Presentation on theme: "New Frontiers in Neurotherapy for Multiple Sclerosis"— Presentation transcript:
1New Frontiers in Neurotherapy for Multiple Sclerosis Investigations • Innovation • Clinical ApplicationNew Frontiers in Neurotherapyfor Multiple SclerosisFocus on the Foundation Role of Immunomodulation for Long-Term Efficacy, Safety, Neuronal Preservation, and Disability MitigationProgram ChairmanBruce A. Cree, MD, PhD, MCRAssistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, California
2Program Faculty ROHIT BAKSHI, MD, FAAN BRUCE A. CREE, MD, PhD, MCR Assistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, CaliforniaMARK J. TULLMAN, MDDirector, Multiple Sclerosis Clinical CareCenterThe Neurological Institute of New YorkColumbia University Medical CenterNew York, New YorkROHIT BAKSHI, MD, FAANAssociate Professor of Neurology &RadiologyDirector, Laboratory for NeuroimagingResearchMS Center, Brigham & Women’s HospitalHarvard Medical SchoolBoston, MAGUY J. BUCKLE, MD, MPHDirector of MS Clinical Care Partners Multiple Sclerosis CenterBrigham and Women’s HospitalAssistant Professor of NeurologyBoston, Massachusetts
3The Evidence for First Line Therapy with Immune-Modulating Agents Investigations • Innovation • Clinical ApplicationThe Evidence for First Line Therapy with Immune-Modulating AgentsFrom Mechanisms to Therapy—Landmark Trials, Long-Term Safety Data and Clinical ExperienceProgram ChairmanBruce A. Cree, MD, PhD, MCRAssistant Professor of NeurologyDepartment of NeurologyUniversity of CaliforniaSan Francisco Multiple Sclerosis CenterSan Francisco, California
4Overview Mechanisms of action of first line therapies Outcome measures in clinical trialsComparison of landmark trialsLongitudinal studies: what do they tell us?
5Goals 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
6Immunopathogenesis 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
7Adapted 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:
8Glatiramer 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:
9Long-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
10Development of Disability Effect of Early Clinical CourseClinical CharacteristicSignificance*Number of Attacks, 1st 2 yearsp <0.001Interval Between 1st 2 AttacksDSS at 2 yearsp < 0.001DSS at 5 years* Controlled for age at onset, remitting at onset, cerebellar, cerebralWeinshenker B et al. Brain. 1991;114 ( Pt 2):
11Relapses in MSRelapses 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
12% Reduction in relapse rates Effect on Annualized Relapse Rates: Summary of Phase III Trials – 2 years in-study3531%8 MIU qodIFN beta-1bP=0.000129%4.4 MIU tiwIFN beta-1aP<0.00132%8.8 MIU tiwIFN beta-1aP<0.000129%20 mg qdglatiramer acetateP=0.055302520% Reduction in relapse rates18%15P=0.041056 MIU qwIFN beta-1aN.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.
13Is 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
14Proportion 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%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.
15How is Sustained Progression Measured? Most clinical trials define progression by comparing the change in EDSS from baseline to study conclusion, and then confirm the change in EDSS at 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
16Does 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.
17Effect on Sustained Disability*: Summary of Phase III Trials 37%4029%30%p=0.0230sustained disability progression (%)Reduction in22%p<0.0520p=NSp<0.0512%10p=NS20 mg qdglatiramer acetate8 MIU qodIFN beta-1b6 MIU qwIFN beta-1a4.4 MIU tiwIFN beta-1a8.8 MIU tiwIFN beta-1a*1 EDSS point sustained for 6 months in 6 MIU qw phase III trial and for 3 months in all other 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;352:14981. Jacobs et al. Ann Neurol. 1996;39: IFNB MS Study Group. Neurology. 1993;43: Johnson et al. Neurology. 1995:45:1268.4. PRISMS Study Group. Lancet. 1998;352:1498.
