. Tysabri ® prescribing information. Biogen Idec Inc. Phase III completed In Phase III Approved therapies Gilenya ® (fingolimod) Cladribine Campath ® (alemtuzumab) Fumarate (BG-12) Teriflunomide Extavia ® (IFNβ-1b) Tysabri ® (natalizumab) Betaseron ® (IFNβ-1b) Copaxone ® (glatiramer acetate) Avonex ® (IFNβ-1a) Rebif ® (IFNβ-1a) Novantrone ® (mitoxantrone) Laquinimod Approval date Estimated launch date Rituximab/Ocriliz umab

113 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

114 114 What therapy characteristic will be the key driver for future therapy decisions? Efficacy Safety Tolerability Other Considerations

115 115 How will patient characteristics, risk aversion and cost play a role in our therapy decisions? Demographics: Age Gender Genetic load Present disability Disease Prognosis Risk Tolerance Risk Aversion Other Considerations: Price of Rx and care, Resource utilization Delivery process

116 116 Multiple situations are encompassed by the term suboptimal response 1-5 Efficacy Relapses New lesions Brain atrophy Worsening EDSS Neutralizing antibodies Tolerability Compliance Immediate postinjection reaction (IPIR) Injection-site reactions (ISRs) Flu-like symptoms Depression Safety Clinically recognizable organ toxicity Opportunistic infection Abnormal laboratory values Other Considerations Fatigue Worsening cognition 1. Cohen BA, et al. Neurology. 2004;63:S33-S Freedman MS, et al. Can J Neurol Sci. 2004;31: National Multiple Sclerosis Society Expert Opinion Paper International Working Group for Treatment Optimization in MS. Eur J Neurol. 2004;11: Coyle PK. J Neurol. 2008;255(suppl 1):44-50.

117 117 What is our ethical approach to prescribing therapies with better efficacy but risks? Suitable for all patients? Only for heavily treatment-experienced patients? Only for those with worsening disease? Choose other established therapy? For patients who request therapy?

118 My Take Home Points on MS Therapy Diagnose High Risk Presumptive and Definite MS early Diagnose High Risk Presumptive and Definite MS early Treat early as aggressively as seems reasonable, to interrupt inflammatory cascade and possible secondary degeneration Treat early as aggressively as seems reasonable, to interrupt inflammatory cascade and possible secondary degeneration Consider how to predict disease course using accurate surrogate markers Consider how to predict disease course using accurate surrogate markers Make risk tolerance/aversion decisions on therapy on a patient by patient basis Make risk tolerance/aversion decisions on therapy on a patient by patient basis Involve patients in clinical research as able Involve patients in clinical research as able

119 Questions to Consider 1.How will new molecular mechanisms of action and comparative analysis of injectable and new oral MS agents under investigation and/or in the FDA approval process; and, based on the reported risks, unknowns, safety signals, and therapeutic efficacy of such agents, affect MS treatment pathways in the MC setting? 2.What are the potential risks and cautionary notes- medico-legal and otherwise-of embarking on a course of therapy with unknown safety risks and lack of comparative studies, especially when a safe platform therapy is already established and available?

120 Questions to Consider 3.Who will actually make the risk-benefit decisions? Pharmacist? Formulary committee? Physician? Patient advocacy groups? 4.Will managed care organizations need to set up their own registries? And how will Phase 4 data be communicated? 5.In the absence of risk-stratification criteria, which are lacking for MS, how will MCO pharmacists and physicians select patients for new therapies?

121 The Changing MS Therapeutic Landscape: Perspectives of an MS- Focused Pharmacist How Will We Need to Adapt to and Analyze the New Generation of MS Therapies? Ronald J. DeBellis, Pharm.D., FCCP Professor and Chair Department of Pharmacy Practice Albany College of Pharmacy and Health Sciences-Vermont The Evolving Landscape of MS Therapy

122 Changing Directions Oral Agents Oral Agents Pharmacist Advanced Provision of Care Pharmacist Advanced Provision of Care Education Education Cost Cost Adherence Adherence

123 Oral Agents for Multiple Sclerosis FDA data accessed 10/14/10 Oral Agent Mechanism of Action Status Expected Dosing Dalfampridine Potassium channel blocker Approved for use by the FDA 10.0 mg twice daily LaquinimodImmunomdulator Granted fast-track review by FDA 0.6 mg daily Cladribine Purine nucleoside analogue prodrug FDA issued a refuse- to-file letter for the New Drug Application due to reports of patients developing solid malignancies 1 (0.2) Fingolimod Partial sphingosine 1- phosphate- receptor agonist Approved for use by FDA 0.5 mg daily

124 Considerations as Therapy Shifts from Injectable to Oral Agents Adherence Adherence Pharmacists will play a larger role in that time spent with patients in clinic will decrease due to less need to teach patients how to inject Pharmacists will play a larger role in that time spent with patients in clinic will decrease due to less need to teach patients how to inject May be an initial increase in adherence since medications will be easier to take May be an initial increase in adherence since medications will be easier to take May eventually result in a decrease in adherence as undesirable side effects may emerge May eventually result in a decrease in adherence as undesirable side effects may emerge Increased amount of follow-up and coaching by pharmacists (particularly where high cost/high stakes therapy is involved) Increased amount of follow-up and coaching by pharmacists (particularly where high cost/high stakes therapy is involved) Seek Continuing Education in Motivational Interviewing over the telephone Seek Continuing Education in Motivational Interviewing over the telephone Consider setting up follow-up schedule with MS patients Consider setting up follow-up schedule with MS patients Schedule and provide detailed counseling sessions for patients when they come for prescription pick up Schedule and provide detailed counseling sessions for patients when they come for prescription pick up Keep note to fax to MD after each visit to utilize team approach to care of patients with MS Keep note to fax to MD after each visit to utilize team approach to care of patients with MS Utilize SWOT analysis to achieve realistic approach to MS patient care in a pharmacy setting Utilize SWOT analysis to achieve realistic approach to MS patient care in a pharmacy setting

