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  • 1. Progressive MS Trials Gavin Giovannoni Barts and The London
  • 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 the pharmaceutical companies and collaborators for making available their data and slides for this presentation.
  • 3. The current dogma wrong  “autoimmune endophenotype” Gd-enhancement immune activation innate and adaptive responses Clinical Recovery axonal plasticity & remyelination - biology  T2 & T1 lesions  BBB breakdown Clinical Attack focal inflammation   Acute axonal transection and loss release of soluble markers - clinical outcomes - biomarkers  oligodendrocyte toxicity & demyelination brain & spinal cord atrophy   delayed neuroaxonal loss and gliosis  Disease Progression
  • 4. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108.
  • 5. The current dogma wrong “autoimmune endophenotype” immune activation innate and adaptive responses Clinical Recovery axonal plasticity & remyelination - biology   T2 & T1 lesions Gd-enhancement  BBB breakdown Clinical Attack focal inflammation  ? Acute axonal transection and loss release of soluble markers - clinical outcomes - biomarkers  oligodendrocyte toxicity & demyelination brain & spinal cord atrophy ? ? delayed neuroaxonal loss and gliosis ? Disease Progression
  • 6. Brain atrophy
  • 7. Brain atrophy: the pathological integrator Control Multiple sclerosis
  • 8. Brain atrophy occurs across all stages of the disease n= 963 MSers De Stefano, et al. Neurology 2010
  • 9. Treatment effect on brain atrophy correlates with treatment effect on disability in MS Sormani et al. Ann Neurol 2013, In Press.
  • 10. Treatment effect on brain atrophy correlates with treatment effect on disability in MS Sormani et al. Ann Neurol 2013, In Press.
  • 11. Rationale for sodium channel blockade Bechtold et al. Ann Neurol 2004;55:607–616 Videos courtesy Hugh Bostock, Inst. Neurol., UCL Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
  • 12. Kapoor et al. Lancet Neurol 2010; 9: 681–88.
  • 13. Gnanapavan et al. PLoS One. 2013 Aug 1;8(8):e70019.
  • 14. MS-STAT trial: high dose oral simvastatin in secondary progressive MS change whole brain volume (%/yr) BSI Boundary Shift Integral 1. Whole brain atrophy (mean Δ) 2. EDSS 3. MSIS-29 CTN:NCT00647348 EUDRACT NUMBER 2006-006347-31 = -0.254%/year [95% CI -0.423 to -0.085], = -0.254 [-0.464 to -0.069], = -4.78 [-9.39 to -0.02], p=0.003 p<0.01 p<0.05 Chataway et al. in press 2013.
  • 15. EDSS
  • 16. Secondary progressive EAE 4.5 4.0 Neuroprotection Mean Clinical Score ± SEM 3.5 3.0 2.5 2.0 1.5 Vehicle Cannabinoids 1.0 0.5 TREATMENT 0.0 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Time (Days) Pryce et al. Brain 2003;126:2191-202.
  • 17. Cannabinoid use in progressive inflammatory brain disease: CUPID study 1.0 P(EDSS progression) 0.8 0.6 0.4 0.2 Treatment group Active Placebo 0.0 0 200 400 600 800 1000 1200 Time to EDSS progression (days) Slides courtesy of Prof. John Zajicek
  • 18. Cannabinoid use in progressive inflammatory brain disease: CUPID study 1.0 P(EDSS progression) 0.8 0.6 0.4 Baseline EDSS score 4 4.5 5 5.5 6 6.5 0.2 0.0 0 200 400 600 800 1000 1200 Time to EDSS progression (days) Slides courtesy of Prof. John Zajicek
  • 19. Cannabinoid use in progressive inflammatory brain disease: CUPID study 1.0 P(EDSS progression) 0.8 0.6 0.4 0.2 Treatment group Log rank test P = 0.01 Active Placebo 0.0 0 200 400 600 800 1000 1200 Time to EDSS progression (days) Slides courtesy of Prof. John Zajicek
  • 20. Placebo tablet 300 MS’ers Year 1 Year 2 600 MS’ers 300 MS’ers Active tablet Year 3
  • 21. Interferon beta-1b for the treatment of primary progressive MS 5-year clinical trial follow-up Year +1 Year +2 IFNbeta-1b Placebo Year +3 Year +4 Year +5 No treatment Tur et al. Arch Neurol. 2011;68(11):1421-1427.
