Treat 2-target MS Trust Meeting November 2013

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  • 1. The new treatment paradigm for MS: treat-2-target of NEDA Zero Tolerance = ZeTo Gavin Giovannoni Barts and The London
  • 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 and Merck-Serono for making available data slides on natalizumab, alemtuzumab and oral cladribine for this presentation.
  • 3. Who should decide?
  • 4. WWW.MS-RES.ORG
  • 5. WWW.MS-RES.ORG
  • 6. RRMS Active MS Clinical or MRI
  • 7. What are the arguments for early treatment?
  • 8. 21-year long-term follow-up of IFNb-1b study time from study randomization to death Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment Proportion of patients who are still alive 100% 95% IFNB-1b 250 µg 90% Placebo 85% 80% 75% HR=0.532 (95% CI: 0.314–0.902) 46.8% reduction in hazard ratio Log rank, P=0.0173 70% 65% 0 At risk: IFNB-1b 250 µg Placebo 124 123 2 4 6 124 120 8 10 12 14 16 18 20 22 Time (Years) 121 117 118 109 104 88 Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.
  • 9. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  • 10. 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
  • 11. How bad is MS?
  • 12. Untreated MS is a devastating disease Cognitive Dysfunction • Prevalence: 43% to 65%1,2 • Affects employment, activities of daily living, and social functioning2 Life Shortening • • • 5- to 11-year decrease in life expectancy3-7 2- to 7-fold increase in suicide risk5,8 50% MS patients die of disease-related causes5,6,8 QOL EDSS and utility* have shown a significant inverse relationship9 MS has a negative impact on… Mortality Mortality ratio of patients with MS exceeds CV disease,†,10 stroke,‡,11 and early breast cancer12 Employment 50% of patients with MS are unemployed as of EDSS 3.0 and/or after 10 years from diagnosis13 Healthcare costs Relationships Bulk of cost attributed to services (28.5%) and long-term sick leave and early retirement (30%)§,14 Compared with general population, patients with MS have a higher probability of separating/divorcing and doing so sooner13 *In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County, Minnesota; §MS patients with EDSS ≥6. EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular; EQ-5D=European Quality of Life-5 Dimensions. 1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994; 4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler. 2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196; 9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126; 14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.
  • 13. 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. 14 14
  • 14. The effect of MS on quality of life a EDSS and utility show a significant inverse relationship 1,b Utility • MS is one of the most common causes of neurological disability in young adults2 • Natural history studies indicate that it takes a median time of 8, 20, and 30 years to reach the irreversible disability levels of EDSS 4, 6, and 7, respectively3 EDSS Status aUtility measures are derived from EQ-5D using the EuroQoL instrument. bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5. bError 1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF. http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 15 &codcol=15&codcch=747. Accessed October 6, 2010. 3. Confavreaux, Compston. 2005. 4. Compston A, Coles A. Lancet 2008
  • 15. What about benign MS?
  • 16. What prognostic group does the Mser fall Into? Good Prognosis: Poor Prognosis:  Younger age at onset1,2  Older age of onset1,2  Female sex1-3  Male sex1-3  Optic neuritis4  “Multifocal” onset4  Isolated sensory symptoms4  Efferent systems affected (motor, cerebellar, bladder)4  Complete recovery from first attack5  Long interval to second relapse4  No disability after 5 years4  Incomplete recovery from first attack5  High relapse rate in the first 2–5 years4  Normal MRI / low lesion load4  Substantial disability after 5 years4  CSF negative for oligoclonal bands2,6  Abnormal MRI with large lesion load4  CSF positive for oligoclonal bands2,6 CSF=cerebrospinal fluid 1. Scalfari A et al. J Neurol Neurosurg Pschiatry 2013;00:1-9; 2. Fernandez O. J Neurol Sci 2013;331:10-3; 3. Damasceno A et al. J Neurol Sci 2013;324:29-33; 4. Miller D et al. Lancet Neurol 2005:4;281-8; 5. Confavreux C et al. Brain 2003;126:770-82; 6. Villar LM et al. J Clin Invest 2005;115:187-94. 17
  • 17. 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.
