2 The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy PracticeEmerging Challenges on the Therapeutic Landscape of Multiple SclerosisThe Managed Care Pharmacy and Medical Director’s PerspectiveProgram ChairmanDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis CenterAdvance NeurologyAdvance, NC
3 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.
4 Program Faculty Program Chairman Ronald J. DeBellis, PharmD, FCCP Douglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis CenterAdvance NeurologyAdvance, NCNorman Kachuck, MD Associate Professor of Neurology Chief, Neuroimmunology Division, Department of Neurology Director, Multiple Sclerosis Comprehensive Care Center and Research Group Vice-Chair, Health Sciences IRB University of Southern California KeckSchool of Medicine Los Angeles, California Ronald J. DeBellis, PharmD, FCCPProfessor and ChairmanDepartment of Pharmacy Practice-VermontCampusAlbany College of Pharmacy and HealthSciencesColchester, VTJacquelyn Bainbridge, PharmD, FCCP Associate Professor Department of ClinicalPharmacy/Department of Neurology University of Colorado DenverAurora, CO
5 Program Agenda and Format 8:00 AM — 8:20 AMWelcome and IntroductionThe Evolving and Complex Therapeutic Landscape for Multiple Sclerosis: Achieving the Ideal Balance Between Safety and Efficacy for Long-Term Treatment In the Managed Care SettingWhat Will Goals of MS Management in the Managed Care Setting Be? How Should MCO Pharmacists, Medical Directors, and Neurologists Respond?Program ChairmanDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis Center │ Advance Neurology │ Advance, NC8:20 AM — 8:40 AMGroup Discussion: Discuss Emerging Concerns, Challenges, and Strategic Needs for Optimizing MS Care in the Managed Care Environment
6 Program Agenda and Format 8:40 AM — 9:05 AMTrial-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 EnvironmentCurrent Foundations of MS Care in the Managed Care Setting: What Has Worked? What Hasn’t? Where Is the Room for Improvement?Program ChairmanDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis Center │ Advance Neurology │ Advance, NC9:05 AM — 9:20 AMGroup Discussion: Discuss Current Strategies and MS Treatment Paradigms Using IMT-Based Platforms for Initial Therapy for MS in the Managed Care Setting
7 Program Agenda and Format 9:20 AM — 9:45 AMThe Emergence of Oral Immunosuppressive and Other Agents for MS: What Do We Know (or Not Know) About Their Safety and Efficacy?Cautionary Notes for Managed Care Pharmacy and Medical Directors, and MS Treaters in Managed Care: How Do We Monitor Adverse Events, Risks for Infection, and Signals for Malignancy Over the Long Term?Norman Kachuck, MD Associate Professor of Neurology │ Chief, Neuroimmunology Division, Department of Neurology │ Director, Multiple Sclerosis Comprehensive Care │ Center and Research Group │ Vice-Chair, Health Sciences IRB │ University of Southern California Keck School of Medicine │ Los Angeles, California9:45 AM — 10:00 AMGroup Discussion: Discuss Complexity of Evolving Agents for MS and Approaches to Making a Risk-Benefit Analysis
8 Program Agenda and Format 10:00 AM — 10:20 AMThe 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, FCCPProfessor and Chairman │Department of Pharmacy Practice-Vermont Campus │Albany College of Pharmacy and Health Sciences │Colchester, VT10:20 AM — 10:40 AMGroup Discussion: The Near Future of MS Care
9 Program Agenda and Format 10:40 AM — 11:00 AMThe Role of Comparative Effectiveness Guidelines, Long Term Safety Considerations, and Monitoring Costs for Evaluating Therapies for MSImpact on Managed Care-Based Management for Improving Health Outcomes and Providing Value for their Health Plans—The Managed Care Medical and Pharmacy Director’s PerspectiveJacquelyn Bainbridge, PharmD, FCCP Associate Professor │ Department of Clinical │ Pharmacy/ Department of Neurology │ University of ColoradoDenver │ Aurora, CO11:00 AM — 11:30 AMGroup 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?
10 Format: We Want a Dialogue PROGRAM FORMATFollowing 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.”
11 Epidemiology of Multiple Sclerosis The most common chronic disease affecting the CNS in young adultsApproximately 400,000 cases in the United StatesEstimates range from 250,000 to 500,000The chances of developing MS are 1:1000 in the general populationEstimated 2.5 million cases worldwideHighest incidence in CaucasiansHigher incidence in women (approximately 3:1)MS strikes individuals between the ages 20-50, normally a time of peak productivityAccording 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 sclerosispart 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):
12 Age of Onset of Multiple Sclerosis Distribution of Patients According tothe Decade of Life of MS Symptoms Onset35302520Patients (%)151050-1011-2021-3031-4041-5051-60YearsCardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):
13 Clinical Manifestations of MS FatiguePainDepressionNumbness/paresthesiasCognitive dysfunctionWeaknessSpasticityOptic neuritisBladder dysfunctionBowel dysfunctionCerebellar dysfunctionSexual dysfunctionGait abnormalitiesPartial/complete paralysisNational Multiple Sclerosis Society. Accessed February 21, 2010.
14 Natural History of MS and Cost of MS CISRRMSSPMSPre-clinicalPredicted CostEarly Intervention*MRI lesion activityClinical ThresholdAtrophy and Axonal DegradationUS$ per YearIt 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 EDSSBurks 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):
15 Progression of Disability: EDSS 10.0 = Death due to MS9.0–9.5 = Completely dependentIncreasing disease burden8.0–8.5 = Confined to bed or chair7.0–7.5 = Confined to wheelchair6.0–6.5 = Walking assistance is needed5.0–5.5 = Increasing limitation in ability to walk4.0–4.5 = Disability is moderateAll 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 ambulatoryRating 5 to 9.5 are defined by impact on ambulation.Critique: weighted too heavily on gaitIn 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 1983To 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 moderate2.0–2.5 = Disability is minimal1.0–1.5 = No disability0 = Normal neurologic examEDSS = Expanded Disability Status Scale.Kurtzke JF. Neurology. 1983;33:
16 Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:
17 Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:
18 Immunopathogenesis of the MS Lesion CD8Ab+C9neogdTMOOligoNOOiTNFaMMPPlVirusBHistamineProteasesTNFaNAA, ATPNOO25-HTIFNgTNFTh17Th2/Th3TregIL-10TGFbGlutamateB7CD28MCP-1MIP-1aIP-10RANTESCD4+CD25+Th1Th17MicrogliaMast CellAstrocyteCD40CD40LBBBVCAM-1Mast CellICAM-1VCAM-1MMP-2/9IL-4IL-5IL-6IL-13TGFbTregTh2/Th3BComplementLFA-1VLA-4gdTTh1Th17MonocyteIFNgTNFIL-17IL-23IL-4 & IL-10GranutocyteCD8IL-12B7CD28CD4APCCD4HLAAPCTCRThpThpMyelin AgMicrobial AgFigure courtesy of Dhib-Jalbut S, 2008CD40CD40L
19 Trends Across MS Clinical Trials Annualized Relapse Rate (ARR) Johnson1995Polman2006REGARD2007BECOMEKapposTRANSFORMSJacobs1996IFNβ-1bstudygroup,1993PRISMS-21998BEYONDCAMMS22320083 yearsHERMES48 weeksFORTE1 yearCLARITY2009
20 Goals of Treatment Reduce frequency of relapse Slow progression of disabilityReduce MRI activityPrevent morbidity from symptoms and provide palliative careMaintain adherenceProvide long-term efficacy and safety
21 Existing and Emerging MS Therapies 2005200620072010201120122013OralInjectablesBG12CladribineBG12CladribineRebifRebifFingolimodBetaseronAmpyraAmpyraTeriflunomideTeriflunomideCopaxoneExtaviaExtaviaLaquinimodLaquinimodAvonexOcrelizumabOcrelizumabIVNovantroneTysabriTysabriIVGenericMitoxantrone(oncology) MSGeneric Mitoxantrone(oncology) (MS)AlemtuzumabAlemtuzumabFiledApprovedIn phase IIIn phase III
22 The Evolving Landscape of MS Therapy New generation of multiple sclerosis therapies is currently emergingAmong them are four oral agents: dalfampridine, laquinimod, cladribine, and fingolimod, that have been or likely will be approved for managing patients with MSEfficacy data for these new oral agents are impressive and demonstrate that they have the potential to replace or complement injectable treatment options for MS
23 The Evolving Landscape of MS Therapy However, there are concerns relating to safety and cost, especially for the immunosuppressive agentsIn addition, patients with MS have poor treatment adherence to the current available therapies and it is uncertain if the introduction of oral agents will increase patient adherence
24 Analyzing Risk-to-Benefit Equation for Established and Emerging Agents E F F I C A C YR I S K vs.B E N E F I TV A L U ES A F E T YD O S I N GQ U A L I T Y
25 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?
