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Management of High Disease Activity RRMS Patients
DR SUDHIR KUMAR MD DM
CONSULTANT NEUROLOGIST
Apollo Hospitals, Hyderabad
Inflammation
Regeneration
Destruction
Time since onset of disease
MS is characterized by acute inflammation, demyelination,
axonal damage and brain atrophy
MS=multiple sclerosis
Martino G et al. J Neuroimmunol 2000;109:3–9; Trapp BD et al. N Engl J Med 1998;338:278–85; Kuhlmann T et al. Brain 2002;125:2202–12; Lucchinetti C et al. Ann Neurol
2000;47:707–17; Fisher E et al. Neurology 2002;59:1412–20
2. Demyelination 3. Axonal loss 4. Atrophy1. Inflammation
Disability evolution in MS
Years from Clinical Onset of MS
Phase 2
Phase 1
DSSScore
0 5 10 15 20 25 30
0
1
2
3
4
5
6
7
DSS=Disability Status Scale.
Leray E et al. Brain. 2010
APP and disease duration
I II III IV
0
100
200
300
400
500APP-positive
axons/mm
2
I: < 1y; II: 1-5ys; III: 5-10ys; IV: > 10ys
Courtesy of Dr Brück
Acute axonal damage in MS is most extensive in early disease stages
Goals of Therapy in MS Have Evolved as
New Treatment Options Have Become Available
1983 1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014
IFNβ-1b
1995
IM IFNβ-1a
1997
SC IFNβ-
1a
1998
Natalizumab
2006
GA
2001
Fingolimod*
2010
Introduction of RRMS therapies in the EU
?
MSFC2
1995
Freedom from clinical
and MRI activity3
2009
Sustained
improvement4
2011
Establishment of Disability Outcome Measures
EDSS1
1983
Address
Symptoms
Slow Disease Progression Stop Disease Progression
MS=multiple sclerosis; EDSS=Expanded Disability Status Scale; MSFC=Multiple Sclerosis Functional Composite; MRI=magnetic resonance imaging;
IFNβ=interferon beta; IM=intramuscular; SC=subcutaneous; GA=glatiramer acetate; RRMS=relapsing-remitting MS; EU=European Union.
1. Kurtzke J. Neurology. 1983;33:1444-1452; 2. Whitaker J et al. Mult Scler. 1995;1:37-47;
3. Havrdova E et al. Lancet Neurol. 2009;8:254-260; 4. Phillips J et al. Mult Scler. 2011;17:970-979.
Mitoxantrone
2000
Molecules currently in
studies
•Daclizumab*
•Laquinimod*
Teriflunomide*
2012
Dimethyl Fumarate,
PEG-IFNβ-1a
Alemtuzumab*
2015
* Not Approved In India
1. Inhibition 2. Stabilization
3. Improvement 4. Cure
Goals of Therapy in MS Have Evolved as
Treatment Options Have Increased
Key Decision Points in the Treatment of MS Are Also Evolving as
Goals Change
7
Disease
progression
Initiating therapy
• When to start
• Choice of first-line therapy
Escalating therapy/efficacy
• Persisting clinical/MRI activity
• Choice of second-line therapy
High Disease Activity
Patients with high disease activity despite treatment with a beta-interferon.
Patients who have failed to respond to a full and adequate course* of beta-
interferon.
At least 1 relapse in previous year on therapy
and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-
enhancing lesion
Patients with rapidly evolving, severe relapsing remitting MS
2 or more disabling relapses in one year and 1 or more Gd-enhancing lesion on
brain MRI or a significant increase of T2 burden as compared to a previous recent
MRI
Management of High disease activity
Patients with rapidly evolving, severe relapsing remitting MS
2 or more disabling relapses in one year and 1 or more Gd-enhancing lesion on
brain MRI or a significant increase of T2 burden as compared to a previous recent
MRI
Therapeutic Recommendations for RRMS
Gold, Hemmer, Wiendl, DGN Leitlinien zur MS Therapie, 2016
(Highly) active
disease course
• Natalizumab
mild/moderate
disease course
relapse therapy
• Teriflunomide
• Interferon-ß
• Glatiramer acetate
• Dimethyl fumarate
• Methylprednisolone pulse
• Plasma separation
Do we have guidelines which medication fits best?
