The future of MS treatments for     people living with MS               Gavin Giovannoni                Blizard Institute ...
Holistic approach
Sexual     Balance            Restless                Emotional   Advanced       Fertility Pregnancy                      ...
Sexual     Balance            Restless                Emotional   Advanced       Fertility Pregnancy                      ...
Sexual     Balance            Restless                Emotional   Advanced       Fertility Pregnancy                      ...
Graeme WilsonMSer born 6th December 1973, died 4th December 2012                                      http://viaferria.blo...
Mortality or Survival
Survival in MSers is shortened by 8 to 12 years                                              Survival Probability of Norwe...
21-year long-term follow-up of IFNb-1b study                                                  time from study randomizatio...
Long-term follow-up 16 years                                                  IFN-beta exposure 80% vs. 20%               ...
responders vs. non-responders
100 MSersWho are responders?
~20% - responders~40% - partial-responders-40% - non-responders
1      Clinicalvs.         2        MRI          3        NABs
early vs. delayed treatment
Post-inflammatory neurodegeneration                            Coles et al. J Neurol. 2006 Jan;253(1):98-108..
Treat early                                                    Natural course                                             ...
Progressive MS                      Placebo             1. Reduce rate of disability progression                          ...
Compared to relapsing MS                                                                   Placebo             1.   Delay ...
1   Delayed Progression   2   Stabilised Progression3   Improved Function     4   Recovered Function
WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?       3       2       1                                       ...
Progressive MS Trials
Placebo tablet             280 MS’ers               Year 1        Year 2        Year 3560 MS’ers             280 MS’ers   ...
Placebo                                          ActiveDisability             Year 1     Year 2   Year 3                  ...
Aims of CUPID study• to assess the value of Δ9-THC in slowing progressive  MS over 3 years.• to assess the safety of Δ9-TH...
1.0                      0.8P(EDSS progression)                      0.6                      0.4                      0.2...
1.0                      0.8P(EDSS progression)                      0.6                      0.4                         ...
1.0                      0.8P(EDSS progression)                      0.6                      0.4                      0.2...
30
MS-STAT trial                  High dose oral Simvastatin          in Secondary Progressive Multiple Sclerosis            ...
Brain atrophy    orshrinkage
Whole Brain Atrophy
Change whole brain volume (%/yr)
Secondary outcomes: DisabilityOutcome                      Mean (SD)       Mean (SD)       Difference in means            ...
Where to next?
~300 MS’ersYear 1       Year 2                                        Year 6        Year 7                          Year 3...
New trial designs
Trial 1
Spinal fluid neurofilament levels        Spinal          fluidneurofilament         levels                     Disability ...
Spinal fluid neurofilament levels        Spinal          fluidneurofilament         levels                     Disability ...
Axonal damage in relapsing MS is markedly reduced by natalizumab                                          Gunnarsson et al...
Axonal damage in relapsing MS is markedly reduced by natalizumab                                          Gunnarsson et al...
Axonal damage in relapsing MS is markedly reduced by natalizumab                                     =                    ...
30 MS’ers placebo tablet 6 months                                                    6 months                      6 month...
New paradigm 600 MS’ers for 7 years   60 MS’ers for 2 years3 LPs = 10x as many trials in a ⅓ of the time
Can we make LPs safer?
Two types of spinal needle tips: the Quincke and Sprotte                                                Traumatic         ...
54%
Trial 2
UK Clinical Trial Network (CTN): phase 3 adaptive design                primary outcome EDSS progression                  ...
UK Clinical Trial Network (CTN): phase 3 adaptive design                primary outcome EDSS progression                  ...
Trial 3
Acute optic neuritis   (focal lesion)                                                          Trapp et al. N Engl J Med 1...
Sexual     Balance            Restless                Emotional   Advanced       Fertility Pregnancy                      ...
Sexual     Balance            Restless                Emotional   Advanced       Fertility Pregnancy                      ...
Multiple sclerosis                                                                                                      an...
DEXA OR BONE DENSITY SCAN                            70
Conclusions• MS is a serious disease• Prognostic factors   – Disease course   – Response markers• Treatment   – Effective ...
72
www.ms-res.org                 73
Graeme WilsonMSer born 6th December 1973, died 4th December 2012                                      http://viaferria.blo...
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
Future of MS Treatments
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Future of MS Treatments

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A copy of my talk for the Living with MS meeting that is being hosted by the MS Society in Hammersmith, London on Saturday 24 November 2012.