18SummaryRelapses and disability progression represent different but complimentary aspects of MS natural historyRelapse 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 and glatiramer acetate modestly reduce the relapse rateIFN beta-1a has a statistically significant impact on sustained disability progression over two yearsIFN beta-1a and glatiramer acetate have a statistically significant impact on the mean EDSS over two year
19Are direct comparator studies needed in MS or can we make valid conclusions from cross trial comparisons?
28Glatiramer Acetate 15 year LTFU In a small cohort of patients 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
29IFN β-1a (QW) LTFU Disposition Complete 2-year follow-up(n=172)Unascertained(n=36)Ascertained for ASSURANCE(n=136; 79%)Able to locate,Unable to contact(n=13)Unable to locate(n=23)Living(n=122; 90%)Deceased(n=14; 10%)ICF and question booklet completedLOCFBermel R et al. Mult Scler Feb 18. [Epub ahead of print]
30IFN β-1a QW LTFU Outcomes Currently receiving IM IFN ß-1a (n=56)Not currently receiving IM IFN ß-1a (n=66)P=0.006P=0.062P=0.114P=0.326Patients, %Patients, %EDSS MilestoneBermel R et al. Mult Scler Feb 18. [Epub ahead of print]
31IFN β-1a QW LTFU Conclusions 79% of eligible patients were located for the 15 year follow upAt 15 years, patients currently on IFN β-1a had less progression in EDSS scores than patients not on IFN β-1aHowever, patients not currently on IFN β-1a had higher baseline EDSS scores suggesting more severe baseline MSPropensity scores were used to adjust for these differencesInferences with regard to association with lower EDSS and ongoing treatment were not madeBermel R et al. Mult Scler Feb 18. [Epub ahead of print]
36ConclusionsDisease modifying therapy seems favorably effect the long-term course of MSPropensity score adjusted analysis and other statistical methods for controlling biases inherent in long term, unblinded studies are important statistical advances for interpreting these studiesOnce the MS community agrees on the relevant covariates, these methods can be used to sort out some of these issues without the cost (and ethical dilemmas) posed by long-term placebo-controlled trials.
37Investigations • Innovation • Clinical Application The Emergence of Immunosuppressive Agents for MS Safety, Efficacy, and Cautionary Notes— Patient Monitoring, Risks for Infection, and Mechanisms of ActionMark J. Tullman, MDAssistant Professor of NeurologyDirector, Multiple Sclerosis Clinical Care CenterThe Neurological Institute of New YorkColumbia University Medical CenterNew York, New York
38Existing and Emerging MS Therapies 2005200620072010201120122013OralInjectablesBG12CaldribineBG12CladribineRebifRebifFingolimodBetaseronAmpyraAmpyraTeriflunomideTeriflunomideCopaxoneExtaviaExtaviaLaquinimodLaquinimodAvonexOcrelizumabOcrelizumabIVNovantroneTysabriTysabriIVGenericMitoxantrone(oncology) MSGeneric Mitoxantrone(oncology) (MS)AlemtuzumabAlemtuzumabFiledApprovedIn phase IIIn phase III
39Efficacy in Recent Studies Annualized relapse rate over 2 years58-61% relapse-free over 2 years79-81% without disability progression over 2 years88.3% without disability progression over 96 weeks91.3% without disability progression over 96 weeks74% without disability progression over 3 years75% without EDSS progression 5 years after CIS onset13.3% reduction in MRI T2 lesion load over 3 yearsAll in placebo, interferon, or glatiramer acetate-treated patientsKappos L, et al. Lancet Neurol 2009; 8: 987–97; Giovannoni G, et al. N Engl J Med. 2010;362: ; CAMMS223 Trial Investigators. NEJM 2008;359: ; Kappos L et al. N Engl J Med. 2006;355: ; Mikol et al. Lancet Neurol 2008; 7: 903–14
40Prognostic Signs Favorable Outcome Worse Outcome Female Male Younger age at onsetLittle disability 5 years after onsetOptic neuritis as 1st attackWorse OutcomeMaleOlder age at onsetFrequent attacksShort interval between 1st 2 attacksIncomplete recovery from 1st attackCerebellar involvement as 1st symptomRapidly accumulating disabilityProgressive disease from onset
41Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:
42Baseline Brain MRI Lesion Number 20-Year Clinical Status Fisniku LK. Brain 2008;131:
43Disease Free State Proportion Free of Clinical and MRI Activity Natalizumab PlaceboHardova E, et al. Lancet Neurol 2009;8:
44AlemtuzumabMonoclonal 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:
47Alemtuzumab 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:
48Alemtuzumab 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:
49Alemtuzumab 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:
50Alemtuzumab: 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:
51Cladribine 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;32:120–3.51
52Cladribine 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;362:52
53CLARITY: 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:
54CLARITY: 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:
55mean ± 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:
56CLARITY: 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:
57CLARITY: 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:
58CLARITY: 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.