125 Oral Agents and Managed Care 4 oral agents on the horizon 4 oral agents on the horizon Dalfampridine, laquinimod, cladribine, fingolimod Dalfampridine, laquinimod, cladribine, fingolimod Discontinuation rates with current therapies as high as 46% Discontinuation rates with current therapies as high as 46% Lack of efficacy (perceived and real) Lack of efficacy (perceived and real) Adverse drug reaction Adverse drug reaction Cost to the patient Cost to the patient Injection anxiety Injection anxiety Oral agents and adherence Oral agents and adherence Better tolerated physically and psychologically Better tolerated physically and psychologically Pts prefer receiving oral or inhaled medications Pts prefer receiving oral or inhaled medications Majority of patients did not perceive oral meds interfering with life Majority of patients did not perceive oral meds interfering with life Minority of patients did not take oral meds and perceive them less effective than injectable medications Minority of patients did not take oral meds and perceive them less effective than injectable medications Fallowfield L, Atkins L, Catt S, et al. Ann Oncol 2006;17: Halfdanarson TR, et al.Curr Oncol Rep. 2010;12(4): ; Lipsy RJ et al. J Manag Care Pharm. 2009;15(9-a)(Suppl):S2-S15

126 Oral Agents and Managed Care Trends/Considerations Trends/Considerations Oral medications will require less out-of pocket expenses for members compared with current injectable medications Oral medications will require less out-of pocket expenses for members compared with current injectable medications Preliminary results indicate that oral medications are as effective as, or possibly more effective than, current injectable formulations Preliminary results indicate that oral medications are as effective as, or possibly more effective than, current injectable formulations Patients newly diagnosed with MS may prefer oral agents when they become available Patients newly diagnosed with MS may prefer oral agents when they become available Data presented regarding oral therapy is trending to being significantly positive in the short time from Data presented regarding oral therapy is trending to being significantly positive in the short time from Fallowfield L, Atkins L, Catt S, et al. Ann Oncol 2006;17: Halfdanarson TR, et al.Curr Oncol Rep. 2010;12(4): ; Lipsy RJ et al. J Manag Care Pharm. 2009;15(9-a)(Suppl):S2-S15

127 Changing Directions Oral Agents Oral Agents Pharmacist Advanced Provision of Care Pharmacist Advanced Provision of Care Education Education Cost Cost Adherence Adherence

128 Collaborative Drug Therapy Management CDTM

129 Attributes of State and Federal Regulations Governing Collaborative Practice ACCP Task Force on Collaborative Drug Therapy Management. Collaborative Drug Therapy Management by Pharmacists Pharmacotherapy 2003;23:

130 Pharmacovigilance

131 Pharmacovigilence The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problem (WHO) The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problem (WHO) In recent history, the role of the pharmacist has been to dispense drugs prescribed by a physician and ensure drugs met required standards In recent history, the role of the pharmacist has been to dispense drugs prescribed by a physician and ensure drugs met required standards In healthcare today, the pharmacists role has changed to acting as a consultant on pharmacotherapy, including over the counter products In healthcare today, the pharmacists role has changed to acting as a consultant on pharmacotherapy, including over the counter products WHO. The Importance of Pharmacovigilence, Safety Monitoring of Medical Products. Geneva: WHO; 2002; van Grootheest AC, de Jong-van den Berg LTW. The role of hospital and community pharmacists in pharmacovigilance. Research in Social and Administrative Pharmacy 2005;1:

132 Percentage of Professional ADR Reports Originating from Pharmacists by Country Country% Hospital Pharmacists Community Pharmacists Canada USA68+- Australia Netherlands Japan39?+ Spain Indicates that it is primarily pharmacists from this setting who originate reports - Indicates that pharmacists do not typically originate the reports + indicates that some but infrequent reports originate from pharmacists practicing in this setting ? indicates unknown data Van Grootheest AC, de Jong-van den Berg LTW. The role of hospital and community pharmacists in pharmacovigilance. Social and Administrative Pharmacy 2005;1:

133 Medication Therapy Management in the MS Patient MTM

134 Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version 2.0. American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008.

135 Criteria for Identifying Individuals for MTM Services American College of Clinical Pharmacy 2006 Clinical Practice Affairs Committee. Medication therapy management services: application of the core elements in ambulatory settings. Referral from other health care providers Referral from other health care providers More than one prescriber More than one prescriber Patients on four or more chronic medications Patients on four or more chronic medications Patients with at least once chronic disease requiring pharmacotherapy Patients with at least once chronic disease requiring pharmacotherapy Patients taking a medication with a narrow therapeutic index (e.g. warfarin, phenytoin, theophylline) Patients taking a medication with a narrow therapeutic index (e.g. warfarin, phenytoin, theophylline) Lab values outside the normal range that could be improved with medication therapy Lab values outside the normal range that could be improved with medication therapy Non-adherence for more than 3 months Non-adherence for more than 3 months Patients requiring intensive communication die to literacy and/or cultural issues Patients requiring intensive communication die to literacy and/or cultural issues Total monthly cost of medication in excess of $200 Total monthly cost of medication in excess of $200 Patients discharged from a hospital or skilled nursing facility within 14 days with new medications Patients discharged from a hospital or skilled nursing facility within 14 days with new medications Over-utilization or under-utilization of medications Over-utilization or under-utilization of medications Routinely non-adherent with medication regimens Routinely non-adherent with medication regimens Lack of understanding regarding medication use Lack of understanding regarding medication use Patients confronted with financial barriers Patients confronted with financial barriers

136 Documentation Elements for the Patient Record in an MTM Encounter Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version 2.0. American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008.

