Hit Hard & Early

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Background to why early aggressive treatment is an important emerging treatment strategy!

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Hit Hard & Early

  1. 1. Hit hard and early! Gavin GiovannoniBarts and The London School of Medicine and Dentistry XVIIIth European Charcot Foundation Symposium Marbella , Spain 29th Nov to 1st Dec 2012
  2. 2. DisclosuresI have received personal compensation for participating onAdvisory Boards in relation to clinical trial design, trialsteering committees and data and safety monitoringcommittees from: Bayer-Schering Healthcare; Biogen-Idec;Canbex; Eisai; Elan; Fiveprime; Genzyme; Genentech; GSK;GW Pharma; Ironwood; Merck-Serono; Novartis; Pfizer;Roche; Sanofi-Aventis; Synthon BV; Teva; UCB Pharma; andVertex Pharmaceuticals.
  3. 3. Emerging concepts in MSNEDD; no evidence of detectable diseaseTTT; treat-to-target
  4. 4. Emerging concepts in MSNEDD; no evidence of detectable diseaseTTT; treat-to-target
  5. 5. How would you define a MS cure?"To claim that someone has been cured of MS onewould have to show that the person who had thedisease had no disease activity for at least 15 years.The latter would be a composite of no MRI activity(new gadolinium-enhancing lesions, new T2 orenlarging T2 lesions and a lack of progressive wholebrain atrophy) and no clinical activity (relapses ordisease progression).“ GIOVANNONI; WWW.MS-RES.ORG: FRIDAY, 6 APRIL 2012.
  6. 6. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  7. 7. Hartung et al. Lancet 2002:360:2018-25.
  8. 8. We don’t want to throw the baby out with the bathwater!
  9. 9. Treat early Natural course of disease Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis TimeDisease Onset
  10. 10. Survival in MS: a randomized cohort study 21years after the start of the pivotal IFN-1b trial Goodin et al. Neurology 2012;78:1315-1322.
  11. 11. Establishing long-term efficacy: use of recursive partitioningand propensity score adjustment to estimate outcome in MS Long-term follow-up 16 years % Risk Relative to Low Exposure IFN-beta exposure 80% vs. 20% Any Negative EDSS=6 SPMS Wheelchair Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.
  12. 12. Relationship between early clinical characteristics and long term disabilityoutcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  13. 13. Association between use of interferon beta and progression ofdisability in MSers with relapsing-remitting multiple sclerosis Tremlett et al. JAMA. 2012;308(3):247-256.
  14. 14. Association between use of interferon beta and progression ofdisability in MSers with relapsing-remitting multiple sclerosis Tremlett et al. JAMA. 2012;308(3):247-256.
  15. 15. 100 MSersWho are theresponders?
  16. 16. ~20% responders~40% sub-optimal responders~40% non-responders
  17. 17. 1 Clinicalvs. 2 MRI 3 NABs
  18. 18. Relapses don’t count!
  19. 19. Relapse on IFNβ Therapy Increases Risk of Sustained Disability Progression HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment HR SE P Value 95% CINo relapses (reference=1) 1One relapse 3.41 1.47 0.005 1.46–7.98Two or more relapses 4.37 1.74 0.000 1.90–9.57 1.00 No Relapses One Relapse Survival Probability Two or More Relapses EDSS Progression 0.75 0.50 0.25 HR=hazard ratio; SE=standard error 0 0 20 40 60 80 Analysis Time (Months) Bosca et al. Mult Scler. 2008;14:636-639.
  20. 20. Relapses and residual deficits Lublin FD et al. Neurology. 2003;61:1528-1532.
  21. 21. Predictors of long-term outcome inMSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012; In Press.
  22. 22. Predictors of long-term outcome inMSers treated with interferon beta-a Bermel et al. Ann Neuol 2012; In Press.
  23. 23. Predictors of long-term outcome inMSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012; In Press.
  24. 24. MRI activity doesn’t count!
  25. 25. Predictors of long-term outcome inMSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012; In Press.
  26. 26. MRI to monitor treatment response to IFNβ: a meta-analysis One New T2 Lesion Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Pozzilli 2005 Prosperini 2009 Sormani 2011Total (95% CI) 2.69 (0.72, 10.04) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Two or More New T2 Lesions Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Prosperini 2009Total (95% CI) 9.86 (2.33, 41.70) 0.01 0.1 1 10 100 Favors Experimental Favors Control Dobson et al. Submitted 2012.
  27. 27. MRI to monitor treatment response to IFNβ: a meta-analysis One New Gd+ Lesion Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Pozzilli 2005 Tomassini 2006 Total (95% CI) 3.34 (1.36, 8.22) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Two or More New Gd+ Lesions Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Rio 2008 Total (95% CI) 5.46 (2.48, 12.04) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Dobson et al. Submitted 2012.