59Fingolimod (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.
60Oral 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;362:60
61FREEDOMS: 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:
62FREEDOMS: 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:
63FREEDOMS: 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:
64FREEDOMS: Brain Volume P≤0.03 for both doses of fingolimodvs. placebo at all time pointsKappos L, et al. N Engl J Med. 2010;362:
65Randomization 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:
66TRANSFORMS: 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:
67TRANSFORMS: 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:
68TRANSFORMS: Brain Volume P < 0.001Cohen J, et al. N Engl J Med. 2010;362:
69Fingolimod: 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:
70Malignancies 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:
71Fingolimod: 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:
72FTY720 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
73[PD5.006] Prolonged Reduction in Circulating Lymphocytes after Discontinuation of FTY720 (Fingolimod): Possible Relationship to Duration of Therapy Mark R. Keezer, Yves Lapierre, Igor Shames, David Haegert, Amit Bar-Or, Jack Antel, Montreal, QC, Canada CONCLUSIONS/RELEVANCE: Peripheral lymphocyte counts remained depressed beyond the currently expected time period in 2 patients following cessation of long-term FTY720 therapy. Regional lymph node architecture was preserved in the one available patient. Exploration of larger datasets will determine the true incidence of prolonged lymphopenia and whether time to recovery of circulating lymphocytes may provide a potential biomarker for guiding continued therapy. Category - MS and Related Diseases - Clinical SciencePresented at the AAN Annual Meeting 2010.
74Emerging Therapies: Trading Efficacy for Safety ? Impaired immune surveillance and opportunistic infectionsViral and other infections? MalignanciesLong-lasting effectsAutoimmunityTeratogenicityRare, but serious infusion reactionsThe Unknown
76Evaluated 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:
77October 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:
78Treatment Decisions: Considering Benefits and Risks Benefits RisksMeaningful impactDisease CourseMRI? Better than ABCR? Window of opportunityConvenienceShort-term safetyLong-term safetyPharmacovigilancePost-approval studiesPregnancy issues
79New Frontiers in Neurotherapy The Long Haul: Optimizing Long-Term Functional Status and Financial Outcomes in RRMS with Immunomodulation TherapyWhat Do The Trials Teach Us?Guy J. Buckle, MD, MPHDirector of MS Clinical Care Partners Multiple Sclerosis CenterBrigham and Women’s HospitalAssistant Professor of NeurologyHarvard Medical SchoolBoston, Massachusetts
80Epidemiology of MSThe 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):
81Potential Triggers for MS InfectiousAgentGenetic PredispositionEnvironmental FactorsMS is believed to result from of an abnormal immunologic response to an infectious agent and/or unknown environmental factors in people who have a genetic predisposition to MS.1Besides geography, researchers have concentrated on two other broad areas of inquiry: genetics and infectious agents (bacteria and viruses).Genetics: Numerous studies show that genetics play a role in the development of MS, but are not the sole cause of the disease.Roughly 1%-4% of MS patients will have a first-degree relative, a parent, a sibling, or an aunt or uncle, who also has