Highly effective early induction therapy Canada 2013

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Highly effective early induction therapy Canada 2013

  1. 1. Why treat MS early with highly effective induction therapies? Gavin Giovannoni Barts and The London
  2. 2. Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, 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 and Vertex Pharmaceuticals. Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni. Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.
  3. 3. Getting your ducks in a row! early + therapy highly-effective + therapy induction therapy
  4. 4. Why early?
  5. 5. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial Goodin et al. Neurology 2012;78:1315-1322.
  6. 6. STRATA: subjects had stable EDSS scores for up to 5 years Cessation/ Treatment Gap* Original Placebo Original Natalizumab Mean EDSS Score Original Placebo – Now on Natalizumab n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 1 Year 2 Years 3 Years *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 6 194 427 4 Years 174 393 5 Years
  7. 7. TOP: earlier natalizumab treatment favors annualized relapse rate outcomes P<0.0001 P<0.0001 <3.0 ≥3.0 0 Baseline EDSS Score 1 ≥2 Prior DMTs Used P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor of interest. Error bars represent 95% CIs. DMT=disease-modifying therapy; CI=confidence interval. Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372. 7
  8. 8. Theoretical model: treat early and effectively Time is brain Natural course of disease Disability Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis Time Disease Onset
  9. 9. Does the biology of MS change with time?
  10. 10. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  11. 11. The current dogma RIS RRMS CIS Disease Severity Inflammation Axonal loss Brain volume Time (Years) MRI Events Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17. SPMS
  12. 12. The current paradigm: S&S safe & slow
  13. 13. S&S treatment paradigm High Efficacy Intermediate Efficacy Moderate Efficacy E X M A D Y 3rd-line N 2nd-line B C 1st-line
  14. 14. Baseline number of brain lesions predicts progression to EDSS Score ≥3.0 Queen Square Study The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study. The exact relationship between MRI findings and the clinical status of the patient is unknown. Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503; Brex PA et al. N Engl J Med. 2002;346:158-164.
  15. 15. 100 MSers Who are the responders?
  16. 16. ~20% responders ~40% sub-optimal responders ~40% non-responders
  17. 17. 1 Clinical vs. 2 MRI 3 NABs
  18. 18. How bad is MS?
  19. 19. Consequences of increasing EDSS scores: loss of employment1 Proportion of Patients ≤65 Years Old Working (%) Work Capacity by Disability Level Austria Belgium Germany Italy Netherlands Spain Sweden Switzerland United Kingdom 90 80 70 60 50 40 30 ~10 yrs2 20 10 0 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0 EDSS Score The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger. 1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926; 2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
  20. 20. What about benign MS?
  21. 21. What is benign MS? 163 patients with “benign” MS (disease duration >15 years and EDSS <3.5): 45% cognitive impairment 49% fatigue 54% depression
  22. 22. Impact of MS: cognitive functioning in the CIS stage 60% Patients failing ≥ 2 cognitive tests 40% 57% Deficits were found mainly in memory, speed of information processing, attention and executive functioning 20% 7% 0% p < 0.0001 -20% CIS Patients n = 40 Healthy Controls n = 30 Feuillet et al. MSJ 2007
  23. 23. Relapses don’t count!
  24. 24. Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.
  25. 25. 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 No relapses (reference=1) SE P Value 95% CI 1 One relapse 3.41 1.47 0.005 1.46–7.98 Two or more relapses 4.37 1.74 0.000 1.90–9.57 EDSS Progression Survival Probability 1.00 No Relapses One Relapse Two or More Relapses 0.75 0.50 0.25 HR=hazard ratio; SE=standard error 0 0 20 40 60 Analysis Time (Months) 80 Bosca et al. Mult Scler. 2008;14:636-639.
  26. 26. Relapses and residual deficits Lublin FD et al. Neurology. 2003;61:1528-1532.
  27. 27. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  28. 28. Predictors of long-term outcome in MSers treated with interferon beta-1a Treatment vs. Natural History Bermel et al. Ann Neuol 2012.
  29. 29. MRI activity doesn’t count!