137 Studies Demonstrating Improved Economic and Clinical Outcomes with Pharmacists Interventions or Services Chisolm-Burns MA, et al. Economic effects of pharmacists on health outcomes in the United States: a systematic review. AJHP 2010;67:

138 Changing Directions Oral Agents Oral Agents Pharmacist Advanced Provision of Care Pharmacist Advanced Provision of Care Education Education Cost Cost Adherence Adherence

139 Educational Opportunities for Pharmacist/ Allied Health Involvement in MS Therapy Ross AP. Neurology 2008;71(suppl 3):s21-s23. Optimal MS Management Disease Modification Support System Symptom Management Clinical Findings MRI Findings Wellness

140 Considerations-Education Education Education Increased pharmacist education about MS disease Increased pharmacist education about MS disease Access to quick reference with therapeutic options Access to quick reference with therapeutic options Counseling tips and FAQs to address from MS patients Counseling tips and FAQs to address from MS patients Promote web sites and contact information for pharmacists to chat with MS pharmacy specialists in order to better care for their patients Promote web sites and contact information for pharmacists to chat with MS pharmacy specialists in order to better care for their patients Provide templates and programs specific for pharmacists to have a greater knowledge base than the patient (knowing from previous information that MS patients are smarter the average patient Provide templates and programs specific for pharmacists to have a greater knowledge base than the patient (knowing from previous information that MS patients are smarter the average patient How to manage side effects of medications How to manage side effects of medications Use of alternative therapies to control and manage disease state Use of alternative therapies to control and manage disease state Role of alternatives in treating neurologic diseases Role of alternatives in treating neurologic diseases Use of Motivational Interviewing skills to enhance and foster long-term use of medications in chronic diseases Use of Motivational Interviewing skills to enhance and foster long-term use of medications in chronic diseases Provide continuous professional development or certification in motivational interviewing as part of patient care Provide continuous professional development or certification in motivational interviewing as part of patient care Address specific counseling opportunities and barriers in patient s with chronic neurological disease to colleges of medicine, pharmacy and nursing Address specific counseling opportunities and barriers in patient s with chronic neurological disease to colleges of medicine, pharmacy and nursing

141 Changing Directions Oral Agents Oral Agents Pharmacist Advanced Provision of Care Pharmacist Advanced Provision of Care Education Education Cost Cost Adherence Adherence

142 Total Average Annual MS Cost by Insurance Type and Payer (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52

143 Total Average Annual MS Cost by Presence of Selected Comorbid Conditions (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52

144 MS Component Costs Overall Population (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52

145 Average Total Annual MS Cost by Disease- Modifying Drug Utilization (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52

146 Newer Biologic Treatments in MS Payers are demanding more information on the overall value of these therapies in making coverage decisions Payers are demanding more information on the overall value of these therapies in making coverage decisions Starting a biologic for the treatment of RA or MS was associated with lower use of some types of medical services within 2 to 3 years of initiation Starting a biologic for the treatment of RA or MS was associated with lower use of some types of medical services within 2 to 3 years of initiation Although biologics may reduce other types of service use, the savings do not come close to offsetting the full cost of these drugs Although biologics may reduce other types of service use, the savings do not come close to offsetting the full cost of these drugs Health plans may rightly focus on making sure only patients who will most benefit from biologics receive them. But once such patients are identified, it makes little sense to limit coverage Health plans may rightly focus on making sure only patients who will most benefit from biologics receive them. But once such patients are identified, it makes little sense to limit coverage Considerations/Speculations Considerations/Speculations Consider newer oral therapies for treatment for potentially lower overall cost to both patients and MCOs Consider newer oral therapies for treatment for potentially lower overall cost to both patients and MCOs Joyce GF, et al. Am J Manag Care 2008;14(12):821-82

147 Considerations - Costs Costs Costs Utilize adherence and education strategies to contain costs associated with disease Utilize adherence and education strategies to contain costs associated with disease Shift and reduce costs from acute therapy and health degeneration to medication management, adherence and education Shift and reduce costs from acute therapy and health degeneration to medication management, adherence and education Conduct continual research to demonstrate the value of adherence and education in cost reduction Conduct continual research to demonstrate the value of adherence and education in cost reduction Promote the concept of the disseminated healthcare team working to achieve adherence and education Promote the concept of the disseminated healthcare team working to achieve adherence and education

148 Changing Directions Oral Agents Oral Agents Pharmacist Advanced Provision of Care Pharmacist Advanced Provision of Care Education Education Cost Cost Adherence Adherence

149 Adherence The term adherence is preferred over compliance due to authoritative and paternalistic connotations of the latter The term adherence is preferred over compliance due to authoritative and paternalistic connotations of the latter Adherence: the extent to which a persons behavior– taking medication, following diet guidelines, or enacting lifestyle changescorresponds with recommendations from a health care provider Adherence: the extent to which a persons behavior– taking medication, following diet guidelines, or enacting lifestyle changescorresponds with recommendations from a health care provider Persistence and performance quality are also associated with adherence Persistence and performance quality are also associated with adherence Non adherence rates with DMTs average 25% (13- 46%) Non adherence rates with DMTs average 25% (13- 46%) – Similar to DM Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92

150 Adherent vs. Non-adherent Behavior Adherent Utilization and consequent maintenance of therapy Utilization and consequent maintenance of therapy Keep treatment and aftercare appointments Keep treatment and aftercare appointments Take drugs correctly Take drugs correctly Active change to health lifestyle Active change to health lifestyle Complete treatment-related homework Complete treatment-related homework Reduce risk behaviors Reduce risk behaviorsNon-adherent Complete refusal of therapy Complete refusal of therapy Refusal of specific treatment options Refusal of specific treatment options Arbitrary or unintended modification of prescriptions Arbitrary or unintended modification of prescriptions – Intentional non-adherence Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92

151 Motivations for Non-Adherence Most severe demands of IMT posed on patients Most severe demands of IMT posed on patients – Injectable medications, frequently IM or SQ for months or years – Benefits of IMT will not be positively experienced by patients and outweighed by side effects Flu-like symptoms Flu-like symptoms Flushing Flushing Chest pain Chest pain Palpitations Palpitations Dyspnea Dyspnea Pain on injection Pain on injection Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92

152 Effects of Non-Adherence on Treatment Prevalence Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and miminizing adverse events. Current Medical Research and Opinion 2009;25:77-92.

