The Evolving Landscape of MS Therapy

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 Director’s Perspective Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California

Welcome and Program Overview
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.

Program Faculty Bruce A. Cree, MD, PhD, MCR
Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California Suhayl Dhib-Jalbut, MD Professor and Chairman, Director Robert Wood Johnson Center for Multiple Sclerosis UMDNJ-Robert Wood Johnson Medical School New Brunswick, NJ 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 Professor Department of Clinical Pharmacy/Department of Neurology University of Colorado Denver Aurora, CO

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? BRUCE A. CREE, MD, PhD, MCR Assistant Professor of Neurology │ Department of Neurology │ University of California │ San Francisco Multiple Sclerosis Center │ San Francisco, California 8:20 AM — 8:40 AM Group Discussion: Discuss Emerging Concerns, Challenges, and Strategic Needs for Optimizing MS Care in the Managed Care Environment

8:40 AM — 9:05 AM Trial-Based Evidence for First Line Therapy with Immune- Modulating Agents (IMTs): From Mechanisms to Therapy—Landmark 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 Hasn’t? Where Is the Room for Improvement? BRUCE A. CREE, MD, PhD, MCR Assistant Professor of Neurology │ Department of Neurology │ University of California │ San Francisco Multiple Sclerosis Center │ San Francisco, California 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

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? Suhayl Dhib-Jalbut, MD Professor and Chairman │ Department of Neurology │ Director │ Robert Wood Johnson Center for Multiple Sclerosis │ UMDNJ-Robert Wood Johnson Medical School │ New Brunswick, NJ 9:45 AM — 10:00 AM Group Discussion: Discuss Complexity of Evolving Agents for MS and Approaches to Making a Risk-Benefit Analysis

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 │ Department of Pharmacy Practice-Vermont Campus │ Albany College of Pharmacy and Health Sciences │ Colchester, VT 10:20 AM — 10:40 AM Group Discussion: The Near Future of MS Care

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 Plans—The Managed Care Medical and Pharmacy Director’s Perspective Jacquelyn Bainbridge, PharmD, FCCP 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 Landscape—and New Risk/Benefit Equations—of Oral Agents for MS. Will Patient Registries Be Required?

Format: We Want a Dialogue
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 table—to 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.”

Epidemiology of Multiple Sclerosis
The most common chronic disease affecting the CNS in young adults Approximately 400,000 cases in the United States Estimates range from 250,000 to 500,000 The chances of developing MS are 1:1000 in the general population Estimated 2.5 million cases worldwide Highest incidence in Caucasians Higher incidence in women (approximately 3:1) MS strikes individuals between the ages 20-50, normally a time of peak productivity According to the National Multiple Sclerosis Society, there are an estimated 400,000, up from the 250,000 to 350,000 people estimated in the 1990s with MS in the United States. Furthermore, it is estimated that approximately 2.5 million people suffer with MS worldwide. There is a very high prevalence of MS in northern Europeans, especially in Sweden, Norway, Denmark, and Iceland. Australia, the British Isles, Canada, Ireland, New Zealand, and the United States also have comparatively high prevalence rates. Conversely, prevalence rates are relatively lower in Africa, China, India, Japan, and Southeast Asia. When the relationship of prevalence, incidence rates, and latitude was examined in a recent meta-analysis of population-based studies, crude prevalence and incidence rates were significantly associated with latitude (P < and P = .038, respectively). However, when the rates were age-adjusted to the world population, the level of significance in relation to latitude diminished for prevalence (P = .003) and disappeared for incidence (P = .156), suggesting that age adjustment partially eliminates the apparent effect of latitude seen in many epidemiological studies. Approximately twice as many women as men have MS, similar to the female:male ratio seen in other autoimmune diseases. References: Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359: Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72: The National MS Society Information Sourcebook. Available at: Accessed on July 21, 2003. Zivadinov R, Iona L, Monti-Bragadin L, et al. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. Neuroepidemiology. 2003;22:65-74. 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):

Age of Onset of Multiple Sclerosis
Distribution of Patients According to the Decade of Life of MS Symptoms Onset 35 30 25 20 Patients (%) 15 10 5 0-10 11-20 21-30 31-40 41-50 51-60 Years Cardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):

Clinical Manifestations of MS
Fatigue Pain Depression Numbness/paresthesias Cognitive dysfunction Weakness Spasticity Optic neuritis Bladder dysfunction Bowel dysfunction Cerebellar dysfunction Sexual dysfunction Gait abnormalities Partial/complete paralysis National Multiple Sclerosis Society. Accessed February 21, 2010.

Natural History of MS and Cost of MS
CIS RRMS SPMS Pre-clinical Predicted Cost Early Intervention* MRI lesion activity Clinical Threshold Atrophy and Axonal Degradation US$ per Year It is estimated that for every attack symptomatic enough for a patient to seek care, there are perhaps 10 attacks that can be documented on MRI scans; thus sub-clinical damage is ongoing. The latter phase of MS is characterized by increasing disability (as measured by EDSS scores) as the process of irreversible nerve damage continues. As neurodegeneration progresses, the disease becomes increasingly more difficult to treat. As MS progresses and the level of disability increases, both the direct and indirect costs of care will increase. The objective of early treatment is to lessen the development of disability, and thereby reduce the overall cost of care. *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):

Progression of Disability: EDSS
10.0 = Death due to MS 9.0–9.5 = Completely dependent Increasing disease burden 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 All trials in RRMS have received approvals from the FDA based on relapse rates—just counting the number of relapses—and/or disability as measured by the Kurtzke EDSS scale. Scores range from 0 to 10. Scores from 0 to 4.5 are based on the neurologic exam and reflect a person who is ambulatory Rating 5 to 9.5 are defined by impact on ambulation. Critique: weighted too heavily on gait In higher ranges, it is relatively insensitive to clinical changes that do not impair gait. The most widely used assessment of impact on MS is the Kurtzke Expanded Disability Status Scale (EDSS). The Disability Status Scale (DSS) was published in 1955 and later revised and expanded to the EDSS in 1983 To measure the EDSS score, a standard neurologic exam is used to evaluate functional system abnormalities involving thee: pyramidal, cerebellar, brain stem, sensory, bladder and bowel, visual, and mental. Functional system scores vary from 0 (normal function) to 7 or 8 (complete dysfunction). These assignments determine the EDSS score in half-steps from 0 (normal neurologic function) to 10 (death from MS). For example, and EDSS score of 1.5 means there is no disability, but minimal changes are evident in more than one functional system. An EDSS score of 4.0 to 4.5 means disability is moderate. The patient can only walk 330 to 550 yards without assistance or rest. 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 EDSS = Expanded Disability Status Scale. Kurtzke JF. Neurology. 1983;33:

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

Immunopathogenesis of the MS Lesion
CD8 Ab+C9neo gdT MO Oligo NO Oi TNFa MMP Pl Virus B Histamine Proteases TNFa NAA, ATP NO O2 5-HT IFNg TNF Th17 Th2/ Th3 Treg IL-10 TGFb Glutamate B7 CD28 MCP-1 MIP-1a IP-10 RANTES CD4+CD25+ Th1 Th17 Microglia Mast Cell Astrocyte CD40 CD40L BBB VCAM-1 Mast Cell ICAM-1 VCAM-1 MMP-2/9 IL-4 IL-5 IL-6 IL-13 TGFb Treg Th2/ Th3 B Complement LFA-1 VLA-4 gdT Th1 Th17 Monocyte IFNg TNF IL-17 IL-23 IL-4 & IL-10 Granutocyte CD8 IL-12 B7 CD28 CD4 APC CD4 HLA APC TCR Thp Thp Myelin Ag Microbial Ag Figure courtesy of Dhib-Jalbut S, 2008 CD40 CD40L

Trends Across MS Clinical Trials Annualized Relapse Rate (ARR)
Johnson 1995 Polman 2006 REGARD 2007 BECOME Kappos TRANSFORMS Jacobs 1996 IFNβ-1b study group,1993 PRISMS-2 1998 BEYOND CAMMS223 2008 3 years HERMES 48 weeks FORTE 1 year CLARITY 2009

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

Existing and Emerging MS Therapies
2005 2006 2007 2010 2011 2012 2013 Oral Injectables BG12 Caldribine BG12 Cladribine Rebif Rebif Fingolimod Betaseron Ampyra Ampyra Teriflunomide Teriflunomide Copaxone Extavia Extavia Laquinimod Laquinimod Avonex Ocrelizumab Ocrelizumab IV Novantrone Tysabri Tysabri IV Generic Mitoxantrone (oncology) MS Generic Mitoxantrone (oncology) (MS) Alemtuzumab Alemtuzumab Filed Approved In phase II In phase III

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 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

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

Analyzing Risk-to-Benefit Equation for Established and Emerging Agents
E F F I C A C Y R I S K vs. B E N E F I T V A L U E S A F E T Y D O S I N G Q U A L I T Y

Questions We Will Address Today
How has your organization decided to provide and make decisions about MS care? Who makes these decisions? A formulary committee? Department of Pharmacy? Neurologists and MS Specialists? A consensus among many stakeholders? 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?

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? 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?

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 Evidence for First Line Therapy with Immune-Modulating Agents
Investigations • Innovation • Clinical Application 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 Program Chairman Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California

Overview of Presentation
Mechanisms of action of IMTs Outcome measures in clinical trials Comparison of landmark trials Longitudinal studies: what do they tell us? Price of MS versus cost of treatment

Mechanisms of Action

Adapted from Yong VW. Neurology. 2002;59:802-808.
IFN-: Activity TH1+ Resting T cell MMP Activated (+) T cells BBB Blood CNS TNF-α IFN-γ IL-2 TH1 APC IFN-β Myelin protein Antigen Activity of IFN- IFN-β has the following effects at the BBB.1 It decreases production of matrix metalloproteinases (MMPs) by T cells. It reduces expression of several chemokine receptors. It affects adhesion of T cells onto the endothelium. It reduces influx of T cells into the CNS. It rapidly resolves Gd-enhanced MRI activity. Reference 1. Yong VW. Differential mechanisms of action of interferon- and glatiramer acetate in MS. Neurology. 2002;59: Adapted from Yong VW. Neurology. 2002;59:

Glatiramer Acetate: Activity
BBB Periphery CNS Macrophage Microglia Bystander suppression effect APC MHC GA TCR APC MHC CNS Ag TCR GA therapy IL-4 IL-10 BDNF TCR Anti-inflammatory cytokines Activity of Glatiramer Acetate On the left side, glatiramer acetate is activating Th1 cells to transition to Th2 cells, which cross the BBB into the CNS.1 Once in the CNS, these Th2 cells release cytokines, including IL-10 and TGF-β, which inhibit encephalogenic T cells and prevent neuronal damage. Ziemssen and colleagues have proposed that the efficacy of glatiramer acetate-activated Th2 cells may be related to their ability to produce BDNF, on the right side. BDNF is a potent neurotrophin contributing to neuronal survival and dendritic growth.1 The investigators demonstrated the presence of BDNF in glatiramer acetate-activated long-term T cell lines from human donors using reverse transcription PCR, ELISA, and staining techniques.1 Similar findings in an EAE model have been reported.2 BDNF receptors have been isolated near MS plaques and in reactive astrocytes of MS lesions, suggesting direct access to target tissues. In fact, BDNF has been immunolocalized in active MS lesions.1,3 References 1. Ziemssen T, Kumpfel T, Schneider H, Klinkert WE, Neuhaus O, Hohlfeld R. Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: implications for multiple sclerosis therapy. J Neurol Sci. 2005;233: 2. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A. 2005;102: 3. Stadelmann C, Kerschensteiner M, Misgeld T, Bruck W, Hohlfeld R, Lassmann H. BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interactions between immune and neuronal cells? Brain. 2002;125:75-85. + + Neurotrophins GA- specific T cell Neuroregeneration TH1 TH2 TH2 Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:

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

Laquinimod Induced Immunomodulation on the Molecular Level
Overexpression/downregulation 34

Long-Term Disability Effect of Early Relapses
50 40 30 20 10 60 80 100 Time from onset of MS (years) Percent Pts DSS < 6 p < 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

Relapses in Multiple Sclerosis
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 Total number of relapses during the study period Total in-study person-years

% Reduction in relapse rates
Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study 60% P<.0001 32% % Reduction in relapse rates 31% 29% 29% P<.0001 P=.0001 P=.055 18% P<.001 P=.04 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.