Not at all!
 Individual decision
Advantages Disadvantages
Interferon/GA • long-lasting experience
• no significant long-term side
effects
• PEG-IFN: only every second
week
• to be injected
Dimethyl fumarate • oral
• efficacy (ARR)
• twice daily
Natalizumab • High Efficacy
• Once in month therapy
• Iv infusion
• PML risk
Why Natalizumab could be a right therapy to start for HDA patients?
Natalizumab Provides More Patients with Freedom from Disease
Activity
Post hoc analysis of AFFIRM. Natalizumab vs placebo for both overall and highly active patients.
*Patients with ≥2 relapses in prior year and ≥1 Gd+ lesion at baseline.
Havrdova E et al. Lancet Neurol. 2009;8:254-260.
ProportionofDisease-FreePatients(%)
n=304 n=600 n=59 n=146
Overall Population
P<0.0001
Highly Active Patients*
P<0.0001
7.2
1.7
36.7
27.4
0
10
20
30
40
50
Placebo
Natalizumab
5
vs placebo
16
vs placebo
Natalizumab: Efficacy Outcomes from AFFIRM
5× more than
placebo
42%–54%
reduction of
disability progression
68%
reduction in
relapse rate
53%–64%
reduction of
disability progression
81%
reduction in
relapse rate
27% vs 2%
free of disease activity
36%
vs 15%
improve in
sustained disability
16× more than
placebo
143% more than
placebo (HR=2.43)
Highly Active Patients*Overall Population
30%
vs 19%
improve in
sustained disability
37% vs 7%
free of disease activity
69% more than
placebo (HR=1.69)
*≥2 relapses reported in the year before study entry and ≥1 Gd+ lesion at the time of study entry.
Polman CH et al. N Engl J Med. 2006;354:899-910; Havrdová E et al. Lancet Neurol. 2009;8:254-260; Munschauer F et al.
Presented at ECTRIMS; September 17–20, 2008; Montréal, Quebec, Canada. Abstract P474; Hutchinson M et al. J Neurol.
2009;256:405-415, 1035-1037.
Management after first line therapy failure active MS Patients
Patients with high disease activity despite treatment with a beta-interferon
or GA
Patients who have failed to respond to a full and adequate course* of beta-
interferon or GA
At least 1 relapse in previous year on therapy
and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-
enhancing lesion
How to identify Treatment Failure or Suboptimal Response ??
16
We have different tools to identify treatment failure… 17
Rio J et al. Mult Scler. 2009; 15: 848–853; Sormani MP et al. Mult Scler. 2013;19:605-612.
Why Natalizumab could be right option than cycling within
IFNs and GA?
Escalation to Natalizumab Is More Effective Than Continuing on
Prior IFNβ/GA or Switching Within this Group
*Annualized relapse rate by treatment arm for the first event in the first 12 months.
IFN=interferon; GA=glatiramer acetate; TOP=Tysabri® Observational Program.
Spelman T et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P01.211.
Natalizumab treatment in TOP was associated with a significant reduction in risk of relapse,
compared with a prospective outcome registry of RRMS patients experiencing at least one
relapse on treatment with IFN-GA (MS-COMET).
0.54
0.25
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Unmatched, Unadjusted
n=694 n=3976
AnnualizedRelapseRate*
54%
IFN-GA (MS-COMET)
Natalizumab (TOP)
P<0.0001
0.66
0.11
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Propensity Matched
n=569 n=569
83%
P<0.0001
AnnualizedRelapseRate*
Escalation to Natalizumab Is More Effective Than Switching Among
IFN/GA
0
25
50
75
100
%Patients
Escalate to Natalizumab, n=106
Switch Between IFN/GA, n=161
Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed.
After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161).
*There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI
activity, and combined activity.
IFN=interferon beta.
Prosperini L et al. Mult Scler. 2012;18:64-71.
