Disease-activity free status talk - Cleveland Clinic 20 Sept 2012

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Disease-activity free status talk - Cleveland Clinic 20 Sept 2012

  1. 1. What would disease free status look like in MSand what is the evidence that we can achieve it? Gavin Giovannoni Barts and The London School of Medicine and Dentistry
  2. 2. What would disease free status look like in MS and what is theevidence that we can achieve it?
  3. 3. What would disease free status look like in MS and what is theevidence that we can achieve it?
  4. 4. What is a disease?
  5. 5. What is a disease/what is MS?A. Conventional definition • E.g. “hepatitis is inflammation of the liver”B. Pre-theoretical definition Ludwig Wittgenstein • “SLE is characterised by the ARA criteria” 1889-1951 • Indirect definition • Usually “polythetic” • Inclusive definition using multiple characteristics • According to Wittgensteins model of a "long rope twisted together out of many shorter fibres.“*C. Theoretical definition • E.g. “Down’s syndrome is trisomy 21”. • Usually “monothetic”. *Ludwig Wittgenstein a controversial 20th-century analytical philosopher (1889-1951).
  6. 6. What is multiple sclerosis?
  7. 7. Multiple sclerosis definitionPathological Definition: Inflammatory disease of the CNS characterised by demyelination and variable degrees of axonal loss and gliosis.Clinical Definition: Objective CNS dysfunction, i.e. involvement of two or more white matter structures (space) separated by time, with no other aetiology.
  8. 8. What constitutes a useful set of diagnostic criteria? TARGET DISORDER PRESENT ABSENT DIAGNOSTIC TEST + a b a+b RESULT - c d c+d a+c b+d a+b+c+dFrom these we determine the sensitivity and specificity as follows:SENSITIVITY = a/(a+c) > 80%SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116.
  9. 9. A clinico-pathoanatomical study of MS diagnosis SPECIFICITY = True-ve /(True-ve + False+ve) ?25% of cases diagnosed with MS on post-mortem are undiagnosed in life – asymptomatic – benign cases Engell T. Acta Neurol Scand. 1989 May;79(5):428-30.
  10. 10. The evolving clinical definition of MS is changing the natural history of MS1. Schumacker, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6.5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
  11. 11. Will Rogers phenomenon in MS 1879 - 1935“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
  12. 12. MS diagnosed according the old Poser Criteria RRMSInactive CIS Active CIS
  13. 13. MS diagnosed according the old Poser Criteria RRMS Inactive CIS Active CIS Less active MoreInactive CIS RRMS Active RRMS MS diagnosed according the New McDonald Criteria
  14. 14. Will Rogers Phenomenon in Multiple Sclerosis Poser McDonald Sormani et al. Ann Neurol 2008;64:428–433.
  15. 15. static protective factors dynamic protective factors Favourable disease-modifying factors protective HLA haplotypes Low risk Very low risk At risk High Risk RIS CIS MS static risk factors dynamic risk factors Unfavourable disease-modifying factors age family history place of residence genetics outdoor activity / sun exposure / sun screen sex month of birth diet / vitamin D supplements place of birth age of exposure to EBV smoking 1 Peripheral immunological changes T-regs (), NK cells, CD8 () 2 CNS changes 1. Declining Physiology – “peripheral immunological endophenotype” (OCBs and microscopic pathology) 2. Biological disease threshold – “CNS endophenotype” 3. Asymptomatic disease – RIS (abnormal MRI and/or evoked potentials) 3 4. Clinical disease a. Clinically isolated syndrome (CIS) MRI / evoked potentials changes b. Relapsing MS c. Relapsing secondary progressive MS 2 4a d. Non-relapsing secondary progressive MS 2 4b Clinical disease 2 4c 2 4dIn utero childhood Adolescence / early adulthood adulthood “THE MS ENDOPHENOTYPE” - Giovannoni et al. Lancet Neurol. 2010 Jul;9(7):727-39.
  16. 16. The evolving clinical definition of MS1. Schumacker, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68.2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31.3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6.5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.6. Polman, et al. ……………2016? RIS or asymptomatic/presymptomatic MS
  17. 17. What would disease free status look like in MS and what is theevidence that we can achieve it?What do you want to measure?
