ECTRIM Highlights 17 November 2012
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Lecture at symposium in Barcelona!

Lecture at symposium in Barcelona!

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ECTRIM Highlights 17 November 2012 Presentation Transcript

  • 1. Treatment highlights from ECTRIMS 2012 Gavin Giovannoni
  • 2. Phase III TOWER study (teriflunomide) Kappos L, et al.
  • 3. TOWER: annualized relapse rate (primary endpoint) 0.6 RRR: 22.3% P = 0.0183 Annualized relapse ratea 0.501 0.5 RRR: 36.3% P = 0.0001 0.389 0.4 0.319 0.3 0.2 0.1 0 Placebo Teriflunomide Teriflunomide (n = 388) 7 mg 14 mg (n = 407) (n = 370)RRR, relative risk reductiona Adjusted annualized relapse rate derived using a Poisson regression model with robust errorvariance Intent-to-treat population. Median duration of exposure: 581 days (placebo), 556 days(teriflunomide 7 mg) and 588 days (teriflunomide 14 mg).Kappa L, et al. ECTRIMS 2012. Oral presentation 153.
  • 4. Phase II MS-STAT trial (high-dose simvastatin) Chataway J, et al.
  • 5. 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)Freeborough PA & Fox NC. EEE Trans Med Imaging 1997; 16:623–9.
  • 6. MS-STAT: BBSI change in whole brain volume (primary outcome) Mean (SD) Mean (SD) Difference in P value placebo simvastatin means (95% CI)a Change in WBV 0.589 (0.528) 0.298 –0.254 0.003 (%/year) (0.562) (–0.423 to –0.085) Number of patients 64 66 evaluatedBBSI, brain boundary shift integrala Adjusting for minimisation variables and MRI siteChataway J, et al. ECTRIMS 2012. Oral presentation 38a.
  • 7. MS-STAT: change in whole brain volume 3 2 Change WBV %/year 1 0 –1 –2 0 to 12 months 12 to 25 months 0 to 25 months Mean Individual valuesChataway J, et al. ECTRIMS 2012. Oral presentation 38a.
  • 8. MS-STAT secondary outcomes: disability Outcome Mean (SD) Mean (SD) Difference in means placebo simvastatin (95% CI) EDSS 6.35 (0.83) 5.93 (1.11) –0.254 (score 0 to 10) (–0.464 to –0.069)  MSIS total 76.1 (16.3) 70.1 (15.6) –4.78 (score 29 to 116) (–9.39 to –0.02)  MSIS physical 56.3 (11.8) 51.7 (11.4) –3.73 (score 20 to 80) (–7.18 to –0.28)  MSIS psychological 19.8 (6.0) 18.3 (5.8) –1.09 (score 9 to 36) (–2.83 to 0.84) 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 (speed ft/s) (–0.249 to 0.533) MSFC peg test 0.030 (0.014) 0.033 (0.010) 0.002 (1/s) (–0.001 to 0.004) MSFC PASAT 35.2 (18.0) 38.3 (15.4) 4.45 (score 0 to 60) (–0.11 to 8.84)Model adjusting for minimisation variables and baselineChataway J, et al. ECTRIMS 2012. Oral presentation 38a.
  • 9. Participant characteristicsVariable Placebo (n = 70) Simvastatin (n = 70)Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07) EDSS (score 0 to 10) – Median (range) 6 (4 to 7) 6 (4 to 6.5) – Mean (SD) 5.87 (0.78) 5.75 (0.84)MSIS total (score 29 to 116) 70.0 (14.5) 70.2 (14.0)MSIS physical (score 20 to 80) 51.2 (10.4) 51.4 (10.6)MSIS psychological (score 9 to 36) 18.8 (5.7) 18.9 (5.2)MSFC Z score -0.29 (1.48) -0.03 (0.92)MSFC walk (speed ft/s) 1.50 (0.87) 1.67 (0.91)MSFC peg test (speed 1/s) 0.033 (0.010) 0.034 (0.009)MSFC PASAT (score 0 to 60) 33.7 (16.1) 34.8 (13.8)Values are mean (standard deviation) unless otherwise statedChataway J, et al. ECTRIMS 2012. Oral presentation 38a.
