04 ens 2013 giovannoni_v070613_blog

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  • 1. TIME MATTERSMonday, 10 June 2013, 11:45–13:15Plenary Hall, Fira Barcelona, Convention Centre Gran Via, Barcelona, SpainTreatment decisions debate: motion forswitching to a high-efficacy therapy earlyGavin GiovannoniLondon, UK
  • 2. 38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London• Glatiramer acetate treatment for 3 years (good adherence and tolerance)• Relapse with a mild left sensory loss• Referred for a second opinion• Switched to IFN β-1a IM; (www.msdecisions.org.uk)• Mild persistent flu-like side effects and lymphopenia• 12/12’s neutralizing antibodies screen negative• Volunteers for new research programme, which included a gadolinium-enhanced MRI protocolTeacher
  • 3. 38-year-old teacher with relapsing–remitting MS• As a result of fatigue and cognitive problems she is forced to takeearly retirement• Although fully functional she develops depression and anxiety• In her spare time she spends a lot of time on the web and becomesan expert patient– Widely read– Net savvy; regular follower of www.ms-res.orgTeacherX
  • 4. UnemploymentProbability of remaining actively employed after onset of MS (N = 2,538)Time (years)Probability0.80.60.40.20.01.05 10 15 20 250Control personsMS patientsPfleger CC, et al. Mult Scler 2010; 16:121–126.
  • 5. Costs and quality of lifeof patients with MS in EuropeKobelt G, et al. J Neurol Neurosurg Psychiatry 2006; 77:918–926.Expanded Disability Status Scale scoreProportionofpatients≤65yearsofageworking80706050403020100902 3 4 5 6 6.5 7 8/90/1AustriaBelgiumGermanyItalyThe NetherlandsSpainSwedenSwitzerlandUKProportion of patients employed or on long-term sick leave (N = 13,186)
  • 6. Predictors of long-term outcome inMS patients treated with IFN β-1aIFN, interferon; IM, intramuscular; LOCF, last observation carried forward;MSCRG, Multiple Sclerosis Collaborative Research Group.Bermel RA, et al. Ann Neurol 2013; 73:95–103.2-year participation MSCRG study: 172Patients located: 149 (87%)Consented and enrolled in ASSURANCE: 136 (79%)Alive: 122 (90%)Originallyrandomizedto IM IFN β-1a:63 (52%)Originallyrandomizedto placebo:59 (48%)Died (LOCF): 14 (10%)Originallyrandomizedto IM IFN β-1a:6 (43%)Originallyrandomizedto placebo:8 (57%)
  • 7. Predictors of long-term outcome inMS patients treated with IFN β-1aGd+, gadolinium enhancing; IM, intramuscular. a ≥ 2 gadolinium-enhancing lesions (cumulative) ≥ 3 new T2 lesions onYear 2 MRI compared with baseline; and ≥ 2 relapses over 2 years.Bermel RA, et al. Ann Neurol 2013; 73:95–103.IMinterferonβ-1a403020101PlaceboOdds ratio of advancing into theworst quartile of EDSS change after 15 yearsDisease activityduring the2-year trialaNew T2RelapseGd+New T2RelapseGd+Odds ratio(confidence interval)2.62 (0.93, 7.43)1.53 (0.56, 4.19)1.79 (0.65, 5.16)2.89 (0.88, 9.54)4.44 (1.43, 13.85)8.96 (2.53, 31.65)p value0.0690.4080.2840.0800.010< 0.001
  • 8. Study or subgroupOdds ratioIV, random, 95% CIKinkel 2008Prosperini 2009Total (95% CI) 9.86 (2.33, 41.70)MRI to monitor treatment responseto IFN β: a meta-analysisCI, confidence interval.Dobson et al. Submitted 2013.Study or subgroupOdds ratioIV, random, 95% CIKinkel 2008Pozzilli 2005Prosperini 2009Sormani 2011Total (95% CI) 2.69 (0.72, 10.04)0.01 0.1 1 10 100Disease less likely Disease more likelyOne new T2 lesionTwo or more new T2 lesions1001010.10.01Disease less likely Disease more likely
  • 9. 0.01 0.1 1 10 100Disease less likely Disease more likely0.01 0.1 1 10 100Disease less likely Disease more likelyStudy or subgroupOdds ratioIV, random, 95% CIKinkel 2008Pozzilli 2005Tomassini 2006Total (95% CI) 3.34 (1.36, 8.22)Study or subgroupOdds ratioIV, random, 95% CIKinkel 2008Rio 2008Total (95% CI) 5.46 (2.48, 12.04)One new Gd-enhancing lesionTwo or more new Gd-enhancing lesionsMRI to monitor treatment responseto interferon β: a meta-analysisCI, confidence interval; Gd, gadolinium.Dobson et al. Submitted 2013.