MS.2The identical twin of a person with MS has a 1 in 3 chance of developing MS.2Although these facts are not considered conclusive proof of familial inheritance of MS, they do tell doctors that genetic factors definitely contribute to the risk of developing MS.Infectious agents: There is the possibility that a single germ or combination of germs may increase a person’s risk of developing MS. The viruses that cause measles and herpes, and chlamydia have been considered possible culprits; however, to date, no specific agent has ever been conclusively proven to be the sole cause of MS.2Miller, et al. Immunopathogenesis. In: Continuum: Lifelong Learning in Neurology. Multiple Sclerosis (Part A)What is MS? Available at: http;//mscenter.ucsf.edu/fag.htm. AccessedAbnormal Immunologic ResponseMSCardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):
83Age of Onset of MS Distribution of Patients According to the Decade of Life of MS Symptoms Onset35302520Patients (%)151050-1011-2021-3031-4041-5051-60YearsCardoso E, et al. Arq Neuropsiquiatr. 2006;64(3-B):
84Progression 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:
85Natural 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):
86Early Relapses Affect Long-term Disability 100Low (0-1 attacks in 2 years)Intermediate (2-4 attacks in 2 years)High (≥5 in 2 years)8060Patients (%)40201020304050Time from Onset of MS (years)Actuarial analysis of disability—percentage of patients not having reached EDSS 6:difference between the groups is significant (P < .0001).Weinshenker BG, et al. Brain. 1989;112:
87Relapses 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:
88Long-term Study Design in RRMS Copaxone® (glatiramer acetate injection)20,21N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter open-label extension, and 1 patient received 1 dose of COPAXONE® and never returned for evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort included 108 patients at 10 years and 100 patients at 15 years.Avonex® (IFNβ-1a)9,23Avonex®: N=301; 158 Avonex®, 143 placebo; subset (85 Avonex®, 87 placebo) followed for 2 years. 15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year 15.Betaseron® (IFNβ-1b)24,25Betaseron®: N=372; 125 Betaseron® 1.6 MIU, 124 Betaseron® 8 MIU, 123 placebo.16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but included in the study as identified patients). LTFU data were obtained in an observational study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients were not taking Betaseron®.Rebif® (IFNβ-1a)26N=560; 184 Rebif® 44 mcg, 189 Rebif® 22 mcg, 187 placebo; at end of year 2, 172 placebo patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was continued to year 4.LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8 years after enrollment.Tysabri® (natalizumab)27N=942; Tysabri® 300 mg (n=627) or placebo (n=315).Up to 15 years2 yrs15 years5 yrs16 years4 yrs7-8 years3 yrsKeyProspective study designRetrospective follow-up9. Jacobs LD, et al. Ann Neurol. 1996;39: Ford C, et al. WCTRIMS Abstract P Ford CC, et al. Mult Scler. 2006;12:23. Bermel RA, et al. WCTRIMS Abstract P IFNβ Study Group. Neurology. 1995;45: Ebers G, et al. AAN P26. Kappos L, et al. Neurology. 2006;67: O’Connor PW, et al. AAN P
89Data Supporting Long-Term Use of DMT Disease Duration (Years)Percentage Reaching EDSS 4Percentage Reaching EDSS 6GA 15-year LTFU>18.538%18%High-dose IFN-1aPRISMS 8~1326.8%20%IFN-1b16 Year(> 80)~20Not reported~45%Low-dose IFN-1a15-year14.364%32%Ryan M, et al. J Manag Care Pharm. 2009;15(1)(Suppl S-b):S1-S17.