  30. 30. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  31. 31. MRI to monitor treatment response to IFNβ: a meta-analysis One New T2 Lesion Study or Subgroup Kinkel 2008 Pozzilli 2005 Prosperini 2009 Sormani 2011 Total (95% CI) 2.69 (0.72, 10.04) 0.01 Odds Ratio IV, Random, 95% CI 0.1 1 10 Disease Less Likely Disease More Likely 100 Two or More New T2 Lesions Study or Subgroup Kinkel 2008 Prosperini 2009 Total (95% CI) 9.86 (2.33, 41.70) Odds Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favors Experimental Favors Control Dobson et al. Submitted 2013.
  32. 32. MRI to monitor treatment response to IFNβ: a meta-analysis One New Gd+ Lesion Odds Ratio IV, Random, 95% CI Study or Subgroup 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 IV, Random, 95% CI Study or Subgroup Kinkel 2008 Rio 2008 Total (95% CI) 5.46 (2.48, 12.04) 0.01 0.1 Disease Less Likely 1 10 100 Disease More Likely Dobson et al. Submitted 2013.
  33. 33. Including brain atrophy!
  34. 34. RIP Control Multiple sclerosis
  35. 35. TREATMENT EFFECT ON BRAIN ATROPHY CORRELATES WITH TREATMENT EFFECT ON DISABILITY IN MULTIPLE SCLEROSIS Sormani et al. Ann Neurol 2013, In Press.
  36. 36. TREATMENT EFFECT ON BRAIN ATROPHY CORRELATES WITH TREATMENT EFFECT ON DISABILITY IN MULTIPLE SCLEROSIS Sormani et al. Ann Neurol 2013, In Press.
  37. 37. Disease progression doesn’t count!
  38. 38. 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 (%) (CI) Specificity (%) (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 (–61) 81 (72–88) 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) Group F. No decrease or identical relapse rate compared with 2 years before therapy *EDSS score ≥6.0 or increase in at least 3 EDSS steps. Río J et al. Ann Neurol. 2006;59:344-352.
  39. 39. Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon-beta-1b trial Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  40. 40. Why highly-effective treatments?
  41. 41. STRATA: Patients Had Stable EDSS Scores for up to 5 years Cessation/ Treatment Gap* Original Placebo Original Natalizumab Mean EDSS Score Original Placebo – Now on Natalizumab n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393 1 Year 2 Years 3 Years 4 Years 5 Years *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 50
  42. 42. Alemtuzumab clinical development program vs. high-dose sc IFNB-1a CAMMS2231 (completed) CARE-MS I2 (completed) CARE-MS II3 (completed) Extension4,5,a (ongoing) 2 3 3 3 Active RRMS, treatment-naïve Active RRMS, treatment-naïve Active RRMS, relapsed on prior therapy RRMS patients enrolled into phase 2 and 3 studies 334 581 840 1322 3 2 2 4 Inclusion criteria EDSS ≤3 Onset ≤3 yrs Enhancing lesion EDSS ≤3 Onset ≤5 yrs EDSS ≤5 Onset ≤10 yrs CAMMS223, CARE-MS I & II patients Treatment arms Alemtuzumab 12 mg Alemtuzumab 24 mg SC IFNB-1a 44 µg Alemtuzumab 12 mg — SC IFNB-1a 44 µg Alemtuzumab 12 mg Alemtuzumab 24 mgb SC IFNB-1a 44 µg Alemtuzumab 12 mg (Re-treatment as needed after 2 fixed courses) Relapse rate SAD Long-term safety and efficacy outcomes Phase Patient population Patients, n Study duration, yrs Co-primary outcomes a Enrolling Relapse rate Sustained accumulation of disability (SAD) patients from all 3 studies; b Exploratory arm, discontinued enrollment early CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; EDSS=Expanded Disability Status Scale; SC IFNB=subcutaneous interferon beta 1. Coles AJ et al. N Engl J Med 2008;359:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3. Coles AJ et al. Lancet 2012;380:1829-39; 4. Brinar V et al. ENS 2011. P912; 5. Fox E et al. AAN 2013. S41.001. Rebif® is a registered trademark of EMD Serono, Inc.
