MS treatment and preservation
of end-organ damage in MS
Gavin Giovannoni
Barts and The London
.
Thomas Blizard Curling
1811 – 1888
• Assistant-surgeon to The Royal
London Hospital in 1883 and full
surgeon in 1849
• Pre...
ESRF
end-stage renal failure
Does the brain fail in MS?
Should multiple sclerosis be
redefined as a dementia?
www.multiple-sclerosis-research.org
Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal
activities of daily liv...
Occupational functioning

Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
At what level of physical disability does
unemployment occur?

Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
Cognition in early multiple sclerosis
60%

57%
40%

MSers failing ≥
2 cognitive
tests

20%

p < 0.0001

0%

7%

-20%

CISe...
Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal
activities of daily liv...
What is the pathological
substrate of MS dementia?
11,000 to 1

Trapp, et al. NEJM 1998;338:278-85
Control

Multiple sclerosis
Brain atrophy occurs across all stages of the disease
n= 963 MSers

De Stefano, et al. Neurology 2010
Hypothetical treatment effects

Brain Volume (mL)

Brain atrophy curves
1500
1450
1400
1350
1300
1250
1200
1150
1100
1050
...
Hypothetical treatment effects

Brain Volume (mL)

Brain atrophy curves
1500
1450
1400
1350
1300
1250
1200
1150
1100
1050
...
Laquinimod: Percent of brain volume
change from baseline to month 24
Placebo (n = 1006)
Laquinimod 0.6 mg (n = 984)

POOLE...
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....
Fingolimod has an early and sustained effect on the rate
of brain atrophy compared with placebo and IFNb-1a IM
TRANSFORMS,...
AFFIRM Study: natalizumab and brain atrophy

Mean (SE) percentage change in BPF

0.0%

Years 0-2

Year 0-1*

-0.2%

-0.24%...
Hypothetical treatment effects

Brain Volume (mL)

Brain atrophy curves
1500
1450
1400
1350
1300
1250
1200
1150
1100
1050
...
Hypothetical treatment effects

Brain Volume (mL)

Brain atrophy curves
1500
1450
1400
1350
1300
1250
1200
1150
1100
1050
...
Hypothetical treatment effects

Brain Volume (mL)

Brain atrophy curves
1500
1450
1400
1350
1300
1250
1200
1150
1100
1050
...
Hypothetical treatment effects

Brain Volume (mL)

Brain atrophy curves
1500
1450
1400
1350
1300
1250
1200
1150
1100
1050
...
Treatment Effect on Disability Strongly Predicted by Effect on
T2 Lesion Volume and Brain Atrophy, Combined

Meta-analysis...
Defining the window of
opportunity to treat MS?
Post-inflammatory neurodegeneration

Coles et al. J Neurol. 2006 Jan;253(1):98-108.
21-year long-term follow-up of IFNb-1b study
time from study randomization to death
Early treatment (3 years) with IFNb-1b...
Theoretical model: treat early and effectively

Natural course
of disease

Disability

Later
treatment

Later
intervention...
Defining your
treatment strategy?
What is your treatment philosophy?
maintenance-escalation vs. induction

survival analysis

“hit hard and early ”

MS is a...
Can you name me any diseases
that you don’t treat early?
Conclusion

Time is Brain
Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal
activities of daily liv...
Stigmatizing
Stigmatizing
Brain Health
300 MSers

Year 1

Placebo tablet

Year 2

600 MSers

300 MSers

Active tablet

Year 3
Spinal fluid neurofilament levels

Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Axonal damage in relapsing MS is markedly reduced by natalizumab

=

Gunnarsson et al. Ann Neurol 2010; Epub.
30 MSers placebo tablet

6 months

6 months
6 months

6 months

60 MSers

30 MSers active tablet

LP1
Recruitment

LP2
Tri...
600 MSers for 7 years

60 MSers for 2 years

3 LPs = 10x as many trials in a ⅓ of the time
n = 127
66%

21%
13%
PPMS

RIS

RRMS

CIS

R-SPMS

SPMS

Disease Severity

Inflammation
Neuroaxonal loss

Subclinical
disease

Brain volume los...
PPMS

RIS

RRMS

CIS

R-SPMS

SPMS

Disease Severity

Inflammation
Neuroaxonal loss

Subclinical
disease

Brain volume los...
THANK YOU FOR LISTENING

I would like to thank my team for making things happen!
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
MS Treatment and the prevention of end organ damage
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MS Treatment and the prevention of end organ damage