153 Reasons for Discontinuing MS Medications Lipsy R. Will the newer oral MS agents be welcomed by managed care organizations? Am J Manag Care 2010;16:S227-S223.

154 Poor Compliance Associated with Higher Out-of-Pocket Expenses with MS Drugs Gleason PP, et al. J Manag Care Pharm. 2009;15(8):

155 Motivational Interviewing as Early Vocational Intervention in MS 90% of people with MS have a history of employment, only 20-30% will be employed 5-15 years from diagnosis 90% of people with MS have a history of employment, only 20-30% will be employed 5-15 years from diagnosis Many people with MS do not participate in interventions designed to preserve employment until they experience a work-related crisis because of fatigue, concern about disclosure, or preference to not anticipate future problems Many people with MS do not participate in interventions designed to preserve employment until they experience a work-related crisis because of fatigue, concern about disclosure, or preference to not anticipate future problems MI is a brief, client centered, directive counseling approach that enhances intrinsic motivation to change by exploring and resolving ambivalence MI is a brief, client centered, directive counseling approach that enhances intrinsic motivation to change by exploring and resolving ambivalence U. of Washington MS Rehabilitation Research and Training Center is providing brief telephone MI sessions to individuals with MS to explore costs, benefits, and ambivalence of study participants toward making accommodations at work in efforts to stay employed through the progression of the disease U. of Washington MS Rehabilitation Research and Training Center is providing brief telephone MI sessions to individuals with MS to explore costs, benefits, and ambivalence of study participants toward making accommodations at work in efforts to stay employed through the progression of the disease Hunter C, Johnson K, Fraser R. Motivational Interviewing as Early Vocational Intervention in MS (P09). 21 st Annual Meeting of the Consortium for Multiple Sclerosis Centers, 2007 Washington, DC.

156 Patient Compliance Improves Through Motivational Interviewing Patient often resist the advice of health care providers and thus neglect what is in their best interests Patient often resist the advice of health care providers and thus neglect what is in their best interests Attempts to persuade patients when they are not ready to change Attempts to persuade patients when they are not ready to change A patient may quit taking medication because they feel no improvement A patient may quit taking medication because they feel no improvement Determine motivation and increase probability that they will make good decisions Determine motivation and increase probability that they will make good decisions Software available to aid Pharmacists in MI Software available to aid Pharmacists in MI 8.7% of pts receiving advice from counselors without using software quit taking medications 8.7% of pts receiving advice from counselors without using software quit taking medications 1.2% of pts quit taking medications when software was used 1.2% of pts quit taking medications when software was used Accessed 10/4/2010

157 Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Injury Ongoing study at University of Washington currently recruiting, completion date March 2012 Ongoing study at University of Washington currently recruiting, completion date March 2012 Purpose Purpose – Lack of physical activity has been positively correlated with higher levels of depression – Longitudinal data and treatment trials suggest that increased physical activity is related to improved mood – Condition: MS; Intervention: Behavioral (Motivational Interviewing ) accessed 10/4/2010

158 Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Injury Randomization Randomization – Motivational Interviewing: experimental Motivational interviewing for people aging with MS or spinal cord injury to increase physical activity and decrease depression Motivational interviewing for people aging with MS or spinal cord injury to increase physical activity and decrease depression – Behavioral: motivational interviewing Motivational interviewing, a proven counseling method that centers on individual goals and motivations, to increase exercise and decrease depression Motivational interviewing, a proven counseling method that centers on individual goals and motivations, to increase exercise and decrease depression accessed 10/4/2010

159 Strategies to Enhance Adherence to DMTs Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and miminizing adverse events. Current Medical Research and Opinion 2009;25: Establishing a therapeutic relationship Managing patient expectations Educating patient and family Managing adverse events Addressing patient concerns Increased adherence to treatment

160 Sample Questions Providing Alternative Views for Patients with Injection Anxiety Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and miminizing adverse events. Current Medical Research and Opinion 2009;25: If you could inject <1 min/Week, with minimal anxiety, would it be a burden? If you could inject <1 min/Week, with minimal anxiety, would it be a burden? While the injections may result in side effects in the first months, what are your goals for the next 10 years While the injections may result in side effects in the first months, what are your goals for the next 10 years If you were walking in the desert and had antivenin with you and a rattlesnake bit you, would you self- inject? If you were walking in the desert and had antivenin with you and a rattlesnake bit you, would you self- inject?

161 Male vs. Female MS Characteristics Female patients have greater self-reported symptom awareness and more positive perceptions of ability to manage therapy Female patients have greater self-reported symptom awareness and more positive perceptions of ability to manage therapy 80% of a mailed surveys of commercially insured MS patients were female 80% of a mailed surveys of commercially insured MS patients were female Majority of whom had RRMS Majority of whom had RRMS 68% of whom were on glatiramir acetate or interferon beta-1a 68% of whom were on glatiramir acetate or interferon beta-1a Females more often perceived that DMM made a difference and were more aware of treatment options Females more often perceived that DMM made a difference and were more aware of treatment options Considerations/Speculations Considerations/Speculations Male patients would be a sizeable target for beginning MS therapy Male patients would be a sizeable target for beginning MS therapy Male patients need consistent reminders of importance of therapy as well as treatment options Male patients need consistent reminders of importance of therapy as well as treatment options Vlahiotis A, et al. J Manag Care Pharm 2010;16:

162 Kaplan-Meier Hazards for Probability for Medication Continuance Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:

163 Determinants of Adherence Missing treatment effects or undesirable side effects explain only medium amounts of variance in adherence Missing treatment effects or undesirable side effects explain only medium amounts of variance in adherence – Disease characteristics – Patient variables – Quality of patient therapist relationship – Treatment setting – Influences from social environment Mohr DC, et al. Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on the adherence and ability to self inject. Ann Behav Med 2001;23:

164 Determinants of Adherence Adherence most strongly threatened by disorders that specifically and directly interfere with medication application Adherence most strongly threatened by disorders that specifically and directly interfere with medication application – Injection phobia – Treatment of diabetes mellitus – Depression Non-adherence has been regarded as a risk for patient morbidity and mortality and has an unnecessary economical burden for the health care system Non-adherence has been regarded as a risk for patient morbidity and mortality and has an unnecessary economical burden for the health care system Mohr DC, et al. Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on the adherence and ability to self inject. Ann Behav Med 2001;23:

165 The Society recognizes that the factors that enter into a decision to treat are complex and best analyzed by the individual patients neurologist. The Society recognizes that the factors that enter into a decision to treat are complex and best analyzed by the individual patients neurologist. Initiation of treatment with an interferon beta medication or glatiramer acetate should be considered as soon as possible following a definite diagnosis of MS with active, relapsing disease, and may also be considered for selected patients with a first attack who are at high risk of MS.* Initiation of treatment with an interferon beta medication or glatiramer acetate should be considered as soon as possible following a definite diagnosis of MS with active, relapsing disease, and may also be considered for selected patients with a first attack who are at high risk of MS.* Expert Opinion Paper, National Multiple Sclerosis Society, 2007 RecommendationsNational Multiple Sclerosis Society 2007 Disease Management Consensus Statement

166 Natalizumab is generally recommended by the Food and Drug Administration (FDA) for patients who have had an inadequate response to, or are unable to tolerate, other multiple sclerosis therapies. Natalizumab is generally recommended by the Food and Drug Administration (FDA) for patients who have had an inadequate response to, or are unable to tolerate, other multiple sclerosis therapies. Treatment with mitoxantrone may be considered for selected relapsing patients with worsening disease or patients with secondary-progressive multiple sclerosis who are worsening, whether or not relapses are occurring. Treatment with mitoxantrone may be considered for selected relapsing patients with worsening disease or patients with secondary-progressive multiple sclerosis who are worsening, whether or not relapses are occurring. Expert Opinion Paper, National Multiple Sclerosis Society, 2007 RecommendationsNational Multiple Sclerosis Society 2007

167 Recommendations Continued Patients access to medication should not be limited by the frequency of relapses, age, or level of disability. Patients access to medication should not be limited by the frequency of relapses, age, or level of disability. Treatment is not to be stopped while insurers evaluate for continuing coverage of treatment, as this would put patients at increased risk for recurrent disease activity. Treatment is not to be stopped while insurers evaluate for continuing coverage of treatment, as this would put patients at increased risk for recurrent disease activity. Therapy is to be continued indefinitely, except for the following circumstances: there is clear lack of benefit; there are intolerable side effects; better therapy becomes available. Therapy is to be continued indefinitely, except for the following circumstances: there is clear lack of benefit; there are intolerable side effects; better therapy becomes available. Expert Opinion Paper, National Multiple Sclerosis Society, 2007

168 Recommendations Continued All of these FDA-approved agents should be included in formularies and covered by third party payers so that physicians and patients can determine the most appropriate agent on an individual basis; failure to do so is unethical and discriminatory. All of these FDA-approved agents should be included in formularies and covered by third party payers so that physicians and patients can determine the most appropriate agent on an individual basis; failure to do so is unethical and discriminatory. Movement from one disease-modifying medication to another should occur only for medically appropriate reasons. Movement from one disease-modifying medication to another should occur only for medically appropriate reasons. None of the therapies has been approved for use by women who are trying to become pregnant, are pregnant, or are nursing mothers. None of the therapies has been approved for use by women who are trying to become pregnant, are pregnant, or are nursing mothers. Expert Opinion Paper, National Multiple Sclerosis Society, 2007

169 Dose, Route, Frequency and Common Adverse Effects of Medications Used in MS Treatment Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45: MedicationDoseRouteFrequency Common Adverse Events Interferon beta-1a 30 microgramsIntramuscularOnce weekly Injection site reactions, inflammation, fever, myalgia, chills Interferon beta-1a 44 microgramsSubcutaneous Three times per week Injection site reactions, inflammation, fever, myalgia, chills Interferon beta-1b 0.25 milligramsSubcutaneous Every other day Injection site reactions, inflammation, fever, myalgia, chills Glatiramer acetate 20 milligramsSubcutaneousOnce daily Local injection site reactions and transient, self-limited, facial flushing and chest tightness

170 Direct and Indirect Costs that Should be Considered in Direct Patient Care Services Chisolm-Burns MA, et al. Economic effects of pharmacists on health outcomes in the United States: a systematic review. AJHP 2010;67:

171 Questions to Consider 1. How likely is the approval of new MS therapies including both oral and injectable agentschange the risk- to-benefit analyses for long-term MS treatments and influence management decisions for MS in the managed care setting? 2. How do you anticipate responding to the new MS treatment landscape that will include high cost, oral therapies that require pharmacovigilance measures? 3. In the absence of precise guideline from U.S. FDA, how will your organization decide to tier first-line and second-line therapies? 4. Specifically, to what extent has cost of therapy influenced decision-making at your MCO? And how will it influence therapy moving forward?

