The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy Practice Emerging Challenges on the Therapeutic Landscape of Multiple Sclerosis A Dilemma and Clinical Decision Update for the Managed Care Physician 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

Program Faculty Bruce A. Cree, MD, PhD, MCR Brian Steingo, MD   Bruce A. Cree, MD, PhD, MCR Assistant Professor of Neurology Department of Neurology University of California San Francisco Multiple Sclerosis Center San Francisco, California Brian Steingo, MD Medical Director Neurologic Associates Research Fort Lauderdale MS Center Pompano Beach, FL  

The Evolving Landscape of MS Therapy 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 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

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 < .0001 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;359:1221-1231. Hogancamp W, Rodriguez M, Veinshenker BG. Symposium on multiple sclerosispart III. The epidemiology of multiple sclerosis. Mayo Clin Proc. 1997;72:871-878. The National MS Society Information Sourcebook. Available at: www.nationalmssociety.org/sourcebook.asp. 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):1221-1231. Frohman EM. Med Clin N Am. 2003;87(4): 867-897. Hogancamp WE, et al. Mayo Clin Proc. 1997;72(9):871-878. National Multiple Sclerosis Society. Who gets MS? http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed January 8, 2009. Lage MJ, et al. Work. 2006;27(2):143-151.

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):727-730.

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. http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/symptoms/index.aspx. 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):26-31. [Exhibit 8]. Comi G. Neurol Sci. 2006;27:S8-S12. Kobelt G, et al. Neurology. 2006;66(11):1696-1702.

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;33:1444-1452.

Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:808-817.

Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:808-817.

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 Cladribine 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

The Evolving Landscape of MS Therapy 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  

The Evolving Landscape of MS Therapy 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?  

Questions We Will Address Today 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?  

Investigations • Innovation • Clinical Application A New Era of Oral Therapy for Multiple Sclerosis The Good, The Bad, The Uncertain— Cautionary Notes for Managed Care Physicians   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

The Evolving Landscape of MS Therapy 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;59:802- 808. Adapted from Yong VW. Neurology. 2002;59:802-808.

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;233:109-112. 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;102:19045-19050. 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;233:109-112.

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 27

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 < 0.0001 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;362:387-401; 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;61:1528-1532.

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):419-425. Pope GC, et al. Neurology. 2002;58(1):37-43. Kobelt G, et al. Neurology. 2006;66(11):1696-1702. Patwardhan MB, et al. Mult Scler. 2005;11(2):232-239. O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:918-926.

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. 1989 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;362:387-401; 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

The Evolving Landscape of MS Therapy 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): 0.943 (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;16:342-50.

Glatiramer Acetate 15 year LTFU 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;16:342-50. © Merck KGaA Darmstadt/Germany

Glatiramer Acetate 15 year LTFU 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):1696-1702.

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 0 - 3.5 $3,106 $932 $9,938 $13,976 Moderate EDSS 4.0 - 6.0 $5,100 $3,188 $22,950 $31,238 Severe EDSS 6.5 - 9.5 $12,524 $21,291 $46,339 * 2004 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):44-52. CuraScript 2008 Specialty Drug Trend Report. April 2009. 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 < 0.0001) Risk-adjusted total annual medical costs ($4,393 vs $6,187) and indirect costs ($2,252 vs $3,053) were significantly lower (P < 0.0001) 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):869-877. 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;27:143-151. 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):143-151. 07290601/071401

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. 2007. http://www.nationalmssociety.org. 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 Redefining the Long-Term Benefit-to-Risk Equation for Therapy of Multiple Sclerosis Implications for the Managed Care Setting   Brian Steingo, MD Medical Director Neurologic Associates Research Fort Lauderdale MS Center Pompano Beach, FL

Existing and Emerging MS Therapies 2005 2006 2007 2010 2011 2012 2013 Oral Injectables BG12 Cladribine 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;4:676-692. Coles A, et al. J Neurol. 2006;253:98-108.

Alemtuzumab 12 mg daily IV Alemtuzumab 24 mg daily IV IFNβ-1a 44 mcg thw SC 107 95 80 66 Alemtuzumab 12 mg daily IV 24 77 108 102 101 92 Alemtuzumab 24 mg daily IV 22 88 108 105 104 92 Month 0 Month 12 Month 24 Month 36 CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.

Alemtuzumab CAMMS223: Co-Primary Endpoints (36 months) CAMMS223 Trial Investigators. NEJM 2008;359:1786-1801.