Relapses Can Result in Residual Long-Term Disability
Net Change in EDSS Score from before a Relapse to after a Relapse* 100 86 42.4% increase 0.5 or more 80 28.1% increase 1 or more 60 Number of Subjects 40 32 33 20 20 14 7 8 8 3 4 5 1 1 2 -3.5 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.5 4.0 42% of patients had a residual deficit ≥0.5 point 28% had a residual deficit ≥1.0 point *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:

Medical Costs Per Relapse
$243 $1847 $12,870 Low-Intensity Episode Moderate-Intensity Episode High-Intensity Episode Initial Contact Initial Contact Initial Contact Usual care physician Usual care physician Usual care physician ED ED Symptom-Related Medications IV Methylprednisolone Hospital Admission Hospital day case Post Discharge Services Home administration Outpatient follow-up Rehabilitation Home healthcare Skilled nursing Nursing home Hospital readmissions Follow-Up Office Visits Symptom-Related Medications Follow-Up Office Visits Consults Therapists ED = emergency department; IV = intravenous. O’Brien J, et al. BMC Health Serv Res. 2003;3(1):17-28.

Economic Implications
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) 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 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 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): O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:

Is MS All About Relapses?
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 Assumption: modifying the relapse rate will influence long-term disability Weinshenker et al Brain 112:1419

Proportion of Placebo Groups with Clinical Activity
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% 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.

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 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

Does Sustained Disability Measure Permanent Disability?
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 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 Liu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7.

Effect on Sustained Disability*: Summary of Phase III Trials
37% 6 mon P=.02 37% P=.02 30% 30% 29% P<.05 P=.02 P=NS 22% sustained disability progression (%) Reduction in P<.05 12% P=NS *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.

Summary 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 The generally accepted sustained change in EDSS measure is not a reliable marker of long term disability Phase III trials results showed: 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, glatiramer acetate and fingolimod have statistically significant impacts on the mean change in EDSS over two years

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

Cross Trial Comparisons Relative Efficacy (RR)
July 2006 Cross Trial Comparisons Relative Efficacy (RR) IFNβ-1a 30 µg 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% -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 © Merck KGaA Darmstadt/Germany

The REGARD Trial Time to First Relapse (1o endpoint)
July 2006 The REGARD Trial Time to First Relapse (1o endpoint) 1.00 672 days (96 weeks) 0.75 IFNβ-1a tiw GA Hazard ratio (95% CI): (0.74, 1.21) p = 0.643 Survival distribution function 0.50 0.25 0.00 100 200 300 400 500 600 700 Time to first relapse (days) © Merck KGaA Darmstadt/Germany

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 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 Relative efficacy is best measured by well-designed head to head trials

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

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

Therapeutic Decisions
July 2006 Sources of Bias in LTFU Studies Bias Impact Strategy 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. © Merck KGaA Darmstadt/Germany

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

July 2006 Glatiramer Acetate 15 year LTFU Time to reach confirmed Expanded Disability Status Scale 4, 6, and 8 for the mITT and Ongoing cohorts while they were on glatiramer acetate therapy. The mean disease duration at glatiramer acetate start for the mITT cohort was 8.3 years and for the Ongoing cohort was 8.4 years. Ford C et al. Mult Scler. 2010;16: © Merck KGaA Darmstadt/Germany

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 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 EDSS at baseline predicts EDSS at 15 years

Patients under regular medical care - no trial
July 2006 IFN β-1b LTFU Design Pivotal Study (n=372) IFNβ-1b 250 µg 124 56 Patients under regular medical care - no trial IFNβ-1b 50 µg 125 52 LTF Placebo 123 58 1988 1990 1993 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 Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3 © Merck KGaA Darmstadt/Germany

IFN β-1b LTFU Adjusted Outcome
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. 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<0.001 1 Exposure 2 High Low Ebers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666 Ebers G et al. presented at AAN, October 2006: M-3

Conclusions Disease 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 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 trials

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

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

Approximate Mean Annual Cost*
Cost of Care Cost and functionality 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 $21,291 $46,339 * US Dollars Non-Drug Costs Adapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.

DMT-Associated Costs Agent
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 National trend in MS drug expenditures was +18.3% in 2008 23.5% increase in manufacturer pricing was primary driver of trend Agent Dosage AWP/day AWP/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 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 2010.

Recent Analyses of the Economic Impact of MS Treatment
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 < ) 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 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.

Effect of Immunomodulatory Therapy on Employment Loss Time
60 (P = .003) 50 GA INFbeta-1a 40 INFbeta-1b (P = .04) 30 (P = .09) Fewer Days Absent (P = .03) (P = .18) 20 (P = .47) (P = .71) 10 (P = .33) (P = .39) Database contained records on workplace absence, short-term disability, and worker’s compensation data for 6 Fortune 200 company employees with MS. The total days absent of untreated MS patients over the study period (3 years) gave the baseline values for comparison. Treatment usually (with the exception of short term disability with INFbeta-1b) led to fewer days absent than was seen with the untreated patients. Results: (Compared to untreated patients with MS): Glatiramer acetate short-term disability (18.24 fewer days, P<0.03) worker’s compensation (29.50 fewer days, P<0.04) any reason (53.70 fewer days, P<0.003) Interferon beta-1a short-term disability (5.37 fewer days, P<0.33) worker’s compensation (13.27 fewer days, P<0.18) any reason (20.73 fewer days, P<0.09) Interferon beta-1b short-term disability (8.77 fewer days, P<0.39) worker’s compensation (13.07 fewer days, P<0.47) any reason (8.28 fewer days, P<0.71) Reference Lage MJ, Castelli-Haley J, Oleen-Burkey MA. Effect of immunomodulatory therapy and other factors on employment loss time in multiple sclerosis. Work. 2006;27: Abstract. The factors that influence time missed from work among individuals diagnosed with multiple sclerosis were the focus of this study. Records of individuals who were employed and diagnosed with multiple sclerosis between the years 1999 and 2002 (N = 284) were examined for details pertaining to their medical claims. Multivariate regressions, controlling for demographic characteristics, type of immunomodulatory medication, and overall severity of illness, were used in the examination of the total number of days missed from work for any reason and those missed due to absenteeism, short-term disability, or worker’s compensation. Results indicate that lost work time is affected by severity of illness, and type of immunomodulatory therapy. Comparing individuals treated with the specific immunomodulator glatiramer acetate, interferon beta-1a (intramuscular), or interferon beta-1b, to those who did not receive multiple sclerosis medications of this type; only glatiramer acetate was associated with significantly fewer days missed from work for short term disability (18.24 fewer days,P <0.03), worker’s compensation (29.50 fewer days,P <0.04) or any reason (53.70 fewer days,P <0.003). -10 Short-term Disability Workers Comp Any Reason -20 Fewer days absent from work from 1999–2002 for individuals with MS treated with GA (n = 28), INFb-1a (n = 74), or INFb-1b (n = 16) compared to untreated individuals with MS (n = 166) Lage MJ, et al. Work. 2006;27(2): /071401