  • 10. The relapsing MS DMT doughnutCIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate;IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS.Inactive RRMSCISRIS or asymptomatic MSSuboptimal responders?ActiveRRMSIFN βorGAIFN βHighly active RRMS FingolimodNatalizumab
  • 11. Predictors of long-term outcome inMS patients treated with IFN β-1aGd+, gadolinium enhancing; IM, intramuscular. a ≥ 2 gadolinium-enhancing lesions (cumulative) ≥ 3 new T2 lesions onYear 2 MRI compared with baseline; and ≥ 2 relapses over 2 years.Bermel RA, et al. Ann Neurol 2013; 73:95–103.IMinterferonβ-1a403020101PlaceboOdds ratio of advancing into theworst quartile of EDSS change after 15 yearsDisease activityduring the2-year trialaNew T2RelapseGd+New T2RelapseGd+Odds ratio(confidence interval)2.62 (0.93, 7.43)1.53 (0.56, 4.19)1.79 (0.65, 5.16)2.89 (0.88, 9.54)4.44 (1.43, 13.85)8.96 (2.53, 31.65)p value0.0690.4080.2840.0800.010< 0.001
  • 12. ConsultantNeurologist84%Academic/HonoraryConsultant Neurologist14%Associate specialist2%What is your position? (N = 50)8%26%26%24%16%Yes – routinelyYes – frequentlyYes – occasionallyYes – rarelyNo – never0% 5% 10% 15% 20% 25% 30%MRI – Do you use conventional MRI to monitor for a response or non-response to DMTs? (N = 50)Only 8% of HCPs ‘regularly’ useconventional MRI to monitor for aresponse/non-response to DMTsIs conventional MRI used to monitorresponse or non-response to DMTs?DMT, disease modifying therapy; HCP, healthcare professional.
  • 13. TeacherX
  • 14. TeacherXfingolimodnatalizumab
  • 15. Summary of natalizumab data vs. placeboPolman CH, et al. N Engl J Med 2006; 354:899–910.Study Treatment arms 2-year outcomesAFFIRM• N = 942• Relapsing MS• 18–50 years of age• EDSS score 0–5.0• 2-year study1. Natalizumab 300 mg2. PlaceboOutcome, reduction vs. placebo Natalizumab 300 mgAnnualized relapse rate 68% (p < 0.001)New/enlarging T2 lesions 83% (p < 0.001)Gadolinium-enhancing lesions 92% (p < 0.001)42% relative reduction in riskof progression (p < 0.001)Proportionofpatientswith3-monthsustainedprogressionofdisability29%17%Time (weeks)Placebo(n = 315)Natalizumab(n = 627)120108968472604836241200.40.30.20.10.0AFFIRM: 2-year results
  • 16. Summary of fingolimod data vs. placeboITT, intention-to-treat.a Includes patients who received both 0.5 mg and 1.25 mg fingolimod.1. Kappos L, et al. N Engl J Med 2010; 362:387–401; 2. Kappos L, et al. AAN 2012. S41.004.Study Treatment arms 2-year outcomesFREEDOMS1• N = 1,272• RRMS• 18–55 years of age• EDSS score 0–5.5• 2-year study1. Fingolimod 0.5 mg2. Fingolimod 1.25 mg3. PlaceboOutcome, reduction vs. placebo Fingolimod 0.5 mg/dayAnnualized relapse rate 54% (p < 0.001)New/enlarging T2 lesions 74% (p < 0.001)Gadolinium-enhancing lesions 82% (p < 0.001)0 1 2 3 4 5100908070600Time (years)FREEDOMS extension: > 4-year results (core ITT population)274%66%Fingolimod 0.5 mg(n = 425 core/n = 331 extension)Placebo(Month 0–24, n = 418)Placebo–fingolimod switcha(n = 300)27% relative reduction in riskof progression (p = 0.017)Patientsfreeof3-monthconfirmedEDSSdisabilityprogression(%)
  • 17. TRANSFORMS extension study: fingolimodvs. interferon β-1aa EOS (end of study) is the last available visit for the randomized patients between initiation and completion of the study;b Includes patients who received both 0.5 mg and 1.25 mg fingolimod; c Occurring during Year 1 on treatment;d Positive status defined as a 1-point increase on the EDSS; e Positive status if the sum of the number of new or newly enlarged T2 lesions at Month 12compared with baseline and the number of Gd-enhanced T1 lesions at Month 12 was > 2.1. Khatri B. et al. ENS 2012. O218; 2. Hartung HP, et al. ENS 2013. P380.Between-group comparison of aggregate ARR(up to 4.5 years)1Disease activity status at end of Year 2 in patientsswitched from interferon β-1a to fingolimod20.40.200.10.20.30.40.544.3660255075Disease activity free*(n = 296)Year 1: IFN β-1aYear 2: IFN β-1a–fingolimodb*Disease activity variables: ● confirmed relapsec ● 3-month confirmed disability progressiond ● MRI activityeARRMonth 0-12: IFN β-1aMonth 12-EOSa: IFN β-1a–fingolimodbn = 341n = 431Proportionofpatients