  • 10. Participant characteristicsVariable Placebo (n = 70) Simvastatin (n = 70)Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07) EDSS (score 0 to 10) – Median (range) 6 (4 to 7) 6 (4 to 6.5) – Mean (SD) 5.87 (0.78) 5.75 (0.84)MSIS total (score 29 to 116) 70.0 (14.5) 70.2 (14.0)MSIS physical (score 20 to 80) 51.2 (10.4) 51.4 (10.6)MSIS psychological (score 9 to 36) 18.8 (5.7) 18.9 (5.2)MSFC Z score -0.29 (1.48) -0.03 (0.92)MSFC walk (speed ft/s) 1.50 (0.87) 1.67 (0.91)MSFC peg test (speed 1/s) 0.033 (0.010) 0.034 (0.009)MSFC PASAT (score 0 to 60) 33.7 (16.1) 34.8 (13.8)Values are mean (standard deviation) unless otherwise statedChataway J, et al. ECTRIMS 2012. Oral presentation 38a.
  • 11. Participant characteristicsVariable Placebo (n = 70) Simvastatin (n = 70)Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07) EDSS (score 0 to 10) – Median (range) 6 (4 to 7) 6 (4 to 6.5) – Mean (SD) 5.87 (0.78) 5.75 (0.84)MSIS total (score 29 to 116) 70.0 (14.5) 70.2 (14.0)MSIS physical (score 20 to 80) 51.2 (10.4) 51.4 (10.6)EDSS(score 0 to 10) 6.35 (0.83)MSIS psychological (score 9 to 36) 5.93 (1.11) 18.8 (5.7) –0.254 (–0.464 to –0.069) 18.9 (5.2) MSFC Z score -0.29 (1.48) -0.03 (0.92)MSFC walk (speed ft/s) 1.50 (0.87) 1.67 (0.91)MSFC peg test (speed 1/s) 0.033 (0.010) 0.034 (0.009)MSFC PASAT (score 0 to 60) 33.7 (16.1) 34.8 (13.8)Values are mean (standard deviation) unless otherwise statedChataway J, et al. ECTRIMS 2012. Oral presentation 38a.
  • 12. CUPID study (cannabis) Zajicek J, et al.
  • 13. CUPID: aims • To assess the value of Δ9-THC in slowing progressive MS over 3 years • To assess the safety of Δ9-THC over the long term • To improve research methodology by using new, patient-orientated methodsZajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
  • 14. CUPID: EDSS progression over 3 years 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)Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
  • 15. CUPID: EDSS progression according to baseline EDSS score 1.0 P (EDSS progression) 0.8 0.6 0.4 Baseline EDSS score 4 4.5 0.2 5 5.5 6 6.5 0.0 0 200 400 600 800 1000 1200 Time to EDSS progression (days)Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
  • 16. CUPID: EDSS progression in patients with baseline EDSS <6 (post-hoc analysis) 1.0 n = 110 P (EDSS progression) 0.8 0.6 0.4 0.2 Treatment group Active Log rank test P = 0.01 Placebo 0.0 0 200 400 600 800 1000 1200 Time to EDSS progression (days)Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
  • 17. It is time to change the way we measure change: demonstration, explanation, recommendation Hobart J, et al.
  • 18. What are your expectations of a therapy for progressive MS? 1. Delayed Progression 2. Stabilised Progression 3. Improved Function 4. Recovered Functionwww.ms-res.org
  • 19. What are your expectations of a therapy for progressive MS? Recovery 18% Improvement 18% Stable 44% Slowed 20% 0% 10% 20% 30% 40% 50%www.ms-res.org
  • 20. Phase IIa study (natalizumab) Romme Christensen J, et al.
  • 21. Phase 2A study: CSF markers of inflammation (secondary endpoints) 200 SPMS 1.5 SPMS p=0.02 PPMS p=0.06 PPMS 150CSF CXCL13 pg/ml CSF MMP9 ng/ml 1.0 100 0.5 50 NIND Mean (limit of detection) NIND Mean 0 +/- 95% CI 0.0 Baseline 60 weeks Baseline 60 weeks Natalizumab NatalizumabRomme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
  • 22. Phase2A study: change in CSF osteopontin concentration (primary endpoint) 800 SPMS p=0.0004 PPMS 700 CSF Osteopontin ng/ml 600 500 400 300 200 NIND Mean 100 +/- 95% CI 0 Baseline 60 weeks NatalizumabRomme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
  • 23. Phase 2A study: CSF markers of axonal damage and demyelination (secondary endpoints) 2500 2.5 SPMS SPMS p=0.03 p=0.048 PPMS PPMSCSF Neurofilament llight ng/L 2000 2.0 CSF MBP ng/ml 1500 1.5 1000 1.0 500 0.5 NIND Mean NIND Mean +/- 95% CI +/- 95% CI 0 0.0 Baseline 60 weeks Baseline 60 weeks Natalizumab Natalizumab Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
  • 24. Current dogma “autoimmune endophenotype”  T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses  BBB breakdown Clinical Attack focal inflammationClinical Recovery axonal plasticity & remyelination oligodendrocyte toxicity & demyelination Acute axonal transection and loss   release of soluble markers  delayed neuroaxonal loss and gliosis – biology brain & spinal cord atrophy  Disease Progression – clinical outcomes – biomarkers
  • 25. CARE-MS I trial (alemtuzumab) Cohen J, et al.