MS Consensus Guidelines
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 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 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 Change treatments only for medically appropriate reasons National Clinical Advisory Board of the National MS Society. MS Disease Management Consensus Statement Accessed February 10, 2010.

Conclusion MS is a chronic, debilitating, and progressive disease
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 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

Questions to Consider How do you anticipate responding to the new MS treatment landscape that will include high cost, oral therapies that require monitoring measures? 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?

Questions to Consider 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? 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? How will Obamacare influence MS treatment decisions?

Investigations • Innovation • Clinical Application
Trial-Based Evidence for First Line Therapy with Immune- Modulating Agents (IMTs) From Mechanisms to Therapy—Landmark Studies, Long-Term Safety Data, and Clinical Experience with IMTs in the Managed Care Environment Suhayl Dhib-Jalbut, MD Professor and Chairman Department of Neurology Director Robert Wood Johnson Center for Multiple Sclerosis UMDNJ-Robert Wood Johnson Medical School New Brunswick, NJ

Existing and Emerging MS Therapies
2005 2006 2007 2010 2011 2012 2013 Oral Injectables BG12 Caldribine BG12 Cladribine Rebif Rebif Fingolimod Betaseron Ampyra Ampyra Teriflunomide Teriflunomide Copaxone Extavia Extavia Laquinimod Laquinimod Avonex Ocrelizumab Ocrelizumab IV Novantrone Tysabri Tysabri IV Generic Mitoxantrone (oncology) MS Generic Mitoxantrone (oncology) (MS) Alemtuzumab Alemtuzumab Filed Approved In phase II In phase III

Trends Across Clinical Trials Annualized Relapse Rate (ARR)
GA FTY720 Avonex NTZ 0.87 0.84 Betaseron Campath® Rebif Rituximab 0.67 0.59 0.36 0.37 0.34 0.35 0.32 0.29 0.30 0.28 0.27 0.23 0.16 0.10 Johnson 1995 Jacobs 1996 IFNβ-1b study group, 1993 PRISMS-2 1998 Kappos TRANS- FORMS Polman 2006 REGARD 2007 BEYOND 2007 BECOME 2007 CAMMS223 2008 3 years HERMES 2008 48 weeks FORTE 2008 1 year

Alemtuzumab 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 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 FDA-approved for B-CLL Muraro P, et al. Neurotherapeutics. 2007;4: Coles A, et al. J Neurol. 2006;253:

Alemtuzumab 12 mg daily IV Alemtuzumab 24 mg daily IV
IFNβ-1a 44 mcg thw SC Alemtuzumab 12 mg daily IV 24 77 Alemtuzumab 24 mg daily IV 22 88 Month Month Month Month 36 CAMMS223 Trial Investigators. NEJM 2008;359:

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

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

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

Alemtuzumab CAMMS223: Safety
Infections, % IFN ß-1a (n=107) Alem mg (n=108) Alem mg (n=108) Upper resp. infection* 27.1 44.4 50.9 Lower resp. infection* 1.9 11.1 13.9 Herpes simplex 2.8 8.3 Herpes zoster 0.9 5.6 Meningitis** 1.8 * P<0.001 alemtuzumab vs. IFN ** Listeria or viral meningitis CAMMS223 Trial Investigators. N Engl J Med. 2008;359:

Alemtuzumab: Effects on the Immune System
B cells returned to normal within 3-6 months Median recovery time for CD4+ T cells > 100 cells/µL = 3 months 6-9 months for CD4+ T cells > 200 cells/µL 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:

Cladribine 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 Selectively induces apoptosis in dividing and non-dividing lymphocytes 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 Reduces levels of pro-inflammatory chemokines Crosses the blood brain barrier - CSF concentration = 25% of plasma (patients with no BBB compromise) 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. 80

Cladribine 3.50 mg/kg total dose; 4 courses (n = 433)
X X X X X X Placebo (n = 437) 1326 patients X X X X X X Cladribine 3.50 mg/kg total dose; 4 courses (n = 433) X X X X X X Cladribine 5.25 mg/kg total dose; 6 courses (n = 456) –4 5 9 13 16 24 36 44 48 52 60 72 84 96 Time (weeks) MRI Neurological examination Dosing: 4-5 day courses at month 1 and 2 (3.50 mg/kg) or months 1-4 (5.25 mg/kg) and additional monthly courses beginning at week 48 Giovannoni G, et al. N Engl J Med. 2010;362: 81

