Top seminars biomarkers in MS

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Top seminars biomarkers in MS

  1. 1. Biomarkers in MS (preventing end-organ damage) Gavin Giovannoni Barts and The London
  2. 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, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.
  3. 3. Why MS biomarkers? • Diagnostic testing • Positive & negative predictive testing • Pathogenesis • Immunology • Aetiology • Disease progression & recovery • Disease heterogeneity • Pharmacovigilance • Monitor disease processes • Prognosis (high vs. low risk patients) • Monitoring effect of therapeutic interventions
  4. 4. MS is an iceberg? Clinical MRI Pathology
  5. 5. Unreported relapses Documented relapses Subclinical relapses focal MRI activity – new T2 and Gd-enhancing T1 lesions Focal gray and white matter lesions not detected by MRI Brain atrophy and spinal fluid neurofilament levels “The MS Iceberg” “Above the surface” “Below the surface”
  6. 6. End-organ damage
  7. 7. ESRF end-stage renal failure
  8. 8. Control Multiple sclerosis
  9. 9. Treatment-effect on atrophy correlates with treatment-effect on disability Sormani et al. Ann Neurol 2014;75:43–49.
  10. 10. Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy 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.
  11. 11. Emerging concepts in MS Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340. NEDD – no evidence of detectable disease (oncology) NEDA - no evident disease activity (msologoy) DAF – disease activity free T2T; treat-2-target (rheumatology) 10976543210 8 0.8 0.6 0.4 0.2 0.0 1.0 Adjuvant (n = 50) Salvage (n = 118) p = 0.002 Survival Time since radiotherapy (years) Biochemical relapse-free survival ZeTo; zero tolerance
  12. 12. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. 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
  13. 13. -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
  14. 14. 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
  15. 15. Reduction in brain atrophy on alemtuzumab
  16. 16. Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5 Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8 AAN 2014 Blitz S65-008 1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre, Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
  17. 17. CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)  Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF  For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%) Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I) Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II) MedianChangeFrom Baseline,%(95%CI) Year No. of Patients 371 367 351 323 % Change from Previous Year – –0.59% –0.25% –0.19% MedianChangeFrom Baseline,%(95%CI) Year 428 414 405 359 – –0.48% –0.22% –0.10% No. of Patients % Change from Previous Year 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 AAN 2014 Blitz S65-008
  18. 18. CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity  The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3 MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium; MRI=magnetic resonance imaging; Y=year No. of Patients 359370 336 356370 325 354369 326 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Gd-enhancing lesion-free New/enlarging T2 lesion-free MRI activity-free % MRI Activity Free in Treatment-Naive Patients (CARE-MS I) % MRI Activity Free in Patients Who Relapsed on Prior Therapy (CARE-MS II) No. of Patients 412421 364 405423 361 Gd-enhancing lesion-free New/enlarging MRI activity-free 402414 361 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 T2 lesion-free  Patients were treated with alemtuzumab 12 mg at baseline and 12 months later  Re-treatment in Year 3 was administered upon recurrence of disease activity  18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3 AAN 2014 Blitz S65-008
  19. 19. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University Early or late? 20 MonitoringTreatmentClinicalOccup&social
  20. 20. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University Early or late? 21 MonitoringTreatmentClinicalOccup&social Dec 2007 Jul 2010 Jul 2013
  21. 21. MS is an iceberg? Clinical MRI Pathology
  22. 22. Pathogenic markers
  23. 23. “Inflammation” “Oligodendrocyte Toxicity & Demyelination” Axonal Toxicity (conduction block) Axonal & Neuronal Loss Gliosis Remyelination & Axonal Recovery “Inflammation” Central Adaptation & Plasticity Key pathological processes in MS
  24. 24. The Shredder - 11,000 to 1 Trapp, et al. NEJM 1998;338:278-85
  25. 25. Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
  26. 26. Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
  27. 27. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis Lyke et al. J Neurol Neurosurg Psychiatry 1998;64:402–404.
  28. 28. Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
  29. 29. Axonal damage in R-MS is markedly reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010; Epub.