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Future of MS Treatments

  1. 1. The future of MS treatments for people living with MS Gavin Giovannoni Blizard Institute Barts and The London, United Kingdom 1
  2. 2. Holistic approach
  3. 3. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Visual loss Travel Counselling Fatigue Driving Pressure sores Research Depression Fractures Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Movement Insurance disorders Family Maintenance Escalation Induction Physio- counselling therapy Osteopaenia Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Intrathecal Genetics Legal aid Genetic baclofern counselling Disease Smoking progression Intrathecal Social Lumbar Evoked Tendonotomy services Potentials Disease-free phenol Epstein Bar Virus puncture Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Terminal Tests Prevention DMT Diagnosis Symptomatic An holistic approach to MS; beta ver. 2.1 Therapist Counselling
  4. 4. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Vision Travel Counselling Fatigue Pressure Driving sores Research Depression Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Insurance Family Maintenance Escalation Induction Physio- counselling therapy Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Genetics Intrathecal Family Legal aid counselling Disease baclofern Smoking progression Lumbar Evoked Tendonotomy Social puncture Potentials Disease-free services Epstein Bar Virus Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Tests Prevention DMT Terminal Diagnosis Symptomatic Therapist Counselling
  5. 5. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Vision Travel Counselling Fatigue Pressure Driving sores Research Depression Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Insurance Family Maintenance Escalation Induction Physio- counselling therapy Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Genetics Intrathecal Family Legal aid counselling Disease baclofern Smoking progression Lumbar Evoked Tendonotomy Social puncture Potentials Disease-free services Epstein Bar Virus Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Tests Prevention DMT Terminal Diagnosis Symptomatic Therapist Counselling
  6. 6. Graeme WilsonMSer born 6th December 1973, died 4th December 2012 http://viaferria.blogspot.co.uk/
  7. 7. Mortality or Survival
  8. 8. Survival in MSers is shortened by 8 to 12 years Survival Probability of Norwegian Patients with RRMS (Hordaland County, Western Norway, 1953–2003) 100 General Population 90 RRMS 95% CI 80 70 Survival (%) 60 50 40 30 20 10 0 0 5 10 15 20 25 30 35 40 45 50 Years After Onset 30 35 40 45 50 55 60 65 70 75 80RRMS=relapsing-remitting MS. Approximate Patient AgeAdapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.
  9. 9. 21-year long-term follow-up of IFNb-1b study time from study randomization to deathEarly 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 100% Proportion of patients who are still alive 95% IFNB-1b 250 µg 90% Placebo 85% 80% 75% HR=0.532 (95% CI: 0.314–0.902) 70% 46.8% reduction in hazard ratio Log rank, P=0.0173 65% 0 2 4 6 8 10 12 14 16 18 20 22 Time (Years) At risk: IFNB-1b 250 µg 124 124 121 118 104 Placebo 123 120 117 109 88 Source: Poster Goodin et al AAN 2011
  10. 10. Long-term follow-up 16 years IFN-beta exposure 80% vs. 20% % Risk Relative to Low Exposure Any Negative EDSS=6 SPMS WheelchairSource: Poster Goodin et al AAN 2011
  11. 11. responders vs. non-responders
  12. 12. 100 MSersWho are responders?
  13. 13. ~20% - responders~40% - partial-responders-40% - non-responders
  14. 14. 1 Clinicalvs. 2 MRI 3 NABs
  15. 15. early vs. delayed treatment
  16. 16. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108..
  17. 17. Treat early Natural course of disease Later treatment Later intervention Treatment at diagnosis Intervention at diagnosisDisability Time Disease Onset
  18. 18. Progressive MS Placebo 1. Reduce rate of disability progression ActiveDisability 12 months 24 months 36 months Time
  19. 19. Compared to relapsing MS Placebo 1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS ActiveDisability 6 months 12 months 6 months 24 months Time
  20. 20. 1 Delayed Progression 2 Stabilised Progression3 Improved Function 4 Recovered Function
  21. 21. WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS? 3 2 1 22www.ms-res.org
  22. 22. Progressive MS Trials
  23. 23. Placebo tablet 280 MS’ers Year 1 Year 2 Year 3560 MS’ers 280 MS’ers Active tablet
  24. 24. Placebo ActiveDisability Year 1 Year 2 Year 3 Time
  25. 25. Aims of CUPID study• 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 methods.
  26. 26. 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)
  27. 27. 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)
  28. 28. 1.0 0.8P(EDSS progression) 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)
  29. 29. 30
  30. 30. MS-STAT trial High dose oral Simvastatin in Secondary Progressive Multiple Sclerosis Jeremy Chataway for the MS-STAT CollaboratorsCTN:NCT00647348EUDRACT NUMBER 2006-006347-31
  31. 31. Brain atrophy orshrinkage
  32. 32. Whole Brain Atrophy
  33. 33. Change whole brain volume (%/yr)
  34. 34. 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
  35. 35. Where to next?
  36. 36. ~300 MS’ersYear 1 Year 2 Year 6 Year 7 Year 3 Year 4 Year 5 ~600 MS’ers 300 MS’ers Recruitment Trial Data analysis ? Registration 7 years
  37. 37. New trial designs
  38. 38. Trial 1
  39. 39. Spinal fluid neurofilament levels Spinal fluidneurofilament levels Disability (EDSS) and 3 years Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  40. 40. Spinal fluid neurofilament levels Spinal fluidneurofilament levels Disability (EDSS) and 3 years Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  41. 41. Axonal damage in relapsing MS is markedly reduced by natalizumab Gunnarsson et al. Ann Neurol 2010; Epub.
