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Multiple sclerosis: an unmet need
Biomarkers in MS
Gavin Giovannoni
Barts and The London
Disclosures
Professor Giovannoni has received personal compensation for participating on Advisory
Boards in relation to cl...
Why biomarkers?
• Diagnostic testing
• Positive & negative predictive testing
• Pathogenesis
• Immunology
• Aetiology
• Di...
Diagnostic markers
The evolving clinical definition of MS
1. Schumacher,et al. Problems of Experimental Trials of Therapy in Multiple Scleros...
Will Rogers Phenomenon in Multiple Sclerosis
1879 - 1935
“When the Okies left Oklahoma and moved to California,
they raise...
Will Rogers Phenomenon in Multiple Sclerosis
Sormani et al. Ann Neurol 2008;64:428–433.
Poser
McDonald
Inactive CIS Active CIS RRMS
MS diagnosed according the old Poser Criteria
Inactive CIS
Less active
RRMS
More
Active
RRMS
...
Intrathecal synthesis of IgG
Images courtesy of Prof. Ed Thompson.
Isoelectric focusingwith immunfixation
Diagnostic criteria for Primary Progressive MS
Polman et al. Ann Neurol 2005;58:840-6.
Accumulation of disability in PPMS:
stratified by intrathecal IgG abnormalities
Proportion Progressing as Percent
Epoch CS...
Not PPMS Not PPMS
PPMS
OCB+ve
PPMS MS diagnosed according the initial McDonald Criteria
Not PPMS
PPMS
OCB-ve
PPMS
OCB+ve
P...
Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
Unmet need:
Evidence-based diagnostic criteria
What constitutes a useful diagnostic test or set of criteria?
TARGET DISORDER
PRESENT ABSENT
DIAGNOSTIC TEST
RESULT
+ a b ...
A clinico-pathoanatomical study of multiple sclerosis diagnosis
SENSITIVITY = True+ve /(True+ve + False-ve)
Eye Department...
A clinico-pathoanatomical study of multiple sclerosis diagnosis.
SPECIFICITY = True-ve /(True-ve + False+ve)
~25% of cases...
Potential consequences of a misdiagnosis
Potential consequences of a misdiagnosis
Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.
PML complicating treatment with natalizumab and IFN...
TARGET DISORDER
PRESENT ABSENT
DIAGNOSTIC TEST
RESULT
+ a b a + b
- c d c + d
a + c b + d a + b + c + d
What constitutes a...
Response or non-response markers
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L ...
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L ...
Clinical importance of neutralising antibodies against interferon
beta in patients with relapsing-remitting multiple scler...
Anti-natalizumab Antibodies
Number of Patients at Risk
Placebo
Antibody Negative
Transiently Positive
Persistently Positiv...
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L ...
Natalizumab PML risk stratification tool
Anti-JC virus antibody status
Negative Positive
Prior immunosuppressant use
Natal...
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L ...
Use of JC virus antibody index to stratify risk of progressive multifocal
leukoencephalopathy in natalizumab-treated patie...
www.ms-res.org; >750,000 views
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L ...
Early Detection of PML improves clinical outcome
Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.27...
60,000
70,000
80,000
90,000
100,000
110,000
120,000
130,000
0
5
10
15
20
25
Apr-10
Jun-10
Aug-10
Oct-10
Dec-10
Feb-11
Apr-...
Biomarkers in the near future
Is NEDA good enough?
NEDA = no evident disease activity
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L ...
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white ma...
Rheumatoid arthritis
End-stage joint disease
Control Multiple sclerosis
Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
Treatment effect on disability predicted by effect on
T2-lesion load and brain atrophy
Meta-analysis of treatment effect o...
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0%
Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2...
Fingolimod has an early and sustained effect on the rate
of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2...
Reduction in brain atrophy on alemtuzumab
Alemtuzumab Improves Brain MRI Outcomes
in Patients With Active Relapsing-Remitting
Multiple Sclerosis: Three-Year Follow-...
CARE-MS I & II Three-Year MRI Outcomes
Change in Brain Parenchymal Fraction (BPF)
 Alemtuzumab slowed brain volume loss o...
CARE-MS I & II Three-Year MRI Outcomes
Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity
 The major...