  • 22. EDSS / MSFC / cognition / brain atrophy Delayed effect on disability progression from IFNbeta treatment in years 1 & 2 Progression from inflammation in years -2 and -1 Progression from inflammation in years +1 and +2. Note PPMSers treated with IFNbeta in years +1 and +2 do better in years +3 and + 4 due to the delayed effect of suppressing inflammation. Year -2 Year -1 Year +1 Year +2 Year +3 Year +4 IFNbeta-1b No treatment No treatment Placebo Progression from inflammation in years +3. Note the slopes are parallel because IFNbeta was stopped after year +2 Year +5
  • 23. Neurofilaments
  • 24. Spinal fluid neurofilament levels Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  • 25. CSF NFL Gunnarsson et al. Ann Neurol 2010; Epub.
  • 26. 600 MS’ers for 7 years 60 MS’ers for 2 years 3 LPs = 10x as many trials in a ⅓ of the time
  • 27. OCT
  • 28. Acute mono-focal lesion Baseline 52 weeks 38 year old woman with left optic neuritis sTE fFLAIR images Hickman et al. Neuroradiology 2001;43:123-8. Trapp et al. N Engl J Med 1998.
  • 29. Acute neuroprotection
  • 30. Immunologic penumbra Ischemic penumbra Trapp et al. NEJM 1998 CFMA Induces Neuroprotection in EAE Period of Daily Treatment Mean Neurological Score ± SEM 4.0 Vehicle No Immunosuppression Evident Hindlimb Paralysis CFMA D33-D48 3.5 Hindlimb Paresis 3.0 2.5 300 Measure of Motor Co-ordination *** 250 1.5 200 Time of on Accelerating RotaRod (s) 1.0 Neuroprotection ROTAROD ACTIVITY Impaired Right Reflex Tail Paralysis Neuroprotection 2.0 150 100 50 0.5 Tail Paresis 0 Post- Relapse (Day 48) Pre-Treatment (Day 27) 0.0 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Time Post-Disease Induction (days). Al-Izki et al. 2013 In Press
  • 31. Adaptive design
  • 32. UK Clinical Trial Network (CTN): phase 3 adaptive design primary outcome EDSS progression SMART STUDY Ibudilast Riluzole Amiloride vs. Placebo
  • 33. Targeting pathology
  • 34. B cell follicle-like structures and disease progression Magliozzi et al. Brain (2007), 130, 1089^1104 Schmierer-Lab, Blizard Institute
  • 35. Rituximab in PPMS results of a randomized double-blind placebo-controlled trial. The OLYMPUS STUDY Hawker et al. Ann Neurol 2009;66:460–471.