  • 18. What is benign MS? 163 patients with “benign” MS (disease duration >15 years and EDSS <3.5): 45% cognitive impairment 49% fatigue 54% depression
  • 19. Impact of MS: cognitive functioning in the CIS stage Cognitive test performance in an exploratory study* 60% Patients failing ≥ 2 cognitive tests 40% 57% 20% Deficits were found mainly in memory, speed of information processing, attention and executive functioning 7% 0% p < 0.0001 -20% CIS Patients n = 40 20 Healthy Controls n = 30 Feuillet et al. Mult Scler. 2007.
  • 20. 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
  • 21. Is there any other evidence?
  • 22. 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.
  • 23. Establishing long-term efficacy: use of recursive partitioning and propensity score adjustment to estimate outcome in MS % Risk Relative to Low Exposure Long-term follow-up 16 years 100 IFN-beta exposure 80% vs. 20% 80 60 40 20 0 Any Negative EDSS=6 SPMS Wheelchair Goodin et al. PLoS One. 2011;6(11):e22444.
  • 24. 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 1 Year 2 Years 3 Years *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 25 194 427 4 Years 174 393 5 Years
  • 25. 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. 26
  • 26. Mean Annualized Relapse Rate TOP: Earlier Natalizumab Treatment Favors Annualized Relapse Rate Outcomes 0.50 P<0.0001 0.40 0.45 0.40 0.35 P<0.0001 0.30 0.25 0.24 0.23 0.16 0.28 0.18 0.20 0.15 0.10 0.05 0.00 0 DMT 1 DMT ≥2 DMTs 0 DMT 1 DMT ≥2 DMTs ≥2 Relapses 1 Relapse Baseline Relapse and Treatment History P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0vs ≥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 are 95% CIs. Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain. P372. 27
  • 27. The current paradigm is safe and slow!
  • 28. 100 MSers Who are the responders?
  • 29. ~20% responders ~40% sub-optimal responders ~40% non-responders
  • 30. 1 Clinical vs. 2 MRI 3 NABs
  • 31. Relapses don’t count!
  • 32. Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.
  • 33. 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.
  • 34. Relapses and residual deficits Lublin FD et al. Neurology. 2003;61:1528-1532.
  • 35. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  • 36. Predictors of long-term outcome in MSers treated with interferon beta-a Bermel et al. Ann Neuol 2012.
  • 37. Predictors of long-term outcome in MSers treated with interferon beta-1a Treatment vs. Natural History Bermel et al. Ann Neuol 2012.
  • 38. MRI activity doesn’t count!
  • 39. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  • 40. 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.
  • 41. 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.
  • 42. Disease progression doesn’t count!
  • 43. 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.
  • 44. 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.
  • 45. Do highly-effective treatments stabilise MS?