90Scope of QoL Three important domains in life Physical functioning Psychosocial functioningSymptom-related phenomenon
91The Two Faces of Multiple Sclerosis MSRelapseProgressionMRISymptomsMobilityEmploymentDepressionFatigueCognition
92Mobility and HRQOLImprovement in strength and mobility can lead to improved social interaction and emotional behaviorImproved fitness in MS is associated with improved HRQOLPhysical activity is indirectly associated with improved depression, fatigue, pain, in individuals with MSHRQOL = Health-related quality of life.Petajan JH, et al. Ann Neurol. 1996;39(4): Motl R,W et al. Psychol Health Med. 2009;14(1)
93Multiple Sclerosis MS <5 Years MS >15 Years First Rank (%) 4035MS <5 Years30MS >15 Years25First Rank (%)2015105WalkingPower and Coordination of HandsNormal Skin SensationsLack of PainBladder ControlBowel ControlVisual FunctionAwakefulness and AlertnessThinking and MemorySpeechSwallowingMoodsexualityHeesen C, et al. Mult Scler. 2008;14(7):
94Walking Impairment and Quality of Life 64% of patients report difficulty walkingImpairment worsens with increasing EDSS severityPercent Among Patients who Reported Walking ImpairmentJohanesson et al. J Neurol. 2007;254:
95Trends Across MS Clinical Trials Annualized Relapse Rate (ARR) Johnson1995Polman2006REGARD2007BECOMEKapposTRANSFORMSJacobs1996IFNβ-1bstudygroup,1993PRISMS-21998BEYONDCAMMS22320083 yearsHERMES48 weeksFORTE1 yearCLARITY2009
96Cost of MS Relapse Reducing relapses is key to reducing costs The number of relapses is a significant predictor of total costCost of treating a relapse is difficult to calculateIncludes initial care, acute treatment costs, post-discharge services, daily cost of outpatient medicationsIn one study, using 2002 dollars, costs ranged from $243 to $12,870, depending on level of management neededCost estimates do not differentiate between the different forms of MSMorrow TJ. J Neurol Sci. 2007;256(supp 1):S39-S44.Grudzinski AN, et al. J Manag Care Pharm. 2000;6:19-24.O’Brien JA, et al. BMC Health Serv Res. 2003;3:17-29.96
97Medical 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.
98Economic 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 $47,215 (in 2004 dollars)Mean direct healthcare costs incurred by insured patients with MS are 2 to 3 times higher than those without MSDirect correlation between cost (direct and indirect) and severity of disease has been well-establishedTherapeutics that modify MS activity and severity can result in both clinical and economic benefitsWhetton-Goldstein K, et al. Mult Scler. 1998;4(5): Pope GC, et al. Neurology. 2002;58(1): Kobelt G, et al. Neurology. 2006;66(11): Patwardhan MB, et al. Mult Scler. 2005;11(2): O’Brien JA, et al. J Neurosurg Psychiatry. 2006;77:
99MS Cost Drivers Sick Leave/Reduced Working Time (10%) Informal Care (12%)Adaptations (5%)Services (2%)Other Drugs (6%)Early Retirement (34%)DMTs (22%)Hospital Inpatient Care (3%)Tests (2%)Ambulatory Care (4%)DMT = disease-modifying therapy.Kobelt G, et al. Neurology. 2006;66(11):
100Costs of MS by Disease Severity Informal CareIndirect CostsDirect Costs70,000Other DrugsDMTs60,00050,000Cost ($)40,00030,00020,00010,000Mild EDSS<4.0Moderate EDSSSevere EDSS>6.0AllPatientsDMTs = disease-modifying therapies.Kobelt G, et al. Neurology. 2006;66(11):
101Approximate 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.
102DMT-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 trendComparative AWPs of DMT options:AgentDosageAWP/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$40,187AWP = 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.
103MS 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.
