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Disease Modifying Therapies David Paling - Sheffield Rachel Dorsey-Campbell - Imperial Timeline of treatments Timeline of treatments Lemtrada Cladribine Plegridy Tecfidera Ocrelizumab Aubagio Daclizumab Plegridy Betaferon Avonex

  1. Disease Modifying Therapies David Paling - Sheffield Rachel Dorsey-Campbell - Imperial

  2. Timeline of treatments Timeline of treatments Lemtrada Cladribine Plegridy Tecfidera Ocrelizumab Aubagio Daclizumab Plegridy Betaferon Avonex Copaxone Mitoxantrone Tysabri Fingolimod 1994 2017 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

  3. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  4. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  5. Pathology Pathology of relapsing MS

  6. Treatments 1. Immunomodulation 2. Reduced cell proliferation IFN Beta/ GA Teriflunomide DMF 3. Targeted cell lysis Alemtuzumab Cladribine 4. Anti Migratory Ocrelizumab Fingolimod AHSCT Natalizumab

  7. Mechanisms of action Cell lysis Immuno Modulatory AHSCT Dimethyl fumarate IFNs Glatiramer acetate CD20 Alemtuzumab Modulation of Activation of nrf 2 Activation of CD52 Lysis of mature Th1:Th2 balance IFN-response genes responsive genes B and T cells Cladribine Ocrelizumab BBB Anti-migratory Reduced proliferation Lymph Limits pyrimidine Teriflunomide node availability for Fingolimod Natalizumab rapid cell division S1P1 α 4 - T integrin B Periphery CNS B, B cell; BBB, blood–brain barrier; CNS, central nervous system; IFN, interferon; IL2, interleukin 2; nrf 2, nuclear factor)-like 2; S1P1, sphingosine-1-phosphate receptor 1; T, T cell; Th, T-helper cell Adapted from: 1. Loleit V et al. Curr Pharm Biotechnol. 2014;15:276–96; 2. Scannevin R et al . J Pharmacol Exp Ther. 2012;341:274–84; 3. Chen H et al. J Clin Invest. 2014;124:2188–92. Heckler et al. Mol Neurobiol. 2013;48:737-56

  8. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  9. Mode of administration

  10. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  11. Start Betainterferon May 1 2006 2007 Apr Jun Aug Oct Dec Feb Apr Apr 1 Nov 2 May 1 Screening Blood Tests Blood Test Blood Test Start Teriflunamide Blood Pressure Blood Pressure Blood Pressure Blood Pressure May 1 Aug 1 Nov 1 Feb 1 May 1 2016 2017 Apr Jun Aug Oct Dec Feb Apr Apr 1 Screening Blood Tests 14 Blood Tests in one year Graves Disease Renal Failure Hepatic Failure TTP

  12. Monitoring Blood tests • None – GA • At the time of infusions – 1 monthly Natalizumab (although other MRI monitoring) – 6 monthly Ocrelizumab • 3-6 months – DMF, Beta interferons, Cladribine • 1 monthly – Alemtuzumab • Every 2 weeks for 6 months – Teriflunamide

  14. Monitoring

  15. MS DMT monitoring burden

  16. Admin Support

  17. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  18. Pregnancy

  21. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  22. Side effects

  23. Side effects

  24. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  25. PML

  26. PML Mortality 30 25 20 9 fold 15 10 5 0 Symptoms Asymptomatic Mortality

  27. PML

  28. PML

  30. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  31. Efficacy

  32. Treatments for MS AHSCT Alemtuzumab Natalizumab Cladribine Ocrelizumab Fingolimod Fumarate (BG-12) BIFN Teriflunomide GA Treatment burden

  33. Less effective Less More effective Risk vs Benefit dangerous Restricted indication 2 relapses in 2 years All active MS Copaxone Alemtuzumab Fingolimod Interferon Beta Natalizumab Ocrelizumab Cladribine Dimethyl Fumarate AHSCT Teriflunamide Natalizumab JCV+ Mitoxantrone More dangerous

  34. Decision on treatments • Mechanism of action • Mode of administration • Monitoring and drug frequency • Pregnancy and breast feeding • Side effects • PML • Efficacy • Sequencing vs Escalation

  35. Induction vs escalation

  36. Making treatment decision Risk and burden of treatment Risk of MS Age Plans for pregnancy Method of Administration Severity of relapses Frequency of administration Associated neurological disability Occupation MRI disease activity Other medical conditions Oligoclonal Bands Poor mobility (ulcers / chest infections)

  37. Evidence Base Number of papers in PubMed per year for multiple sclerosis with drug name in the title 140 120 100 80 60 40 20 0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Glatiramer Acetate and Beta Interferon Natalizumab Fingolimod Di Methly Fumarate Alemtuzumab Cladribine

  38. Evidence Base Number of papers in PubMed per year for multiple sclerosis with Beta Interferon, Glatiramer, Natalizumab, Fingolimod, Fumarate, or Cladribine in the title 350 300 250 200 150 100 50 0 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Total Does not include Ocrelizumab, Siponimod, Posenimod, Ofatunumab

  39. 2016/17 Spend on DMTs £249,417,164 5000 physiotherapists 150 per MS centre 15 new schools Courtesy of Prof Coles, Cambridge

  40. Oh Dear YES YES - BUT yes no NO PHEW

  42. DMT algorithm • MDT – 2 neurologists, MS nurse – Pharmacists, Radiology advice

  43. Clinical Case 1 Aug 2015 Aug 2014 Weakness left leg R ON VA 2/6 2015 2016 2014 Level at T10 Oct 15: Sensory signs EDSS 2.0 Steroids Steroids MRI normal MRI lesions

  44. Clinical case 1

  45. Clinical Case 1 • Chose DMF • No need for MDT • Blueteq form

  46. Case 2 Aug 2015 Nov 16 Aug 2014 Weakness left leg Incoordination R ON VA 2/6 2015 2016 2017 2014 2018 Level at T10 EDSS 2.0 Oct 15: Sensory signs Oct 16: EDSS 2.0 Well EDSS 0 Steroids Dimethyl Fumarate Steroids Steroids MRI normal MRI lesions MRI new lesions and contrast enhancing lesions

  47. Case 2

  48. Case 2 Aug 2014 Aug 2015 Nov 16 R ON VA 2/6 Weakness left leg Incoordination 2015 2016 2017 2014 2018 MRI normal Sexual dysfunction EDSS 2.0 Feb 17 Aug 17 Oct 15: Oct 16: Ocrelizumab EDSS 0 Sensory changes leg Well EDSS 1.5 EDSS 2.0 EDSS 0 Steroids Dimethyl Fumarate Ocrelizumab Steroids Steroids

  49. Case 2 Odds ratios of relapses over three years based upon disease activity in the first year 12 * 10 8 6 4 2 0 No relapses or new lesions Relapses without new lesions New lesions without relapses Relapses with new lesions Odds ratio of relapses in next 3 years Rio et al. Multiple Sclerosis 2009;15:848

  50. If that doesn’t work

  51. Disease Modifying Therapies David Paling - Sheffield Rachel Dorsey-Campbell - Imperial

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