  18. 18. Current Dogma“autoimmune endophenotype” immune activationinnate and adaptive responses BBB breakdown focal inflammationaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology delayed neuroaxonal loss and gliosis - clinical outcomes - biomarkers
  19. 19. Current Dogma“autoimmune endophenotype” immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology delayed neuroaxonal loss and gliosis - clinical outcomes - biomarkers Disease Progression
  20. 20. Current Dogma“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology delayed neuroaxonal loss and gliosis - clinical outcomes - biomarkers Disease Progression
  21. 21. Current Dogma“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers Disease Progression brain & spinal cord atrophy
  22. 22. Current Dogma“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers Disease Progression brain & spinal cord atrophy
  23. 23. Current Dogma“autoimmune endophenotype”  T2 & T1 lesions   Gd-enhancement immune activation innate and adaptive responses BBB breakdown focal inflammation Clinical Attack Clinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology - clinical outcomes release of soluble markers e.g. neurofilaments ? delayed neuroaxonal loss and gliosis - biomarkers Disease Progression brain & spinal cord atrophy
  24. 24. Current Dogma“autoimmune endophenotype”   T2 & T1 lesions   Gd-enhancement immune activation  innate and adaptive responses BBB breakdown  focal inflammation Clinical Attack Clinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology - clinical outcomes release of soluble markers e.g. neurofilaments ? delayed neuroaxonal loss and gliosis - biomarkers brain & spinal cord atrophy Disease Progression 
  25. 25. Effect of natalizumab on clinical and radiological disease activity in MS: a retrospectiveanalysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study Gd R 35% vs. 64% T2 Δ = 29% CU DP Gd R T2 14% vs. 58% DP Δ = 44% CU Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
  26. 26. Effect of natalizumab on clinical and radiological disease activity in MS: a retrospectiveanalysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting MS (AFFIRM) study Gd R T2 DP CU 15% vs 47% 13% vs 68% 6% vs 37% Δ 32% Δ 55% Δ 31% Havrdova et al. Lancet Neurol. 2009 Mar;8(3):254-60.
  27. 27. A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple SclerosisGd RT2CU DP Polman et al. N Engl J Med 2006;354:899-910.
  28. 28. Clinical implications
  29. 29. Breakthrough disease after treatment initiationPatients with breakthrough disease can be identified with:• Clinical measures • Relapses • EDSS progression• MRI measures • T2 and Gd+ lesions• Biological markers • IFNb neutralizing antibodies (NAbs)/lack of MxA induction • Anti-natalizumab Abs
  30. 30. Relapse on IFNβ therapy increases risk of sustained disability progression • Risk is not much greater for 2 relapses or more • Sensitivity is only 50%33 Bosca et al. Mult Scler 2008;14:636-39.
  31. 31. MRI to monitor treatment response to IFN-beta: a systematic review One new T2 lesion 2 or more new T2 lesionsMeasurement sensitivity? Dobson et al. Submitted 2012.
  32. 32. MRI to monitor treatment response to IFN-beta: a systematic review One new Gd+ lesion 2 or more Gd+ lesions35 Dobson et al. Submitted 2012.
  33. 33. Strongest predictor of disability progression on IFNβ therapy is progression itself • Disease activity during 2 years of treatment and prediction of disability progression* at 6 years Sensitivity (%) Specificity (%) Group (CI) (CI) A. An increase of at least one EDSS step confirmed at 6 months 85 (64-95) 93 (86-97) B. Occurrence of any relapse 80 (58-92) 51 (41-61) C. Occurrence of two or more relapses 45 (26-66) 81 (72-82) D. A decrease in relapse rate less than 30% compared with 2 years before therapy 40 (22-61) 86 (77-91) E. A decrease in relapse rate less than 50% compared with 2 years before therapy 40 (22-61) 81 (72-88) F. No decrease or identical relapse rate compared with 2 years before therapy 35 (18-57) 88 (79-93) G. Definition A or B 90 (70-97) 48 (38-58) H. Definition A or E 85 (64-95) 76 (66-83) I. Definition A and B 75 (53-89) 97 (91-99) J. Definition A and E 40 (22-61) 99 (94-99)* EDSS ≥6.0 or increase in at least 3 EDSS steps. Rio et al. Ann Neurol. 2006;59:344.
