Broken promises?

1,271 views

Published on

Promise 2010 update to the NMSS Southern California Chapter - annual golden circle fund raising event.

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,271
On SlideShare
0
From Embeds
0
Number of Embeds
651
Actions
Shares
0
Downloads
8
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Broken promises?

  1. 1. Neuroprotective strategies in MS: addressing an unmet need PROMISE 2010 UPDATE Gavin GiovannoniBarts and The London School of Medicine and Dentistry
  2. 2. WWW.MS-RES.ORG
  3. 3. Broken promises?
  4. 4. Our “Promise 2010” goals1. “We will develop and validate effective experimental models for studying theintricate relationship between inflammation, neuroprotection andneurorestoration.”2. “These experimental models will then be used to study specificneuroprotective and neurorestorative therapeutic strategies.“3. “In parallel we will develop novel clinical trial designs aimed at studying focalnervous system repair and more global neuroprotection strategies in peoplewith MS.”4. “Using both the experimental models and clinical studies in subjects with MSwe will identify biomarkers to non-invasively monitor nervous system repair andprotection.”
  5. 5. Goal 41. “We will develop and validate effective experimental models for studying theintricate relationship between inflammation, neuroprotection andneurorestoration.”2. “These experimental models will then be used to study specificneuroprotective and neurorestorative therapeutic strategies.“3. “In parallel we will develop novel clinical trial designs aimed at studying focalnervous system repair and more global neuroprotection strategies in peoplewith MS.”4. “Using both the experimental models and clinical studies in subjects with MSwe will identify biomarkers to non-invasively monitor nervous system repair andprotection.”
  6. 6. Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
  7. 7. Rationale for sodium channel blockade Bechtold et al. Ann Neurol 2004;55:607–616
  8. 8. Kapoor et al. Lancet Neurol 2010; 9: 681–88.
  9. 9. Kapoor et al. Lancet Neurol 2010; 9: 681–88.
  10. 10. Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
  11. 11. Spinal fluid neurofilament levels Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  12. 12. Spinal fluid neurofilament levels Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  13. 13. Blood neurofilament levels & 25-foot walk (secs) 100 90 80 70% complting test 60 50 40 30 20 NfH Absent 10 Below median Above median 0 0 30 60 90 120 150 180 210 240 Seconds Gnanapavan et al. Submitted 2012.
  14. 14. New trial designAre you prepared to have 3 LPs?
  15. 15. 300 MSers Placebo tablet Year 1 Year 2 Year 3600 MSers 300 MSers Active tablet
  16. 16. 300 MSersYear 1 Year 2 Year 6 Year 7 Year 3 Year 4 Year 5 600 MSers 300 MSers Recruitment Trial Data analysis Registration 7 years
  17. 17. Axonal damage in relapsing MS is markedly reduced by natalizumab = Gunnarsson et al. Ann Neurol 2010; Epub.
  18. 18. Natalizumab treatment of progressive multiple sclerosis reduces inflammation and tissue damage - results of a phase 2A proof-of-concept studyJ. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1 ClinicalTrials.gov Identifier: NCT01077466
  19. 19. Results: Secondary endpointsCSF markers of axonal damage and demyelination:
  20. 20. 30 MSers placebo tablet6 months 6 months 6 months 6 months60 MSers 30 MSers active tablet LP1 LP2 LP3 Recruitment Trial Data analysis 2 years
  21. 21. 600 MSers for 7 years 60 MSers for 2 years3 LPs = 10x as many trials in a ⅓ of the time
  22. 22. n = 12766% 21% 13%
  23. 23. The window of therapeutic opportunity in multiple sclerosis Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  24. 24. Goal 11. “We will develop and validate effective experimental models for studying theintricate relationship between inflammation, neuroprotection andneurorestoration.”2. “These experimental models will then be used to study specificneuroprotective and neurorestorative therapeutic strategies.“3. “In parallel we will develop novel clinical trial designs aimed at studying focalnervous system repair and more global neuroprotection strategies in peoplewith MS.”4. “Using both the experimental models and clinical studies in subjects with MSwe will identify biomarkers to non-invasively monitor nervous system repair andprotection.”