104Factors Influencing Adherence with DMT in MS 70605040302010FatigueOtherFinancialDepressionHeadacheWeaknessFlu-Like*Skin ReactionDidn’t RefillForgot to Take*Inj SiteTired of ShotsInjection Anxiety**Didn’t Feel Like ItNot Sure of BenefitsDosing InconvenientPregnant or PlanningNo One Available to Give †Total*P<.05†P<.01.Treadaway K, et al. J Neurol. 2009;256(4):
105Promoting Adherence to Therapeutic Regimens in MS Starting TherapyEducateMake a plan with the patientReconfirm goalsSchedule proper follow-upTreat relapses appropriatelyTreat comorbid conditionsKeep channels of communication openEstablishing a therapeutic relationshipEducating patient and familyIncreased adherence to treatmentManaging patient expectationsManaging adverse eventsAddressing patient concernsBrandes DW, et al. Curr Med Res Opin. 2009;25(1): Figure 2.105
106Optimizing Treatment Outcomes in MS Patients Patient Education Is EssentialUnderstanding diseaseClinical implicationsRationale for treatmentReviewing treatment optionsSetting realistic goals/expectationsPotential adverse effectsWays to minimize and manage adverse effectsMinimizing fear and anxietyProper injection trainingRecognizing relapsesTracking and reporting symptoms/relapses/adverse effectsEmphasizing importance of adherence to therapyTreadaway K, et al. J Neurol. 2009;256(4):
107Challenges to Adherence Cognition and physical limitations negatively impact adherenceUp to half of patients reportedly discontinue because of an AE or a lack of efficacyAssociation of depression carried a 3-fold risk of nonadherenceThird-party reimbursement challengesFormulary statusCopaysAdherence tends to decrease over time due to a variety of factors, such as “treatment fatigue,” loss of motivation, and complacencyRio J, et al. Mult Scler. 2005;11: Twork et al. Curr Med Res Opin. 2007;23(6):O’Rourke KE, et al. Mult Scler. 2005;11(1): Ross AP. Neurology. 2008;71(Suppl 3):S1-S2. DiMatteo MR, et al. Arch Intern Med. 2000;160:
108Recent 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.
109Rates of Unemployment in Individuals with MS StudyCountryDuration of MS Since Onset (Years)Unemployment RateBusche et al., 2003Canada14.8 (median)(range 1-47)Baseline: 49.9%2.5 years later: 59.4%Jackson and Quaal, 1991> 5 in 80% of patients76%*Gronning et al., 1990Norway10 (mean) (range 1-33 years)72% of those with definite MSO’Connor et al., 2005U.K.Employed: 10 (mean)Unemployed: 15 (mean)64%Beatty et al., 1995U.S.15.4 (mean)60-66%Kornblith et al., 198613 (mean)80%*LaRocca et al., 198277%*Proportion of individuals unemployed during the study who had been employed at some time during his or her lives.Dennett SL, et al. Value Health (3):
110Effect of IMT and Other Factors on Employment Loss Time Focus: factors that influence time missed from work among individuals with MS (N = 284)Records were examined for details of medical claimsMultivariate regressions were performed, controlling for demographic characteristics, type of immunomodulatory medication, and overall severity of illnessLooked at total number of days missed from work for any reason and specifically due to absenteeism, short-term disability, or workers compensationResults indicate that lost work time is affected by severity of illness and type of IMTReferenceLage MJ, Castelli-Haley J, Oleen-Burkey MA. Effect of immunomodulatory therapy and other factors on employment loss time in multiple sclerosis. Work. 2006;27:Lage MJ, et al. Work. 2006;27(2):/071401
111Effect 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
112Specialty Pharmacy Overview Key Disease States Managed by a Specialty PharmacyMS, RA, Hep C, hGH, Oral OncolyticsThe number of patients utilizing Specialty Pharmacies continues to increaseCurrently estimated to be 40% - 50% of MS patients
113SP Value Proposition Compliance & Adherence Patient Education Typically 15% - 20% higher than retail*Patient EducationSpecially trained on rare diseases and therapiesCollaborate with manufacturers and MS Specialists to assist with trainingPatient MonitoringEfficacySide effectsCo-Morbid Conditions*2008 IMS Report
114SP Value Proposition Data Tracking and Monitoring Compliance/Adherence EfficacyBaselineRelapsesEDSSSide EffectsFlu like symptomsInjection site reactionsCo-MorbiditiesAsthma, Hypertension, diabetesSymptom ManagementFatigue,BladderDepressionAppropriate and timely interventions