  28. 28. Disease progression doesn’t count!
  29. 29. Strongest predictor of disability progression on IFNβ therapy is progression itselfDisease 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 40 (22–61) 86 (77–91) before therapyE. A decrease in relapse rate less than 50% compared with 2 years 40 (–61) 81 (72–88) before therapyF. No decrease or identical relapse rate compared with 2 years 35 (18–57) 88 (79–93) before therapyG. 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 score ≥6.0 or increase in at least 3 EDSS steps. Río J et al. Ann Neurol. 2006;59:344-352.
  30. 30. Relationship between early clinical characteristics and long term disabilityoutcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  31. 31. Curved Ball
  32. 32. Survival analysis and disability progression 0 3 6 X
  33. 33. Survival analysis and disability progression 0 3 6 X 
  34. 34. Survival analysis and disability progression 0 3 6 X  
  35. 35. 3 X X X X     X X  
  36. 36. survival analysis3 X X X X     X X  
  37. 37. survival analysis3 X X X X    median or mean EDSS  X X  
  38. 38. Impact of early interferon beta-1b on disease evolution over 5-years in MSers with CIS survival analysis median or mean EDSS Freedman et al. WCTRIMS 2008.
  39. 39. Alemtuzumab for patients with relapsing multiple sclerosis afterdisease-modifying therapy: a randomised controlled phase 3 trial Coles et al. Lancet 2012: November 1, http://dx.doi.org/10.1016/
  40. 40. Alemtuzumab for patients with relapsing multiple sclerosis afterdisease-modifying therapy: a randomised controlled phase 3 trial survival analysis median or mean EDSS Coles et al. Lancet 2012: November 1, http://dx.doi.org/10.1016/
  41. 41. CARE-MS I: Disease Activity Status –Proportion of Patients Free of MS Disease Activity 80 p<0.0001 SC IFNB-1a 70 74.0 Alem 12 mg 60 p=0.0388 Patients (%) 56.0 41.1 50 51.0 p=0.0064 40 42.0 39.0 30 27.0 20 10 0 Clinical disease MRI MS disease activity-free activity-free activity-free Note: Clinical disease activity-free defined as absence of relapse or SAD; MRI activity-free defined as absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion; MS disease activity-free defined as absence of clinical disease activity or MRI activity. Giovannoni et al. ENS 2012.
  42. 42. “Every clinical trial is an experiment. In fact every time you treata patient you should view it as an experiment and use it as anopportunity to learn something about the disease!”
  43. 43. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis
  44. 44. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hit hard and early ”
  45. 45. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hit hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment
  46. 46. Who should decide?
  47. 47. WWW.MS-RES.ORG
  48. 48. WWW.MS-RES.ORG
  49. 49. WWW.MS-RES.ORG
  50. 50. Are you prepared to walk where others fear to tread?
  51. 51. Conclusions• NEDD, TTT and DAF are entering the neurology lexicon• We need an acceptable working definition of an MS cure • DAF x 15 years? • Should the definition be disease-stage specific?• How do we deal with maintenance and induction therapies? • Maintenance - absence of DAF status indicates non-response • Induction – absence of DAF status indicates a time to retreat• Improve risk mitigation tool• Who should make the decision re early aggressive treatment? • Regulators • Payers • Neurologists • MSers• Is it fair to make MSers wait 20 years for the outcome of an experiment? • Alemtuzumab extension study• What do we do about post-inflammatory neurodegeneration? • We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels • Neuroprotective treatments
  52. 52. Conclusions• NEDD, TTT and DAF are entering the neurology lexicon• We need an acceptable working definition of an MS cure • DAF x 15 years? • Should the definition be disease-stage specific?• How do we deal with maintenance and induction therapies? • Maintenance - absence of DAF status indicates non-response • Induction – absence of DAF status indicates a time to retreat• Improve risk mitigation tool• Who should make the decision re early aggressive treatment? • Regulators ? • Payers ? • Neurologists • MSers• Is it fair to make MSers wait 20 years for the outcome of an experiment? • Alemtuzumab extension study• What do we do about post-inflammatory neurodegeneration? • We need better outcomes, e.g. regional brain atrophy and CSF neurofilament levels • Neuroprotective treatments

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