CLARITY: Clinical Outcomes
0.33 ( ) 0.14* ( ) 0.15* 57.6% 54.5% Annualized relapse rate (95% CI) Odds Ratio (95% CI) 2.43 ( ) Percent of relapse-free patients at 98 weeks Odds Ratio (95% CI) 2.53 ( ) 78.9* 79.7* 60.9 Placebo (n = 437) Cladribine 3.50 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) * P < 0.001 Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Clinical Outcomes
25 Time to Confirmed EDSS Progression Placebo HR vs Placebo (95% CI) 20 Cladribine 3.50 mg/kg ( ); P = 0.02 Cladribine 5.25 mg/kg ( ); P = 0.03 15 Proportion with confirmed 3-month EDSS progression (%) 10 5 12 24 36 48 60 72 84 96 Weeks Placebo 3.50 mg 5.25 mg Giovannoni G, et al. N Engl J Med. 2010;362:

mean ± SE lesions/patient/scan T1 Gadolinium-Enhancing Lesions
CLARITY: MRI Outcomes 87.9% mean ± SE lesions/patient/scan 0.91 85.7% T1 Gadolinium-Enhancing Lesions Active T2-Weighted Lesions Combined Unique Lesions 1.72 0.43 0.38 74.4% 77.9% 1.43 0.38 0.33 73.4% 76.9% 0.12 0.11 Placebo (n = 437) Cladribine 3.50 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) All P < 0.001 Giovannoni G, et al. N Engl J Med. 2010;362:

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 zoster 8 (1.9) 11 (2.4) 19 (2.1) Herpes zoster oticus 1 (0.2) 1 (0.1) Varicella 2 (0.2) Any infection or infestation 188 (42.5) 205 (47.7) 222 (48.9) 427 (48.3) Deaths 2 (0.5) 2 (0.4) 4 (0.5) 20 patients had 21 zoster events in the cladribine groups 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 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 Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Safety and Tolerability
Malignancies 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 1(0.2) Ovarian 1 (0.1) Pancreatic 1 (0.2) Cervix During post-study surveillance Choriocarcinoma Giovannoni G, et al. N Engl J Med. 2010;362:

CLARITY: Effects on Lymphocyte Subsets
Maximum Effects on CD4 and CD 19 Counts* Weeks Weeks 48-96 mg/kg mg/kg mg/kg mg/kg CD4 (week) Cells/µL CD19 (week) 16 391 9 18 209 14 72 275 52 27 207 31 Add Reference *Median values Rieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, Poster #816.

Fingolimod (FTY720) Sphingosine-1-phosphate (S1P) receptor modulator
Sequesters circulating lymphocytes into secondary lymphoid organs 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 May inhibit the production of IL-17 S1P receptors located within the CNS Fingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE 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.

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 Month Month 24 1272 patients (1:1:1) Clinic visits Kappos L, et al. N Engl J Med. 2010;362: 89

FREEDOMS: Primary Efficacy Endpoint
Annualized Relapse Rate at 24 months -54% vs Placebo p < 0.001 -60% vs Placebo p < 0.001 β Placebo (n = 431) Fingolimod 0.5 mg (n = 429) Fingolimod 1.25 mg (n = 420) Kappos L, et al. N Engl J Med. 2010;362:

FREEDOMS: Disability Data
FTY mg (17%)† Days on study 5 10 15 20 25 30 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 = 0.03 vs placebo † P = 0.01 vs placebo Number at Risk FTY mg FTY mg Placebo Kappos L, et al. N Engl J Med. 2010;362:

FREEDOMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 24 Months -82% P<0.001 -74% P<0.001 Kappos L, et al. N Engl J Med. 2010;362:

FREEDOMS: Brain Volume
P≤0.03 for both doses of fingolimod vs. placebo at all time points Kappos L, et al. N Engl J Med. 2010;362:

Randomization Month 6 Month 12 Ongoing
Optional extension phase Oral fingolimod 0.5 mg once daily and matching weekly placebo injection IM 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 Randomization Month 6 Month 12 Ongoing Cohen J, et al. N Engl J Med. 2010;362:

TRANSFORMS: Primary Efficacy Endpoint
Annualized Relapse Rate at 12 months -52% vs IFNβ-1a, p < 0.001 -38% vs IFNβ-1a, p < 0.001 β IFNβ-1a 30 µg IM once weekly (n = 431) Oral fingolimod 0.5 mg (n = 429) Oral fingolimod 1.25 mg (n = 420) Cohen J, et al. N Engl J Med. 2010;362:

TRANSFORMS: MRI Endpoints
T2 and Gadolinium-Enhancing Lesions at 12 Months -35% vs. IFNß-1a P=0.004 -55% vs. IFNß-1a P<0.001 -42% vs. IFNß-1a P<0.001 -73% vs. IFNß-1a P<0.001 Cohen J, et al. N Engl J Med. 2010;362:

TRANSFORMS: Brain Volume
P < 0.001 Cohen J, et al. N Engl J Med. 2010;362:

Fingolimod: Safety Transient reduction in heart rate on initiation of treatment 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) Elevated liver enzymes ↑LFTs ≥ 3 x ULN 8% for FTY mg, 10% for FTY mg, 1.2% for placebo, 2% for IFNß-1a Macular edema 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%)) Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:

Malignancies and Herpes Infections
Fingolimod: Safety Malignancies and Herpes Infections AE, n (%) FTY mg (n = 854) FTY mg (n = 849) Placebo (n = 418) IFNß-1a (n = 431) Skin Cancers Basal cell carcinoma 7(0.8) 3(0.4) 3(0.7) 1(0.2) Melanoma 1(0.1) Bowen’s Disease 1 (0.1) Infections Herpes infections 46(5.4) 48(5.7) 33(7.9) 12(2.8) Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:

Fingolimod: Safety Two fatal infections in patients treated with FTY mg Herpes encephalitis primary disseminated varicella 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 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:

FTY720 1.25 mg (n = 16) Normal range Treatment duration (yrs),
mean ± SEM 1.9 ± 0.2 - Lymphocyte count (x 109/L), 0.4 ± 0.1 CD4 T cell count (cells/µL), 78 ± 5.6 CD8 T cell count (cells/µL), 149 ± 7.4 Mehling M, et al. Neurology 2008;71:1261–1267

Laquinimod A novel synthetic compound Route of administration – oral
Primary Indication – Relapsing remitting multiple sclerosis; two phase III studies ongoing Additional Indications – Crohn’s Disease; SLE 102