  25. 25. Induction and assessment of chronic relapsing experimental allergic Clinical Score encephalomyelitis Day 0 Day 7 0 Normal (1) 1 Limp tail RemissionSpinal cord homogenate in Freund’s complete adjuvant in ABH 2 Impaired righting reflex 3 partial paralysis 4 hindlimb paralysis 5 Moribund Slide courtesy David Baker
  26. 26. Average disease course RELAPSE 3 CHRONICACUTE RELAPSE 1 RELAPSE 2 Slide courtesy Sam Jackson & Ian Duncan.
  27. 27. Post-inflammatory SPMS ctrl Day 29 Day 58Day 105 Early-tolerisation Late-tolerisation Slide courtesy David Hampton
  28. 28. T cell deletion prior to intravenous antigen induces tolerance that inhibits EAE
  29. 29. Prevention of relapsing CREAE after three paralytic episodesdoes not inhibit secondary progression and deterioration of mobility Pryce et al. J Neuroimmunol 2005.
  30. 30. Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.
  31. 31. Acute mono-focal lesion Baseline 52 weeks 38 year old woman with left optic neuritis Trapp et al. N Engl J Med 1998. sTE fFLAIR imagesHickman et al. Neuroradiology 2001;43:123-8.
  32. 32. NEUROPROTECTIVE STRATEGIES IMMUNE-DEPENDENT NEURODEGENERATION CFM6104 induces neuroprotection in optic neuritis (nerve content) 1900 P<0.01 1800 Reduced Nerve DamageMean retina cell density (cells/mm2) 1700 1600 1500 1400 1300 1200 1100 1000 Normal mouse OPTIC NEURITIS OPTIC NEURITIS + + Vehicle CFM6104
  33. 33. Goal 31. “We will develop and validate effective experimental models for studying theintricate relationship between inflammation, neuroprotection andneurorestoration.”2. “These experimental models will then be used to study specificneuroprotective and neurorestorative therapeutic strategies.“3. “In parallel we will develop novel clinical trial designs aimed at studying focalnervous system repair and more global neuroprotection strategies in peoplewith MS.”4. “Using both the experimental models and clinical studies in subjects with MSwe will identify biomarkers to non-invasively monitor nervous system repair andprotection.”
  34. 34. Acute neuroprotection
  35. 35. 300 MSersYear 1 Year 2 Year 6 Year 7 Year 3 Year 4 Year 5 600 MSers 300 MSers Recruitment Trial Data analysis Registration 7 years
  36. 36. UK Clinical Trial Network (CTN): phase 3 adaptive design primary outcome EDSS progression futility EDSS analysis 1° outcome Placebo  Drug A  Drug B ? Drug C  Drug D  2yrs 3yrs 7yrs
  37. 37. CSF NFLGunnarsson et al. Ann Neurol 2010; Epub.
  38. 38. Goal 21. “We will develop and validate effective experimental models for studying theintricate relationship between inflammation, neuroprotection andneurorestoration.”2. “These experimental models will then be used to study specificneuroprotective and neurorestorative therapeutic strategies.“3. “In parallel we will develop novel clinical trial designs aimed at studying focalnervous system repair and more global neuroprotection strategies in peoplewith MS.”4. “Using both the experimental models and clinical studies in subjects with MSwe will identify biomarkers to non-invasively monitor nervous system repair andprotection.”
  39. 39. Secondary progressive EAE 4.5 4.0 Neuroprotection 3.5Mean Clinical Score ± SEM 3.0 2.5 2.0 1.5 1.0 Vehicle Cannabinoids 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.
  40. 40. 1.0 0.8P(EDSS progression) 0.6 0.4 0.2 Treatment group Active 0.0 Placebo 0 200 400 600 800 1000 1200 Time to EDSS progression (days)
  41. 41. 1.0 0.8P(EDSS progression) 0.6 0.4 Baseline EDSS score 4 4.5 0.2 5 5.5 6 0.0 6.5 0 200 400 600 800 1000 1200 Time to EDSS progression (days)
  42. 42. X 1.0 0.8P(EDSS progression) X 0.6 0.4 0.2 Treatment group Log rank test P = 0.01 Active 0.0 Placebo 0 200 400 600 800 1000 1200 Time to EDSS progression (days)
  43. 43. Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) 300 MSers Year 1 Year 2 Year 6 Year 7 Year 3 Year 4 Year 5 600 MSers 300 MSers Recruitment Trial Data analysis Registration Not 7 years, but 10 years
  44. 44. Managing expectations