  43. 43. Demographics and baseline clinical characteristics in treatment-naïve subjects CAMMS2231-2,a CARE-MS I3,b Pooled CAMMS223 and CARE-MS I1-3 SC IFNB-1a 44 μg N=111 Alemtuzumab 12 mg N=112 SC IFNB-1a 44 μg N=187 Alemtuzumab 12 mg N=376 SC IFNB-1a 44 μg N=294 Alemtuzumab 12 mg N=483 32.8 (8.8) 31.9 (8.0) 33.2 (8.5) 33.0 (8.0) 33.1 (8.6) 32.9 (8.0) 64 64 65 65 65 65 Time since first relapse, years, mean (SD) 1.6 (1.0) 1.4 (0.84) 2.0 (1.3) 2.1 (1.4) 1.8 (1.2) 1.9 (1.3) EDSS, mean (SD) 1.9 (0.8) 1.9 (0.7) 2.0 (0.8) 2.0 (0.8) 1.9 (0.8) 2.0 (0.8) No. of relapses in prior year, mean (SD) 1.6 (0.8) 1.7 (0.9) 1.8 (0.8) 1.8 (0.8) 1.8 (0.8) 1.8 (0.8) Patients with Gd-enhancing lesions,% 100 100 51 46 69.7 58.6 Age, years mean (SD) Gender, % female Gd=gadolinium; SD=standard deviation a Inclusion criteria included EDSS ≤3, onset of symptoms within 3 years, ≥2 relapses in the previous 2 years, and ≥1 Gd-enhancing lesion. b Inclusion criteria included EDSS ≤3, disease duration ≤ 5 years, ≥2 relapses in the previous 2 years and ≥1 relapse in the previous year; 1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Data on file, Genzyme Corporation; 3. Cohen JA et al. Lancet 2012;380:1819-28.
  44. 44. Alemtuzumab significantly reduces annualized relapse rate vs. SC IFNB-1a in treatment-naïve subjects CAMMS223 (Co-primary endpoint)1 SC IFNB-1a 44 µg Alemtuzumab 12 mg 0.6 69% Risk reduction vs. SC IFNB-1a p<0.001 0.5 0.4 0.36 0.2 0.1 0.11 0 Annualized Relapse Rate Annualized Relapse Rate 0.6 0.3 CARE-MS I (Co-primary endpoint)2 54.9% Risk reduction vs. SC IFNB-1a p<0.0001 0.5 0.4 0.39 0.3 0.2 0.18 0.1 0 N=111 N=112 1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28. N=187 N=376 53
  45. 45. Alemtuzumab reduces the risk of 6-month sustained accumulation of disability in treatment-naïve subjects Treatment-naïve: CARE-MS I1 (Co-primary Endpoint) 25 20 30% Risk reduction vs. SC IFNB-1a p=0.22 15 11.1% SC IFNB-1a 44 μg 10 8.0% Patients with SAD (%) Patients with SAD (%) 25 Pooled Treatment-naïve2,a (Post Hoc Analysis) 20 50% Risk reduction vs. SC IFNB-1a p=0.0029 15 13.9% SC IFNB-1a 44 μg 10 7.1% 5 5 Alemtuzumab 12 mg Alemtuzumab 12 mg 0 0 0 3 6 9 12 15 18 Follow-up Month 21 24 0 3 6 9 12 15 18 Follow-up Month 21 I and CAMMS223 pooled data; b Sustained accumulation of disability (SAD) is defined as a ≥1 point increase in Expanded Disability Status Scale (EDSS) lasting ≥6 months (or ≥1.5 point increase if baseline EDSS=0). 1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Data on file, Genzyme Corporation. 24 a CARE-MS 54
  46. 46. Treatment-naïve subjects are more Likely to be disease activity-free with alemtuzumab vs. sc IFNB-1a Treatment-naïve: CARE-MS I1,2 (Tertiary Endpoints) SC IFNB-1a 44 µg Alemtuzumab 12 mg p<0.0001 p=0.0388 OR=1.75 p=0.0064 CDA-freea aClinical MRI Activity-freeb MS Disease Activityfreec disease activity (CDA)-free: Absence of relapse or SAD; bMRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesion; cMS disease activity-free: Absence of CDA or MRI activity. OR=odds ratio; 1. Giovannoni G et al. ENS 2012; 2. Cohen JA et al. Lancet 2012;380:1819-28.
