DMT Update MS Life Manchester 2014

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DMT Update MS Life Manchester 2014

  1. 1. DMT Update Gavin Giovannoni Barts and The London
  2. 2. The DMT pipeline
  3. 3. Interferons Phase I Phase II Phase III Marketed Anti-proliferation agents Avonex Atacicept Campath Rituximab Novantrone Rebif Betaferon/ Extavia Teriflunomide Tysabri Zenapax Pixantrone Targeted mAbs/Fc-Ab Cladribine Fingolimod Azathioprine = oral administration = injectable Riluzole Symptomatic Tx Vaccine, tolerisation Tovaxin ATL-1102 MM-093 BG12 AJM-300 Nerispirdine Interferon Tau Interferon omega Peg IFNb (BIIB017) Fc- IFb ATX-MS-1467 Firategrast Ofatumumab Sativex Lymphocyte trafficking TBC4746 MLN-0002 Targeted Immune regulation PI2301 R1295 Copaxone Laquinimod Fampridine SR 683699 (T-0047) Ocrelizumab LY-2127399
  4. 4. The ideal DMT
  5. 5. Therapeutic Ideal Reliable long-term efficacy Maintaining QOL Maintaining independence Maintaining the ability to work No issue for pregnancy/fertility Maximum reduction of MS disease activity Maximum tolerability Maximum safety Ease of use Minor impact on everyday life
  6. 6. Treatment strategy
  7. 7. Treat early and effectively Natural history Delayed intervention Later treatment Treatment at diagnosis Early intervention Time Disease Onset Disability Time is brain
  8. 8. 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. Regular Medical Care* Primary Endpoint: All cause mortality free survival comparison between IFNβ-1b 250 µg eod vs. placebo per ITT *Group approximately matched between DMTs IFB-beta-1b approved N=372 250 mcg 50 mcg Placebo 1988 1993 2005 2006 2009 2010 98.4% ascertainment Pivotal Trial 16-Year LTF 21-Year LTF
  9. 9. 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.
  10. 10. Consequences of increasing EDSS scores: loss of employment 0 10 20 30 40 50 60 70 80 90 Work Capacity by Disability Level 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0 EDSS Score ProportionofPatients≤65YearsOld Working(%) 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. Spain Sweden Switzerland United Kingdom Netherlands Italy Germany Belgium Austria ~10 yrs2
  11. 11. MS patient’s QoL decreases tremendously dependent on the EDSS score Mean utility Utilities at early disease Utility at severe disease Austria 0.55 0.90 0.05 Belgium 0.51 0.85 0.06 Germany 0.62 0.86 0.10 Italy 0.53 0.80 0.06 Netherlands 0.61 0.85 0.05 Spain 0.55 0.87 0.08 Sweden 0.546 0.825 0.047 Switzerland 0.59 0.89 0.1 UK 0.51 0.92 0.18 EQ-5D was used to calculate utilities: Utility is a measure of people's well-being or preferences for outcomes. Mean utilities and EDSS in Germany 1= perfect health; 0 = worst health/dead Source: based on G. Kobelt et al.: The European Journal of Health Economics, Volume 7; suppl. 2006
  12. 12. Treatment strategies A B C D E N M YX Moderate Efficacy Intermediate Efficacy High Efficacy 1st-line 2nd-line 3rd-line
  13. 13. Survival Analysis “Hit hard and early” MS is an autoimmune disease hypothesis 15–20 year experiment What is your treatment philosophy?
  14. 14. How bad is MS?
  15. 15. Question: What prognostic group do you fall into? Potential Consequences of the Disease www.ms-res.org
  16. 16. Monitoring is important
  17. 17. Predictors of long-term outcome in MSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012.