  • 36. Ocrelizumab phase 2 extension study: reduction in Gd-enhancing T1 lesions by OCR is maintained through 144 Weeks *p<0.0001 for both OCR doses vs placebo, N (for primary analysis): Placebo=54, OCR 600 mg=51, OCR 1000 mg=52, IFN-β1a=522 aPatients who withdrew during earlier treatment cycles were also included in the follow-up periods 1. Kappos L, et al. Lancet. 2011;378(9805):1779–87; 2. Kappos L, et al. Abstract presented (P362) ECTRIMS 2012 , October 12
  • 37. The therapeutic pyramid: combination therapies NEURO RESTORATION REMYELINATION NEUROPROTECTION ANTI-INFLAMMATORY
  • 38. Existing strategies or drugs in progressive MS
  • 39. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM TRANSFORMS, 1 year FREEDOMS, 2 years Time (months) -0.2 -0.4 12 *** −40% vs IFNb-1a IM p<0.001 -0.6 -0.8 -1.0 Change in mean BV from baseline (%) Change in mean BV from baseline (%) 0 0.0 Time (months) 0 6 12 0 24 ** -0.4 -0.8 -1.2 * *** −38% vs placebo p<0.001 -1.6 -2.0 Fingolimod 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
  • 40. AFFIRM: natalizumab and brain atrophy Mean (SE) percentage change in BPF 0.0% Years 0-2 Year 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) †Difference Year 1-2 Natalizumab (N=627) between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
  • 41. Other potential drugs for progressive MS
  • 42. BRAVO: reduced rate of brain volume loss PLACEBO 0 -0.2 -0.4 Percent Brain Volume -0.6 Change* (Months 0-24) -0.8 -1 -1.2 -1.4 LAQUINIMOD 0.6mg AVONEX® 30mcg 27.5% 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 Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507. 44
  • 43. Laquinimod: Percent of brain volume change from baseline to month 24 Placebo (n = 1006) Laquinimod 0.6 mg (n = 984) POOLED % Change From Baseline 0 -0.4 -0.8 -0.834 -1.188 -1.2 30% P<0.0001 -1.6 Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007
  • 44. BG12 or DMF Nrf2 signaling pathway regulates cellular response to oxidative stress Cell Body O O O O Nrf2 Nrf2 Keap1 DMF (BG00012) ARE Maf Jun ATF4 • Detoxification enzymes • Antioxidant enzymes • NADPH-generating enzymes (NQ01) • GSH biosynthesis enzymes • Chaperones • Ubiquitination / proteasome Keap1 Nucleus Kappos L et al. Lancet 2008; 372:1463–72 • Detoxification • Normalization of energy metabolism • Repair / degradation of damaged proteins
  • 45. BG12: brain atrophy in the DEFINE study Arnold et al. ECTRIMS 2012, Lyon.
  • 46. Alemtuzumab: brain atrophy in the CARE-MS I & II studies
  • 47. Daclizumab HYP in RRMS: SELECTION extension study Giovannoni et al. AAN 2013, San Diego.
  • 48. Brain atrophy: daclizumab SELECTION study Radue et al. ECTRIMS 2013, Copenhagen.
  • 49. 1) OCT 2) CSF NF 3) Adaptive Design
  • 50. Conclusions • Shift in paradigm to prevention of progressive MS • • Treatment pyramid • • PPMS – fingolimod, ocrelizumab SPMS – natalizumab, siponimod More in the pipeline Several phase 2 trials in progress What to do about the repurposing of existing drugs? • • Present from the outset; CIS and the pre-symptomatic stage Brain atrophy and other biomarkers, in particular CSF neurofilament levels, are very promising Time course of neurodegeneration needs to be better defined; may need 4-5 year studies Combination therapy trials needed; for example alemtuzumab and laquinimod Large number of targets Several phase 3 studies underway • • • • • anti-inflammatory – neuroprotection – remyelination - neurorestoration Neurodegeneration • • • • • • Could early highly effective treatments, particularly induction therapies, prevent SPMS? Big Pharma Alternative Manage expectations of people with MS
  • 51. WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS? 3 2 1 53 www.ms-res.org
  • 52. Acknowledgements • Giovannoni • • Sharmilee Gnanapavan David Baker • • • Gareth Pryce Sam Jackson Yuti Chernajovsky Alex Annenkov • Anne Rigby • Michelle Sclanders Larry Steinman • • • Katie Lidster • • • Sarah Al-Izki • • • 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
  • 53. Theoretical model: treat early and effectively Time is brain Natural course of disease Disability Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis Time Disease Onset
  • 54. The current dogma RIS RRMS CIS Disease Severity Inflammation Axonal loss Brain volume Time (Years) MRI Events Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17. SPMS