26 The Evolving Landscape of MS Therapy 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?
27 The Evolving Landscape of MS Therapy MISSION STATEMENTThe purpose of this “Challenges and Solutions” Workshop is to discuss possible approaches for evaluating the risk-benefit-cost profiles of these new oral agents; to compare them against established IMTs and each other; to evaluate the implications for long-term safety monitoring and pharmacovigilance that will be required, especially for immunosuppressive agents; how placement of these oral agents on managed care organization (MCO) formularies may also influence and/or modify use of established IMTs; and what impact this landscape change might have on clinical outcomes of MS patients managed in MCOs.
28 The Evidence for First Line Therapy with Immune-Modulating Agents Investigations • Innovation • Clinical ApplicationThe Evidence for First Line Therapy with Immune-Modulating AgentsLandmark Trials, Perils and Pitfalls of Cross-Trial Comparisons, and What can be Learned from Long Term StudiesProgram ChairmanDouglas R. Jeffery, MD, PhDDirector, Multiple Sclerosis CenterAdvance NeurologyAdvance, NC
29 Overview of Presentation Mechanisms of action of IMTsOutcome measures in clinical trialsComparison of landmark trialsLongitudinal studies: what do they tell us?Price of MS versus cost of treatment
30 The Evolving Landscape of MS Therapy Mechanisms of Action
31 Adapted from Yong VW. Neurology. 2002;59:802-808. IFN-: ActivityTH1+Resting T cellMMPActivated (+) T cellsBBBBloodCNSTNF-αIFN-γIL-2TH1APCIFN-βMyelin proteinAntigenActivity of IFN-IFN-β has the following effects at the BBB.1It 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:
32 Glatiramer Acetate: Activity BBBPeripheryCNSMacrophageMicrogliaBystander suppression effectAPCMHCGATCRAPCMHCCNS AgTCRGA therapyIL-4IL-10BDNFTCRAnti-inflammatory cytokinesActivity of Glatiramer AcetateOn 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.1,3References1. 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.++NeurotrophinsGA- specific T cellNeuroregenerationTH1TH2TH2Adapted from Ziemssen T et al. J Neurol Sci. 2005;233:
33 Fingolimod: modulates S1P1 receptors LNS1P receptorPrevents T cell invasion of CNST cellFTY720-PFTY720 traps circulating lymphocytes in peripheral lymph nodesFTY720 results in internalisation of the S1P1 receptor This blocks lymphocyte egress from lymph nodes while sparing immune surveillance by circulating memory T cells
34 Laquinimod Induced Immunomodulation on the Molecular Level Overexpression/downregulation34
35 Long-Term Disability Effect of Early Relapses 50403020106080100Time from onset of MS (years)Percent Pts DSS < 6p <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
36 Relapses in Multiple Sclerosis Relapses are the most obvious evidence of inflammatory disease activity in RRMSRelapse frequency in typical untreated RRMS populations enables treatment effect to be rapidly assessable in a 12-month clinical studyTotal number of relapses during the study periodTotal in-study person-years
37 FREEDOMS Primary Endpoint: Annualized Relapse Rate 0.40.40p<0.001p<0.0010.354% reduction60% reductionAnnualized relapse rate0.20.180.160.1% relative reduction vs Placebo is 54% for fingolimod 0.5mg and 60% for fingolimod 1.25mg respectivelyPlacebo(n=418)Fingolimod 0.5 mg(n=425)Fingolimod 1.25 mg(n=429)ARR was consistently reduced in both treatment-naïve patients and patients previously treated with DMT (p<0.01 for all comparisons)ITT populationNegative binomial regression model adjusted for treatment group, country, number of relapses in previous two years and baseline Expanded Disability Status ScaleARR, annualized relapse rate; DMT, disease-modifying therapy3737
38 % Reduction in relapse rates Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study60%P<.000132%% Reduction in relapse rates31%29%29%P<.0001P=.0001P=.05518%P<.001P=.04N.B.: Results are from separate clinical trialsJacobs 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.
39 Relapses Can Result in Residual Long-Term Disability Net Change in EDSS Score from before a Relapse to after a Relapse*1008642.4% increase 0.5 or more8028.1% increase 1 or more60Number of Subjects403233202014788345112-3.5-2.5-2.0-1.5-1.0-0.50.00.51.01.52.02.53.54.042% of patients had a residual deficit ≥0.5 point28% 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:
40 Medical Costs Per Relapse $243$1847$12,870Low-Intensity EpisodeModerate-Intensity EpisodeHigh-Intensity EpisodeInitial ContactInitial ContactInitial ContactUsual care physicianUsual care physicianUsual care physicianEDEDSymptom-Related MedicationsIV MethylprednisoloneHospital AdmissionHospital day casePost Discharge ServicesHome administrationOutpatient follow-upRehabilitationHome healthcareSkilled nursingNursing homeHospital readmissionsFollow-Up Office VisitsSymptom-Related MedicationsFollow-Up Office VisitsConsultsTherapistsED = emergency department; IV = intravenous.O’Brien J, et al. BMC Health Serv Res. 2003;3(1):17-28.
41 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 MSDirect correlation between cost (direct and indirect) and severity of disease has been well-establishedTherapeutics that modify MS activity and severity can result in both clinical and economic benefitsWhetton-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:
42 Is MS All About Relapses? Hypothesis: if relapses cause long-term disability then patients with frequent relapses should be at higher risk for disabilityFrom the London Ontario natural history studies patients with frequent attacks are at highest risk for future ambulatory disabilityAssumption: modifying the relapse rate will influence long-term disabilityWeinshenker et al Brain 112:1419
43 Proportion of Placebo Groups with Clinical Activity RelapsesEDSS ProgressIFNβ-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.
44 How is Sustained Progression Measured? Most clinical trials define progression by demonstrating a 1 point change in the EDSS, and then confirming the change in 3 or 6 monthsDoes 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
45 Does Sustained Disability Measure Permanent Disability? 50% of patients with a 1 point change, confirmed at 3 months will improve to a lower EDSS33% of patients with a 1 point change, confirmed at 6 months, will improve to a lower EDSSMore stringent measures of change are harder to demonstrate in 2-year trials because relatively few MS patients will progressConclusions: 6 months sustained EDSS change is more rigorous than a 3-month sustained change, but neither is a good predictor of long term disabilityLiu C & Blumhardt LD J Neurol Neurosurg Psychiatry. 2000;68:450-7.
46 Effect on Sustained Disability*: Summary of Phase III Trials 37%6 monP=.0237%P=.0230%30%29%P<.05P=.02P=NS22%sustained disability progression (%)Reduction inP<.0512%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;43:655IFNB MS Study Group and University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277Johnson et al. Neurology. 1995:45:1268; Johnson et al. Neurology. 1998;50:701PRISMS Study Group. Lancet. 1998;352:1498Kappos et al. N Engl J Med 2010;362: ; Gilenya package insert.
47 SummaryDisability progression in clinical trials with RRMS patients is for the primarily related to disability from relapsesRelapse rate reduction and the mean change in EDSS are the most sensitive clinical outcome measures in MS trialsThe generally accepted sustained change in EDSS measure is not a reliable marker of long term disabilityPhase III trials results showed:The interferons, glatiramer acetate and fingolimod reduce the relapse rateIFN beta-1a and fingolimod have statistically significant effects on sustained change in EDSS measure over two yearsIFN beta-1a, glatiramer acetate and fingolimod have statistically significant impacts on the mean change in EDSS over two years
48 The Evolving Landscape of MS Therapy Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons?
51 Head to Head Studies and Cross Trial Comparisons Head to head studies of glatiramer acetate and interferon β underscore the problem with cross trial comparisonsDifferences in patients enrolled in different studies heavily influence disease activity observed during trialsDifferences 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 comparisonsRelative efficacy is best measured by well-designed head to head trials
52 What can be learned from long-term follow up studies? The Evolving Landscape of MS TherapyWhat can be learned from long-term follow up studies?
53 Long-Term Follow UpDo 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?
57 Glatiramer Acetate 15 year LTFU In a small cohort of patients (N=100) followed for 15 years, glatiramer acetate was safe and well tolerated65% of continuously treated patients did not progress to SPMS41% of patients withdrawing from the study did so because of disease progressionPropensity scores were used to try to adjust for differences between ongoing and withdrawing patientsEDSS at baseline predicts EDSS at 15 years
59 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 treatmentFor 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 treatmentAny Variable + Any Exposure Weighting – Any Negative OutcomeEDSSp<0.0011Exposure2HighLowEbers G et al. presented at ECTRIMS, Madrid, Spain, September 2006: P666Ebers G et al. presented at AAN, October 2006: M-3
60 ConclusionsDisease modifying therapy seems to favorably effect the long-term course of MSPropensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, open label studies are important statistical advances for interpreting these studiesThese 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
61 Price of MS versus Cost of Care. Is Treatment Worth It? The Evolving Landscape of MS TherapyPrice of MS versus Cost of Care. Is Treatment Worth It?