  47. 47. Baseline demographics and clinical characteristics of alemtuzumab-treated subjects Pooled treatment-naïve (CAMMS223 and CARE-MS I) N=4831-3 Age, years Mean (SD) Gender Female, % 32.9 (8.03) Patients Who Relapsed on Prior Therapy (CARE-MS II) N=4264 34.8 (8.4) 64.6 66.0 Years since initial episode Mean (SD) 1.9 (1.30) 4.5 (2.7) EDSS Mean (SD) 2.0 (0.80) 2.7 (1.3) No. of relapses in prior year Mean (SD) 1.8 (0.80) 1.7 (0.86) Prior therapy, % SC IFNB-1a (22 or 44 μg) IM IFNB-1a SC IFNB-1b Glatiramer acetate Natalizumab  34 28 36 34 4 Patients with Gd-enhancing lesions, % 58.6 42.4 1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Data on file, Genzyme Corporation; 3. Cohen JA et al. Lancet 2012;380:1819-28; 4. Coles AJ et al. Lancet 2012;380(9856):1829-39.
  48. 48. Alemtuzumab significantly reduced clinical disease activity in subjects who relapsed on prior therapy ARR Years 0–2: CARE-MS II1 (Co-primary Endpoint) Risk reduction: 49.4% p<0.0001 6-Month Sustained Accumulation of Disability: CARE-MS II (Co-primary Endpoint) HR: 0.58 42% Risk reduction p=0.0084 21.1% 12.7% SC IFNB-1aAlemtuzumab 12 44 µg mg (n=202) (n=426) SAD defined as EDSS score increase ≥1.0 point for ≥6 months (or ≥1.5 points when baseline EDSS = 0); bNumber of events among patients who received prior natalizumab is too small to draw meaningful conclusions. CI=confidence interval; HR=hazard ratio 1. Coles AJ et al. Lancet 2012;380:1829-39; 2. Freedman MS et al. AAN 2013, P07.111. aSix-month 57
  49. 49. Subjects who relapsed on prior therapy were more likely to be disease activity-free with alemtuzumab vs. sc IFNB-1a Relapsed on Prior Therapy: CARE-MS II (Tertiary Endpoints)1,2 p<0.0001 p<0.0001 OR=3.03 p<0.0001 Clinical disease activity-free: absence of relapse or SAD; MRI activity-free: absence of new Gd-enhancing lesion or new or enlarging T2 hyperintense lesions; MS disease activity-free: absence of clinical disease activity and MRI activity; SAD: Increase of ≥1.0 EDSS point for ≥6 months (or ≥1.5 points if baseline EDSS = 0). SC IFNB-1a=subcutaneous interferon beta-1a 1. Hartung HP et al AAN 2013; P07.093; 2. Coles AJ et al. Lancet 2012;380:1829-39.
  50. 50. Alemtuzumab improved pre-existing disability vs. sc IFNB-1a in subjects who relapsed on prior therapy Sustained Reduction of Disabilitya Relapsed on Prior Therapy: CARE-MS II1,2 HR: 2.57 p=0.0002 HR: 3.00 p=0.0001 HR: 3.02 p=0.0003 SC IFNB-1a 44 µg Alemtuzumab 12 mg SRD Timeframeb (Tertiary Endpoint) a SRD (Post Hoc Analyses) defined as a reduction from baselilne of ≥1 EDSS point for ≥6, 9, OR 12 months; assessed in patients with baseline EDSS score ≥ 2. events that initiated in the core studies and continued into the extension. 1. Coles AJ et al. Lancet 2012;380:1829-39 ; 2. Data on file, Genzyme Corporation. b Includes
  51. 51. CARE-MS extension study designed to evaluate long-term outcomes with alemtuzumab CARE-MS I or II Pivotal Studies Extension Study (Safety & Efficacy Follow-up) Received alemtuzumab (Month 0 and 12) Monitor for MS activity through extension trial Month 48 Received SC IFNB-1a Administer 2 annual alemtuzumab treatment courses Relapse or 2 active MRI lesions? Yes May receive optional re-treatment course(s) not sooner than 12 months after the previous course No  Extension study treatments used alemtuzumab 12 mg IV  ~80% of patients did not receive re-treatment or other DMT during Year 3  <2% of patients received another DMT during Year 3 Fox E et al. AAN 2013, S41.001.