  • 46. 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. 47
  • 47. 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 Relapse rate Sustained accumulation of disability (SAD) a Enrolling 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. 48
  • 48. Demographics and Baseline Clinical Characteristics in Treatment-naïve Patients 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  CARE-MS I and CAMMS223 were pooled to increase the sample size for subpopulation analyses − Similar study designs, eligibility rules, baseline demographic characteristics, assessment schedules, and definitions of the co-primary efficacy endpoints 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. 49
  • 49. Alemtuzumab Significantly Reduced Annualized Relapse Rate vs. SC IFNB-1a in Treatment-naïve Patients CAMMS223 (Co-primary endpoint)1 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 CARE-MS I (Co-primary endpoint)2 0.6 0.6 0.3 SC IFNB-1a 44 µg Alemtuzumab 12 mg 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 N=187 N=376  Alemtuzumab provided superior reduction in annualized relapse rate: – 69% reduction beyond SC IFNB-1a at 3 years in CAMMS2231 – ~55% reduction beyond SC IFNB-1a at 2 years in CARE-MS I2 1. Coles AJ et al. N Engl J Med 2008;259:1786-801; 2. Cohen JA et al. Lancet 2012;380:1819-28. 50
  • 50. Alemtuzumab Reduced the Risk of 6-month Sustained Accumulation of Disability in Treatment-naïve Patients 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 24  In CARE-MS I, fewer SC IFNB-1a patients accumulated disability than expected, which may have reduced the ability to detect a significant treatment effect1  In a pooled analysis of treatment-naïve patients, alemtuzumab reduced risk of 6-month SADb by 50% vs. SC IFNB-1a2 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. a CARE-MS 51
  • 51. Treatment-naïve Patients Were More Likely to be Disease ActivityFree 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 MRI Activity-freeb MS Disease Activity-freec  Alemtuzumab-treated patients were ~2 times more likely to be free of overall MS disease activity compared with SC IFNB-1a–treated patients over 2 years1,2 aClinical 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. 52
  • 52. Baseline Demographics and Clinical Characteristics of Alemtuzumab-treated Patients 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  As expected, baseline EDSS and duration of disease were higher for patients who relapsed on prior compared with treatment-naïve patients 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. 53
  • 53. Alemtuzumab Significantly Reduced Clinical Disease Activity in Patients 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-1a Alemtuzumab 44 µg 12 mg (n=202) (n=426)  Alemtuzumab significantly reduced relapse rate and risk of 6-month SADa by an additional 49.4% and 42% beyond SC IFNB-1a, respectively, in patients who relapsed on prior therapy1  Benefits on clinical disease activity were similar regardless of type, duration, or number of prior treatments2,b 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 54
  • 54. Patients 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  Alemtuzumab-treated patients were 3 times more likely to be free of overall MS disease activity compared with SC IFNB-1a–treated patients over 2 years 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. 55
  • 55. Alemtuzumab Improved Pre-existing Disability vs. SC IFNB-1a in Patients 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) (Post Hoc Analyses)  Alemtuzumab-treated patients were 2.5–3 times more likely to have disability improvement sustained over intervals of up to 1 year vs. SC IFNB-1a a SRD 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 56
  • 56. 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. 57
  • 57. CARE-MS Extension: Majority of Patients Treated with Alemtuzumab Remained Relapse-free at Year 3 Relapse-free Patients Relapsed on Prior Therapy (CARE-MS II) %Patients Treatment-naïve (CARE-MS I) N=376 N=349 N=425 N=387  Relapse reduction with alemtuzumab treatment was durable; majority of patients remained relapse-free through Year 3 Fox E et al. AAN 2013, S41.001. 58
  • 58. CARE-MS Extension: Majority of Patients Experienced 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) • The majority of patients who relapsed on prior therapy and whose EDSS score improved or remained stable in the core studies (Years 0–2) remained stable or improved further through Year 3 • Results were consistent with observations in treatment-naïve patients in CARE-MS I Data shown are for alemtuzumab 12-mg groups. Hartung HP et al. ECTRIMS 2013, P592. 59
  • 59. 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 60
  • 60. What is your team’s treatment philosophy?
  • 61. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hit hard and early ”
  • 62. What is your team’s treatment philosophy? maintenance-escalation vs. induction survival analysis “hit hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment
  • 63. Another example: treat early and effectively
  • 64. 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
  • 65. Emerging concepts in MS NEDA - no evidence of disease activity 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 Time since radiotherapy (years) T2T; treat-2-target Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340. 8 9 10
  • 66. 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.
  • 67. Treatment objectives in relapsing MS Improved Quality of Life Treat Early Freedom from disease activity/disease activity free Reduced ongoing damage 68 T2T - NEDA Zero Tolerance
  • 68. Treatment objectives in relapsing MS Improved Quality of Life Treat Early Freedom from disease activity/disease activity free CNS Repair Reduced ongoing damage 69 Functional T2T - NEDA Improvement Maintain reserve Zero Tolerance capacity Healthy ageing
  • 69. Ian Rogers. ACNR 2007: 7(3);14.
  • 70. Conclusions • MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc. • Early aggressive 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, natalizumab, cladribine extension studies.
  • 71. WWW.MS-RES.ORG