172 5. How will your organization respond to pricing issues for MS? For example, fingolimod is priced at $48,000 one year of treatment? How will that influence your MS treatment decisions when safe and effective therapies currently cost from $32,000 to $40,000? 6. How will you respond to additional demands for safety monitoring for new agents, such as fingolimod and other immunosuppressives? What are these monitoring dimensions? Questions to Consider

173 The Role of Comparative Effectiveness, Long Term Safety Considerations, and Monitoring Costs for Evaluating Therapies for MS The Evolving Landscape of MS Therapy Jacquelyn Bainbridge, PharmD, FCCP Professor Department of Clinical Pharmacy/Department of Neurology University of Colorado Denver Aurora, CO

174 To Treat or Not to Treat? Does early treatment of patients with CIS delay the development of a second clinical event (CDMS diagnosis)? Does early treatment of patients with CIS delay the development of a second clinical event (CDMS diagnosis)? Four randomized, placebo-controlled, phase III trials have addressed that question Four randomized, placebo-controlled, phase III trials have addressed that question PreCISe: Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS of Subjects Presenting with CIS PreCISe: Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS of Subjects Presenting with CIS BENEFIT: Betaseron ® (SC IFNβ-1b) in Newly Emerging MS for Initial Treatment BENEFIT: Betaseron ® (SC IFNβ-1b) in Newly Emerging MS for Initial Treatment CHAMPS: Controlled High-Risk Subjects (IM IFNβ-1a) Avenox ® Multiple Sclerosis Prevention CHAMPS: Controlled High-Risk Subjects (IM IFNβ-1a) Avenox ® Multiple Sclerosis Prevention ETOMS: Early Treatment of MS ETOMS: Early Treatment of MS One additional ongoing study One additional ongoing study REFLEX: Rebif ® (SC IFNβ-1a) FLEXible Dosing in Early MS REFLEX: Rebif ® (SC IFNβ-1a) FLEXible Dosing in Early MS IFN = interferon; IM = intramuscular; SC = subcutaneous.

175 Clinically Isolated Syndrome (CIS) CIS: single, symptomatic neurologic episode consistent with MS, first attack CIS: single, symptomatic neurologic episode consistent with MS, first attack Common symptoms: optic neuritis, ocular motor syndromes, ataxia, dysarthria, sensory or motor signs, partial myelitis, and bladder or bowel dysfunction Common symptoms: optic neuritis, ocular motor syndromes, ataxia, dysarthria, sensory or motor signs, partial myelitis, and bladder or bowel dysfunction Patient may already have lesions on MRI Patient may already have lesions on MRI Clinically definite MS (CDMS): second attack consistent with MS Clinically definite MS (CDMS): second attack consistent with MS CIS = clinically isolated syndrome; MRI = magnetic resonance imaging; MS = multiple sclerosis.

176 Prognosis in CIS Rate of Conversion to CDMS Years % Converting to CDMS Baseline Measure Adapted with permission from Brex et al. N Engl J Med. 2002;346:

177 Treatment All of the clinical trials in patients with CIS showed statistically significant reductions (39%–50%) in risk of developing CDMS when early treatment was initiated. All of the clinical trials in patients with CIS showed statistically significant reductions (39%–50%) in risk of developing CDMS when early treatment was initiated. All of the clinical trials showed a delay in physical disability and a significant reduction in either the number and/or volume of brain lesions. All of the clinical trials showed a delay in physical disability and a significant reduction in either the number and/or volume of brain lesions.

178 MS Prognosis Without Therapy 10–20% have benign MS 10–20% have benign MS Rare attacks, little disability Rare attacks, little disability Post-hoc determination Post-hoc determination About 5% have malignant MS About 5% have malignant MS Rapid accumulation of disability Rapid accumulation of disability Wheelchair-bound in 5 years, bed bound in 10 years Wheelchair-bound in 5 years, bed bound in 10 years Most are between these extremes Most are between these extremes Newer data suggests overall better prognosis Newer data suggests overall better prognosis

179 Economic Impact of Multiple Sclerosis Impact in the work place (MS vs non-MS) Impact in the work place (MS vs non-MS) Higher percentage of employees claiming short- or long-term disability (21.4% vs 5.2%) (P <.0001) 1 Higher percentage of employees claiming short- or long-term disability (21.4% vs 5.2%) (P <.0001) 1 More disability days per year (29.8 vs 4.5) (P <.0001) 1 More disability days per year (29.8 vs 4.5) (P <.0001) 1 Average annual costs for disability $3868 vs $414 US (P <.0001) 1 Average annual costs for disability $3868 vs $414 US (P <.0001) 1 1. Ivanova JI, et al. Pharmacoecomonics. 2009;27:

180 Key Parameters in MS Management: Disability Expanded Disability Status Scale = Rating system used by neurologists and clinical trial investigators to follow the progression of disability in MS Patient Disability Classification Normal neurologic exam Minimal disability Increased limitation in walking ability Need for walking assistance Restriction to wheelchair Helpless bed patient Death Kurtzke. Neurology. 1983;33:

181 Seven Approved Disease-Modifying Therapies First-linetherapiesSecond-line Therapy ? Worsening/progressivedisease IM IFNβ-1a SC IFNβ-1a SC IFNβ-1b Glatiramer acetate FingolimodNatalizumab Other first-line Mitoxantrone Graphic courtesy of Dr. Robert J. Lipsy. Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.

182 FDA-Approved Therapies for MS Parenteral Immunomodulators Agents*Indications Doses and Administration Glatiramer acetate 1 (Copaxone ® )CISRRMS 20 mg/d SC Low-dose IFNβ-1a 2 (Avonex ® )CISRRMS 30 mcg/wk IM High-dose IFNβ-1a 3 (Rebif ® )RRMS CIS CIS 22 mcg or 44 mcg TIW SC High-dose IFNβ-1b 4,5 (Betaseron ®, Extavia ® )CISRRMS 250 mcg QOD SC *Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name. Pending FDA approval (REFLEX trial). 1. Glatiramer acetate (Copaxone ® ). 2. Low-dose IFNβ-1a (Avonex ® ). 3. High-dose IFNβ-1a (Rebif ® ). 4. High-dose IFNβ-1b (Betaseron ® ). 5. High-dose IFNβ-1b (Extavia ® ).