Phase IIb Laquinimod Study Patient Disposition
Screened (n=720) Randomized (n=306) Placebo (n=102) Laquinimod 0.3 mg (n=98) Laquinimod 0.6 mg (n=106) N=91 Completers (89.2%) N=92 Completers (93.8%) N=100 Completers (94.3%) Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:

Effect on T1 Gd Enhancing Lesions
Phase IIb - Laquinimod Effect on T1 Gd Enhancing Lesions Mean Median 51% reduction P < 60% reduction P=0.01 Mean Number of Cumulative Gd Enhancing Lesions (week 12-36) Median Number of Cumulative Gd Enhancing Lesions (week 12-36) PBO LQ 0.3mg LQ 0.6mg PBO LQ 0.3mg LQ 0.6mg * Adjusted means Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:

Phase IIb Laquinimod Study Effect on Annualized Relapse Rate
33% 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 Annualized Relapse Rate PBO LQ 0.3mg LQ 0.6mg Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:

Phase IIb Laquinimod Study Conclusions
An oral, once-daily dose of laquinimod 0.6mg has shown: A robust, consistent and early effect on MRI activity in RRMS patients A trend in reducing the number of relapses A trend in slowing the progression of brain atrophy Laquinimod 0.6mg is safe and tolerable

Elevations to Potentially Clinically Significant Levels
Phase IIb Laquinimod Study Safety No deaths No effect on vital signs No effect on ECG No specific pattern of adverse events Elevations to Potentially Clinically Significant Levels 0.6mg (n=106) 0.3mg (n=98) Placebo (n=102) 8 (7.5%) 2 (2.0%) 2 (1.9%) ALT (x3) 1 (0.9%) 3 (2.9%) AST (x3) Bilirubin (x2) Liver Enzyme Elevation: All cases are reversible Most normalized while on laquinimod No signs of liver damage/failure No concomitant bilirubinemia Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:

Laquinimod Does Not Cause Immunosuppression
It does not affect viability or proliferation of human PBMCs It does not affect the ability of animals to mount cellular or humoral immune responses It does not affect graft survival No clinical signs of opportunistic infections

Laquinimod is an Immunomodulator
Modulation of cytokine profile Reduction of leukocyte infiltration Down regulation of inflammatory genes Down regulation of MHC class II expression Effects on dendritic cells (DC) compartment

Laquinimod MoA In Multiple Sclerosis Summary
Laquinimod is an immunomodulator with both anti-inflammatory & neuroprotective properties: Shifts the cytokine balance towards a Th2/Th3 profile Reduces immune cell infiltration into the CNS Induces myelin and axonal preservation

Oral Laquinimod for RRMS Phase III Program
Completed enrollment of ~1100 RRMS patients ORAL LAQUINIMOD 0.6 MG 24 MONTHS OF TREATMENT OPEN LABEL EXTENSION ORAL MATCHING PLACEBO Completed enrollment of ~1300 RRMS patients ORAL LAQUINIMOD 0.6 MG AVONEX® 30MCG/WEEK OPEN LABEL EXTENSION 24 MONTHS OF TREATMENT ORAL MATCHING PLACEBO

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

Natalizumab and the Risk of PML

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

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

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

Questions to Consider 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? 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?

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

Questions to Consider How are changes made in MS therapy in your MCO? What criteria do new agents have to fulfill to merit inclusion on your clinical pathways? Do you need to fail one therapy, or multiple therapies, to accelerate therapy to a more intensive agent? Are treatment changes based on a consensus or is treatment individualized by the treating neurologist in the MCO setting?

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

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

Oral Agents for Multiple Sclerosis
Mechanism of Action Status Expected Dosing Dalfampridine Potassium channel blocker Approved for use by the FDA 10.0 mg twice daily Laquinimod Immunomdulator 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 FDA data accessed 10/14/10

Considerations as Therapy Shifts from Injectable to Oral Agents
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 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 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 Consider setting up follow-up schedule with MS patients 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 Utilize SWOT analysis to achieve realistic approach to MS patient care in a pharmacy setting

Oral Agents and Managed Care
4 oral agents on the horizon Dalfampridine, laquinimod, cladribine, fingolimod Discontinuation rates with current therapies as high as 46% Lack of efficacy (perceived and real) Adverse drug reaction Cost to the patient Injection anxiety Oral agents and adherence Better tolerated physically and psychologically Pts prefer receiving oral or inhaled medications 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 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

Oral Agents and Managed Care
Trends/Considerations 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 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 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

Collaborative Drug Therapy Management CDTM

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:

Pharmacovigilance

Pharmacovigilence 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 healthcare today, the pharmacist’s 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:

Community Pharmacists
Percentage of Professional ADR Reports Originating from Pharmacists by Country Country % Hospital Pharmacists Community Pharmacists Canada 88.3 + - USA 68 Australia 40.3 Netherlands 40.2 Japan 39 ? Spain 25.9 “+” 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:

Medication Therapy Management in the MS Patient MTM

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

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

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

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:

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

Considerations-Education
Increased pharmacist education about MS disease Access to quick reference with therapeutic options Counseling tips and FAQ’s 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 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 Use of alternative therapies to control and manage disease state Role of alternatives in treating neurologic 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 Address specific counseling opportunities and barriers in patient s with chronic neurological disease to colleges of medicine, pharmacy and nursing

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

Total Average Annual MS Cost by Presence of Selected Comorbid Conditions (2004)

MS Component Costs— Overall Population (2004)

Average Total Annual MS Cost by Disease-Modifying Drug Utilization (2004)

Newer Biologic Treatments in MS
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 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 Considerations/Speculations Consider newer oral therapies for treatment for potentially lower overall cost to both patients and MCO’s Joyce GF, et al. Am J Manag Care 2008;14(12):821-82

Considerations - Costs
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 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

Adherence The term adherence is preferred over compliance due to authoritative and paternalistic connotations of the latter Adherence: the extent to which a person’s behavior–taking medication, following diet guidelines, or enacting lifestyle changes—corresponds with recommendations from a health care provider Persistence and performance quality are also associated with adherence Non adherence rates with DMT’s 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

Adherent vs. Non-adherent Behavior
Utilization and consequent maintenance of therapy Keep treatment and aftercare appointments Take drugs correctly Active change to health lifestyle Complete treatment-related homework Reduce risk behaviors Non-adherent Complete refusal of therapy Refusal of specific treatment options 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

Motivations for Non-Adherence
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 Flushing Chest pain Palpitations Dyspnea Pain on injection Klauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92

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.