CARE-MS I & II Three-Year MRI Outcomes
Change in Brain Parenchymal Fraction (BPF)
 Alemtuzumab slowed brain volume loss o...
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white ma...
Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
Neurofilament protein in cerebrospinal fluid: a
potential marker of activity in multiple sclerosis
Lyke et al. J Neurol Ne...
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Axonal damage in R-MS is markedly reduced by Natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
Natalizumab treatment of progressive MS reduces inflammation
and tissue damage: CSF markers of axonal damage
Romme Christe...
B
aseline
Follow
-up
0
500
1000
1500
2000
2500
NfL(pg/ml)
Cerebrospinal fluid NfL
Fingolimod 0.5mg/1.25 mg versus placebo ...
Axonal damage in R-MS is markedly reduced by Natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white ma...
NEDA
Gd, gadolinium.
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:3...
Biomarkers are also needed to optimise the
risks associated with the emerging therapies
Conclusions
• MS is a bad disease
• Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• Early highl...
Back-up slides
Control Multiple sclerosis
Another infographic: end-organ damage
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Treatment-effect on atrophy correlates with treatment-effect on disability
Sormani et al. Ann Neurol 2014;75:43–49.
Coles et al. J Neurol. 2006 Jan;253(1):98-108.
Post-inflammatory neurodegeneration
Biomarkers in MS - EFNS-ENS Meeting Istanbul 2014
Biomarkers in MS - EFNS-ENS Meeting Istanbul 2014
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Transcript of "Biomarkers in MS - EFNS-ENS Meeting Istanbul 2014"

  1. 1. Multiple sclerosis: an unmet need Biomarkers in MS Gavin Giovannoni Barts and The London
  2. 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 Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.
  3. 3. Why biomarkers? • Diagnostic testing • Positive & negative predictive testing • Pathogenesis • Immunology • Aetiology • Disease progression & recovery • Disease heterogeneity • Pharmacovigilance • Monitor disease processes • Prognosis (high vs. low risk patients) • Monitoring effect of therapeutic interventions
  4. 4. Diagnostic markers
  5. 5. The evolving clinical definition of MS 1. Schumacher,et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552-68. 2. Poser,et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-31. 3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7. 4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005;58:840-6. 5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
  6. 6. Will Rogers Phenomenon in Multiple Sclerosis 1879 - 1935 “When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”
  7. 7. Will Rogers Phenomenon in Multiple Sclerosis Sormani et al. Ann Neurol 2008;64:428–433. Poser McDonald
  8. 8. Inactive CIS Active CIS RRMS MS diagnosed according the old Poser Criteria Inactive CIS Less active RRMS More Active RRMS MS diagnosed according the New McDonald Criteria
  9. 9. Intrathecal synthesis of IgG Images courtesy of Prof. Ed Thompson. Isoelectric focusingwith immunfixation
  10. 10. Diagnostic criteria for Primary Progressive MS Polman et al. Ann Neurol 2005;58:840-6.
  11. 11. Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities Proportion Progressing as Percent Epoch CSF- CSF+ 6 mo 7.3 9.8 12 mo 15.0 20.4 18 mo 22.8 28.1 24 mo 25.4 34.3 Years to Progression 2.43 2.26 Based on data from a second meeting of the DSMB and assume no therapeutic effect Slide courtesy of Jerry Wolinsky 0 1 2 3 Years 0.0 0.2 0.4 0.6 0.8 1.0 ProportionProgressing Positive Negative CSF P =0.03
  12. 12. Not PPMS Not PPMS PPMS OCB+ve PPMS MS diagnosed according the initial McDonald Criteria Not PPMS PPMS OCB-ve PPMS OCB+ve PPMS diagnosed according the New McDonald Criteria
  13. 13. Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.