62 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):
63 Approximate Mean Annual Cost* Cost of CareCost and functionalityEDSS ScoreApproximate Mean Annual Cost*MedicalUnpaid Caregiver TimeLost Work TimeTotalMildEDSS$3,106$932$9,938$13,976ModerateEDSS$5,100$3,188$22,950$31,238SevereEDSS$12,524$21,291$46,339* US Dollars Non-Drug CostsAdapted from: Kobelt G, Berg J, Atherly D et al. Neurology. 2006; 66:1696–1702.
64 DMT-Associated Costs Agent Approximately 65% of annual direct per patient healthcare costs in MS are attributable to drug therapyMS drugs represent 20.2% of specialty drug expenditures within managed care plansNational trend in MS drug expenditures was +18.3% in 200823.5% increase in manufacturer pricing was primary driver of trendAgentDosageAWP/dayAWP/yearInterferon beta-1b0.25 mg SC every other day$105.41$38,475Interferon beta-1a IM30 mcg IM once weekly$98.66$36,010Interferon beta-1a SC44 mcg SC 3 times weekly$106.20$38,761Glatiramer acetate20 mg SC daily$110.10$40,187Fingolimod0.5 mg PO daily$131.51$48,000AWP = 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.
65 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 MSStudy limitation: lack of clinical detail on MS severityEarly use of DMTs in patients with CIS that delayed conversion to CDMS provided a positive incremental cost-effectiveness ratio (ICER) per patient-year compared with no treatment (Euros 2,574.94)Birnbaum HG, et al. Curr Med Res Opin. 2009;25(4):Lazzaro C, et al. Neurol Sci. 2009;30:21-31.
66 Effect of Immunomodulatory Therapy on Employment Loss Time 60(P = .003)50GAINFbeta-1a40INFbeta-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 acetateshort-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-1ashort-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-1bshort-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)ReferenceLage 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 focusof 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 demographiccharacteristics, type of immunomodulatory medication, and overall severity of illness, were used in the examination of thetotal number of days missed from work for any reason and those missed due to absenteeism, short-term disability, or worker’scompensation. 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), orinterferon beta-1b, to those who did not receive multiple sclerosis medications of this type; only glatiramer acetate was associatedwith 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).-10Short-termDisabilityWorkersCompAnyReason-20Fewer 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
67 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 acetateDrug therapy should also be considered in patients with first attack at high risk of MSAccess to medications should not be limited by age, level of disability, or frequency of relapsesContinue treatment indefinitely unless lack of benefit, intolerant adverse effects, or better treatment becomes availableEnsure adequate accessibility of all FDA-approved drugs for MSChange treatments only for medically appropriate reasonsNational Clinical Advisory Board of the National MS Society. MS Disease Management Consensus Statement Accessed February 10, 2010.
68 Conclusion MS is a chronic, debilitating, and progressive disease Economic implications are significant and appear directly correlated with disease severityAlthough costly, long-term data and expert consensus support the primary role of DMT in managing disease progressionOptimal therapeutic benefit with DMT hinges strongly on multidimensional support from the healthcare systemPatient education and careful monitoring are key factors driving success in MS therapy
69 Questions to ConsiderHow 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?
70 Questions to ConsiderGiven 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?
71 Investigations • Innovation • Clinical Application The Next Generation of Immune-Modulating Therapies for MS What do we know (and not know) about their safety and efficacy How will their usefulness be established?Norman Kachuck, MD Associate Professor of Neurology Chief, Neuroimmunology Division, Department of Neurology Director, Multiple Sclerosis Comprehensive Care Center and Research Group Vice-Chair, Health Sciences IRB University of Southern California Keck School of Medicine Los Angeles, California
72 Existing and Emerging MS Therapies 2005200620072010201120122013OralInjectablesBG12CladribineBG12CladribineRebifRebifFingolimodBetaseronAmpyraAmpyraTeriflunomideTeriflunomideCopaxoneExtaviaExtaviaLaquinimodLaquinimodAvonexOcrelizumabOcrelizumabIVNovantroneTysabriTysabriIVGenericMitoxantrone(oncology) MSGeneric Mitoxantrone(oncology) (MS)AlemtuzumabAlemtuzumabFiledApprovedIn phase IIIn phase III
73 What We Do Not Know What initiates MS? Can we identify the different pathogenetic mechanisms in different individuals?Which occurs first: Myelin breakdown or oligodendrocyte destruction?What are the mechanisms of axonal injury/loss?What mediates regeneration of axons/myelinating elementsWhy does repair ultimately fail?Despite a great deal of effort, the cause of MS is still unknown.Research suggests that the dominant immunologic players in MS are the T cells. Initial research suggested that MS results from infiltrating T cells secreting chemical messengers (cytokines).1 The trigger that activates the T cells that are specific for components in the CNS has not yet been identified.Patients with progressive MS without any periods of remission have significantly less inflammation than patients with secondary progressive MS.2 We still do not know why this is.Although indirect evidence suggests that MS is an autoimmune disease, an immune response to the CNS is not seen consistently in patients with MS.1,2Researchers do not yet know whether oligodendrocyte loss or injury occurs prior to myelin breakdown.Remyelination ultimately fails in subacute and long-standing MS lesions. This is in contrast to the remyelination that does appear in newly formed lesions.2 Researchers have still not been able to explain this difference.References:Hemmer B, Cepok S, Nessler S, Sommer N. Pathogenesis of multiple sclerosis: an update on immunology. Curr Opin Neurol. 2002;15:Prineas JW. Pathology of multiple sclerosis. In: Cook SD, ed. Handbook of Multiple Sclerosis. 3rd ed. New York, NY: Marcel Dekker, Inc; 2001:
74 Implications of the Paradigm Shift Homogeneity of lesion type in an individualHeterogeneity in the phenotype of disease across individualsVariable response to a given intervention due to this heterogeneityLikely need to create combinations of therapies based on an individual’s diseaseBiomarkers and noninvasive metrics are critical to evaluate, target, and follow disease and its injury and repair response to treatmentBielekova B, Martin R. Brain. 2004;127;
75 How do we keep such decisions rational, evidence-based, AND ETHICAL? What We Do Not KnowHow can we optimize therapy for a given patient using this information?How do we optimize therapy for a heterogeneous MS population under managed care, using this informationHow do we keep such decisions rational, evidence-based, AND ETHICAL?And when we can’t know with certainty, how do we communicate and act on that uncertainty?Despite a great deal of effort, the cause of MS is still unknown.Research suggests that the dominant immunologic players in MS are the T cells. Initial research suggested that MS results from infiltrating T cells secreting chemical messengers (cytokines).1 The trigger that activates the T cells that are specific for components in the CNS has not yet been identified.Patients with progressive MS without any periods of remission have significantly less inflammation than patients with secondary progressive MS.2 We still do not know why this is.Although indirect evidence suggests that MS is an autoimmune disease, an immune response to the CNS is not seen consistently in patients with MS.1,2Researchers do not yet know whether oligodendrocyte loss or injury occurs prior to myelin breakdown.Remyelination ultimately fails in subacute and long-standing MS lesions. This is in contrast to the remyelination that does appear in newly formed lesions.2 Researchers have still not been able to explain this difference.References:Hemmer B, Cepok S, Nessler S, Sommer N. Pathogenesis of multiple sclerosis: an update on immunology. Curr Opin Neurol. 2002;15:Prineas JW. Pathology of multiple sclerosis. In: Cook SD, ed. Handbook of Multiple Sclerosis. 3rd ed. New York, NY: Marcel Dekker, Inc; 2001:
77 Alemtuzumab (Campath®) Monoclonal humanized antibody directed against CD52 antigenCD52 antigen is a cell surface glycoprotein that is present on >95% of T lymphocytes, B lymphocytes, monocytes, and eosinophilsResults in prolonged depletion of B cells, T cells, and monocytesWithin an hour following a single 5- to 10-mg dose, lymphocytes and monocytes are no longer detectable in circulationFDA-approved for B-CLLMuraro P, et al. Neurotherapeutics. 2007;4: Coles A, et al. J Neurol. 2006;253:
79 Alemtuzumab CAMMS223: Co-Primary Endpoints (36 months) Patients on Campath had an annualized relapse rate of 0.11, while for those getting Rebif the rate was 0.35 at the end of five years, according to data presented today at the European Committee for Treatment and Research in Multiple Sclerosis meetingObjective: To present long-term safety and efficacy follow-up of CAMMS223Background: Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulatinglymphocyte pool. Alemtuzumab significantly reduced the relapse rate and risk for sustained accumulation ofdisability (SAD) compared to subcutaneous interferon beta-1a (SC IFNB-1a) (all p-values<0.001, pooleddose groups) in a 3 year, phase 2, safety and efficacy trial with relapsing-remitting multiple sclerosis (RRMS)patients (CAMMS223). Notable alemtuzumab-related adverse events included infusion reactions, immunethrombocytopenia, thyroid dysfunction, and predominantly mild to moderate infections.Methods: 334 early, active, treatment-naive RRMS patients were initially randomized 1:1:1 to IFNB-1a(44mcg SC 3x/week), 24 mg or 12 mg/day alemtuzumab IV-administered during 2 or 3 brief annual cycles (atmonths 0, 12, 24). SC IFNB-1a was administered through 36 months. A subset of patients has been followedfor up to 24 months after the initial 36 month study period (60 months total). Rater-blinded EDSS wasassessed quarterly, relapses as needed, and adverse events continuously. Patients could receive alternativedisease-modifying therapy during the follow-up period; a few were retreated with alemtuzumab. SAD wasanalyzed by Kaplan-Meier estimation, and annualized relapse rate (ARR) by Poisson regression.Results: 68.0% of alemtuzumab patients participated in the follow-up period, with 59.9% evaluable at 60months. The ARR in alemtuzumab patients assessed over various intervals was 0.11 (month 0-60); 0.14(month 36-60). At 60 months, 13% had experienced SAD. Mean EDSS change from baseline was -0.30points at 60 months. 42.3% of SC IFNB-1a patients participated in the follow-up period, with 35.1%evaluable at 60 months. The ARR in SC IFNB-1a patients assessed over various intervals was 0.35 (month0-60); 0.28 (month 36-60). At 60 months, 38% had experienced SAD. Mean EDSS change from baselinewas points. Updated safety information will be provided.Conclusions: Alemtuzumab patients experienced sustained benefit at 60 months of follow-up. The efficacy ofalemtuzumab appears durable in many patients as much as 4 years after last dose. Ongoing phase 3studies are further evaluating the benefit/risk of alemtuzumab therapy in RRMS.CAMMS223 Trial Investigators. NEJM 2008;359:
80 Alemtuzumab CAMMS223: MRI Outcomes MonthsP=0.04P=0.03n=75P=0.04n=91n=60n=87P=0.16n=96n=80n=100n=96n=91MonthsP≤0.03 for both doses of alemtuzumab vs. IFN at m 0-12 and P=NS at m 0-36CAMMS223 Trial Investigators. N Engl J Med. 2008;359:
81 Alemtuzumab CAMMS223: Safety Principal AEs associated with alemtuzumab included:Infusion reactionsMild-to-moderate infectionsAutoimmunityImmune thrombocytopenia in 6 of 216 patients (2.8%) including one deathThyroid disorders (28% vs. 3% for IFNβ-1a)1 case of Goodpasture’s syndromeCAMMS223 Trial Investigators. N Engl J Med. 2008;359:
82 Alemtuzumab CAMMS223: Safety Infections, %IFN ß-1a (n=107)Alem mg (n=108)Alem mg (n=108)Upper resp. infection*27.144.450.9Lower resp. infection*1.911.113.9Herpes simplex2.88.3Herpes zoster0.95.6Meningitis**1.8* P<0.001 alemtuzumab vs. IFN** Listeria or viral meningitisCAMMS223 Trial Investigators. N Engl J Med. 2008;359:
83 Alemtuzumab: Effects on the Immune System B cells returned to normal within 3-6 monthsMedian recovery time for CD4+ T cells > 100 cells/µL = 3 months6-9 months for CD4+ T cells > 200 cells/µLMedian recovery time to baseline levels of CD4+ T cells = 61 monthsThompson S, et al. J Clin Immunol 2010;30:99–105. Coles A, et al. J Neurol. 2006;253:
84 Alemtuzumab long term efficacy at 5 years – ECTRIMS 2010 68% Alem in follow-upARRmonths 0-60 = 0.11Months = 0.1460 = .13Mean EDSS -0.3042% IFNB-1a follow-upARRMonths 0-60 = .35Months 36-60= .2860 = .38Mean EDSS +0.46ARR=annualized relapse rate; SAD-sustained accumulation of disability
85 Alemtuzumab – Current Status (CARE-MS I/II) Phase III Studies in Progress CAMMS323 - Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study OneRandomized, Rater- and Dose-Blinded Study Comparing 2 Annual Cycles of IV 12 mg and 24 mg Alemtuzumab to 3x Weekly SC Interferon Beta-1a (Rebif®) in Relapsing-Remitting Multiple Sclerosis Patients Who Have Relapsed on TherapyEnrollment: 840 Study Start Date: October 2007 Estimated Study Completion Date: September 2011CAMMS Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Study TwoRandomized, Rater-Blinded Study Comparing Two Annual Cycles of Intravenous Alemtuzumab to Three-Times Weekly Subcutaneous Interferon Beta-1a (Rebif®) in Treatment-Naïve Patients With Relapsing-Remitting Multiple SclerosisEnrollment: 581 Study Start Date: September 2007 Estimated Study Completion Date: May 2011Source: Clinicaltrials.gov
86 Cladribine (Leustatin) Synthetic purine nucleoside analogue prodrugAccumulates and is incorporated into the DNA of lymphocytes as a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase activitySelectively induces apoptosis in dividing and non-dividing lymphocytesSustained reduction in lymphocyte subtypes (CD4+ T cells, CD8+ T cells and B cellsRelatively transient effects on other immune cells such as neutrophils and monocytesReduces levels of pro-inflammatory chemokinesCrosses the blood brain barrier - CSF concentration = 25% of plasma (patients with no BBB compromise)FDA-approved for hairy cell leukemiaCarson 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;32:120–3.86
87 Cladribine 3.50 mg/kg total dose; 4 courses (n = 433) X X X XX XPlacebo (n = 437)1326 patientsX X X XX XCladribine 3.50 mg/kg total dose; 4 courses (n = 433)X X X XX XCladribine 5.25 mg/kg total dose; 6 courses (n = 456)–4591316243644485260728496 Time (weeks)MRINeurological examinationDosing: 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 48Giovannoni G, et al. N Engl J Med. 2010;362:87
88 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 weeksOdds Ratio (95% CI)2.53 ( )78.9*79.7*60.9Placebo (n = 437)Cladribine 3.50 mg/kg (n = 433)Cladribine 5.25 mg/kg (n = 456)* P < 0.001Giovannoni G, et al. N Engl J Med. 2010;362:
89 CLARITY: Clinical Outcomes 25Time to Confirmed EDSS ProgressionPlaceboHR vs Placebo (95% CI)20Cladribine 3.50 mg/kg ( ); P = 0.02Cladribine 5.25 mg/kg ( ); P = 0.0315Proportion with confirmed 3-month EDSS progression (%)1051224364860728496WeeksPlacebo3.50 mg5.25 mgGiovannoni G, et al. N Engl J Med. 2010;362:
90 mean ± SE lesions/patient/scan T1 Gadolinium-Enhancing Lesions CLARITY: MRI Outcomes87.9%mean ± SE lesions/patient/scan0.9185.7%T1 Gadolinium-Enhancing LesionsActive T2-Weighted LesionsCombined Unique Lesions1.720.430.3874.4%77.9%1.430.380.3373.4%76.9%0.120.11Placebo (n = 437)Cladribine 3.50 mg/kg (n = 433)Cladribine 5.25 mg/kg (n = 456)All P < 0.001Giovannoni G, et al. N Engl J Med. 2010;362:
91 CLARITY: Safety and Tolerability Preferred term, n (%) patientsPlacebo (n = 435)Cladribine 3.5 mg/kg (n = 430)Cladribine 5.25 mg/kg (n = 454)Cladribine overall (n = 884)Herpes zoster8 (1.9)11 (2.4)19 (2.1)Herpes zoster oticus1 (0.2)1 (0.1)Varicella2 (0.2)Any infection or infestation188 (42.5)205 (47.7)222 (48.9)427 (48.3)Deaths2 (0.5)2 (0.4)4 (0.5)20 patients had 21 zoster events in the cladribine groupsAll 21 cases were self-limiting and dermatomal; no cases were disseminated3.2% of patients developing grade 3 or 4 lymphopenia at any time during the study developed zoster versus 1.8% of those that did not70% of patients with zoster had normal lymphocyte count or lesser grade lymphopenia at the approximate time zoster developedDeaths - Placebo: Hemorrhagic CVA, suicide; cladribine 3.5 mg/kg: acute MI, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardio-respiratory arrestGiovannoni G, et al. N Engl J Med. 2010;362:
92 CLARITY: Safety and Tolerability MalignanciesPreferred term, n (%)Placebo (n = 435)Cladribine 3.5 mg/kg (n = 430)Cladribine 5.25 mg/kg (n = 454)Cladribine overall (n = 884)During StudyMelanoma1(0.2)Ovarian1 (0.1)Pancreatic1 (0.2)CervixDuring post-study surveillanceChoriocarcinomaGiovannoni G, et al. N Engl J Med. 2010;362:
93 CLARITY: Effects on Lymphocyte Subsets Maximum Effects on CD4 and CD 19 Counts*Weeks Weeks 48-96mg/kg mg/kg mg/kg mg/kgCD4 (week)Cells/µLCD19 (week)163919182091472275522720731Add Reference*Median valuesRieckmann P, et al. Presented at ECTRIMS, Düsseldorf, Germany, September 9-12, Poster #816.