  45. 45. Key milestones in the development of Fingolimod1992: Fingolimod (FTY720) first synthesized by Japanese scientists1997: Fingolimod in-licensed by Novartis for clinical development1998: First studies in man (Phase 1 trials) and subsequent start of transplantation trials2003: Start of MS Phase II trialJune 2005: Presentation of Phase II study results followed by publication in NEJM 2006Jan 2006: Start of Phase III FREEDOMS study in RRMSMay 2006: Start of Phase III TRANSFORMS study in RRMSJune 2006: Start of Phase III FREEDOMS II study in RRMSJuly 2008: Start of Phase III INFORMS trial to assess suitability for treatment of PPMSDec 2008: Release of TRANSFORMS study results and presentation at AAN April 2009Sep 2009: Release of FREEDOMS study results and presentation at AAN April 2010Dec 2009: Regulatory submission to FDA and EMA (ROW submissions in Q1 2010)Feb 2010: Results of Phase III TRANSFORMS & FREEDOMS studies published in NEJMSep 2010: Approval by Russian Health AuthoritySep 2010: Approval by the US FDA for relapsing MS ? 2015: ? approval by the US FDA for PPMS
  46. 46. Broken promises?
  47. 47. Did we achieve our “Promise 2010” goals?1. “We will develop and validate effective experimental models for studying theintricate relationship between inflammation, neuroprotection andneurorestoration.”2. “These experimental models will then be used to study specificneuroprotective and neurorestorative therapeutic strategies.“3. “In parallel we will develop novel clinical trial designs aimed at studying focalnervous system repair and more global neuroprotection strategies in peoplewith MS.”4. “Using both the experimental models and clinical studies in subjects with MSwe will identify biomarkers to non-invasively monitor nervous system repair andprotection.”
  48. 48. Follow-on grants – clinical trials1) OCT2) CSF NF3) Adaptive Design
  49. 49. Follow-on grants – basic science or preclinical1. David Selwood & David Baker, NMSS FastForward: Development of a selective cyclophilin D (CyP-D) blocker as a new MS drug.2. David Baker, Yuti Chernajovsky, Robin Franklin, Charles ffrench-Constant, Siddharthan Chandran. NMSS. Engineered precursors as a delivery mechanism for neuroprotective therapies.3. David Baker, Pete Coffey, Gianvito Martino: UK Stem cell Foundation & MS Society. Transplanting neural stem cells in optic neuritis.
  50. 50. MS-STAT trial High dose oral Simvastatin in Secondary Progressive Multiple Sclerosis Jeremy Chataway for the MS-STAT CollaboratorsCTN:NCT00647348EUDRACT NUMBER 2006-006347-31
  51. 51. Segmentation Whole brain segmentation 3D rendered image in Native Space Whole brain volumes generated• Then repeat and screening scans are registered using a 12dof affine registration. – Linear transformation (rotation, translation, scaling and shear) to spatially align repeat scan to the baseline scan.• This registration step allows for the automatic quantification of longitudinal changes with the BSI (Boundary Shift Integral).
  52. 52. Change whole brain volume (%/yr)
  53. 53. Secondary outcomes: DisabilityOutcome Mean (SD) Mean (SD) Difference in means placebo simvastatin (95% CI)EDSS 6.35 (0.83) 5.93 (1.11) -0.254 (-0.464 to -0.069)(score 0 to 10) MSIS total 76.1 (16.3) 70.1 (15.6) -4.78 (-9.39 to -0.02)(score 29 to 116) MSIS physical 56.3 (11.8) 51.7 (11.4) -3.73 (-7.18 to -0.28)(score 20 to 80) MSIS psychological 19.8 (6.0) 18.3 (5.8) -1.09 (-2.83 to 0.84)(score 9 to 36)MSFC Z score -1.21 (2.59) -0.78 (2.06) 0.289 (-0.333 to 0.961)MSFC walk 1.55 (1.19) 1.83 (1.61) 0.085 (-0.249 to 0.533)(speed ft/s)MSFC peg test 0.030 (0.014) 0.033 (0.010) 0.002 (-0.001 to 0.004)(1/s)MSFC PASAT 35.2 (18.0) 38.3 (15.4) 4.45 (-0.11 to 8.84)(score 0 to 60)Model adjusting for minimisation variables and baseline
  54. 54. Where to next?
  55. 55. Acknowledgements• Giovannoni • Charles ffrench-Constant • Robin Franklin • Sharmilee Gnanapavan • Siddharthan Chandran• David Baker • David Hampton • Gareth Pryce • Ian Duncan • Sarah Al-Izki • Sam Jackson• Sam Jackson • Peter Calabresi • Katie Lidster • Avi Nath• Yuti Chernajovsky • Raj Kapoor • Alex Annenkov • Jeremy Chataway • Anne Rigby • David Miller • Michelle Sclanders • Alan Thompson• Larry Steinman • Klaus Schmierer • Peggy Ho • Ben Turner • Dan Altman • John Zajicek • Doug Brown • UK MS Clinical Trial Network • BioMS
  56. 56. Questions

×