  14. 14. Unmet need: Evidence-based diagnostic criteria
  15. 15. What constitutes a useful diagnostic test or set of criteria? TARGET DISORDER PRESENT ABSENT DIAGNOSTIC TEST RESULT + a b a + b - c d c + d a + c b + d a + b + c + d From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116. Pathological diagnosis DiagnosticCriteria
  16. 16. A clinico-pathoanatomical study of multiple sclerosis diagnosis SENSITIVITY = True+ve /(True+ve + False-ve) Eye Department, Hvidovre Hospital, Denmark. • Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%). • Clinical diagnosis had been established by a neurologist in all cases. • Erroneous diagnosis included a variety of other neurological disorders. • Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS: • post mortem confirmation of MS was obtained in circa 66%. • The remainder the error pattern was similar to the above. Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.
  17. 17. A clinico-pathoanatomical study of multiple sclerosis diagnosis. SPECIFICITY = True-ve /(True-ve + False+ve) ~25% of cases of MS are undiagnosed in life (asymptomatic or benign cases) Engell T. Acta Neurol Scand. 1989 May;79(5):428-30..
  18. 18. Potential consequences of a misdiagnosis
  19. 19. Potential consequences of a misdiagnosis
  20. 20. Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74. PML complicating treatment with natalizumab and IFNb-1a for MS Potential fatal consequences of a misdiagnosis
  21. 21. TARGET DISORDER PRESENT ABSENT DIAGNOSTIC TEST RESULT + a b a + b - c d c + d a + c b + d a + b + c + d What constitutes a useful diagnostic test or set of criteria? From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116. Poser Criteria McDonaldCriteria XDiagnostic tautology McDonald MS Poser MS
  22. 22. Response or non-response markers
  23. 23. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University 24 MonitoringTreatmentClinicalOccup&social NAB -ve
  24. 24. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University 25 MonitoringTreatmentClinicalOccup&social NAB -ve
  25. 25. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis Sorensen et al. Lancet 2003; 362: 1184–91.
  26. 26. Anti-natalizumab Antibodies Number of Patients at Risk Placebo Antibody Negative Transiently Positive Persistently Positive 315 568 20 37 296 550 19 32 283 538 18 26 264 526 16 25 248 506 16 24 240 487 16 22 229 480 15 22 216 470 14 19 208 460 14 16 200 449 14 15 Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0 12 24 36 48 60 72 84 96 108 120 29% Placebo 17% Antibody Negative 17% Transiently Antibody Positive 34%Persistently Antibody Positive CumulativeProportionofPatients withSustainedDisability Progression(EDSS) *,† *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo Number of Patients at Risk Placebo Antibody Negative Transiently Positive Persistently Positive 315 568 20 37 296 550 19 32 283 538 18 26 264 526 16 25 248 506 16 24 240 487 16 22 229 480 15 22 216 470 14 19 208 460 14 16 200 449 14 15 Weeks 0.0 0.1 0.2 0.3 0.4 0.5 0 12 24 36 48 60 72 84 96 108 120 29% Placebo 17% Antibody Negative 17% Transiently Antibody Positive 34%Persistently Antibody Positive CumulativeProportionofPatients withSustainedDisability Progression(EDSS) *,† *p ≤0.05 vs. antibody-negative patients †p=0.66 vs. placebo 0.73 0.22 0.16 0.48* 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 AdjustedAnnualizedRelapseRate(95%CI) Placebo (n=315) Antibody Negative (n=568) Transiently Antibody Positive ( n=20) Persistently Antibody Positive (n=37) *p=0.009 vs. antibody-negative patients 0.73 0.22 0.16 0.48* 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 AdjustedAnnualizedRelapseRate(95%CI) Placebo (n=315) Antibody Negative (n=568) Transiently Antibody Positive ( n=20) Persistently Antibody Positive (n=37) *p=0.009 vs. antibody-negative patients Calabresi et al, Neurol 2007 Impact of anti-natalizumab antibodies on . . . . . Annualized relapse rate Progressive disability
  27. 27. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University 28 MonitoringTreatmentClinicalOccup&social NAB -ve
  28. 28. Natalizumab PML risk stratification tool Anti-JC virus antibody status Negative Positive Prior immunosuppressant use Natalizumab treatment >2 Years Natalizumab treatment >2 Years No Yes No Yes No Yes Lowest HighestRelative PML Risk < 1 in 10,000 1 in 941 in 256 1 in 6681 in 1887 Mitoxantrone Azathioprine Methotrexate Cyclophosphamide Mycophenolate Cladribine Rituximab Etc.