94 Cladribine – Current Status Approved in Australia and Russia (Movectro®)Applications pending elsewhere9/24/2010 Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) says noFDA application granted Priority Review
95 Fingolimod (FTY720) (Gilenya®) Sphingosine-1-phosphate (S1P) receptor modulator (S1PR1 and 5 > 2,3,4)Sequesters circulating lymphocytes into secondary lymphoid organsPeripheral reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells), CD45RO+ (memory T cells) and CD19+ cellsNo effect on lymphocyte induction, proliferation, or memory functionMay inhibit the production of IL-17Crosses BBB, and S1P receptors shown to function within the CNS, but unknown clinical relevanceFingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE and can stimulate OPC maturation1. 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.
96 Oral fingolimod 0.50 mg once daily (n = 425) MRIOral fingolimod 1.25 mg once daily (n = 429)Placebo once daily (n = 418)Randomization Month Month Month 241272 patients(1:1:1)Clinic visitsKappos L, et al. N Engl J Med. 2010;362:96
97 FREEDOMS: Primary Efficacy Endpoint Annualized Relapse Rate at 24 months-54% vs Placebo p < 0.001-60% vs Placebo p < 0.001βPlacebo (n = 431)Fingolimod 0.5 mg (n = 429)Fingolimod 1.25 mg (n = 420)Kappos L, et al. N Engl J Med. 2010;362:
98 FREEDOMS: Disability Data FTY mg (17%)†Days on study51015202530Placebo (24%)FTY mg (18%)*Percent with 3-month confirmedEDSS progressionFTY mg vs placebo HR 0.70P = 0.02 in time to disabilityProgressionFTY mg vs placebo HR 0.68* P = 0.03 vs placebo† P = 0.01 vs placeboNumber at RiskFTY mgFTY mgPlaceboKappos L, et al. N Engl J Med. 2010;362:
99 FREEDOMS: MRI Endpoints T2 and Gadolinium-Enhancing Lesions at 24 Months-82% P<0.001-74% P<0.001Kappos L, et al. N Engl J Med. 2010;362:
100 FREEDOMS: Brain Volume P≤0.03 for both doses of fingolimodvs. placebo at all time pointsKappos L, et al. N Engl J Med. 2010;362:
101 Randomization Month 6 Month 12 Ongoing Optional extension phaseOral fingolimod 0.5 mg once daily and matching weekly placebo injection IMOral fingolimod 1.25 mg once daily and matching weekly placebo injection IMIFNβ-1a 30 µg IM once weekly and matching daily oral placebo capsuleAssessmentsMRIEDSSClinical visitRandomizationMonth 6Month 12OngoingCohen J, et al. N Engl J Med. 2010;362:
102 TRANSFORMS: Primary Efficacy Endpoint Annualized Relapse Rate at 12 months-52% vs IFNβ-1a, p < 0.001-38% vs IFNβ-1a, p < 0.001βIFNβ-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:
103 TRANSFORMS: MRI Endpoints T2 and Gadolinium-Enhancing Lesions at 12 Months-35% vs. IFNß-1aP=0.004-55% vs. IFNß-1aP<0.001-42% vs. IFNß-1aP<0.001-73% vs.IFNß-1aP<0.001Cohen J, et al. N Engl J Med. 2010;362:
104 TRANSFORMS: Brain Volume P < 0.001Cohen J, et al. N Engl J Med. 2010;362:
105 Gilenya®: SafetyTransient reduction in heart rate on initiation of treatmentElevated 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-1aMacular edemaFREEDOMS - 7 cases in the 1.25 mg dose group (1.6%) and none in the 0.5 mg dose groupTRANSFORMS – 6 cases (4 in the 1.25 mg dose group (1%) and 2 in the 0.5 mg dose group (0.5%))Kappos L, et al. N Engl J Med. 2010;362: Cohen J, et al. N Engl J Med. 2010;362:
106 Fingolimod (Gilenya®): Safety Malignancies and Herpes InfectionsAE, n (%)FTY mg (n = 854)FTY mg (n = 849)Placebo (n = 418)IFNß-1a (n = 431)Skin CancersBasal cell carcinoma7(0.8)3(0.4)3(0.7)1(0.2)Melanoma1(0.1)Bowen’s Disease1 (0.1)InfectionsHerpes infections46(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:
107 Fingolimod (Gilenya®): Safety Two fatal infections in patients treated with FTY mgHerpes encephalitisprimary disseminated varicellaHemorrhagic encephalitis in a patient treated with FTY mgPosterior reversible encephalopathy syndrome in a patient treated with 5 mg in the phase 2 studyCohen J, et al. N Engl J Med. 2010;362: ; Kappos L et al. N Engl J Med. 2006;355: ; Leypoldt F, et al. LK. Neurology 2009;72:
108 FTY720 1.25 mg (n = 16) Normal range Treatment duration (yrs), mean ± SEM1.9 ± 0.2-Lymphocyte count (x 109/L),0.4 ± 0.1CD4 T cell count (cells/µL),78 ± 5.6CD8 T cell count (cells/µL),149 ± 7.4Mehling M, et al. Neurology 2008;71:1261–1267
109 Gilenya®: Current Status Sept 22, 2010 FDA approval, indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.Recommended dose: 0.5 mg orally once daily, with or without foodREMS includes outreach letters, with recommendations for 6 hour initiation observation period, monitoring for infections, ophthalmologic, dermatologic and hepatic toxicity; NO REGISTRY or restricted distribution process
110 Emerging Therapies: Trading Efficacy for Safety ? Impaired immune surveillance and opportunistic infectionsViral and other infections? MalignanciesLong-lasting effectsAutoimmunityTeratogenicityRare, but serious infusion reactionsThe Unknown
112 Changing therapy options5-19 Rituximab/OcrilizumabBetaseron®(IFNβ-1b)Tysabri® (natalizumab)Campath® (alemtuzumab)Avonex® (IFNβ-1a)Extavia®(IFNβ-1b)LaquinimodCopaxone® (glatiramer acetate)CladribineFumarate(BG-12)Novantrone® (mitoxantrone)Gilenya® (fingolimod)Rebif ® (IFNβ-1a)Teriflunomide199520002005200920102011Over the last 15 to 20 years, we have accumulated a great deal of trial data and clinical experience with COPAXONE® (glatiramer acetate injection) and the interferons. Other therapies, including Novantrone® (mitoxantrone) and Tysabri® (natalizumab), tend to be used in a limited way in practiceOver the next few years, the first oral MS therapies may become available. In this discussion, we are going to focus on cladribine and fingolimod (FTY720)In the next few slides, we will review the Phase III efficacy data for cladribine and fingolimod and discuss these findings in the context of currently approved therapiesApproval dateEstimated launch dateApproved therapiesPhase III completedIn Phase III5. MS treatment side effects. 6. Company news; F.D.A. approves a multiple sclerosis drug. 7. Biotechnology medications move closer to the market. 8. Serono's rebif(R) receives FDA approval. 9. Immunex gets FDA OK. 10. Multiple sclerosis (relapsing-remitting): emerging therapies that offer improved convenience will not unseat current drugs. Decision Base Giovannoni G, et al ECTRIMS. Abstract P Cohen J, et al ECTRIMS. Abstract P Study results: multiple sclerosis patients have significant and sustained reduction in disability and risk of relapse on alemtuzumab versus approved therapy. 14. Clinicaltrials.gov Web site. ALLEGRO study. 15. Clinicaltrials.gov Web site. BRAVO study. 16. Biogen Idec showcases more than 70 data presentations at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis [news release]. 17. Study of teriflunomide in reducing the frequency of relapses and accumulation of disability in patients with multiple sclerosis (TEMSO). 18. Novantrone® (mitoxantrone). National Multiple Sclerosis Society Web site. 19. Tysabri® prescribing information. Biogen Idec Inc.