183 FDA-Approved Therapies for MS Parenteral Immunosuppressive Agents*Indications Doses and Administration Natalizumab 1 (Tysabri ® ) Relapsing forms of MS 300 mg q4wk IV Mitoxantrone 2 (Novantrone ® ) SPMS, PRMS, Worsening RRMS 12 mg/m 2 over 5–15 min q3mo IV infusion *Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name. Currently used as 2nd-line therapy. Only indicated for progressive and/or worsening disease; cumulative dose should not exceed 140 mg/m Natalizumab (Tysabri ® ). 2. Mitoxantrone (Novantrone ® ) s030s031lbl.pdf

184 Newly Approved Oral MS Therapies Disease-Modifying Therapy Mechanisms of Action Fingolimod (FTY720) Sphingosine-1P (S-1P) receptor agonist Blocks lymphocyte migration Symptomatic Management Mechanisms of Action Dalfampridine Blocks voltage-dependent K+ channels May restore conduction in poorly myelinated nerve fibers

185 Safety Considerations: Fingolimod & Natalizumab Fingolimod Fingolimod Lymphopenia is common because the drug sequesters lymphocytes in peripheral lymph nodes 1,2 Lymphopenia is common because the drug sequesters lymphocytes in peripheral lymph nodes 1,2 Reversal of lymphopenia can take ~ 2 to 4 weeks after the end of dosing, depending on the dose 3 Reversal of lymphopenia can take ~ 2 to 4 weeks after the end of dosing, depending on the dose 3 First dose problems within 6 hours First dose problems within 6 hours Bradycardia 1 Bradycardia 1 Second-degree Wenckebach atrioventricular block Second-degree Wenckebach atrioventricular block Infections and malignancies Infections and malignancies Overall the 3 most important monitoring parameters: Overall the 3 most important monitoring parameters: Heart rate Heart rate Macular edema Macular edema Pulmonary function tests (decrease FEV1) Pulmonary function tests (decrease FEV1) Natalizumab Natalizumab TOUCH program = Progressive multifocal leucoencephalopathy (PML) TOUCH program = Progressive multifocal leucoencephalopathy (PML) Infusion reactions Infusion reactions When stopping Natalizumab bridging needs to occur to prevent immune reconstitution inflammatory syndrome (IRIS) 4 When stopping Natalizumab bridging needs to occur to prevent immune reconstitution inflammatory syndrome (IRIS) 4 1 Brown et al. Ann Pharmacother ;41: ; 3 Kappos et al. N Engl J Med. 2006;355: Robinson R. Neurology Today. 07 OCT 2010;10(19):1,21. TOUCH = Tysabri Outreach Unified Commitment to Health FEV1 = forced expiratory volume in 1 second.

186 Phase IIb Laquinimod Study

187 Effect on Annualized Relapse Rate LAQ/5062 Study was not powered to detect a statistically significant effect on relapse rate LAQ/5062 Study was not powered to detect a statistically significant effect on relapse rate Trend (p=0.0978) toward reduction of annualized relapse rate Trend (p=0.0978) toward reduction of annualized relapse rate Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371: PBOLQ 0.3mgLQ 0.6mg 33% Annualized Relapse Rate

188 Phase IIb Laquinimod Study Gd-T1 Lesion Count 0.3 mg 0.6 mg Placebo Laquinimod 0.6mg Reduced MRI Lesion Counts Early during the Treatment Course Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:

189 Conclusions & Summary Laquinimod showed a robust, reproducible, sustained and early effect on MRI activity Laquinimod showed a robust, reproducible, sustained and early effect on MRI activity Laquinimod 0.6mg is safe and tolerable Laquinimod 0.6mg is safe and tolerable Transitory elevations of liver enzymes, most in the first 3 months of Tx Transitory elevations of liver enzymes, most in the first 3 months of Tx No signs of immunosuppression following prolonged exposure No signs of immunosuppression following prolonged exposure Current data suggest a favorable, balanced benefit-to-risk ratio of laquinimod as a potential treatment for RRMS patients Current data suggest a favorable, balanced benefit-to-risk ratio of laquinimod as a potential treatment for RRMS patients

190 Which ABCR Drug Is Best? INF β vs INF β EVIDENCE = Evidence of Interferon Dose-response: European North American Comparative Efficacy; INCOMIN = Independent Comparison of Interferon; BEYOND = Betaseron Efficacy Yielding Outcomes of A New Dose; IM = Intramuscular; INF = Interferon; SC = Subcutaneously. 1 Durelli et al. Lancet. 2002;359: ; 2 Panitch et al. Neurology 2002;59: ; 3 Clanet et al. Neurology 2002;59: ; 4 Comi G. Presented at: American Academy of Neurology 60th Annual Meeting; April 16, 2008; Chicago, IL. Abstract: LBS.003.

191 Which ABCR Drug Is Best? INF β vs GA BEYOND = Betaseron Efficacy Yielding Outcomes of a New Dose; REGARD = Rebif vs Glatiramer Acetate in Relapsing Multiple Sclerosis Disease; BECOME = Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-T MRI Endpoints. 1. Information presented at American Academy of Neurology 60 th Annual Meeting, Abstract LBS.003; 2. Mikol et al.Lancet Neurol. 2008:7: ; 3.Wolansky et al. Mult Scler. 2007;12(suppl2):S58. Poster 206.;4. Cadavid et al. Mult Scler. 2007;12(suppl2):S58. Poster Haas J, Firzlaff M. Eur J Neurol. 2005;12:

192 Which New Agent is Best? New Agent vs. INF β SENTINEL trial 1 Natalizumab + INFβ-1a IM vs INFβ-1a IM : The combination group was significantly more effective. The risk of relapse was 50% lower with combination therapy. Combination therapy represented 83% reduction in the number of new T 2 -lesions and an 89% reduction with gadolinium-enhancing lesions. TRANSFORMS trial 2 Fingolimod 0.5 mg or 1.25 mg vs INFβ-1a IM: Superior efficacy of fingolimod with respect to relapse and MRI outcomes. Fingolimod reduced the annualized relapse rate to a range of 0.16 to 0.20 as compared to 0.33 for the INFβ-1a = a relative reduction of 38%-52% SENTINEL= The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis TRANSFORMS= Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis 1 Rudick RA et al. Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis. The New England Journal of Medicine. 02 Mar 2006;354; Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. The New England Journal of Medicine. 04 Feb 2010;362:

193 First-line therapies Consistent effect on relapses and MRI Unclear effect on long-term disability Potential to further enhance efficacy and ease of use Oral agents Cladribine Laquinimod Teriflunomide Fumaric acid Monoclonal antibodies Daclizumab Alemtuzumab Rituximab Ocrelizumab Combination therapy IFN -based GA-based Novel agents Main emerging therapies and strategies GA IFN Fingolimod Natalizumab Tx-naive patients MS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at: Abbreviations: GA, glatiramer acetate; IFN, interferon beta. Emerging MS Therapies

194 Patient Adherence to MS Medication MS poses unusual challenges to adherence MS poses unusual challenges to adherence Needle phobia Needle phobia New daily routines New daily routines Perceived lack of efficacy Perceived lack of efficacy According to adherence studies According to adherence studies Many patients display new or increased depression within 6 months of treatment initiation 1 Many patients display new or increased depression within 6 months of treatment initiation 1 Depressed patients displayed decreased adherence 1 Depressed patients displayed decreased adherence 1 Treating depression may prevent treatment discontinuation 1 Treating depression may prevent treatment discontinuation 1 Most frequent cause of stopping treatment is perceived lack of efficacy 2 Most frequent cause of stopping treatment is perceived lack of efficacy 2 Most treatment withdrawals occur within 1st year of treatment 2 Most treatment withdrawals occur within 1st year of treatment 2 Side effects and tolerability issues can result in nonadherence or discontinuation of medications Side effects and tolerability issues can result in nonadherence or discontinuation of medications 1. Mohr DC, et al. Arch Neurol. 1997;54: Clerico M, et al. J Neurol Sci. 2007;259:

195 Adherence Between 17% and 40% of patients stop taking disease-modifying drugs within 1 year of initiation 1-3 Between 17% and 40% of patients stop taking disease-modifying drugs within 1 year of initiation 1-3 Multifactorial Multifactorial Perceived lack of efficacy 1,2 Perceived lack of efficacy 1,2 Adverse effects 2,3 Adverse effects 2,3 Depression Depression Within 6 months of treatment initiation, 41% of patients had new or increased depression 4 Within 6 months of treatment initiation, 41% of patients had new or increased depression 4 Decreased adherence in patients with untreated depression 4 Decreased adherence in patients with untreated depression 4 1. Clerico M, et al. J Neurol Sci. 2007;259: Rio J, et al. Mult Scler. 2005;11: Daugherty KK, et al. J Am Pharm Assoc. 2005;45: Mohr DC, et al. Arch Neurol. 1997;54:

196 Studies of Patient Adherence to MS Medications Longitudinal, prospective study of 199 patients with definite MS Longitudinal, prospective study of 199 patients with definite MS Of 97 patients taking DMT Of 97 patients taking DMT 73% missed doses 73% missed doses 10% missed >10 doses in a 6-month period 10% missed >10 doses in a 6-month period 25% stopped DMT 25% stopped DMT Missed doses were associated with alcohol intake Missed doses were associated with alcohol intake History of missed doses predicted future missed doses History of missed doses predicted future missed doses Numerous and divergent factors influenced missed doses and stopping DMT Numerous and divergent factors influenced missed doses and stopping DMT Indicates need for multifaceted approach to improving adherence Indicates need for multifaceted approach to improving adherence Tremlett H, et al. Pharmacoepidemiol Drug Saf. 2008;17:

197 Patients in United States Find it Harder to Pay for Care Patients stating that they often have difficulty paying for medications or other care costs Graphic courtesy of Dr. Robert J. Lipsy. The Commonwealth Health Fund 2009 International Healthy Policy Survey of Primary Care Doctors. Health Affairs. 5 November 2009.

198 Anti-TNF Prescription Abandonment As out-of-pocket expenses increase, treatment abandonment increases With permission from Gleason PP, et al. J Manag Care Pharm. 2009;15:

199 Promoting Adherence to Therapeutic Regimens in MS Establishing Realistic Expectations Therapies have been shown to reduce relapses, reduce MRI activity, and attenuate disease activity Therapies have been shown to reduce relapses, reduce MRI activity, and attenuate disease activity Attenuated disease activity may lead to more patients retaining employment Attenuated disease activity may lead to more patients retaining employment Patients with MS must also realize that DMTs Patients with MS must also realize that DMTs Only work if patients take them Only work if patients take them Are not cures for MS Are not cures for MS May not eliminate MS symptoms May not eliminate MS symptoms Do not completely eliminate future disease activity Do not completely eliminate future disease activity Cerghet M, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P Putzki N, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P

200 Disease-Modifying Therapies Relapse free at 1 year 51%–80% Relapse free at 1 year 51%–80% Relative decrease in annual relapse rate 30%–80% Relative decrease in annual relapse rate 30%–80% Absolute annual relapse rate 0.15–0.7 Absolute annual relapse rate 0.15–0.7 Relative decrease in sustained progression 31%–42% Relative decrease in sustained progression 31%–42% Absolute rate of disease progression 9%–18% Absolute rate of disease progression 9%–18% Workers with MS on a DMT and not on a DMT 1 Workers with MS on a DMT and not on a DMT 1 N=258 vs. N=322 N=258 vs. N=322 Treatment with DMT = reduced medical and indirect costs Treatment with DMT = reduced medical and indirect costs Data courtesy of Dr. Robert J. Lipsy.1. Birnbaum et al Curr Med Res Opin. 2009;25(4):

201 Questions to Consider 1.How will pharmacoviligance programs for MS therapies used in managed care settings will need to adapt and change when potentially new, immunosuppressive therapies with a variable range of adverse effects and toxicities become available? 2.How, depending on the risk-to- benefit ratio and pharmacovigilance requirements for new therapies, will managed care pharmacy and medical directors respond to a new landscape for MS as oral agents with potentially less favorable side effect profiles become available? 3.What will be the role that electronic records and meticulous documentation of MS treatment plans play in the near future as multiple agents, with potentially additive immunosuppressive properties, become available for treating MS in the managed care setting?


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