  18. 18. Bermel et al. Ann Neuol 2012. Predictors of long-term outcome in MSers treated with interferon beta-1a Treatment vs. Natural History
  19. 19. MS is an iceberg? Clinical MRI Pathology
  20. 20. Treat-2-target No evident disease activity (NEDA)
  21. 21. NICE
  22. 22. The relapsing MS DMT doughnut
  23. 23. The relapsing MS DMT doughnut Inactive RRMS CIS RIS or asymptomatic MS Suboptimal responders ? Active RRMS Highly active RRMS
  24. 24. The relapsing MS DMT doughnut Inactive RRMS CIS RIS or asymptomatic MS Suboptimal responders ? Active RRMSIFNbeta / GA IFNbeta / GA Highly active RRMS Fingolimod Natalizumab
  25. 25. Current UK practice
  26. 26. 100 MSers Who are the responders?
  27. 27. ~20% responders ~40% sub-optimal responders ~40% non-responders
  28. 28. Question: Do you have active MS? vs 1 2 3 Clinical MRI Biomarkers Giovannoni G. Barts & The London, UK, February 2014.
  29. 29. The reality
  30. 30. Relapsing-remitting MS (RRMS) Active disease? Randomise RES disease? Y N N Rx with Nz Observation Y Current practice T2T-NEDA Current 1st-line treatments IFNb, GA (Teri, BG12) Current 1st-line treatments IFNb, GA (Teri, BG12) 6-monthly* clinical F- UP Clinical responder? Y N HAD or RES? N Y Escalation/switch to upper tier natalizumab, fingolimod (Alemz) Switch in lower tier IFNb, GA (Teri, BG12) 6-monthly* clinical/MRI F- UP Clinical/MRI responder? Y N Escalation/switch in upper tier natalizumab, fingolimod (Alemz) 3-yr 1° outcome: confirmed disability progression 5-yr 1° outcome: time to confirmed EDSS 4.0 2° outcomes: MRI etc. PROPOSED NEDA Rx Trial NEDA = No Evident of Disease Activity T2T = treat-2-target RES = rapidly evolving severe MS HAD = highly-active disease activity * A clinical relapse between 6-monthly visits will trigger an unscheduled assessment for switching/escalation GG, version 1.0 3rd Jan 2014
  31. 31. Treating-2-target Choosing therapy X Y Z Define the Individual’s MS No Treatment failure? Yes • Patient’s preferences? • Your choice? Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers? Monitoring • MS prognosis • Life style and goals • Shared goals for therapy Rebaseline Rebaseline: • IFNβ, natalizumab, fingolimod, teriflunomide, DMF=3-6 months • Glatiramer acetate=9 months • Alemtuzumab=24 months DMF=dimethyl fumarate.
  32. 32. DMT Summary
  33. 33. Efficacy Risks + +- - GA BMT Mx Alemz aCD20 Lq BG12 Dac Nz JCV+ Nz JCV- IFNb Teri Not licensed (but available in the NHS) Licensed (available in the NHS) Licensed (not available via NHS yet) Late stage development (phase 3) Fingo KEY DMT SUMMARY
  34. 34. What about pregnancy?
  35. 35. Questions MSers ask about pregnancy 1. Does MS affect my fertility? 2. Will pregnancy affect the course of my MS? 3. Will I be able to breast feed after delivery? 4. How long before I fall pregnant must I stop my DMT? 5. If I fall pregnant on a DMT will this affect the baby? 6. Can I breast feed on my DMT? 7. Will I be able to be a good parent if I become disabled from my MS? 8. If I become disabled or unemployed as a result of MS will I be able to support my children? 9. What is the risk of my children getting MS? 10. Can I do anything to prevent them from getting MS? 11. Am I more likely to need an assisted delivery because I have MS? 12. Will I be able to have a normal vaginal delivery? 13. Will I be able to have an epidural during labour? 14. How you treat hyperemesis gravidarum during pregnancy? 15. Should I continue taking my other drugs for my MS symptoms during pregnancy? 16. What is the best treatment strategy for my MS? Should I go onto a DMT and get my MS under control before starting a family or should I first start my family? 17. What is the best treatment strategy for my MS to maximise my chances of having a family and keeping my MS under control? 18. How will having neutralizing anti-interferon beta antibodies affect my baby? 19. Can I have IVF? Will the drugs that are used to induce ovulation affect my MS? 20. What dose of vitamin D do you advise during pregnancy? 21. Are oral contraceptive safer for my MS? Which contraceptive do you recommend?