113 Treatment Decisions: Considering Benefits and Risks Benefits RisksMeaningful impactDisease CourseMRI? Better than ABCR? Window of opportunityConvenienceShort-term safetyLong-term safetyPharmacovigilancePost-approval studiesPregnancy issues
114 What therapy characteristic will be the key driver for future therapy decisions? EfficacyTolerabilityWhat therapy characteristic will be the key driver for future therapy decisions?Other ConsiderationsSafety
115 How will patient characteristics, risk aversion and cost play a role in our therapy decisions? Demographics:AgeGenderGenetic loadRisk ToleranceRisk AversionOther Considerations:Price of Rx and care,Resource utilizationDelivery processWhat therapy characteristic will be the key driver for future therapy decisions?Present disabilityDisease Prognosis
116 Multiple situations are encompassed by the term “suboptimal response”1-5 EfficacyRelapsesNew lesionsBrain atrophyWorsening EDSSNeutralizing antibodiesSafetyClinically recognizable organ toxicityOpportunistic infectionAbnormal laboratory valuesTolerabilityComplianceImmediate postinjection reaction (IPIR)Injection-site reactions (ISRs)Flu-like symptomsDepressionOther ConsiderationsFatigueWorsening cognitionThe term “suboptimal response” can encompass multiple situations. Although there are no generally accepted criteria for measuring a suboptimal response, in essence, it can mean that a therapy is not achieving its desired results in 1 or more areas.EfficacyFailure to demonstrate relapse rate reduction after at least 6 months of continuous use of an IMT, or more than 1 relapse per year could be considered a suboptimal responseAn increase in 2 of the following: number or volume of T2 lesions, new Gd+ lesions, or new or enlarged T1 hypointense lesions could be cause for concernWorsening EDSS in the absence of clinical attacks could also indicate treatment failureAnother factor to consider that may affect response to therapy is the incidence of neutralizing antibodiesTolerability issues, such as immediate postinjection reactions, injection-site reactions, flu-like symptoms, and depression, could lead to suboptimal response and could require a change in treatmentSuboptimal response can also manifest symptomatically through fatigue and cognitive dysfunction, which can disrupt daily living1. Cohen BA, et al. Neurology. 2004;63:S33-S40.2. Freedman MS, et al. Can J Neurol Sci. 2004;31:3. National Multiple Sclerosis Society Expert Opinion Paper4. International Working Group for Treatment Optimization in MS. Eur J Neurol. 2004;11:43-47.5. Coyle PK. J Neurol. 2008;255(suppl 1):44-50.
117 What is our ethical approach to prescribing therapies with better efficacy but risks? Suitable for all patients?For patients who request therapy?Only for heavily treatment-experienced patients?What is your approach to new therapies?How will you decide the appropriate patient types for each therapy?Choose other established therapy?Only for those with worsening disease?
118 My Take Home Points on MS Therapy Diagnose High Risk Presumptive and Definite MS earlyTreat early as aggressively as seems reasonable, to interrupt inflammatory cascade and possible secondary degenerationConsider how to predict disease course using accurate surrogate markersMake risk tolerance/aversion decisions on therapy on a patient by patient basisInvolve patients in clinical research as able
119 Questions to ConsiderHow 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?
120 Questions to ConsiderWho 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?
121 The Evolving Landscape of MS Therapy 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., FCCPProfessor and ChairDepartment of Pharmacy PracticeAlbany College of Pharmacy andHealth Sciences-Vermont
122 Changing Directions Oral Agents Pharmacist Advanced Provision of Care EducationCostAdherence
123 Oral Agents for Multiple Sclerosis Mechanism of ActionStatusExpected DosingDalfampridinePotassium channel blockerApproved for use by the FDA10.0 mg twice dailyLaquinimodImmunomdulatorGranted fast-track review by FDA0.6 mg dailyCladribinePurine nucleoside analogue prodrugFDA issued a refuse-to-file letter for the New Drug Application due to reports of patients developing solid malignancies1 (0.2)FingolimodPartial sphingosine 1-phosphate-receptor agonistApproved for use by FDA0.5 mg dailyFDA data accessed 10/14/10
124 Considerations as Therapy Shifts from Injectable to Oral Agents AdherencePharmacists will play a larger role in that time spent with patients in clinic will decrease due to less need to teach patients how to injectMay be an initial increase in adherence since medications will be easier to takeMay eventually result in a decrease in adherence as undesirable side effects may emergeIncreased 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 telephoneConsider setting up follow-up schedule with MS patientsSchedule and provide detailed counseling sessions for patients when they come for prescription pick upKeep note to fax to MD after each visit to utilize team approach to care of patients with MSUtilize SWOT analysis to achieve realistic approach to MS patient care in a pharmacy setting
125 Oral Agents and Managed Care 4 oral agents on the horizonDalfampridine, laquinimod, cladribine, fingolimodDiscontinuation rates with current therapies as high as 46%Lack of efficacy (perceived and real)Adverse drug reactionCost to the patientInjection anxietyOral agents and adherenceBetter tolerated physically and psychologicallyPts prefer receiving oral or inhaled medicationsMajority of patients did not perceive oral meds interfering with lifeMinority of patients did not take oral meds and perceive them less effective than injectable medicationsFallowfield L, Atkins L, Catt S, et al. Ann Oncol 2006;17: Halfdanarson TR, et al.Curr Oncol Rep. 2010;12(4): ; Lipsy RJ et al. J Manag Care Pharm. 2009;15(9-a)(Suppl):S2-S15
126 Oral Agents and Managed Care Trends/ConsiderationsOral medications will require less out-of pocket expenses for members compared with current injectable medicationsPreliminary results indicate that oral medications are as effective as, or possibly more effective than, current injectable formulationsPatients newly diagnosed with MS may prefer oral agents when they become availableData presented regarding oral therapy is trending to being significantly positive in the short time fromFallowfield L, Atkins L, Catt S, et al. Ann Oncol 2006;17: Halfdanarson TR, et al.Curr Oncol Rep. 2010;12(4): ; Lipsy RJ et al. J Manag Care Pharm. 2009;15(9-a)(Suppl):S2-S15
127 Changing Directions Oral Agents Pharmacist Advanced Provision of Care EducationCostAdherence
129 Attributes of State and Federal Regulations Governing Collaborative Practice ACCP Task Force on Collaborative Drug Therapy Management. Collaborative Drug Therapy Management by Pharmacists Pharmacotherapy 2003;23:
131 PharmacovigilenceThe 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 standardsIn healthcare today, the pharmacist’s role has changed to acting as a consultant on pharmacotherapy, including over the counter productsWHO. The Importance of Pharmacovigilence, Safety Monitoring of Medical Products. Geneva: WHO; 2002; van Grootheest AC, de Jong-van den Berg LTW. The role of hospital and community pharmacists in pharmacovigilance. Research in Social and Administrative Pharmacy 2005;1:
132 Community Pharmacists Percentage of Professional ADR Reports Originating from Pharmacists by CountryCountry%Hospital PharmacistsCommunity PharmacistsCanada88.3+-USA68Australia40.3Netherlands40.2Japan39?Spain25.9“+” 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 dataVan Grootheest AC, de Jong-van den Berg LTW. The role of hospital and community pharmacists in pharmacovigilance. Social and Administrative Pharmacy 2005;1:
133 Medication Therapy Management in the MS Patient MTM
134 Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008.
135 Criteria for Identifying Individuals for MTM Services Referral from other health care providersMore than one prescriberPatients on four or more chronic medicationsPatients with at least once chronic disease requiring pharmacotherapyPatients 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 therapyNon-adherence for more than 3 monthsPatients requiring intensive communication die to literacy and/or cultural issuesTotal monthly cost of medication in excess of $200Patients discharged from a hospital or skilled nursing facility within 14 days with new medicationsOver-utilization or under-utilization of medicationsRoutinely non-adherent with medication regimensLack of understanding regarding medication usePatients confronted with financial barriersAmerican College of Clinical Pharmacy 2006 Clinical Practice Affairs Committee. Medication therapy management services: application of the core elements in ambulatory settings.
136 Documentation Elements for the Patient Record in an MTM Encounter Medication Therapy Management in Pharmacy Practice: Core Elements of an MTM Service Model Version American Pharmacists Association and National Association of Chain Drug Stores Foundation, 2008.
137 Studies Demonstrating Improved Economic and Clinical Outcomes with Pharmacists’ Interventions or ServicesChisolm-Burns MA, et al. Economic effects of pharmacists on health outcomes in the United States: a systematic review. AJHP 2010;67:
138 Changing Directions Oral Agents Pharmacist Advanced Provision of Care EducationCostAdherence
139 Educational Opportunities for Pharmacist/ Allied Health Involvement in MS Therapy SupportSystemDiseaseModificationOptimal MS ManagementSymptom ManagementWellnessClinicalFindingsMRIFindingsRoss AP. Neurology 2008;71(suppl 3):s21-s23.
