2 The Evolving Landscape of MS Therapy New Frontiers in Managed Care Pharmacy PracticeEmerging Challenges on the Therapeutic Landscape of Multiple SclerosisA Dilemma and Clinical Decision Updatefor the Managed Care PhysicianProgram ChairmanBruce A. Cree, MD, PhD, MCRAssistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, California
3 Program Faculty Bruce A. Cree, MD, PhD, MCR Brian Steingo, MD Bruce A. Cree, MD, PhD, MCRAssistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, CaliforniaBrian Steingo, MDMedical DirectorNeurologic Associates ResearchFort Lauderdale MS CenterPompano Beach, FL
4 The Evolving Landscape of MS Therapy The Evolving and Complex Therapeutic Landscape for Multiple SclerosisAchieving the Ideal Balance Between Safety and Efficacyfor Long-Term Treatment In the Managed Care SettingProgram ChairmanBruce A. Cree, MD, PhD, MCRAssistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, California
5 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):
6 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):
7 Clinical Manifestations of MS FatiguePainDepressionNumbness/paresthesiasCognitive dysfunctionWeaknessSpasticityOptic neuritisBladder dysfunctionBowel dysfunctionCerebellar dysfunctionSexual dysfunctionGait abnormalitiesPartial/complete paralysisNational Multiple Sclerosis Society. Accessed February 21, 2010.
8 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):
9 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:
10 Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:
11 Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:
12 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
13 Trends Across MS Clinical Trials Annualized Relapse Rate (ARR) Johnson1995Polman2006REGARD2007BECOMEKapposTRANSFORMSJacobs1996IFNβ-1bstudygroup,1993PRISMS-21998BEYONDCAMMS22320083 yearsHERMES48 weeksFORTE1 yearCLARITY2009
14 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
15 Existing and Emerging MS Therapies 2005200620072010201120122013OralInjectablesBG12CladribineBG12CladribineRebifRebifFingolimodBetaseronAmpyraAmpyraTeriflunomideTeriflunomideCopaxoneExtaviaExtaviaLaquinimodLaquinimodAvonexOcrelizumabOcrelizumabIVNovantroneTysabriTysabriIVGenericMitoxantrone(oncology) MSGeneric Mitoxantrone(oncology) (MS)AlemtuzumabAlemtuzumabFiledApprovedIn phase IIIn phase III
16 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
17 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
18 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
19 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?
20 Questions We Will Address Today Do you employ a formalized pathway for MS care in your MCO? For first-line treatment? Second line treatment? Or are these decisions left to the treating physicians?What is the patient's role in determining the initial MS therapy offered to them? Is it a dialogue? If so, what is the shape of the dialogue? If not, how is the decision made?
21 Investigations • Innovation • Clinical Application A New Era of Oral Therapy for Multiple Sclerosis The Good, The Bad, The Uncertain— Cautionary Notes for Managed Care Physicians Program ChairmanBruce A. Cree, MD, PhD, MCRAssistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, California
22 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
23 The Evolving Landscape of MS Therapy Mechanisms of Action
24 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:
25 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:
26 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
27 Laquinimod Induced Immunomodulation on the Molecular Level Overexpression/downregulation27
28 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
29 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
30 % 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.
31 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:
32 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.
33 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:
34 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
35 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.
36 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
37 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.
38 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.
39 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
40 The Evolving Landscape of MS Therapy Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons?
43 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
44 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?
45 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?
49 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
51 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
52 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
53 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?
54 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):
55 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.
56 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.
57 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.
58 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
59 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.
60 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
61 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?
62 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?
63 Investigations • Innovation • Clinical Application Redefining the Long-Term Benefit-to-Risk Equation for Therapy of Multiple Sclerosis Implications for the Managed Care Setting Brian Steingo, MDMedical DirectorNeurologic Associates ResearchFort Lauderdale MS CenterPompano Beach, FL
64 Existing and Emerging MS Therapies 2005200620072010201120122013OralInjectablesBG12CladribineBG12CladribineRebifRebifFingolimodBetaseronAmpyraAmpyraTeriflunomideTeriflunomideCopaxoneExtaviaExtaviaLaquinimodLaquinimodAvonexOcrelizumabOcrelizumabIVNovantroneTysabriTysabriIVGenericMitoxantrone(oncology) MSGeneric Mitoxantrone(oncology) (MS)AlemtuzumabAlemtuzumabFiledApprovedIn phase IIIn phase III
65 Trends Across Clinical Trials Annualized Relapse Rate (ARR) GAFTY720AvonexNTZ0.870.84BetaseronCampath®RebifRituximab0.670.590.360.370.340.350.320.290.300.280.2126.96.36.199Johnson1995Jacobs1996IFNβ-1bstudygroup,1993PRISMS-21998KapposTRANS- FORMSPolman2006REGARD2007BEYOND2007BECOME2007CAMMS22320083 yearsHERMES200848 weeksFORTE20081 year
66 AlemtuzumabMonoclonal 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:
69 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:
70 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:
71 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:
72 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:
73 Cladribine Synthetic purine nucleoside analogue prodrug Accumulates and is incorporated into the DNA of lymphocytes as a result of a high ratio of deoxycytidinekinaseto 5' nucleotidase 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;32:120–3.73
74 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;362:74
75 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:
76 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:
77 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:
78 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:
79 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:
80 Fingolimod (FTY720) Sphingosine-1-phosphate (S1P) receptor modulator 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-17S1P receptors located within the CNSFingolimod or deletion of S1P1 from neural cells reduces astrogliosis in EAE1. 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.