  1. 1. MS treatment and preservation of end-organ damage in MS Gavin Giovannoni Barts and The London
  2. 2. .
  3. 3. Thomas Blizard Curling 1811 – 1888 • Assistant-surgeon to The Royal London Hospital in 1883 and full surgeon in 1849 • President of the Royal College of Surgeons • Seminal work on tetanus, winning the Jacksonian prize for his work • Famous for his skill in treating diseases of the testes and rectum
  4. 4. ESRF end-stage renal failure
  5. 5. Does the brain fail in MS?
  6. 6. Should multiple sclerosis be redefined as a dementia?
  7. 7. www.multiple-sclerosis-research.org
  8. 8. Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • • • • Physical  Mental  Social Occupational • Lasting more than six months  • Not present since birth  • Not associated with a loss or alteration of consciousness 
  9. 9. Occupational functioning Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
  10. 10. At what level of physical disability does unemployment occur? Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
  11. 11. Cognition in early multiple sclerosis 60% 57% 40% MSers failing ≥ 2 cognitive tests 20% p < 0.0001 0% 7% -20% CISers n = 40 Healthy Controls n = 30 Deficits were found mainly in memory, speed of information processing, attention and executive functioning. Feuillet et al. Mult Scler. 2007.
  12. 12. Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • • • • Physical  Mental  Social  Occupational  • Lasting more than six months  • Not present since birth  • Not associated with a loss or alteration of consciousness  “Multiple sclerosis is therefore a dementia.”
  13. 13. What is the pathological substrate of MS dementia?
  14. 14. 11,000 to 1 Trapp, et al. NEJM 1998;338:278-85
  15. 15. Control Multiple sclerosis
  16. 16. Brain atrophy occurs across all stages of the disease n= 963 MSers De Stefano, et al. Neurology 2010
  17. 17. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 Lower limit of normal Average Upper limit of normal 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  18. 18. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -30% MS lower limit MS Average MS Upper limit 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  19. 19. 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
  20. 20. 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 35 Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507.
  21. 21. 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
  22. 22. AFFIRM Study: 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.
  23. 23. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -30% MS Average 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  24. 24. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -20% late treatment 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  25. 25. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% -18% early treatment late treatment 30 35 40 45 50 55 Age (years) 60 65 70 75 80
  26. 26. Hypothetical treatment effects Brain Volume (mL) Brain atrophy curves 1500 1450 1400 1350 1300 1250 1200 1150 1100 1050 1000 950 900 850 800 750 -5% early very highlyeffective treatment 30 35 late very highlyeffective treatment 40 45 50 55 Age (years) 60 65 70 75 80 -11% -15%
  27. 27. Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebocontrolled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75:43-49.
  28. 28. Defining the window of opportunity to treat MS?
  29. 29. Post-inflammatory neurodegeneration Coles et al. J Neurol. 2006 Jan;253(1):98-108.
  30. 30. 21-year long-term follow-up of IFNb-1b study time from study randomization to death Early 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 Proportion of patients who are still alive 100% 95% IFNB-1b 250 µg 90% Placebo 85% 80% 75% HR=0.532 (95% CI: 0.314–0.902) 46.8% reduction in hazard ratio Log rank, P=0.0173 70% 65% 0 At risk: IFNB-1b 250 µg Placebo 124 123 2 4 6 124 120 8 10 12 14 16 18 20 22 Time (Years) 121 117 118 109 104 88 Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.
  31. 31. Theoretical model: treat early and effectively Natural course of disease Disability Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis Time Disease Onset
  32. 32. Defining your treatment strategy?
  33. 33. What is your treatment philosophy? maintenance-escalation vs. induction survival analysis “hit hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment
  34. 34. Can you name me any diseases that you don’t treat early?
  35. 35. Conclusion Time is Brain
  36. 36. Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • • • • Physical  Mental  Social  Occupational  • Lasting more than six months  • Not present since birth  • Not associated with a loss or alteration of consciousness  “Multiple sclerosis is therefore a preventable dementia.”
  37. 37. Stigmatizing
  38. 38. Stigmatizing
  39. 39. Brain Health
  40. 40. 300 MSers Year 1 Placebo tablet Year 2 600 MSers 300 MSers Active tablet Year 3
  41. 41. Spinal fluid neurofilament levels Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
  42. 42. Axonal damage in relapsing MS is markedly reduced by natalizumab = Gunnarsson et al. Ann Neurol 2010; Epub.
  43. 43. 30 MSers placebo tablet 6 months 6 months 6 months 6 months 60 MSers 30 MSers active tablet LP1 Recruitment LP2 Trial 2 years LP3 Data analysis
  44. 44. 600 MSers for 7 years 60 MSers for 2 years 3 LPs = 10x as many trials in a ⅓ of the time
  45. 45. n = 127 66% 21% 13%
  46. 46. PPMS RIS RRMS CIS R-SPMS SPMS Disease Severity Inflammation Neuroaxonal loss Subclinical disease Brain volume loss 1st clinical attack Relapses 1st MRI lesion MRI Events Time (Years) PPMS: Fingolimod, Ocrelizumab, Laquinimod SPMS: Natalizumab, Siponimod CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY Early SPMS: PROXIMUS oxcarbazepine Late SPMS: SMART STUDY ibudilast, amiloride, riluzole 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
  47. 47. PPMS RIS RRMS CIS R-SPMS SPMS Disease Severity Inflammation Neuroaxonal loss Subclinical disease Brain volume loss 1st clinical attack Relapses 1st MRI lesion MRI Events Time (Years) PPMS: Fingolimod, Ocrelizumab, Laquinimod SPMS: Natalizumab, Siponimod CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY Early SPMS: PROXIMUS oxcarbazepine Late SPMS: SMART STUDY ibudilast, amiloride, riluzole 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
  48. 48. THANK YOU FOR LISTENING I would like to thank my team for making things happen!

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