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.

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

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 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 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). 21st Annual Meeting of the Consortium for Multiple Sclerosis Centers, 2007 Washington, DC.

Patient Compliance Improves Through “Motivational Interviewing”
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 A patient may quit taking medication because they feel no improvement Determine motivation and increase probability that they will make good decisions Software available to aid Pharmacists in MI 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 Accessed 10/4/2010

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 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

Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Injury
Randomization Motivational Interviewing: experimental 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 accessed 10/4/2010

Strategies to Enhance Adherence to DMT’s
Establishing a therapeutic relationship Educating patient and family Increased adherence to treatment Managing patient expectations Managing adverse events Addressing patient concerns 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.

Sample Questions Providing Alternative Views for Patients with Injection Anxiety
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 If you were walking in the desert and had antivenin with you and a rattlesnake bit you, would you self-inject? 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.

Male vs. Female MS Characteristics
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 Majority of whom had RRMS 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 Considerations/Speculations 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 Vlahiotis A, et al. J Manag Care Pharm 2010;16:

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:

Determinants of 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:

Determinants of Adherence
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 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:

Disease Management Consensus Statement
Recommendations—National Multiple Sclerosis Society 2007 The Society recognizes that the factors that enter into a decision to treat are complex and best analyzed by the individual patient’s 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.* Expert Opinion Paper, National Multiple Sclerosis Society, 2007

Disease Management Consensus Statement
Recommendations—National Multiple Sclerosis Society 2007 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. Expert Opinion Paper, National Multiple Sclerosis Society, 2007

Recommendations Continued
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. 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

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. 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. Expert Opinion Paper, National Multiple Sclerosis Society, 2007

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

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:

Questions to Consider 1. How likely is the approval of new MS therapies— including both oral and injectable agents—change 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?

Questions to Consider 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. To what extent are your MS treatment decisions made based on ability to maintain patient employability? 7. To what extent do indirect vs direct costs influence your choice of MS therapy? 8. 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 9. Will oral therapies need regimen adherence monitoring? If so, how will this change your current approach for the injectables? 10. Given these considerations, in the absence of long-term data, how do you get to the bottom of benefit-risk-cost decision for MS therapy in the managed care setting? How will that play out?

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

To Treat or Not to Treat? 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 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 CHAMPS: Controlled High-Risk Subjects (IM IFNβ-1a) Avenox® Multiple Sclerosis Prevention ETOMS: Early Treatment of MS One additional ongoing study REFLEX: Rebif® (SC IFNβ-1a) FLEXible Dosing in Early MS IFN = interferon; IM = intramuscular; SC = subcutaneous.

Clinically Isolated Syndrome (CIS)
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 Patient may already have lesions on MRI Clinically definite MS (CDMS): second attack consistent with MS CIS = clinically isolated syndrome; MRI = magnetic resonance imaging; MS = multiple sclerosis.

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

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 showed a delay in physical disability and a significant reduction in either the number and/or volume of brain lesions.

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

Economic Impact of Multiple Sclerosis
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 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 1. Ivanova JI, et al. Pharmacoecomonics. 2009;27:

Key Parameters in MS Management: Disability
Death Normal neurologic exam Minimal disability Increased limitation in walking ability Need for walking assistance Restriction to wheelchair Helpless bed patient 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.0 4.5 3.5 2.5 3.0 2.0 1.5 1.0 0.5 Patient Disability Classification Expanded Disability Status Scale = Rating system used by neurologists and clinical trial investigators to follow the progression of disability in MS Kurtzke. Neurology. 1983;33:

Seven Approved Disease-Modifying Therapies
IM IFNβ-1a SC IFNβ-1a SC IFNβ-1b Glatiramer acetate Fingolimod Natalizumab Other first-line Mitoxantrone First-line therapies Second-line Therapy ? Worsening/ progressive disease Graphic courtesy of Dr. Robert J. Lipsy. Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.

FDA-Approved Therapies for MS Parenteral Immunomodulators
Agents* Indications Doses and Administration Glatiramer acetate1 (Copaxone®) CIS RRMS 20 mg/d SC Low-dose IFNβ-1a2 (Avonex®) 30 mcg/wk IM High-dose IFNβ-1a3 (Rebif®) CIS† 22 mcg or 44 mcg TIW SC High-dose IFNβ-1b4,5 (Betaseron®, Extavia®) 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®).

FDA-Approved Therapies for MS Parenteral Immunosuppressive
Agents* Indications Doses and Administration Natalizumab1 (Tysabri®) † Relapsing forms of MS 300 mg q4wk IV Mitoxantrone2 (Novantrone®) †† SPMS, PRMS, Worsening RRMS 12 mg/m2 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/m2. 1. Natalizumab (Tysabri®). 2. Mitoxantrone (Novantrone®) s030s031lbl.pdf

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

Safety Considerations: Fingolimod & Natalizumab
Lymphopenia is common because the drug sequesters lymphocytes in peripheral lymph nodes1,2 Reversal of lymphopenia can take ~ 2 to 4 weeks after the end of dosing, depending on the dose3 First dose problems within 6 hours Bradycardia1 Second-degree Wenckebach atrioventricular block Infections and malignancies Overall the 3 most important monitoring parameters: Heart rate Macular edema Pulmonary function tests (decrease FEV1) Natalizumab TOUCH program = Progressive multifocal leucoencephalopathy (PML) Infusion reactions When stopping Natalizumab bridging needs to occur to prevent immune reconstitution inflammatory syndrome (IRIS)4 TOUCH = Tysabri Outreach Unified Commitment to Health FEV1 = forced expiratory volume in 1 second. 1Brown et al. Ann Pharmacother ;41: ; 3Kappos et al. N Engl J Med. 2006;355: Robinson R. Neurology Today. 07 OCT 2010;10(19):1,21.