  42. 42. Axonal damage in relapsing MS is markedly reduced by natalizumab Gunnarsson et al. Ann Neurol 2010; Epub.
  43. 43. Axonal damage in relapsing MS is markedly reduced by natalizumab = Gunnarsson et al. Ann Neurol 2010; Epub.
  44. 44. 30 MS’ers placebo tablet 6 months 6 months 6 months 6 months60 MS’ers 30 MS’ers active tablet LP1 LP2 LP3 Recruitment Trial Data analysis 2 years
  45. 45. New paradigm 600 MS’ers for 7 years 60 MS’ers for 2 years3 LPs = 10x as many trials in a ⅓ of the time
  46. 46. Can we make LPs safer?
  47. 47. Two types of spinal needle tips: the Quincke and Sprotte Traumatic or cutting needle Atraumatic or non-cutting needleEvans R W et al. Neurology 2000;55:909-914
  48. 48. 54%
  49. 49. Trial 2
  50. 50. 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
  51. 51. UK Clinical Trial Network (CTN): phase 3 adaptive design primary outcome EDSS progression futility EDSS analysis 1° outcome Placebo  riluzole Drug A  amiloride Drug B  ibudlast Drug C  Drug D  2yrs 3yrs 7yrs
  52. 52. Trial 3
  53. 53. Acute optic neuritis (focal lesion) Trapp et al. N Engl J Med 1998. Baseline 52 weeks38 year old woman with left optic neuritissTE fFLAIR images Phenytoin Amiloride Anti-Lingo-1Hickman et al. Neuroradiology 2001;43:123-8. Romani et al. Clini Neurophys 2000;111:1602-6.
  54. 54. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Visual loss Travel Counselling Fatigue Driving Pressure sores Research Depression Fractures Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Movement Insurance disorders Family Maintenance Escalation Induction Physio- counselling therapy Osteopaenia Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Intrathecal Genetics Legal aid Genetic baclofern counselling Disease Smoking progression Intrathecal Social Lumbar Evoked Tendonotomy services Potentials Disease-free phenol Epstein Bar Virus puncture Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Terminal Tests Prevention DMT Diagnosis Symptomatic An holistic approach to MS; beta ver. 2.1 Therapist Counselling
  55. 55. Sexual Balance Restless Emotional Advanced Fertility Pregnancy Bladder dysfunction problems legs Tremor Insomnia lability Directive Breast Feeding Oscillopsia Vaccination Studying Bowel Gait Falls Spasticity Cognition Seizures Employment Swallowing PainRelationships Clinical trials Vision Travel Counselling Fatigue Pressure Driving sores Research Depression Exercise Occupational Nurse Rehab Therapy Anxiety specialists Diet Insurance Family Maintenance Escalation Induction Physio- counselling therapy Side Effects Speech Alternative Risks therapy Palliative Care Medicine 2nd line Adverse Suprapubic DMTs 1st line events catheter Genetics Intrathecal Family Legal aid counselling Disease baclofern Smoking progression Lumbar Evoked Tendonotomy Social puncture Potentials Disease-free services Epstein Bar Virus Colostomy Monitoring Gastrostomy Differential Vitamin D Diagnosis Relapses Functional Assisted neurosurgery suicide Diagnostic Criteria Blood MRI Tests Prevention DMT Terminal Diagnosis Symptomatic Therapist Counselling
  56. 56. Multiple sclerosis annually 1Fallsrisk low assessment? medium/high Falls reduction OT home assessment Targeted physiotherapy Visual assessment and treatment Falls education Management of medical co-morbidities 2 years Medication review (antidepressants, sedatives etc). low Fracture risk Qfracture/FRAX Investigate for secondary osteoporosis • Vitamin D levels2 • Thyroid function tests3 medium/high • Renal & liver function tests2 years Address lifestyle factors DXA imaging • Diet • Smoking cessation • Alcohol 2 years • Exercise low Bone Mineral low Treatment of osteopaenia Density Refer to NICE guidelines TA160 above treatment below treatment threshold threshold normal 1. To add separate falls risk assessment scales for MS and PD 2. New vD supplementation guidelines 3. Statement of frequency of checking TFTs
  57. 57. DEXA OR BONE DENSITY SCAN 70
  58. 58. Conclusions• MS is a serious disease• Prognostic factors – Disease course – Response markers• Treatment – Effective DMTs for RRMS with an exciting Definitive phase 3 PPMS & SPMS trials underway – New strategies and trial designs for neuroprotection and remyelination in progressive MS• Holistic approach to MS – Falls, fractures, ect. www.ms-res.org
  59. 59. 72
  60. 60. www.ms-res.org 73
  61. 61. Graeme WilsonMSer born 6th December 1973, died 4th December 2012 http://viaferria.blogspot.co.uk/
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