  34. 34. Post-hoc analysis, disease-activity free: Patients with no relapse, no sustained disability progression and no new MRI lesion activity Weeks 0–24 Weeks 0–48 Weeks 0–96 OR (95% CI): OR (95% CI): OR (95% CI): 3.68 (2.73, 4.97) 4.13 (3.02, 5.66) 4.58 (3.26, 6.43) OR (95% CI): 80 3.31 (2.46, 4.46)Patients disease activity-free (%) OR (95% CI): 3.80 (2.77, 5.22) OR (95% CI): 4.26 (3.03, 5.99) 69.7 67.3 60 56.1 54.2 44.2 45.7 40 38.9 20 23.9 p<0.001 p<0.001 p<0.001 15.8 0 Placebo 3.5 mg/kg 5.25 mg/kg Placebo 3.5 mg/kg 5.25 mg/kg Placebo 3.5 mg/kg 5.25 mg/kg (n=373*) (n=395*) (n=406*) (n=360*) (n=384*) (n=396*) (n=379*) (n=403*) (n=411*)Gd R Cladribine tablets Cladribine tablets Cladribine tabletsT2CU DP OR = odds ratio *Based on observed data; no imputation used
  35. 35. Fingolimod treatment increases the proportion of patients who are free from diseaseactivity in multiple sclerosis; results from a phase 3, placebo-controlled study (FREEDOMS)Gd RT2CU DP Kappos et al., AAN 2011
  36. 36. BG-12 Increases the Proportion of Patients Free of Clinical and Radiologic Disease Activity in Relapsing–Remitting Multiple Sclerosis: Findings from a DEFINE Post Hoc AnalysisGd RT2CU DP Giovannoni et al., AAN 2012
  37. 37. Fingolimod Treatment Increases the Proportion of Patients who are Free from Disease Activity in Multiple Sclerosis Compared to Interferon beta-1a: Results from a Phase 3 Active-Controlled Study (TRANSFORMS)Gd RT2CU DP Khatri et al. AAN 2012.
  38. 38. Disease Activity-Free Status in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis I (CARE-MS I) - Phase 3 Study p<0.0001 p=0.0388 p=0.0064 CDA-Free MRI Activity–Free MS Disease Activity-Free Odds of experiencing MS disease activity for SC IFNB-1a patients was 1.75 times higherGd than alemtuzumab patients; odds ratio=1.75 (95% CI: 1.17, 2.61), p=0.0064 RT2CU DP Giovannoni et al. ENS 2012 41
  39. 39. Power calculations from CLARITY study Absolute difference 90% power treatment rate - placebo rate 10% 20% 30% Placebo 1 group 1 group 1 group rate 15% 354 108 54 +10% 389 118 59 30% 496 134 63 +10% 546 147 69Gd RT2CU DP Giovannoni et al. Unpublished observations
  40. 40.  Current Dogma“autoimmune endophenotype” T2 & T1 lesions   Gd-enhancement immune activation innate and adaptive responses BBB breakdown focal inflammation Clinical Attack Clinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss ? ? - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers ? ? ? Disease Progression brain & spinal cord atrophy
  41. 41. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  42. 42. Axonal Damage in Relapsing Multiple Sclerosis is Markedly Reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010.
  43. 43. Conclusions / Questions• What would disease free-status look like? • Absence of any clinical and biomarker evidence of disease activity • Current definition = relapse, disease-progression, Gd-enhancing lesions and new T2 lesions • What about brain atrophy and CSF neurofilament levels?• Should the definition be stage specific? • CIS/RRMS vs. R-SPMS vs. NR-SP/PPMS• What do we do about post-inflammatory neurodegeneraton?• What about the potential effects of superimposed accelerated or premature aging?• How do we define an appropriate baseline for comparison? • We need to optimise the time fore re-base lining MRI when looking for a change; this may need to be agent specific.• How do we deal with the difference between maintenance and induction therapies? • Maintenance - absence of DAF status indicated non-response • Induction – absence of DAF status indicates a time to retreat.• How do we standardise (or improve) on the metrics?
  44. 44. Do we need to challenge the dogma?“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss - biology release of soluble markers delayed neuroaxonal loss and gliosis e.g. neurofilaments - clinical outcomes - biomarkers Disease Progression brain & spinal cord atrophy
  45. 45. Do we need to challenge the dogma?“autoimmune endophenotype” T2 & T1 lesions Gd-enhancement immune activationinnate and adaptive responses BBB breakdown focal inflammation Clinical AttackClinical Recoveryaxonal plasticity oligodendrocyte toxicity & demyelination& remyelination Acute axonal transection and loss release of soluble markersViral infection delayed neuroaxonal loss and gliosis e.g. neurofilaments brain & spinal cord atrophy Disease Progression
  46. 46. What will a cure in MS look like?
  47. 47. www.ms-res.org

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