140 Considerations-Education Increased pharmacist education about MS diseaseAccess to quick reference with therapeutic optionsCounseling tips and FAQ’s to address from MS patientsPromote web sites and contact information for pharmacists to “chat” with MS pharmacy specialists in order to better care for their patientsProvide 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 patientHow to manage side effects of medicationsUse of alternative therapies to control and manage disease stateRole of alternatives in treating neurologic diseasesUse of Motivational Interviewing skills to enhance and foster long-term use of medications in chronic diseasesProvide continuous professional development or certification in motivational interviewing as part of patient careAddress specific counseling opportunities and barriers in patient s with chronic neurological disease to colleges of medicine, pharmacy and nursing
141 Changing Directions Oral Agents Pharmacist Advanced Provision of Care EducationCostAdherence
142 Total Average Annual MS Cost by Insurance Type and Payer (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
143 Total Average Annual MS Cost by Presence of Selected Comorbid Conditions (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
144 MS Component Costs— Overall Population (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
145 Average Total Annual MS Cost by Disease-Modifying Drug Utilization (2004) Prescott JD, et al. J Manag Care Pharm 2007;13(1):44-52
146 Newer Biologic Treatments in MS Payers are demanding more information on the overall value of these therapies in making coverage decisionsStarting 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 initiationAlthough biologics may reduce other types of service use, the savings do not come close to offsetting the full cost of these drugsHealth 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 coverageConsiderations/SpeculationsConsider newer oral therapies for treatment for potentially lower overall cost to both patients and MCO’sJoyce GF, et al. Am J Manag Care 2008;14(12):821-82
147 Considerations - Costs Utilize adherence and education strategies to contain costs associated with diseaseShift and reduce costs from acute therapy and health degeneration to medication management, adherence and educationConduct continual research to demonstrate the value of adherence and education in cost reductionPromote the concept of the “disseminated” healthcare team working to achieve adherence and education
148 Changing Directions Oral Agents Pharmacist Advanced Provision of Care EducationCostAdherence
149 AdherenceThe term adherence is preferred over compliance due to authoritative and paternalistic connotations of the latterAdherence: the extent to which a person’s behavior–taking medication, following diet guidelines, or enacting lifestyle changes—corresponds with recommendations from a health care providerPersistence and performance quality are also associated with adherenceNon adherence rates with DMT’s average 25% (13-46%)Similar to DMKlauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92
150 Adherent vs. Non-adherent Behavior Utilization and consequent maintenance of therapyKeep treatment and aftercare appointmentsTake drugs correctlyActive change to health lifestyleComplete treatment-related homeworkReduce risk behaviorsNon-adherentComplete refusal of therapyRefusal of specific treatment optionsArbitrary or unintended modification of prescriptionsIntentional non-adherenceKlauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92
151 Motivations for Non-Adherence Most severe demands of IMT posed on patientsInjectable medications, frequently IM or SQ for months or yearsBenefits of IMT will not be positively experienced by patients and outweighed by side effectsFlu-like symptomsFlushingChest painPalpitationsDyspneaPain on injectionKlauer T, Zettl UK. Compliance, adherence and the treatment of multiple sclerosis. J Neurol 2008;255 (suppl 6):87-92
152 Effects of Non-Adherence on Treatment Prevalence Brandes DW, et al. A review of disease-modifying therapies for MS: maximizing adherence and miminizing adverse events. Current Medical Research and Opinion 2009;25:77-92.
153 Reasons for Discontinuing MS Medications Lipsy R. Will the newer oral MS agents be welcomed by managed care organizations? Am J Manag Care 2010;16:S227-S223.
154 Poor Compliance Associated with Higher Out-of-Pocket Expenses with MS Drugs Gleason PP, et al. J Manag Care Pharm. 2009;15(8):
155 Motivational Interviewing as Early Vocational Intervention in MS 90% of people with MS have a history of employment, only 20-30% will be employed 5-15 years from diagnosisMany 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 problemsMI is a brief, client centered, directive counseling approach that enhances intrinsic motivation to change by exploring and resolving ambivalenceU. 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 diseaseHunter 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.
156 Patient Compliance Improves Through “Motivational Interviewing” Patient often resist the advice of health care providers and thus neglect what is in their best interestsAttempts to persuade patients when they are not ready to changeA patient may quit taking medication because they feel no improvementDetermine motivation and increase probability that they will make good decisionsSoftware available to aid Pharmacists in MI8.7% of pts receiving advice from counselors without using software quit taking medications1.2% of pts quit taking medications when software was usedAccessed 10/4/2010
157 Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Injury Ongoing study at University of Washington currently recruiting, completion date March 2012PurposeLack of physical activity has been positively correlated with higher levels of depressionLongitudinal data and treatment trials suggest that increased physical activity is related to improved moodCondition: MS; Intervention: Behavioral (Motivational Interviewing)accessed 10/4/2010
158 Physical Activity for Depression in People Aging with Multiple Sclerosis and Spinal Cord Injury RandomizationMotivational Interviewing: experimentalMotivational interviewing for people aging with MS or spinal cord injury to increase physical activity and decrease depressionBehavioral: motivational interviewingMotivational interviewing, a proven counseling method that centers on individual goals and motivations, to increase exercise and decrease depressionaccessed 10/4/2010
159 Strategies to Enhance Adherence to DMT’s Establishing a therapeutic relationshipEducating patient and familyIncreased adherence to treatmentManagingpatient expectationsManaging adverse eventsAddressing patient concernsBrandes 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.
160 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 yearsIf 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.
161 Male vs. Female MS Characteristics Female patients have greater self-reported symptom awareness and more positive perceptions of ability to manage therapy80% of a mailed surveys of commercially insured MS patients were femaleMajority of whom had RRMS68% of whom were on glatiramir acetate or interferon beta-1aFemales more often perceived that DMM made a difference and were more aware of treatment optionsConsiderations/SpeculationsMale patients would be a sizeable target for beginning MS therapyMale patients need consistent reminders of importance of therapy as well as treatment optionsVlahiotis A, et al. J Manag Care Pharm 2010;16:
162 Kaplan-Meier Hazards for Probability for Medication Continuance Daugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:
163 Determinants of Adherence Missing treatment effects or undesirable side effects explain only medium amounts of variance in adherenceDisease characteristicsPatient variablesQuality of patient therapist relationshipTreatment settingInfluences from social environmentMohr DC, et al. Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on the adherence and ability to self inject. Ann Behav Med 2001;23:
164 Determinants of Adherence Adherence most strongly threatened by disorders that specifically and directly interfere with medication applicationInjection phobiaTreatment of diabetes mellitusDepressionNon-adherence has been regarded as a risk for patient morbidity and mortality and has an unnecessary economical burden for the health care systemMohr DC, et al. Injectable medication for the treatment of multiple sclerosis: The influence of self-efficacy expectations and injection anxiety on the adherence and ability to self inject. Ann Behav Med 2001;23:
165 Disease Management Consensus Statement Recommendations—National Multiple Sclerosis Society 2007The 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
166 Disease Management Consensus Statement Recommendations—National Multiple Sclerosis Society 2007Natalizumab 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
167 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
168 Recommendations Continued All of these FDA-approved agents should be included in formularies and covered by third party payers so that physicians and patients can determine the most appropriate agent on an individual basis; failure to do so is unethical and discriminatory.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
169 Injection site reactions, inflammation, fever, myalgia, chills Dose, Route, Frequency and Common Adverse Effects of Medications Used in MS TreatmentMedicationDoseRouteFrequencyCommon Adverse EventsInterferon beta-1a30 microgramsIntramuscularOnce weeklyInjection site reactions, inflammation, fever, myalgia, chills44 microgramsSubcutaneousThree times per weekInterferon beta-1b0.25 milligramsEvery other dayGlatiramer acetate20 milligramsOnce dailyLocal injection site reactions and transient, self-limited, facial flushing and chest tightnessDaugherty KK, et al. Factors leading patients to discontinue multiple sclerosis therapies. J Am Pharm Assoc 2005;45:
170 Direct and Indirect Costs that Should be Considered in Direct Patient Care Services Chisolm-Burns MA, et al. Economic effects of pharmacists on health outcomes in the United States: a systematic review. AJHP 2010;67:
171 Questions to Consider1. 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?
172 Questions to Consider5. How will your organization respond to pricing issues for MS? For example, fingolimod is priced at $48,000 one year of treatment? How will that influence your MS treatment decisions when safe and effective therapies currently cost from $32,000 to $40,000? 6. How will you respond to additional demands for safety monitoring for new agents, such as fingolimod and other immunosuppressives? What are these monitoring dimensions?
173 The Evolving Landscape of MS Therapy The Role of Comparative Effectiveness, Long Term Safety Considerations, and Monitoring Costs for Evaluating Therapies for MSJacquelyn Bainbridge, PharmD, FCCPProfessor Department of ClinicalPharmacy/Department of Neurology University of Colorado DenverAurora, CO
174 To Treat or Not to Treat?Does early treatment of patients with CIS delay the development of a second clinical event (CDMS diagnosis)?Four randomized, placebo-controlled, phase III trials have addressed that questionPreCISe: Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS of Subjects Presenting with CISBENEFIT: Betaseron® (SC IFNβ-1b) in Newly Emerging MS for Initial TreatmentCHAMPS: Controlled High-Risk Subjects (IM IFNβ-1a) Avenox® Multiple Sclerosis PreventionETOMS: Early Treatment of MSOne additional ongoing studyREFLEX: Rebif® (SC IFNβ-1a) FLEXible Dosing in Early MSIFN = interferon; IM = intramuscular; SC = subcutaneous.
175 Clinically Isolated Syndrome (CIS) CIS: single, symptomatic neurologic episode consistent with MS, first attackCommon symptoms: optic neuritis, ocular motor syndromes, ataxia, dysarthria, sensory or motor signs, partial myelitis, and bladder or bowel dysfunctionPatient may already have lesions on MRIClinically definite MS (CDMS): second attack consistent with MSCIS = clinically isolated syndrome; MRI = magnetic resonance imaging; MS = multiple sclerosis.