Alemtuzumab CAMMS223: MRI Outcomes Months 0-12 0-24 0-36 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 0-36 12-36 P≤0.03 for both doses of alemtuzumab vs. IFN at m 0-12 and 0-24. P=NS at m 0-36 CAMMS223 Trial Investigators. N Engl J Med. 2008;359:1786-1801.

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;359:1786-1801.

Alemtuzumab CAMMS223: Safety Infections, % IFN ß-1a (n=107) Alem 12 mg (n=108) Alem 24 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;359:1786-1801.

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;253:98-108.

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. 73

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 2 additional monthly courses beginning at week 48 Giovannoni G, et al. N Engl J Med. 2010;362:416-426. 74

CLARITY: Clinical Outcomes 0.33 (0.29-0.38) 0.14* (0.12-0.17) 0.15* 57.6% 54.5% Annualized relapse rate (95% CI) Odds Ratio (95% CI) 2.43 (1.81-3.27) Percent of relapse-free patients at 98 weeks Odds Ratio (95% CI) 2.53 (1.87-3.43) 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;362:416-426.

CLARITY: Clinical Outcomes 25 Time to Confirmed EDSS Progression Placebo HR vs Placebo (95% CI) 20 Cladribine 3.50 mg/kg 0.67 (0.48-0.93); P = 0.02 Cladribine 5.25 mg/kg 0.69 (0.49-0.96); P = 0.03 15 Proportion with confirmed 3-month EDSS progression (%) 10 5 12 24 36 48 60 72 84 96 Weeks Placebo 437 424 399 373 355 333 315 304 304 3.50 mg 433 424 407 389 379 364 355 347 347 5.25 mg 456 447 425 404 388 375 363 350 350 Giovannoni G, et al. N Engl J Med. 2010;362:416-426.

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;362:416-426.

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;362:416-426.

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;362:416-426.

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;41:1660-1668. 2. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 3. 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 6 Month 12 Month 24 1272 patients (1:1:1) Clinic visits Kappos L, et al. N Engl J Med. 2010;362:387-401. 81

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;362:387-401.

FREEDOMS: Disability Data FTY720 1.25 mg (17%)† Days on study 90 180 270 360 450 540 630 720 5 10 15 20 25 30 Placebo (24%) FTY720 0.50 mg (18%)* Percent with 3-month confirmed EDSS progression FTY720 0.50 mg vs placebo HR 0.70 P = 0.02 in time to disability Progression FTY720 1.25 mg vs placebo HR 0.68 * P = 0.03 vs placebo † P = 0.01 vs placebo Number at Risk FTY720 1.25 mg 429 401 373 356 344 332 322 305 165 FTY720 0.50 mg 425 416 388 370 354 340 332 321 152 Placebo 418 391 371 341 320 308 290 279 143 Kappos L, et al. N Engl J Med. 2010;362:387-401.

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;362:387-401.

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;362:412-415.

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;362:412-415.

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;362:412-415.

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 FTY720 0.5 mg, 10% for FTY720 1.25 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;362:387-401. Cohen J, et al. N Engl J Med. 2010;362:412-415.

Malignancies and Herpes Infections Fingolimod: Safety Malignancies and Herpes Infections AE, n (%) FTY720 0.5 mg (n = 854) FTY720 1.25 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;362:387-401. Cohen J, et al. N Engl J Med. 2010;362:412-415.

Fingolimod: Safety Two fatal infections in patients treated with FTY720 1.25 mg Herpes encephalitis primary disseminated varicella Hemorrhagic encephalitis in a patient treated with FTY720 1.25 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;362:412-415; Kappos L et al. N Engl J Med. 2006;355:1124-40; Leypoldt F, et al. LK. Neurology 2009;72:1022-24.

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 0.9-3.3 CD4 T cell count (cells/µL), 78 ± 5.6 700-1100 CD8 T cell count (cells/µL), 149 ± 7.4 500-900 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 92

Effect on T1 Gd Enhancing Lesions Phase IIb - Laquinimod Effect on T1 Gd Enhancing Lesions Mean Median 51% reduction P < 0.0001 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;371:2085-92.

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;371:2085-92.

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;371:2085-92.

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 ALLEGRO 24 MONTHS OF TREATMENT OPEN LABEL EXTENSION ORAL MATCHING PLACEBO Completed enrollment of ~1300 RRMS patients ORAL LAQUINIMOD 0.6 MG BRAVO 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;145:1037-39.

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;145:1037-39.

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?