  29. 29. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University 30 MonitoringTreatmentClinicalOccup&social NAB -ve
  30. 30. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis Plavina et al. ENS 2013
  31. 31. www.ms-res.org; >750,000 views
  32. 32. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University 33 MonitoringTreatmentClinicalOccup&social NAB -ve
  33. 33. Early Detection of PML improves clinical outcome Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271. Months From PML Diagnosis
  34. 34. 60,000 70,000 80,000 90,000 100,000 110,000 120,000 130,000 0 5 10 15 20 25 Apr-10 Jun-10 Aug-10 Oct-10 Dec-10 Feb-11 Apr-11 Jun-11 Aug-11 Oct-11 Dec-11 Feb-12 Apr-12 Jun-12 Aug-12 Oct-12 Dec-12 Feb-13 Apr-13 Jun-13 Aug-13 Oct-13 Dec-13 Feb-14 Apr-14 Totalnumberonnatalizumabtreatment NumberofPMLcasespermonth Month As of the 3rd April 2014 there are 454 confirmed cases of PML De-risking natalizumab treatment Source: Data has been taken from Biogen-Idec’s monthly natalizumab risk/benefit and PML stratification update.
  35. 35. Biomarkers in the near future Is NEDA good enough? NEDA = no evident disease activity
  36. 36. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University Early or late? 37 MonitoringTreatmentClinicalOccup&social Dec 2007 Jul 2010 Jul 2013
  37. 37. Relapses Unreported relapses Clinical disease progression Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Spinal fluid neurofilament levels The unmet need: treating-2-target Clinical activity Focal MRI activity Hidden focal and diffuse MRI activity Microscopic or biochemical pathology Biomarkers
  38. 38. Rheumatoid arthritis End-stage joint disease
  39. 39. Control Multiple sclerosis
  40. 40. Brain atrophy occurs across all stages of the disease De Stefano, et al. Neurology 2010 n= 963 MSers
  41. 41. Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75:43-49.
  42. 42. -1.0% -0.8% -0.6% -0.4% -0.2% 0.0% Years 0-2 -0.82% -0.80% P=0.822† Placebo (N=315) Natalizumab (N=627) Year 0-1* Year 1-2 -0.40% -0.56% -0.43% -0.24% P=0.004† P=0.002† †Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401. AFFIRM Study: natalizumab and brain atrophy Mean(SE)percentagechangeinBPF
  43. 43. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM FREEDOMS, 2 years Fingolimod 0.5 mg (n = 356) Placebo (n = 329) *** * ** 60 12 24 Time (months) 0 -0.4 -0.8 -1.2 -1.6 -2.0 −38% vs placebo p<0.001 ChangeinmeanBVfrom baseline(%) TRANSFORMS, 1 year 0 12 Time (months) 0.0 -0.4 -0.6 -1.0 IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 368) −40% vs IFNb-1a IM p<0.001 ***-0.2 -0.8 ChangeinmeanBVfrom baseline(%) 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
  44. 44. Reduction in brain atrophy on alemtuzumab
  45. 45. Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5 Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8 AAN 2014 Blitz S65-008 1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre, Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
  46. 46. CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)  Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF  For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%) Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I) Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II) MedianChangeFrom Baseline,%(95%CI) Year No. of Patients 371 367 351 323 % Change from Previous Year – –0.59% –0.25% –0.19% MedianChangeFrom Baseline,%(95%CI) Year 428 414 405 359 – –0.48% –0.22% –0.10% No. of Patients % Change from Previous Year 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 AAN 2014 Blitz S65-008
  47. 47. CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity  The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3 MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium; MRI=magnetic resonance imaging; Y=year No. of Patients 359370 336 356370 325 354369 326 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Gd-enhancing lesion-free New/enlarging T2 lesion-free MRI activity-free % MRI Activity Free in Treatment-Naive Patients (CARE-MS I) % MRI Activity Free in Patients Who Relapsed on Prior Therapy (CARE-MS II) No. of Patients 412421 364 405423 361 Gd-enhancing lesion-free New/enlarging MRI activity-free 402414 361 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 T2 lesion-free  Patients were treated with alemtuzumab 12 mg at baseline and 12 months later  Re-treatment in Year 3 was administered upon recurrence of disease activity  18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3 AAN 2014 Blitz S65-008
  48. 48. CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)  Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF  For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%) Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I) Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II) MedianChangeFrom Baseline,%(95%CI) Year No. of Patients 371 367 351 323 % Change from Previous Year – –0.59% –0.25% –0.19% MedianChangeFrom Baseline,%(95%CI) Year 428 414 405 359 – –0.48% –0.22% –0.10% No. of Patients % Change from Previous Year 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 AAN 2014 Blitz S65-008
  49. 49. Relapses Unreported relapses Clinical disease progression Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Spinal fluid neurofilament levels The unmet need: treating-2-target Clinical activity Focal MRI activity Hidden focal and diffuse MRI activity Microscopic or biochemical pathology Biomarkers
  50. 50. Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.