176 Prognosis in CIS Rate of Conversion to CDMS Baseline Measure% Converting to CDMSYearsAdapted with permission from Brex et al. N Engl J Med. 2002;346:
177 TreatmentAll 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.
178 MS Prognosis Without Therapy 10–20% have “benign MS”Rare attacks, little disabilityPost-hoc determinationAbout 5% have “malignant MS”Rapid accumulation of disabilityWheelchair-bound in 5 years, bed bound in 10 yearsMost are between these extremesNewer data suggests overall better prognosis
179 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)1More disability days per year (29.8 vs 4.5) (P <.0001)1Average annual costs for disability $3868 vs $414 US (P <.0001)11. Ivanova JI, et al. Pharmacoecomonics. 2009;27:
180 Key Parameters in MS Management: Disability DeathNormal neurologic examMinimal disabilityIncreased limitation in walking abilityNeed for walking assistanceRestriction to wheelchairHelpless bed patient10.09.59.08.58.07.57.06.56.05.55.04.04.53.52.53.02.01.51.00.5Patient Disability ClassificationExpanded Disability Status Scale = Rating system used by neurologists and clinical trial investigators to follow the progression of disability in MSKurtzke. Neurology. 1983;33:
181 Seven Approved Disease-Modifying Therapies IM IFNβ-1aSC IFNβ-1aSC IFNβ-1bGlatiramer acetateFingolimodNatalizumabOther first-lineMitoxantroneFirst-linetherapiesSecond-lineTherapy ?Worsening/progressivediseaseGraphic courtesy of Dr. Robert J. Lipsy.Abbreviations: IFNβ, interferon beta; IM, intramuscular; SC, subcutaneous.
182 FDA-Approved Therapies for MS Parenteral Immunomodulators Agents*IndicationsDoses and AdministrationGlatiramer acetate1 (Copaxone®)CISRRMS20 mg/d SCLow-dose IFNβ-1a2(Avonex®)30 mcg/wk IMHigh-dose IFNβ-1a3 (Rebif®)CIS†22 mcg or 44 mcg TIW SCHigh-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®).
183 FDA-Approved Therapies for MS Parenteral Immunosuppressive Agents*IndicationsDoses and AdministrationNatalizumab1 (Tysabri®) †Relapsing forms of MS300 mg q4wk IVMitoxantrone2(Novantrone®) ††SPMS, PRMS,Worsening RRMS12 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
184 Newly Approved Oral MS Therapies Disease-Modifying TherapyMechanisms of ActionFingolimod (FTY720)Sphingosine-1P (S-1P) receptor agonistBlocks lymphocyte migrationSymptomatic ManagementDalfampridineBlocks voltage-dependent K+ channelsMay restore conduction in poorly myelinated nerve fibers
185 Safety Considerations: Fingolimod & Natalizumab Lymphopenia is common because the drug sequesters lymphocytes in peripheral lymph nodes1,2Reversal of lymphopenia can take ~ 2 to 4 weeks after the end of dosing, depending on the dose3First dose problems within 6 hoursBradycardia1Second-degree Wenckebach atrioventricular blockInfections and malignanciesOverall the 3 most important monitoring parameters:Heart rateMacular edemaPulmonary function tests (decrease FEV1)NatalizumabTOUCH program = Progressive multifocal leucoencephalopathy (PML)Infusion reactionsWhen stopping Natalizumab bridging needs to occur to prevent immune reconstitution inflammatory syndrome (IRIS)4TOUCH = Tysabri Outreach Unified Commitment to HealthFEV1 = 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.
187 Phase IIb Laquinimod Study Effect on Annualized Relapse Rate 33%LAQ/5062 Study was not powered to detect a statistically significant effect on relapse rateTrend (p=0.0978) toward reduction of annualized relapse rateAnnualized Relapse RatePBOLQ 0.3mgLQ 0.6mgComi, et al (LAQ/5062 Study Group). Lancet. 2008;371:
188 Phase IIb Laquinimod Study Laquinimod 0.6mg Reduced MRI Lesion Counts Earlyduring the Treatment CourseGd-T1 LesionCount0.3 mg mg PlaceboComi, et al (LAQ/5062 Study Group). Lancet. 2008;371:
189 Conclusions & SummaryLaquinimod showed a robust, reproducible, sustained and early effect on MRI activityLaquinimod 0.6mg is safe and tolerableTransitory elevations of liver enzymes, most in the first 3 months of TxNo signs of immunosuppression following prolonged exposureCurrent data suggest a favorable, balanced benefit-to-risk ratio of laquinimod as a potential treatment for RRMS patients
190 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.003.190
191 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;12:191
192 Which New Agent is Best? New Agent vs. INFβ SENTINELtrial1Natalizumab + 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.TRANSFORMStrial2Fingolimod 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 RelapsingRemitting Multiple SclerosisTRANSFORMS= Trial Assessing Injectable Interferon Versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis1Rudick RA et al. Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis. The New England Journal ofMedicine. 02 Mar 2006;354; Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for RelapsingMultiple Sclerosis. The New England Journal of Medicine. 04 Feb 2010;362:
193 Emerging MS Therapies First-line therapies GAIFNbFingolimodNatalizumabTx-naivepatientsFirst-line therapiesConsistent effect on relapses and MRIUnclear effect on long-term disabilityPotential to further enhance efficacy and ease of useMain emerging therapies and strategiesOral agentsCladribineLaquinimodTeriflunomideFumaric acidMonoclonal antibodiesDaclizumabAlemtuzumabRituximabOcrelizumabCombination therapyIFNb-basedGA-basedNovel agentsMS Forum Modern Management Workshop, February 2006, Glasgow, Scotland. Available at:Abbreviations: GA, glatiramer acetate; IFNb, interferon beta.
194 Patient Adherence to MS Medication MS poses unusual challenges to adherenceNeedle phobiaNew daily routinesPerceived lack of efficacyAccording to adherence studiesMany patients display new or increased depression within 6 months of treatment initiation1Depressed patients displayed decreased adherence1Treating depression may prevent treatment discontinuation1Most frequent cause of stopping treatment is perceived lack of efficacy2Most treatment withdrawals occur within 1st year of treatment2Side effects and tolerability issues can result in nonadherence or discontinuation of medicationsMultiple 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;259:194
195 AdherenceBetween 17% and 40% of patients stop taking disease-modifying drugs within 1 year of initiation1-3MultifactorialPerceived lack of efficacy1,2Adverse effects2,3DepressionWithin 6 months of treatment initiation, 41% of patients had new or increased depression4Decreased adherence in patients with untreated depression4Multiple 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 IMDMore patients with SPMS stopped than RRMS½ stopped because of lack of efficacy¼ stopped because of side effects¼ stopped for reasons unrelated to efficacy or side effects1. 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;54:195195
196 Studies of Patient Adherence to MS Medications Longitudinal, prospective study of 199 patients with definite MSOf 97 patients taking DMT73% missed doses10% missed >10 doses in a 6-month period25% stopped DMTMissed doses were associated with alcohol intakeHistory of missed doses predicted future missed dosesNumerous and divergent factors influenced missed doses and stopping DMTIndicates need for multifaceted approach to improving adherenceTremlett H, et al. Pharmacoepidemiol Drug Saf. 2008;17:196
197 Patients in United States Find it Harder to Pay for Care Patients stating that they often have difficulty paying for medications or other care costsGraphic courtesy of Dr. Robert J. Lipsy. The Commonwealth Health Fund 2009 International Healthy Policy Survey of Primary Care Doctors. Health Affairs. 5 November 2009.
198 Anti-TNF Prescription Abandonment As out-of-pocket expenses increase, treatment abandonment increasesWith permission from Gleason PP, et al. J Manag Care Pharm. 2009;15:
199 Promoting Adherence to Therapeutic Regimens in MS Establishing Realistic Expectations Therapies have been shown to reduce relapses, reduce MRI activity, and attenuate disease activityAttenuated disease activity may lead to more patients retaining employmentPatients with MS must also realize that DMTsOnly work if patients take themAre not cures for MSMay not eliminate MS symptomsDo not completely eliminate future disease activityCerghet M, et al. 60th AAN; April 12-19, 2008; Chicago, IL. PPutzki N, et al. 60th AAN; April 12-19, 2008; Chicago, IL. P199
200 Disease-Modifying Therapies Relapse free at 1 year 51%–80%Relative decrease in annual relapse rate 30%–80%Absolute annual relapse rate 0.15–0.7Relative decrease in sustained progression 31%–42%Absolute rate of disease progression 9%–18%Workers with MS on a DMT and not on a DMT1N=258 vs. N=322Treatment with DMT = reduced medical and indirect costsData courtesy of Dr. Robert J. Lipsy.1. Birnbaum et al Curr Med Res Opin ;25(4):
201 Questions to ConsiderHow 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?