  52. 52. CARE-MS extension: majority of subjects treated with alemtuzumab remain relapse-free at year 3 Relapse-free Patients Relapsed on Prior Therapy (CARE-MS II) %Patients Treatment-naïve (CARE-MS I) N=376 Fox E et al. AAN 2013, S41.001. N=349 N=425 N=387
  53. 53. CARE-MS extension: majority of subjects experience further benefits on disability through year 3 Relapsed on Prior Treatment (CARE-MS II) Remained stable Years 2-3 Improved Years 2-3 EDSS change (baseline to Year 2) Yr-1 Yr-2 Yr-3 Data shown are for alemtuzumab 12-mg groups. Hartung HP et al. ECTRIMS 2013, P592. Yr-1 Yr-2 Yr-3
  54. 54. Summary of safety in clinical study population 2-year controlled experience Treatment-naïve Patients1,a Relapsed on Prior Therapy2 Alemtuzumab 12 mg (N=483) (%) SC IFNB-1a (N=202) (%) Alemtuzumab 12 mg (N=435) (%) 96.7 94.6 98.4 16.0 17.1 21.8 19.5 IARs — 91.7 — 90.3 Thyroid disorders 5.4 17.4 5.0 15.9 ITP3,4 0 1.0 0 0.9 Glomerulonephritis 0 0 0 0.2 Serious infections 0.7 1.9 1.5 3.7 SC IFNB-1a (N=294) (%) AEs SAEs 94.6 Identified risks aData pooled for CAMMS223 and CARE-MS I studies. 1. Data on File. Genzyme Corporation; 2. Cohen JA et al. Lancet 2012;380:1819-28; 3.Coles AJ et al. Lancet 2012;380:1829-39; 4. Fox E et al. AAN 2013, S41.001.
  55. 55. Alemtuzumab summary of safety  Well-characterized safety and tolerability profile across alemtuzumab clinical development program1-3 – Most common adverse events were mild/moderate infusion reactions, which were manageable with appropriate pre-medication and/or treatment, and patient education1-3 – Low rates of serious infection, consistent with relative sparing of both innate immune cells and specific lymphocyte subpopulations1,2 – Autoimmune adverse events, including thyroid-related events, ITP, and nephropathies, were detected with safety monitoring program and generally responded to conventional therapy1-3  Incorporation of proactive risk-minimization procedures into clinical trials allowed for early detection and management of identified risks1-3 – Clinical trial experience has informed the Risk Mitigation Plan for alemtuzumab in the EU 1. Cohen JA et al. Lancet 2012;380:1819-28; 2. Coles AJ et al. Lancet 2012;380:1829-39; 3. Fox E et al. AAN 2013, S41.001.
  56. 56. Summary of recommended risk mitigation strategies for alemtuzumab in the EU Identified Risks Infusion-associated reactions (IARs) Timing Mitigation Strategies Corticosteroids Immediately prior to alemtuzumab administration Antihistamines and/or antipyretics (optional) Prior to alemtuzumab administration Oral prophylaxis for herpes infection Starting on the first day of each treatment course HPV screening Annually for female patients Active or inactive (“latent”) tuberculosis infection evaluation Before initiation of therapy Immune thrombocytopenia (ITP) and other cytopenias Complete blood count with differential Prior to initiating alemtuzumab treatment Monthly until 48 months after last infusion.a Nephropathies, including anti-GBM disease Serum creatinine Prior to initiating alemtuzumab treatment Monthly until 48 months after last infusiona Urinalysis with microscopy Prior to initiating alemtuzumab treatment Monthly until 48 months after last infusiona Thyroid disorders Thyroid function tests (such as TSH) Prior to initiating alemtuzumab treatment Every 3 months until 48 months after last infusiona Serious infections aAfter 48 months, testing should be performed based on clinical findings suggestive of the adverse event. LEMTRADA EU Summary of Product Characteristics, September 2013. On each of the first 3 days of any treatment course Continuing for a minimum of 1 month following treatment with alemtuzumab
  57. 57. What is your treatment philosophy?