  • 18. –0.6–0.2–1.0–0.9–0.8–0.7–0.6–0.5–0.4–0.3–0.2–0.10.0PRIMUS activities–0.30–0.5–0.4–0.3–0.2–0.10.0FSS–3.2–0.8–4.0–3.5–3.0–2.5–2.0–1.5–1.0–0.50.0BDI-IIBeneficial effect of fingolimod onfatigue and depressive symptomsBDI-II, Beck Depression Inventory-II; CI, confidence interval; FSS, Fatigue Severity Scale; LOCF, last observationcarried forward; PRIMUS, Patient-Reported Indices for Multiple Sclerosis.Higher scores indicate worse functioning, fatigue or depressive symptoms.Crayton H, et al. CMSC 2013. DX20.Difference, 0.3(95% CI, 0.18 to 0.51)p < 0.001Difference, 2.5(95% CI, 1.50 to 3.44)p < 0.001ChangefrombaselinetoMonth6(LOCF),leastsquaresmeanFingolimod 0.5 mg Standard of care disease-modifying therapyDifference, 0.4(95% CI, –0.26 to 0.96)p = 0.258Activities of daily living Fatigue Depressive symptom score
  • 19. Beneficial effect of fingolimod onphysical and mental aspects of HRQoLCI, confidence interval; DMT, disease-modifying therapy; HRQoL, health-related quality of life;LOCF, last observation carried forward; SF-36 Short Form (36) Health Survey v2 standard.Lower scores indicate worse quality of life.Crayton H, et al. CMSC 2013. DX20.SF-36 summary score changes1.72.20.4 0.40.00.51.01.52.02.53.0Physical Component Summary Mental Component SummaryChangefrombaselinetoMonth6(LOCF),leastsquaresmeanDifference, 1.3(95% CI, 0.30 to 2.31)p = 0.011Difference, 1.7(95% CI, 0.41 to 3.07)p = 0.011Fingolimod 0.5 mg Standard of care DMT
  • 20. Adjuvant (n = 50)Salvage (n = 118)p = 0.002Emerging concepts in MSHagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.NEDA; no evidence of disease activityT2T; treat-2-target10976543210 80.80.60.40.20.01.0SurvivalTime since radiotherapy (years)Biochemical relapse-free survival
  • 21. No evidence of disease activityGd, gadolinium.1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.Treat-2-targetShould brain volume loss be included in our definition for‘no evidence of disease activity’?No evidence of disease activity defined as:1,2No relapsesNo sustained disability progressionNo MRI activity• No new or enlarging T2 lesions• No Gd-enhancing lesions
  • 22. Effect of natalizumab onbrain paraenchymal fractionMiller D, et al. Neurology 2007; 68:1390−1401.0 12 2400.20.40.60.81.0Time (months)AFFIRM: 2-year results2Meanreductioninbrainparenchymalfraction(%)P = 0.822NatalizumabPlaceboP = 0.002P = 0.004**
  • 23. Effect of fingolimod on brain volume lossIFN, interferon; IM, intramuscular; PBVC, percentage brain volume change.TRANSFORMS *** p < 0.001 versus interferon -1a. p value calculated using Wilcoxon rank sum test.FREEDOMS/FREEDOMS II * p < 0.05; ** p < 0.01; *** p < 0.001 versus placebo. p values calculated using rank analysis ofcovariance adjusted for treatment, region and baseline normalized brain volume.Cohen J, et al. AAN 2013. S51.006.0 6 12 24Fingolimod 0.5 mg (n = 358)Placebo (n = 355)0 6 12 24Fingolimod 0.5 mg (n = 425)Placebo (n = 418)TRANSFORMS–1.4–1.2–1.0–0.8–0.6–0.4–0.20.00 12Fingolimod 0.5 mg (n = 429)IFN beta-1a IM (n = 431)FREEDOMS FREEDOMS II****************33%reduction32% reduction35% reductionMeanPBVCfrombaselineMonths
  • 24. Is it time for a paradigm shift?Early treatment with a high-efficacy therapyFigure: http://multiple-sclerosis-research.blogspot.co.uk/2012/06/research-dmt-slow-onset-of-progression.html;Accessed 4 June 2013. Based on a review of Bergamaschi R, et al. Mult Scler 2012; Epub ahead of print.DisabilityDiseaseonsetTimeLatertreatmentTreatmentat diagnosisInterventionat diagnosisLaterinterventionNatural courseof disease
  • 25. Treatment ladder1st-lineA1st-lineB1st-lineC1st-lineD1st-lineE2nd-lineN2nd-lineM3rd-lineY3rd-lineX
  • 26. ConclusionsMS is a bad disease Disability (physical and cognitive) High societal costs (unemployment,healthcare costs, divorce) Survival compromised Treat early and aggressively(TIME MATTERS)Prognostic factors Clinical findings, MRI activity andother emerging biomarkersTreatment response markers Clinical (relapses and disabilityprogression) MRI (T2 and Gd-enhancing lesions) Neutralizing antibodies (efficacyand safety)Treat-2-Target No evidence of disease activity Concerns about using a treatmentladder (TIME MATTERS) No fixed treatment algorithms;no 1st-, 2nd- or 3rd-line therapies(TIME MATTERS)