  • 26. CARE-MS I: proportion of patients free of clinical disease and MRI activity at 24 months IFN β-1a SC Alemtuzumab 12 mg/day P < 0.0001 100 93 90 P < 0.0001 81 80 74 P = 0.04 Patients (%) 70 60 56 56 P = 0.0064 50 42 39 40 30 27 20 10 0 Clinical disease MS disease No new or No Gd-enhancing activity-freeᵃ activity-freeᵇ enlarging lesions T2-hyperintense lesions • A significantly greater proportion of patients were disease-free with alemtuzumab vs. IFN β-1a SC in CARE-MS IaDefined as absence of relapse or SAD. b Defined as absence of clinical disease activity or MRI activity.Cohen J, et al. Lancet 2012; 31 Oct [Epub ahead of print].
  • 27. SELECT study (daclizumab) Giovannoni G, et al.
  • 28. SELECT: proportion of patients free of disease activity at Week 52 P < 0.0001 OR: 6.18 (95% CI, 3.71–10.32) 45 40 39% Disease-activity free (%) 35 30 25 20 15 11% 10 5 0 Placebo DAC HYP (n = 196) (n = 404)CI, confidence interval; DAC HYP, daclizumab high-yield process; OR, odds ratio.Giovannoni G, et al. ECTRIMS 2012. P921.
  • 29. ALLEGRO and BRAVO studies (laquinimod) Comi G, et al.
  • 30. Pooled analysis of ALLEGRO and BRAVO Phase III trials: annualized relapse rate 0.4 0.38 0.3 Adjusted AARa 0.3 21% reduction 0.2 in annualized relapse rates (P = 0.0005) 0.1 0 Placebo LaquinimodaAAR analysis was a baseline adjusted Quasi-likelihood Poisson regression analysis, includingbaseline EDSS score, log of prior 2 year relapse rate + 1 and country or geographic region as covariatesVollmer T, et al. AAN 2012. S01.007.
  • 31. Pooled analysis of ALLEGRO and BRAVO: risk for 3-month confirmed disability progression Placebo (n = 1006) Laquinimod 0.6 mg (n = 984) 20%% of patients with confirmed Hazard ratio = 0.658 progression at 3 months P = 0.0017 15% 34.2% 10% 5% 0% Day 0 Day 100 Day 200 Day 300 Day 400 Day 500 Day 600 Day 700Vollmer T, et al. AAN 2012. S01.007.
  • 32. Pooled analysis of ALLEGRO and BRAVO: risk for 6-month confirmed disability progression Placebo (n = 1006) Laquinimod 0.6 mg (n = 984) 20%% of patients with confirmed Hazard ratio = 0.54 progression at 6 months P = 0 .0001 15% 10% 46% 5% 0% Day 0 Day 100 Day 200 Day 300 Day 400 Day 500 Day 600 Day 700Vollmer T, et al. AAN 2012. S01.007.
  • 33. ALLEGRO: confirmed disability progression for patients completing 1 year in OLE Delayed Start Early Start 30% 25% Patients (%) 20% 15% 10% 5% 0% Days 0 Days 150 Days 300 Days 450 Days 600 Days 750 Days 900 Days 1050Delayed start n = 363 346 337 321 316 308 298 293Early start n = 372 365 362 358 347 337 337 330 Time to progression (days)OLE, open-label extensionComi G, et al. ECTRIMS 2012. P156.
