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MS Treatment and the prevention of end organ damage

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  • 1.MS treatment and preservation of end-organ damage in MS Gavin Giovannoni Barts and The London
  • 2. .
  • 3. Thomas Blizard Curling 1811 – 1888 • Assistant-surgeon to The Royal London Hospital in 1883 and full surgeon in 1849 • President of the Royal College of Surgeons • Seminal work on tetanus, winning the Jacksonian prize for his work • Famous for his skill in treating diseases of the testes and rectum
  • 4. ESRF end-stage renal failure
  • 5. Does the brain fail in MS?
  • 6. Should multiple sclerosis be redefined as a dementia?
  • 7. www.multiple-sclerosis-research.org
  • 8. 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 
  • 9. Occupational functioningPfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
  • 10. At what level of physical disability does unemployment occur?Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
  • 11. Cognition in early multiple sclerosis 60%57% 40%MSers failing ≥ 2 cognitive tests20%p < 0.00010%7%-20%CISers n = 40Healthy Controls n = 30Deficits were found mainly in memory, speed of information processing, attention and executive functioning.Feuillet et al. Mult Scler. 2007.
  • 12. 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 therefore a dementia.”
  • 13. What is the pathological substrate of MS dementia?
  • 14. 11,000 to 1Trapp, et al. NEJM 1998;338:278-85
  • 15. ControlMultiple sclerosis
  • 16. Brain atrophy occurs across all stages of the disease n= 963 MSersDe Stefano, et al. Neurology 2010
  • 17. Hypothetical treatment effectsBrain Volume (mL)Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750Lower limit of normal Average Upper limit of normal303540455055 Age (years)6065707580
  • 18. Hypothetical treatment effectsBrain Volume (mL)Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750-5%-30%MS lower limitMS Average MS Upper limit 303540455055 Age (years)6065707580
  • 19. Laquinimod: Percent of brain volume change from baseline to month 24 Placebo (n = 1006) Laquinimod 0.6 mg (n = 984)POOLED% Change From Baseline0-0.4-0.8-0.834 -1.188-1.230% P<0.0001 -1.6Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007
  • 20. BRAVO: reduced rate of brain volume lossPLACEBO0 -0.2 -0.4 Percent Brain Volume -0.6 Change* (Months 0-24) -0.8 -1 -1.2 -1.4LAQUINIMOD 0.6mgAVONEX® 30mcg27.5% Reduction P<0.0001-1.14%-0.83%-1.25%-27.4% Improvement P<0.0001 +9% Deterioration P=0.14*Adjusted for baseline characteristics. Reference: 1. Vollmer T et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in 35 Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507.
  • 21. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM TRANSFORMS, 1 yearFREEDOMS, 2 yearsTime (months)-0.2 -0.412*** −40% vs IFNb-1a IM p<0.001-0.6 -0.8-1.0Change in mean BV from baseline (%)Change in mean BV from baseline (%)0 0.0Time (months) 0 6 12 024**-0.4-0.8 -1.2**** −38% vs placebo p<0.001-1.6-2.0Fingolimod 0.5 mg (n = 368) IFNb-1a IM (n = 359)Fingolimod 0.5 mg (n = 356) Placebo (n = 329)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
  • 22. AFFIRM Study: natalizumab and brain atrophyMean (SE) percentage change in BPF0.0%Years 0-2Year 0-1*-0.2%-0.24% -0.4% -0.40% -0.6%-0.43% P=0.004†-0.56%P=0.002† -0.8%-0.80% -0.82% -1.0%P=0.822† Placebo (N=315)†DifferenceYear 1-2Natalizumab (N=627)between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
  • 23. Hypothetical treatment effectsBrain Volume (mL)Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750-5%-30%MS Average303540455055 Age (years)6065707580
  • 24. Hypothetical treatment effectsBrain Volume (mL)Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750-5% -20%late treatment303540455055 Age (years)6065707580
  • 25. Hypothetical treatment effectsBrain Volume (mL)Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750-5% -18% early treatmentlate treatment303540455055 Age (years)6065707580
  • 26. Hypothetical treatment effectsBrain Volume (mL)Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750-5% early very highlyeffective treatment3035late very highlyeffective treatment40455055 Age (years)6065707580-11% -15%
  • 27. Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, CombinedMeta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebocontrolled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75:43-49.
  • 28. Defining the window of opportunity to treat MS?
  • 29. Post-inflammatory neurodegenerationColes et al. J Neurol. 2006 Jan;253(1):98-108.
  • 30. 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 alive100%95% IFNB-1b 250 µg 90%Placebo85% 80% 75%HR=0.532 (95% CI: 0.314–0.902) 46.8% reduction in hazard ratio Log rank, P=0.017370%65% 0 At risk: IFNB-1b 250 µg Placebo124 123246124 1208 10 12 14 16 18 20 22 Time (Years) 121 117118 109104 88Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.
  • 31. Theoretical model: treat early and effectivelyNatural course of diseaseDisabilityLater treatmentLater interventionTreatment at diagnosisIntervention at diagnosisTime Disease Onset
  • 32. Defining your treatment strategy?
  • 33. What is your treatment philosophy? maintenance-escalation vs. inductionsurvival analysis“hit hard and early ”MS is an autoimmune disease hypothesis15-20 year experiment
  • 34. Can you name me any diseases that you don’t treat early?
  • 35. ConclusionTime is Brain
  • 36. 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 therefore a preventable dementia.”
  • 37. Stigmatizing
  • 38. Stigmatizing
  • 39. Brain Health
  • 40. 300 MSersYear 1Placebo tabletYear 2600 MSers300 MSersActive tabletYear 3
  • 41. Spinal fluid neurofilament levelsPetzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  • 42. Axonal damage in relapsing MS is markedly reduced by natalizumab=Gunnarsson et al. Ann Neurol 2010; Epub.
  • 43. 30 MSers placebo tablet6 months6 months 6 months6 months60 MSers30 MSers active tabletLP1 RecruitmentLP2 Trial2 yearsLP3 Data analysis
  • 44. 600 MSers for 7 years60 MSers for 2 years3 LPs = 10x as many trials in a ⅓ of the time
  • 45. n = 127 66%21% 13%
  • 46. PPMSRISRRMSCISR-SPMSSPMSDisease SeverityInflammation Neuroaxonal lossSubclinical diseaseBrain volume loss1st clinical attackRelapses1st MRI lesionMRI Events Time (Years) PPMS: Fingolimod, Ocrelizumab, Laquinimod SPMS: Natalizumab, SiponimodCIS: PHENYTOINRRMS: ? DE-FLAMES STUDYEarly SPMS: PROXIMUS oxcarbazepineLate SPMS: SMART STUDY ibudilast, amiloride, riluzoleRIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS
  • 47. PPMSRISRRMSCISR-SPMSSPMSDisease SeverityInflammation Neuroaxonal lossSubclinical diseaseBrain volume loss1st clinical attackRelapses1st MRI lesionMRI Events Time (Years) PPMS: Fingolimod, Ocrelizumab, Laquinimod SPMS: Natalizumab, SiponimodCIS: PHENYTOINRRMS: ? DE-FLAMES STUDYEarly SPMS: PROXIMUS oxcarbazepineLate SPMS: SMART STUDY ibudilast, amiloride, riluzoleRIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS
  • 48. THANK YOU FOR LISTENINGI would like to thank my team for making things happen!
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