  36. 36. What about vitamin D?
  37. 37. The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis James et al. Mult Scler. 2013 Oct;19(12):1571-9. There is no evidence that vD supplements modify the course of MS. Low vD levels in MS can be due to reverse causation, i.e. MS results in low vD levels.
  38. 38. Osteopaenia: z-scores are lower in MSers Lumbar spine Femoral neck (NS) Dobson et al. Mult Scler. 2012 Nov;18(11):1522-8.
  39. 39. The future? Preventing end-organ damage
  40. 40. Control Multiple sclerosis
  41. 41. Brain atrophy occurs across all stages of the disease De Stefano, et al. Neurology 2010 n= 963 MSers
  42. 42. Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo- controlled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75:43-49.
  43. 43. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves Lower limit of normal Average Upper limit of normal Hypothetical treatment effects
  44. 44. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves MS lower limit MS Average MS Upper limit -5% -30% Hypothetical treatment effects
  45. 45. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM FREEDOMS, 2 years Fingolimod 0.5 mg (n = 356) Placebo (n = 329) *** * ** 60 12 24 Time (months) 0 -0.4 -0.8 -1.2 -1.6 -2.0 −38% vs placebo p<0.001 ChangeinmeanBVfrom baseline(%) TRANSFORMS, 1 year 0 12 Time (months) 0.0 -0.4 -0.6 -1.0 IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 368) −40% vs IFNb-1a IM p<0.001 ***-0.2 -0.8 ChangeinmeanBVfrom baseline(%) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
  46. 46. -1.0% -0.8% -0.6% -0.4% -0.2% 0.0% Years 0-2 -0.82% -0.80% P=0.822† Placebo (N=315) Natalizumab (N=627) Year 0-1* Year 1-2 -0.40% -0.56% -0.43% -0.24% P=0.004† P=0.002† †Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401. AFFIRM Study: natalizumab and brain atrophy Mean(SE)percentagechangeinBPF
  47. 47. -5% -30% 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves MS Average Hypothetical treatment effects
  48. 48. -5% -20% 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves late treatment Hypothetical treatment effects
  49. 49. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves -5% -18% early treatment late treatment Hypothetical treatment effects
  50. 50. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves -5% -11% early very highly- effective treatment late very highly- effective treatment -15% Hypothetical treatment effects
  51. 51. Conclusions 1. Current 1st-line or platform therapies are only moderately effective a. Safe, but are associated with troublesome side effects and poor adherence 2. Escalation therapies (Fingolimod, Natalizumab & Mitoxantrone) a. More effective but potential for more serious adverse effects b. Tools and strategies have been developed to optimise risk:benefit; e.g natalizumab (PLEX & JCV serology) 3. Emerging therapies a. oral agents i. Fingolimod – currently 2nd-line, may promote remyelination; if PPMS trial positive major advantage over other emerging oral therapies (the halo effect) ii. Teriflunomide – 1st-line therapy with a predictable SE profile based on the RA drug leflunomide (the tortoise) iii. BG12 or DMF – 1st-line, higher efficacy, interesting mode of action; ideal for combination therapy (potential combi-tab) iv. Laquinimod – not that effective as an anti-inflammatory, but has the neuroprotective effects (the dark horse, ultimate combi-tab) b. Alemtuzumab, 1st, 2nd or 3rd line; most potent of the DMTs but associated with risks c. Daclizumab (biomarker) and anti-CD20 most exciting of the parenteral therapies in development 4. Patient factors ; risk assessment tools, education and a focus on wellness 5. Neuroprotection – several phase 2 trials currently been undertaken with oral agents 6. New target preventing end-organ damage

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