  • 34. Pooled analysis of ALLEGRO and BRAVO: brain volume change from baseline to 24 months Placebo (n = 1006) Laquinimod 0.6 mg (n = 984) 0.0 Change from baseline (%) –0.4 –0.834 –0.8 –1.188 –1.2 30% P < 0.0001 –1.6Vollmer T, et al. AAN 2012. S01.007.
  • 35. BRAVO: brain volume change from baseline to 24 monthsa Placebo Laquinimod IFN β-1a IM 0.6 mg 30 mcg 0.0 Change from baseline (%) –0.2 –0.4 –0.82% –0.6 –1.14% –1.24% –0.8 –1.0 –1.2 –27.4% –1.4 improvement P < 0.0001 +9% deterioration P = 0.14aAdjusted for baseline characteristics.Vollmer T, et al. ECTRIMS 2011. Oral presentation 148.
  • 36. FREEDOMS: overview of placebo-controlled data FREEDOMS: 2-year results 0.4 54% relative Time (months) 0.4 reduction Annualized relapse rate P < 0.001 0 6 12 24 0.3 0 0.2 0.18 P = 0.006 –0.2 0.1 * volume from baseline (%)a P = 0.03 Mean change in brain –0.4 0 Placebo Fingolimod * 0.5 mg –0.6 P < 0.001 (n = 418) (n = 425) –0.84 Significant reduction in risk of 6-month confirmed disability progression –0.8 30 *progression confirmed Placebo –1.0 Patients with EDSS after 6 months (%) 25 38% Fingolimod 0.5 mg 19.0% 20 relative 12.5% Fingolimod 0.5 mg (n = 356) reduction 15 –1.2 Placebo (n = 329) 10 37% risk reduction 5 (HR: 0.63; P = 0.012)a,b –1.4 –1.31 0 0 90 180 270 360 450 540 630 720 Time to first progression (days) P = 0.001aLog-rank test comparing the survival distributions between treatment groups.bCox proportional hazard model adjusted for treatment, country, baseline EDSS and age.Significant change in the rate of brain atrophy vs placebo. Rank ANCOVA adjusted for treatment group, country and baseline normalized brain volume.Kappos L et al. N Engl J Med 2010; 362:387–401.
  • 37. SELECTION trial (daclizumab HYP) Giovannoni G, et al.
  • 38. SELECTION: annualized relapse rate during years 1 and 2 0.5 0.434 (0.347, 0.544) 0.45 Annualized relapse rate 0.4 0.35 Year 1 of DAC HYP Year 2 of DAC HYP 66% reduction vs. 62% reduction vs. 0.3 SELECT pbo SELECT pbo 0.25 0.165 0.2 0.148 (0.105, 0.260) (0.096, 0.229) 0.15 0.1 0.05 0 Year 1 Year 1 Year 2 Placebo DAC HYP DAC HYP n = 163 n = 129 n = 1292Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
  • 39. SELECTION: confirmed disability progression over 2 years 0.3 Placebo DAC HYP continuesProportion of patients with confirmed DAC HYP after placebo disability progression 0.2 13% 0.1 6% DAC HYP Placebo 0.0 0 3 6 9 12 15 18 21 24 Time on study (months)Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
  • 40. SELECTION: confirmed disability progression over 2 years 0.3 Placebo DAC HYP continuesProportion of patients with confirmed DAC HYP after placebo disability progression 0.2 Placebo patients start DAC HYP 16% DAC HYP 13% 50% risk reduction DAC HYP 12% 0.1 (95% CI 12-71%; P=0.015) 6% DAC HYP Placebo 0.0 0 3 6 9 12 15 18 21 24 Time on study (months)Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
  • 41. Confirmed 3-month disability progression after initiation of DAC HYP Patients with confirmed disability 12% 10% 10% progression (%) Reduction = 50% 8% P = 0.033 6% 5% 4% 2% 17 subjects 7 subjects 0% with progression with progression Year 1 Year 2 Placebo DAC HYP n = 1632 n = 1632Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
  • 42. SELECT trial (daclizumab HYP) Havrdova E, et al.
  • 43. SELECT: confirmed disability progression in patients who did and did not experience a disabling relapse confirmed disability progression (%) 20 Disabling relapse No disabling relapse Patients with 3-month 15 10 7% 5 4% 6% 2% 0 Placebo DAC HYP (n = 196) (n = 404)Havrdova E, et al. ECTRIMS 2012. Oral presentation 949.
  • 44. Do these two examples suggest that relapsesare not related to disease progression?