Phase IIb Laquinimod Study Effect on Annualized Relapse Rate
33% 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 Annualized Relapse Rate PBO LQ 0.3mg LQ 0.6mg Comi, et al (LAQ/5062 Study Group). Lancet. 2008;371:

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

Conclusions & Summary Laquinimod showed a robust, reproducible, sustained and early effect on MRI activity Laquinimod 0.6mg is safe and tolerable Transitory elevations of liver enzymes, most in the first 3 months of Tx 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

Which ABCR Drug Is Best? INFβ vs INFβ
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. 1Durelli et al. Lancet ;359: ; 2Panitch et al. Neurology 2002;59: ; 3Clanet et al. Neurology 2002;59: ; 4Comi G. Presented at: American Academy of Neurology 60th Annual Meeting; April 16, 2008; Chicago, IL. Abstract: LBS.003. 189

Which ABCR Drug Is Best? INFβ 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 60th 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: 190

Which New Agent is Best? New Agent vs. INFβ
SENTINEL trial1 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 T2-lesions and an 89% reduction with gadolinium-enhancing lesions. TRANSFORMS trial2 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 1Rudick 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:

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

Patient Adherence to MS Medication
MS poses unusual challenges to adherence Needle phobia New daily routines Perceived lack of efficacy According to adherence studies Many patients display new or increased depression within 6 months of treatment initiation1 Depressed patients displayed decreased adherence1 Treating depression may prevent treatment discontinuation1 Most frequent cause of stopping treatment is perceived lack of efficacy2 Most treatment withdrawals occur within 1st year of treatment2 Side effects and tolerability issues can result in nonadherence or discontinuation of medications Multiple sclerosis is a complicated disease and may not be well-understood among the patient population. Patients suffering from aichmophobia (fear of needles) may not only have difficulty with initiating parenteral therapy but also with continuing therapy if the phobia is never overcome. Patients may encounter barriers in adopting a new daily routine, especially one that involves injections. Additional barriers arise if the patient expects low treatment efficacy. With the introduction of oral therapy to the market, patient adherence to disease-modifying drugs may increase. This less invasive route of administration will eliminate non-adherence stemming from aichmophobia and reluctance to adapt a new daily routine involving injections. Oral medications can also be taken “on-the-go,” allowing for more flexible lifestyles, while parenteral therapy must be administered at home or in a medical facility. In a 1997 study in the Archives of Neurology, 41% of patients reported new or increased depression within 6 months of starting interferon treatment. Patients experiencing symptoms of depression were more likely than others to discontinue treatment. The study’s concluding remarks suggested that treating patient-reported depression may increase adherence to disease-modifying therapy. In a more recent study (2007) in the Journal of Neurological Sciences, it was concluded that the most frequent cause of stopping treatment is the perceived lack of efficacy. The study also determined that most withdrawals from treatment occur during the first year. This information illustrates again the importance of patient education and overall well-being. 1. Mohr DC, et al. Arch Neurol. 1997;54: Clerico M, et al. J Neurol Sci. 2007;259: 193

Adherence Between 17% and 40% of patients stop taking disease-modifying drugs within 1 year of initiation1-3 Multifactorial Perceived lack of efficacy1,2 Adverse effects2,3 Depression Within 6 months of treatment initiation, 41% of patients had new or increased depression4 Decreased adherence in patients with untreated depression4 Multiple sclerosis is a complicated disease and may not be well-understood among the patient population. Patients suffering from aichmophobia (fear of needles) may not only have difficulty with initiating parenteral therapy but also with continuing therapy if the phobia is never overcome. Patients may encounter barriers in adopting a new daily routine, especially one that involves injections. Additional barriers arise if the patient expects low treatment efficacy. With the introduction of oral therapy to the market, patient adherence to disease-modifying drugs may increase. This less invasive route of administration will eliminate non-adherence stemming from aichmophobia and reluctance to adapt a new daily routine involving injections. Oral medications can also be taken “on-the-go,” allowing for more flexible lifestyles, while parenteral therapy must be administered at home or in a medical facility. In a 1997 study in the Archives of Neurology, 41% of patients reported new or increased depression within 6 months of starting interferon treatment. Patients experiencing symptoms of depression were more likely than others to discontinue treatment. The study’s concluding remarks suggested that treating patient-reported depression may increase adherence to disease-modifying therapy. In a more recent study (2007) in the Journal of Neurological Sciences, it was concluded that the most frequent cause of stopping treatment is the perceived lack of efficacy. The study also determined that most withdrawals from treatment occur during the first year. This information illustrates again the importance of patient education and overall well-being. Rio J, et al. 17% (107/632) had stopped IMD More patients with SPMS stopped than RRMS ½ stopped because of lack of efficacy ¼ stopped because of side effects ¼ stopped for reasons unrelated to efficacy or side effects 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: 194 194

Studies of Patient Adherence to MS Medications
Longitudinal, prospective study of 199 patients with definite MS Of 97 patients taking DMT 73% missed doses 10% missed >10 doses in a 6-month period 25% stopped DMT Missed doses were associated with alcohol intake History of missed doses predicted future missed doses Numerous and divergent factors influenced missed doses and stopping DMT Indicates need for multifaceted approach to improving adherence Tremlett H, et al. Pharmacoepidemiol Drug Saf. 2008;17: 195

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.

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:

Promoting Adherence to Therapeutic Regimens in MS Establishing Realistic Expectations
Therapies have been shown to reduce relapses, reduce MRI activity, and attenuate disease activity Attenuated disease activity may lead to more patients retaining employment Patients with MS must also realize that DMTs Only work if patients take them Are not cures for MS May not eliminate MS symptoms 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 198

Disease-Modifying Therapies
Relapse free at 1 year 51%–80% Relative decrease in annual relapse rate 30%–80% Absolute annual relapse rate 0.15–0.7 Relative decrease in sustained progression 31%–42% Absolute rate of disease progression 9%–18% Workers with MS on a DMT and not on a DMT1 N=258 vs. N=322 Treatment with DMT = reduced medical and indirect costs Data courtesy of Dr. Robert J. Lipsy.1. Birnbaum et al Curr Med Res Opin ;25(4):

Questions to Consider 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? 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? 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?

The Evolving Landscape of MS Therapy

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