  30. 30. -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
  31. 31. Natalizumab treatment of progressive multiple sclerosis reduces inflammation and tissue damage - results of a phase 2A proof-of-concept study ClinicalTrials.gov Identifier: NCT01077466 J. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1
  32. 32. Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage Romme Christensen et al. ECTRIMS 2012.
  33. 33. B aseline Follow -up 0 500 1000 1500 2000 2500 NfL(pg/ml) Cerebrospinal fluid NfL Fingolimod 0.5mg/1.25 mg versus placebo treated patients p<0.001 Fingolimod, n=23 Placebo, n=12 p=0.470 Fingolimod 0.5 mg Fingolimod 1.25 mg Baseline Follow-up Baseline Follow-up Median (pg/ml) 644 321 (-50%) 886 738 (-17%) *Non-parametric Wilcoxon matched pairs test; p value is calculated with inclusion of outliers Dr Jens Khule, ECTRIMS 2013 0 1000 2000 10000 NfL(pg/ml)
  34. 34. 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
  35. 35. Coles et al. J Neurol. 2006 Jan;253(1):98-108. Post-inflammatory neurodegeneration
  36. 36. Axonal damage in R-MS is markedly reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010; Epub.
  37. 37. Gunnarsson et al. Ann Neurol 2010; Epub. CSF NFL
  38. 38. Active tablet Placebo tablet Year 1 Year 2 Year 3 600 MSers 300 MSers 300 MSers
  39. 39. Recruitment Trial Data analysis 6 months 6 months 60 MSers 6 months LP1 LP2 LP3 30 MSers active tablet 30 MSers placebo tablet 2 years 6 months
  40. 40. 600 MSers for 7 years 60 MSers for 2 years 3 LPs = 10x as many trials in a ⅓ of the time
  41. 41. 13% 66% 21% n = 127
  42. 42. MRI Events 1st clinical attack Time (Years) Subclinical disease Inflammation Brain volume loss Neuroaxonal loss DiseaseSeverity SPMSRRMS 1st MRI lesion Relapses CISRIS R-SPMS RIS = 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 SPMS: Natalizumab, Siponimod Late SPMS: SMART STUDY ibudilast, amiloride, riluzole Early SPMS: PROXIMUS oxcarbazepine CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY PPMS PPMS: Fingolimod, Ocrelizumab, Laquinimod
  43. 43. Brain atrophy occurs across all stages of the disease De Stefano, et al. Neurology 2010 n= 963 MSers
  44. 44. MRI Events 1st clinical attack Time (Years) Subclinical disease Inflammation Brain volume loss Neuroaxonal loss DiseaseSeverity SPMSRRMS 1st MRI lesion Relapses CISRIS R-SPMS RIS = 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 SPMS: Natalizumab, Siponimod Late SPMS: SMART STUDY ibudilast, amiloride, riluzole Early SPMS: PROXIMUS oxcarbazepine CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY PPMS PPMS: Fingolimod, Ocrelizumab, Laquinimod
  45. 45. Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7. Therapeutic Lag
  46. 46. Motor system to legs Cerebellar or balance systems BladderTherapeutic window 1 Therapeutic window 2 Therapeutic window 3 Upper limbs Sensory Cognition Vision Etc. Therapeutic window 4 Therapeutic window 5 Therapeutic window 6 Therapeutic window 7 Therapeutic window 8, etc…. Diagnosis of Progressive MS Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems The Asynchronous Progressive MS hypothesis
  47. 47. Control Multiple sclerosis End-organ damage
  48. 48. 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
  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 MS lower limit MS Average MS Upper limit -5% -30% Hypothetical treatment effects
  50. 50. -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
  51. 51. -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
  52. 52. 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
  53. 53. 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
  54. 54. NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target Brain volume loss and CSF neurofilament levels should be included in our definition for NEDA 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
  55. 55. Conclusions • MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc. • Early highly-effective therapy is the only realistic option of preventing end-organ damage • Now an established treatment option in the EU • NEDA (DAF) and T2T are entering the neurology lexicon • Zero tolerance or ZeTo • We need an acceptable working definition of an MS cure • NEDA x 15 years? • Only possible with induction therapies (alemtuzumab, cladribine, BMT, ? anti-CD20) • Is it fair to make people with MS wait 20 years for the outcome of an ongoing experiment?
  56. 56. Acknowledgements • Giovannoni • Sharmilee Gnanapavan • David Baker • Gareth Pryce • Sarah Al-Izki • Sam Jackson • Katie Lidster • Yuti Chernajovsky • Alex Annenkov • Anne Rigby • Michelle Sclanders • Larry Steinman • Peggy Ho • Charles ffrench-Constant • Robin Franklin • Siddharthan Chandran • David Hampton • Ian Duncan • Sam Jackson • Peter Calabresi • Avi Nath • Raj Kapoor • John Zajicek • Doug Brown • UK MS Clinical Trial Network • BioMS • Co-investigators • NABINMS • Affirm study • Care MS 1 & 2 studies • Select trial

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