  • 45. Is the current dogma wrong? “autoimmune endophenotype”  T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses  BBB breakdown Clinical Attack focal inflammationClinical Recovery axonal plasticity & oligodendrocyte toxicity & demyelination remyelination Acute axonal transection and loss delayed neuroaxonal loss release of soluble markers and gliosis – biology brain & spinal cord atrophy Disease Progression – clinical outcomes – biomarkers
  • 46. Is the current dogma wrong? “autoimmune endophenotype”  T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses  BBB breakdown Clinical Attack focal inflammationClinical Recovery axonal plasticity & oligodendrocyte toxicity & demyelination remyelination Acute axonal transection and loss delayed neuroaxonal loss release of soluble markers and gliosis – biology brain & spinal cord atrophy Disease Progression – clinical outcomes – biomarkers
  • 47. Post-inflammatory neurodegeneration Change in EDSS from baseline Change in EDSS from baseline 5.0 5.0 3.0 3.0 1.0 1.0 –1.0 –1.0 –3.0 –3.0 –5.0 –5.0 –7.0 –7.0 0 6 12 0 18 24 2 4 6 8 30 36 16 Years after Campath-1H Months after Campath-1HColes A, et al. J Neurol 2006; 253:98–108.
  • 48. CARE-MS II: alemtuzumab disability improvement Sustained reduction in Mean EDSS change from disability (SRD)a1 baseline1 40 3.25 Hazard ratio: 2.57 IFN β-1a SC p = 0.0002Patients with SRD (%) 29% Mean EDSS Score 30 3.00 0.24 Alemtuzumab 12 mg p = 0.0064 2.75 p < 0.0001 20 13% ‒0.17 2.50 p = 0.0044 10 IFN β-1a SC Alemtuzumab 12 mg 2.25 0 0 3 6 9 12 15 18 21 24 0 3 6 9 12 15 18 21 24 Follow-up Month Follow-up Month • In CARE-MS I, there was no significant difference between treatments on EDSS-based endpoints2aDefined as a decrease of at least 1 EDSS point lasting at least 6 months, assessed in patientswith a baseline EDSS ≥ 2.0.1. Coles A, et al. Lancet 2012; 31 Oct [Epub ahead of print].2. Cohen J, et al. Lancet 2012; 31 Oct [Epub ahead of print].
  • 49. Is the current dogma wrong? “autoimmune endophenotype”  T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses  BBB breakdown Clinical Attack focal inflammationClinical Recovery axonal plasticity & oligodendrocyte toxicity & demyelination remyelination Acute axonal transection and loss delayed neuroaxonal loss release of soluble markers and gliosis – biology brain & spinal cord atrophy Disease Progression – clinical outcomes – biomarkers
  • 50. Is the current dogma wrong? “autoimmune endophenotype”  T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses  BBB breakdown Clinical Attack focal inflammationClinical Recovery axonal plasticity & oligodendrocyte toxicity & demyelination remyelination Acute axonal transection and loss Virus? delayed neuroaxonal loss release of soluble markers and gliosis – biology brain & spinal cord atrophy Disease Progression – clinical outcomes – biomarkers
  • 51. Is the current dogma wrong? “autoimmune endophenotype”  T2 & T1 lesions Gd-enhancement immune activation innate and adaptive responses  BBB breakdown Clinical Attack focal inflammationClinical Recovery axonal plasticity & oligodendrocyte toxicity & demyelination remyelination Acute axonal transection and loss Virus? delayed neuroaxonal loss release of soluble markers and gliosis – biology brain & spinal cord atrophy Disease Progression – clinical outcomes – biomarkers
  • 52. TOWERFrom environment to MS
  • 53. Perron H, et al. ECTRIMS 2012. P470; Curtin F, et al. ECTRIMS 2012. P558.
  • 54. Perron H, et al. ECTRIMS 2012. P470; Curtin F, et al. ECTRIMS 2012. P558.
  • 55. Conclusions• Has the emergence of monoclonal therapies cracked relapsing disease? – How do we define a cure? – Is DAF status the new treatment aim?• Progressive MS remains a problem – The challenge is doing affordable Phase II and III trials – Do we need new outcome measures (including CSF)?• How do relapses and progression relate to each other? – Are the laquinimod and daclizumab results trying to tell us something?• Is the dogma wrong? – Does MS need a paradigm shift?• We need a holistic approach to MS – MS is a life-long disease with many problems that need to be solved