115Therapy OPtimization in MS (TOP MS) An Outcomes Study of disease management (DM) for MS based in Specialty Pharmacies who have demonstrated commitment to DM:Therapy Adherence and ComplianceDisease CharacteristicsRelapsesDisability ProgressionQuality of LifeWork / Usual Activity Productivity
116Therapy OPtimization in MS (TOP MS) Brief Outline:3 Specialty Pharmacies~3,000 patients followed for 2 yearsPatient-specific clinical reports to physiciansDe-identified data collected in a research-quality database will be available to address outcomes research questions
117Study PopulationSubjects who are treated with glatiramer acetate or interferon (IFN)-β and receive their therapy from a Specialty Pharmacy:Copaxone®Avonex®Betaseron®Rebif®Extavia®
118Study ObjectiveTo demonstrate the benefits of compliance and adherence to MS therapy with patient outcomes:RelapsesDisability progressionQuality of lifeWork and usual activities productivity
119Advocacy Assist patients with resources and support Assist patients with navigation of health care system and insurance coverageSpeak with third-party payors to advocate for coverage for all DMTsBecome involved with advocacy organizationsIOMSNCMSCNMSSMSAAMSFEducational activities for professionals and patientsDevelopment of written materialsWorking at organizational level for FDA approvals, third-party reimbursementIOMSN = International Organization of MS Nurses; CMSC = Consortium of MS Centers; NMSS = National MS Society; MSAA = MS Association of America.
120Conclusion 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
121Challenging Cases in the Management of Multiple Sclerosis Case StudiesChallenging Cases in theManagement of Multiple Sclerosis
122Multiple Sclerosis Case #1 24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusualBack in Houston another ophthalmologist called it ‘some type of optic nerve inflammation’ and gave her 5 days of oral steroids2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia and oscillopsia
125Multiple Sclerosis Case #1 4 days later continued double vision on looking to the rightExtensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoningNystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normalCSF with 10 lymphocytes, IgG index 1.15 and 3 OCBsIntravenous methylprednisolone course started
128Multiple Sclerosis Case #1 The Issues The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this?When you have CIS and can’t diagnose more than suspect MS by McDonald’s or Swanton’s, do you just treat, use Frohman?When asked about the familial risk of MS in the company of the patients twin sister, what is the best course?
129Multiple Sclerosis Case #2 30-year-old Caucasian female presented initially with right optic neuritis.Vision improved after high dose intravenous methylprednisolone treatmentT2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and subcortical white matter.No disease modifying therapy was started at that time.
130Multiple Sclerosis Case #2 1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days.MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1.MRI brain- one new periventricular white matter lesion without enhancement in comparison to last year’s.Motor symptoms improved with high dose corticosteroid therapyResidual numbness in the feet and bladder control difficulties.
131Multiple Sclerosis Case #2 Given diagnosis of MS and therapy with once weekly IM interferon beta was begun.6 months later she complained of markedly increased fatigue and “fuzzy thinking.”Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new enhancing lesions around the corpus callosum.Disease modifying therapy was changed to a high dose subcutaneous interferon beta.
132Multiple Sclerosis Case #2 Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan.After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue.MRI scan showed additional Gd+ enhancing lesions.A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100.
133Multiple Sclerosis Case #2 The same interferon treatment was continued but after several months she complained of ongoing problems with memory.Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged.
134Multiple Sclerosis Case #3 Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst.18 months later, follow-up MRI shows unchanged cyst but single periventricular non- enhancing white matter lesion.Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities.
135Is it Multiple Sclerosis? While hiking with physician husband on hot afternoon, she notes numbness in left foot.Spinal cord MRI shows enhancing lesion at T17.Is it MS?Treatment recommendations?