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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 A Dilemma and Clinical Decision Update for the Managed Care Physician. Program Chairman Bruce A. Cree, MD, PhD, MCR

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The Evolving Landscape of MS Therapy

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  1. 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

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

  3. 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

  4. 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 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.

  5. 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 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.

  6. 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.

  7. Pre-clinical CIS RRMS SPMS Clinical Threshold Atrophy and Axonal Degradation Predicted Cost Early Intervention* MRI lesion activity Natural History of MS and Cost of MS US$ per Year *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.

  8. 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 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.

  9. Baseline Brain MRI Lesion Number20-Year Clinical Status Fisniku LK. Brain 2008;131:808-817.

  10. Baseline Brain MRI Lesion Number20-Year Clinical Status Fisniku LK. Brain 2008;131:808-817.

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

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

  13. 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

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

  15. 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

  16. 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

  17. Analyzing Risk-to-Benefit Equation forEstablished 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

  18. 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?

  19. 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?

  20. Investigations • Innovation • Clinical Application A New Era of Oral Therapy for Multiple SclerosisThe 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

  21. 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

  22. The Evolving Landscape of MS Therapy Mechanisms of Action

  23. Blood BBB CNS MMP TH1+ IFN-β IFN-β Myelinprotein Antigen TH1+ TH1+ TH1 APC APC MMP IL-2 TH1+ RestingT cell TNF-α IFN-γ Activated (+)T cells IFN-: Activity Adapted from Yong VW. Neurology. 2002;59:802-808.

  24. APC Glatiramer Acetate: Activity BBB Periphery CNS Macrophage Microglia Bystandersuppressioneffect APC MHC GA TCR MHC CNS Ag TCR GA therapy IL-4 IL-10 BDNF TCR Anti-inflammatory cytokines + + Neurotrophins GA-specificT cell Neuroregeneration TH1 TH2 TH2 Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:109-112.

  25. Fingolimod: Modulates S1P1 receptors S1Preceptor Prevents T cell invasion of CNS T cell FTY720-P LN FTY720 traps circulating lymphocytes in peripheral lymph nodes FTY720 results in internalisation of the S1P1receptor This blocks lymphocyte egress from lymph nodes while sparing immune surveillance by circulating memory T cells

  26. Laquinimod Induced Immunomodulation on the Molecular Level Overexpression/downregulation

  27. Low (0-1 attacks in 2 years) Intermediate (2-4 attacks in 2 years) High (> 5 in 2 years) Long-Term DisabilityEffect of Early Relapses 100 80 60 Percent Pts DSS < 6 40 p < 0.0001 20 0 0 10 20 30 40 50 Time from onset of MS (years) Weinhenker B et al. Brain. 1989;112:1422

  28. 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

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

  30. Relapses Can Result inResidual Long-Term Disability Net Change in EDSS Score from before a Relapse to after a Relapse* 100 42.4% increase 0.5 or more 86 80 28.1% increase 1 or more 60 Number of Subjects 33 40 32 20 14 20 8 8 7 5 4 3 2 1 1 0 -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.

  31. 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.

  32. 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. MultScler. 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. MultScler. 2005;11(2):232-239. O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:918-926.

  33. 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

  34. Proportion of Placebo Groups with Clinical Activity Jacobs et al. Ann Neurol. 1996;39:285; IFNB MS Study Group. Neurology. 1993;43:655; IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277; Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701; PRISMS Study Group. Lancet. 1998;352:1498.

  35. 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

  36. 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.

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

  38. 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

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

  40. Cross Trial ComparisonsRelative Efficacy (RR) Predict: IFNβ-1a tiw will be superior to GA for relapse free outcome

  41. The REGARD TrialTime to First Relapse (1o endpoint) 1.00 672 days (96 weeks) IFNβ-1a tiw 0.75 GA Hazard ratio (95% CI): 0.943 (0.74, 1.21) p = 0.643 Survival distribution function 0.50 0.25 0.00 0 100 200 500 300 400 600 700 Time to first relapse (days)

  42. 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

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

  44. 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?

  45. Sources of Bias in LTFU Studies

  46. Glatiramer Acetate 15 year LTFU Ford C et al. MultScler. 2010;16:342-50.

  47. Glatiramer Acetate 15 year LTFU Ford C et al. MultScler. 2010;16:342-50.

  48. 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

  49. 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 LTF 125 52 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

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