EMA Workshop staggered 2-step approach

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EMA Workshop staggered 2-step approach

  1. 1. The staggered 2-step approach for treatments with profound effect on immunity Gavin Giovannoni Barts and The London
  2. 2. Disclosures I 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, Almirall, 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.
  3. 3. The Multiple Sclerosis Spectrum PPMS CIS Subclinical disease Disease Severity RIS First clinical event RRMS R-SPMS RRMS NR-SPMS SPMS Inflammation Axonal loss Brain volume Time (Years) MRI Events Subclinical inflammation, demyelination, and neurodegeneration may be present for months, or even years, before a patient experiences clinical symptoms1 MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
  4. 4. Control Multiple sclerosis
  5. 5. Brain atrophy occurs across all stages of the disease n= 963 MSers De Stefano, et al. Neurology 2010
  6. 6. Cognition in early multiple sclerosis 60% 57% 40% MSers failing ≥ 2 cognitive tests 20% p < 0.0001 7% 0% -20% CISers n = 40 Healthy Controls n = 30 Deficits were found mainly in memory, speed of information processing, attention and executive functioning. Feuillet et al. Mult Scler. 2007.
  7. 7. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108.
  8. 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. 9. Occupational functioning Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
  10. 10. At what level of physical disability does unemployment occur? Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
  11. 11. Quality of life of patients with MS in Europe Kobelt et al. J Neurol Neurosurg Psychiatry 2006;77:918–926.
  12. 12. The Effect of MS on Quality of Life Utility Utility EDSS and Utility* Show a Significant Inverse Relationship 1† • 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 –0.1 –0.2 –0.3 –0.4 • 0.0 1.0 2.0 3.0 4.0 5.0 6.0 EDSS Status 6.5 7.0 8.0 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 scores 4.0, 6.0, and 7.0, respectively3 9.0 *Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CIs. Half points on EDSS are not shown on graph axis, except at EDSS score 6.5. EDSS=Expanded Disability Status Scale; EQ-5D=European Quality of Life-5 Dimensions; QoL=quality of life. 1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MS International Foundation (MSIF). http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed March 6, 2012; 3. Confavreaux C et al. Brain 2003; 176:770-782. 4. Compston A, Coles A. Lancet. 2008;372:1502-1517. 16
  13. 13. Theoretical model: treat early and effectively Natural course of disease Disability Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis Time Disease Onset
  14. 14. Escalation to Natalizumab Is More Effective Than Switching Between IFN/GA Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161 Over 24 months* % Patients 100 P<0.0001 75 P=0.0003 P<0.0001 83 77 50 P<0.0045 67 51 59 51 36 25 21 0 No Relapses No EDSS Progression No MRI Activity Disease Activity Free Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. Prosperini L et al. Mult Scler. 2012;18:64-71. 18
  15. 15. Escalation to Natalizumab Is More Effective Than Switching Between IFN/GA Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161 Over 24 months* % Patients 100 P<0.0001 75 P=0.0003 P<0.0001 83 77 50 P<0.0045 67 51 59 × 25 0 No Relapses No EDSS Progression 51 36 21 No MRI Activity  Disease Activity Free Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. Prosperini L et al. Mult Scler. 2012;18:64-71. 19
  16. 16. Should multiple sclerosis be redefined as a dementia?
  17. 17. Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • • • • Physical  Mental  Social  Occupational  • Lasting more than six months  • Not present since birth  • Not associated with a loss or alteration of consciousness 
  18. 18. www.multiple-sclerosis-research.org
  19. 19. What is the pathological substrate of MS dementia?
  20. 20. 11,000 to 1 Trapp, et al. NEJM 1998;338:278-85
  21. 21. Defining the window of opportunity to treat MS?
  22. 22. “The window of opportunity” PPMS CIS Subclinical disease Disease Severity RIS First clinical event RRMS R-SPMS RRMS NR-SPMS SPMS Inflammation Axonal loss Brain volume Time (Years) MRI Events MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
  23. 23. “The window of opportunity” PPMS CIS Subclinical disease Disease Severity RIS First clinical event RRMS R-SPMS RRMS NR-SPMS SPMS Inflammation Axonal loss Brain volume Time (Years) MRI Events MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.
  24. 24. Choosing a treatment strategy?
  25. 25. 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
  26. 26. Ian Rogers. ACNR 2007: 7(3);14.
  27. 27. STRATA: Patients Had Stable EDSS Scores for Up to 5 Years Cessation/ Treatment Gap* Original Placebo Original Natalizumab 4.0 Original Placebo – Now on Natalizumab Mean EDSS Score 3.5 3.13 2.90 3.0 2.69 2.54 2.69 2.36 2.38 2.36 381 707 280 552 2.72 3.21 2.84 3.15 2.85 2.79 2.39 n = 380 707 2.5 3.24 3.22 3.07 2.0 1.5 1.0 0.5 0.0 Feeder Study Baseline Feeder Study End Safety Study End 385 709 STRATA Baseline 274 569 205 462 194 427 174 393 STRATA STRATA STRATA STRATA STRATA 48 Weeks 96 Weeks 144 Weeks 192 Weeks 240 Weeks 1 Year *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 32 230 479 2 Years 3 Years 4 Years 5 Years
  28. 28. WWW.MS-RES.ORG
  29. 29. WWW.MS-RES.ORG
  30. 30. CARE-MS II CARE-MS II: Risk of Sustained Disability over Intervals of up to 1 Year Proportion of Patients (%) 40 35 30 42% reduction p=0.0084 43% reduction p=0.0127 39% reduction p=0.0446 SC IFNB-1a 44 µg Alemtuzumab 12 mg 25 20 21.1 18.8 15 10 15.2 12.7 11.1 9.5 5 0 6-month (Primary Endpoint) 9-month 12-month (Post Hoc Analyses) SAD Timeframe Alemtuzumab reduced the risk of disability accumulation sustained for intervals of up to 1 year vs. SC IFNB-1a Includes events with onset during 2-year core study, and confirmation in the extension. Data on file, Genzyme Corporation.
  31. 31. Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • • • • Physical  Mental  Social  Occupational  • Lasting more than six months  • Not present since birth  • Not associated with a loss or alteration of consciousness  “Multiple sclerosis is possibly a preventable dementia.”

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