81 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;362:81
82 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:
83 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:
84 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:
85 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:
86 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:
87 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:
88 Fingolimod: 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:
89 Malignancies and Herpes Infections Fingolimod: SafetyMalignancies 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:
90 Fingolimod: SafetyTwo 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:
91 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
92 Laquinimod A novel synthetic compound Route of administration – oral Primary Indication – Relapsing remitting multiple sclerosis; two phase III studies ongoingAdditional Indications – Crohn’s Disease; SLE92
93 Effect on T1 Gd Enhancing Lesions Phase IIb - LaquinimodEffect on T1 Gd Enhancing LesionsMeanMedian51% reductionP <60% reductionP=0.01Mean Number of Cumulative Gd Enhancing Lesions (week 12-36)Median Number of Cumulative Gd Enhancing Lesions (week 12-36)PBOLQ 0.3mgLQ 0.6mgPBOLQ 0.3mgLQ 0.6mg* Adjusted meansComi, et al (LAQ/5062 Study Group). Lancet. 2008;371:
94 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:
95 Phase IIb Laquinimod Study Conclusions An oral, once-daily dose of laquinimod 0.6mg has shown:A robust, consistent and early effect on MRI activity in RRMS patientsA trend in reducing the number of relapsesA trend in slowing the progression of brain atrophyLaquinimod 0.6mg is safe and tolerable
96 Elevations to Potentially Clinically Significant Levels Phase IIb Laquinimod StudySafetyNo deathsNo effect on vital signsNo effect on ECGNo specific pattern of adverse eventsElevations to Potentially Clinically Significant Levels0.6mg (n=106)0.3mg (n=98)Placebo (n=102)8 (7.5%)2 (2.0%)2 (1.9%)ALT (x3)1 (0.9%)3 (2.9%)AST (x3)Bilirubin (x2)Liver Enzyme Elevation:All cases are reversibleMost normalized while on laquinimodNo signs of liver damage/failureNo concomitant bilirubinemiaComi, et al (LAQ/5062 Study Group). Lancet. 2008;371:
97 Laquinimod Does Not Cause Immunosuppression It does not affect viability or proliferation of human PBMCsIt does not affect the ability of animals to mount cellular or humoral immune responsesIt does not affect graft survivalNo clinical signs of opportunistic infections
98 Laquinimod is an Immunomodulator Modulation of cytokine profileReduction of leukocyte infiltrationDown regulation of inflammatory genesDown regulation of MHC class II expressionEffects on dendritic cells (DC) compartment
99 Laquinimod MoA In Multiple Sclerosis Summary Laquinimod is an immunomodulator with both anti-inflammatory & neuroprotective properties:Shifts the cytokine balance towards a Th2/Th3 profileReduces immune cell infiltration into the CNSInduces myelin and axonal preservation
100 Oral Laquinimod for RRMS Phase III Program Completed enrollment of~1100 RRMS patientsORAL LAQUINIMOD 0.6 MGALLEGRO24 MONTHS OF TREATMENTOPEN LABELEXTENSIONORAL MATCHING PLACEBOCompleted enrollment of~1300 RRMS patientsORAL LAQUINIMOD 0.6 MGBRAVOAVONEX® 30MCG/WEEKOPEN LABELEXTENSION24 MONTHS OF TREATMENTORAL MATCHING PLACEBO
101 Emerging Therapies: Trading Efficacy for Safety ? Impaired immune surveillance and opportunistic infectionsViral and other infections? MalignanciesLong-lasting effectsAutoimmunityTeratogenicityRare, but serious infusion reactionsThe Unknown
103 Evaluated in 4 randomized, double-blind, placebo-controlled trials Humanized monoclonal antibody directed against CD11a affecting T-lymphocyte activation, migration, and reactivationEvaluated in 4 randomized, double-blind, placebo-controlled trialsFDA-approved for psoriasis in 2003At the time of approval, 2764 patients had been treated218 treated for ≥ 1 yearNijsten T, et al. Arch Dermatol 2009;145:
104 October 2008: Label update to include PML February 2009: FDA issued a Public Health Advisory and changed the label to include a “black box” warning for PMLAt the time, 48,000 patients treated with efalizumab, but only 14,000 for > 1 year, 5,100 for > 2 years, and 1,900 for > 3 yearsEMEA recommends suspension of marketingHealth Canada suspends marketingApril 2009: Genentech announced plans for a voluntary withdrawal from the U.S. marketNijsten T, et al. Arch Dermatol 2009;145:
105 Treatment Decisions: Considering Benefits and Risks Benefits RisksMeaningful impactDisease CourseMRI? Better than ABCR? Window of opportunityConvenienceShort-term safetyLong-term safetyPharmacovigilancePost-approval studiesPregnancy issues
106 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?
107 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?