  51. 51. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis Lyke et al. J Neurol Neurosurg Psychiatry 1998;64:402–404.
  52. 52. Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
  53. 53. Axonal damage in R-MS is markedly reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010; Epub.
  54. 54. Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage Romme Christensen et al. ECTRIMS 2012.
  55. 55. B aseline Follow -up 0 500 1000 1500 2000 2500 NfL(pg/ml) Cerebrospinal fluid NfL Fingolimod 0.5mg/1.25 mg versus placebo treated patients p<0.001 Fingolimod, n=23 Placebo, n=12 p=0.470 Fingolimod 0.5 mg Fingolimod 1.25 mg Baseline Follow-up Baseline Follow-up Median (pg/ml) 644 321 (-50%) 886 738 (-17%) *Non-parametric Wilcoxon matched pairs test; p value is calculated with inclusion of outliers Dr Jens Khule, ECTRIMS 2013 0 1000 2000 10000 NfL(pg/ml)
  56. 56. Axonal damage in R-MS is markedly reduced by Natalizumab Gunnarsson et al. Ann Neurol 2010; Epub.
  57. 57. Gunnarsson et al. Ann Neurol 2010; Epub. CSF NFL
  58. 58. Relapses Unreported relapses Clinical disease progression Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Spinal fluid neurofilament levels The unmet need: treating-2-target Clinical activity Focal MRI activity Hidden focal and diffuse MRI activity Microscopic or biochemical pathology Biomarkers
  59. 59. NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target Should brain volume loss and CSF neurofilament levels be included in future definitions of NEDA? No evidence of disease activity defined as:1,2 × No relapses × No sustained disability progression × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions
  60. 60. Biomarkers are also needed to optimise the risks associated with the emerging therapies
  61. 61. Conclusions • MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc. • Early highly-effective therapy is the only realistic option of preventing end-organ damage • Now an established treatment option in the EU • NEDA (DAF) and T2T are entering the neurology lexicon • Zero tolerance or ZeTo • We need an acceptable working definition of an MS cure • NEDA x 15 years? • We will need to include other biomarkers in the definition If you want a copyof these slides you can downloadfrom www.ms-res.org
  62. 62. Back-up slides
  63. 63. Control Multiple sclerosis Another infographic: end-organ damage
  64. 64. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves Lower limit of normal Average Upper limit of normal Hypothetical treatment effects
  65. 65. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves MS lower limit MS Average MS Upper limit -5% -30% Hypothetical treatment effects
  66. 66. -5% -30% 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves MS Average Hypothetical treatment effects
  67. 67. -5% -20% 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves late treatment Hypothetical treatment effects
  68. 68. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves -5% -18% early treatment late treatment Hypothetical treatment effects
  69. 69. 750 800 850 900 950 1000 1050 1100 1150 1200 1250 1300 1350 1400 1450 1500 30 35 40 45 50 55 60 65 70 75 80 BrainVolume(mL) Age (years) Brain atrophy curves -5% -11% early very highly- effective treatment late very highly- effective treatment -15% Hypothetical treatment effects
  70. 70. Treatment-effect on atrophy correlates with treatment-effect on disability Sormani et al. Ann Neurol 2014;75:43–49.
  71. 71. Coles et al. J Neurol. 2006 Jan;253(1):98-108. Post-inflammatory neurodegeneration
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