  58. 58. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hard and early ”
  59. 59. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment
  60. 60. Another example: treat early and effectively
  61. 61. Emerging concepts in MS NEDD – no evidence of detectable disease (oncology) NEDA - no evidence of disease activity (msologoy) DAF – disease activity free Biochemical relapse-free survival 1.0 Adjuvant (n = 50) Survival 0.8 0.6 0.4 Salvage (n = 118) p = 0.002 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 Time since radiotherapy (years) T2T; treat-2-target (rheumatology) Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340. ZeTo; zero tolerance
  62. 62. No evidence of disease activity: NEDA Treat-2-target 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 Should brain volume loss and CSF neurofilament levels be included in our definition for ‘no evidence of disease activity’? Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
  63. 63. Treatment objectives in relapsing MS Improved Quality of Life Treat Early Freedom from disease activity/disease activity free CNS Repair Reduced ongoing damage 73 Functional T2T - NEDA Improvement Maintain reserve Zero Tolerance capacity Healthy ageing
  64. 64. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate Early or late? natalizumab Monitoring ? fingolimod 74 JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive 3-monthly MRI monitoring
  65. 65. clinical Occup. & social What does the future hold? Splits from her partner Final year of school 17yr female, diagnosed with CIS after presenting with myelitis Graduate trainee marketing University 18yr, 1st year university diagnosed with MS after having L optic neuritis 2000 depression , anxiety and fatigue Full time employment clumsy left hand pins & needles in legs R optic neuritis 2001 2001 Off work ~3 months of the year Bladder dysfunction 2003 2004 Brainstem syndrome; diplopia and ataxia Dec 2007 Pregnancy New partner New job junior management position Occupational health assessment Reduced mobility Cervical cord relapse weak L arm with pain Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Jan 2008 treatment IFN-beta ? glatiramer acetate natalizumab monitoring ? fingolimod JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 High lesion load with brain atrophy 75 Gd-enhancing lesion of upper cervical cord Annual MRI monitoring JCV high positive 3-monthly MRI monitoring Old Age
  66. 66. Occup & social Final year of school Clinical 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis clumsy left hand pins & needles in legs 2000 2001 2002 2003 Splits from her partner Graduate trainee marketing University depression , anxiety and fatigue Full time employment Off work ~3 months of the year Bladder dysfunction New partner New job junior management position Occupational health assessment Reduced mobility R optic neuritis Brainstem syndrome; diplopia and ataxia Cervical cord relapse weak L arm with pain 2004 Dec 2007 Jan 2008 Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Oct 2013 Treatment IFN-beta ? glatiramer acetate Early or late? natalizumab Monitoring ? fingolimod JCV positive Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 Dec 2007 High lesion load with brain atrophy Jul 2010 Gd-enhancing lesion of upper cervical cord Annual MRI monitoring Jul 2013 JCV high positive 3-monthly MRI monitoring
  67. 67. Maintenance vs. Induction Maintenance therapies • • • • • Continuous treatment Low to very high efficacy Reversible Perceived to be lower risk Examples • • • • • • • Rebound SPMS & progressive brain atrophy Less likely Unlikely to be life-threatening Pregnancy • • Marker for retreatment NEDA unreliable to assess efficacy Rebound activity • • • Mitoxantrone, cladribine, alemtuzumab, antiCD20 (?), BMT Breakthrough disease • • Contra-indicated No potential for a cure • • • Highly likely Can be life threatening Pregnancy Short-courses or pulsed therapy Very high efficacy Irreversible Perceived to be higher risk Examples • Suboptimal or failure to respond NEDA reliable metric for efficacy Rebound activity • • • • • • • Laquinimod, GA, IFN-beta, teriflunomide, BG12, fingolimod, natalizumab, daclizumab Breakthrough disease • • Induction therapies Strategy of choice Potentially curative • • 15-20 year experiment BMT, alemtuzumab, cladribine
  68. 68. Who should decide?
  69. 69. WWW.MS-RES.ORG
  70. 70. WWW.MS-RES.ORG
  71. 71. Case studies
  72. 72. Ian Rogers. ACNR 2007: 7(3);14.
  73. 73. Conclusions • MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc. • Early highly-effective treatment is the only realistic option of offering a cure • Now an established treatment option, which has become safer • NEDA, T2T and DAF are entering the neurology lexicon • Zero tolerance or ZeTo • We need an acceptable working definition of an MS cure • NEDA x 15 years? • Induction therapies (alemtuzumab, cladribine) • Improved risk mitigation tools • Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment? • Alemtuzumab, BMT, natalizumab, cladribine extension studies
  74. 74. Any questions? early + therapy highly-effective + therapy induction therapy
  75. 75. ZeTo – zero tolerance Treat-2-Target proposed NEDA treatment algorithm for relapsing MS High Efficacy Intermediate Efficacy Moderate Efficacy E M A D B C NEDA=no evidence of disease activity. X N Y
  76. 76. Risks BMT Mx Nz ? Dac Alemz Clad ? CD20 FTY Efficacy - IFNb Teri + BG12 Lq GA + Nz

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