No EDSS
Progression
No MRI Activity Disease
Activity Free
P<0.0001 P=0.0003 P<0.0001
51
36
51
21
83
67
72
59
No Relapses
P<0.0045
Over 24 months*
Natalizumab Improves Walking Performance in RRMS Patients
After Previous Therapy Failure
Belachew S et al. Eur J Neurol. 2011;18:240-245.
33.3
38.1
28.6
23.8
0
10
20
30
40
Patientswith3-MonthSustained
>20%Improvement(%)
Treatment Duration
20 Weeks
Dose 6
44 Weeks
Dose 12
Prior Treatment
IFNβ
GA
Anti-JCV Antibody Status
Prior
Immunosuppressant Use
Positive
Treatment Duration >2
years
Treatment Duration ≤2
years
Negative
No Prior Immunosuppressant
Use
Low Index High Index
• Yearly brain MRI
• Anti-JCV antibody testing
every 6 months
• Yearly brain MRI • Yearly brain MRI
• Abbreviated brain MRI protocol
(T2, FLAIR and DWI) every 3-6 months
• Yearly brain MRI
• Anti-JCV antibody testing
every 6 months with Index
Summary of the Recommended Monitoring
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Tysabri_20/Opinion_provided_by_Committee_fo
Use/WC500203426.pdf
Early Detection of PML and Clinical Outcome
• Detection of PML on routine MRI (confirmed by CSF analysis) has
been demonstrated in asymptomatic patients1–5
– Asymptomatic PML patients have improved survival and less
functional disability compared with symptomatic patients6
FLAIR=fluid-attenuated inversion recovery.
1. Vermersch P et al. Neurology. 2011;76:1697-1704; 2. Phan-Ba R et al. Neurology. 2012;79:1067-1069;
3. Blair NF et al. Neurology. 2012;78:507-508; 4. Ayzenberg I et al. J Neurol. 2012;259:1732-1733; 5. Yousry TA et al. Ann Neurol. 2012;72:779-787;
6. Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271.
Months from PML Diagnosis
Thank you

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Management of High Disease Activity in Multiple Sclerosis (MS)

  • 1. Management of High Disease Activity RRMS Patients DR SUDHIR KUMAR MD DM CONSULTANT NEUROLOGIST Apollo Hospitals, Hyderabad
  • 2. Inflammation Regeneration Destruction Time since onset of disease MS is characterized by acute inflammation, demyelination, axonal damage and brain atrophy MS=multiple sclerosis Martino G et al. J Neuroimmunol 2000;109:3–9; Trapp BD et al. N Engl J Med 1998;338:278–85; Kuhlmann T et al. Brain 2002;125:2202–12; Lucchinetti C et al. Ann Neurol 2000;47:707–17; Fisher E et al. Neurology 2002;59:1412–20 2. Demyelination 3. Axonal loss 4. Atrophy1. Inflammation
  • 3. Disability evolution in MS Years from Clinical Onset of MS Phase 2 Phase 1 DSSScore 0 5 10 15 20 25 30 0 1 2 3 4 5 6 7 DSS=Disability Status Scale. Leray E et al. Brain. 2010
  • 4. APP and disease duration I II III IV 0 100 200 300 400 500APP-positive axons/mm 2 I: < 1y; II: 1-5ys; III: 5-10ys; IV: > 10ys Courtesy of Dr Brück Acute axonal damage in MS is most extensive in early disease stages
  • 5. Goals of Therapy in MS Have Evolved as New Treatment Options Have Become Available 1983 1994 1996 20001998 2002 2004 2006 2008 2010 2012 2014 IFNβ-1b 1995 IM IFNβ-1a 1997 SC IFNβ- 1a 1998 Natalizumab 2006 GA 2001 Fingolimod* 2010 Introduction of RRMS therapies in the EU ? MSFC2 1995 Freedom from clinical and MRI activity3 2009 Sustained improvement4 2011 Establishment of Disability Outcome Measures EDSS1 1983 Address Symptoms Slow Disease Progression Stop Disease Progression MS=multiple sclerosis; EDSS=Expanded Disability Status Scale; MSFC=Multiple Sclerosis Functional Composite; MRI=magnetic resonance imaging; IFNβ=interferon beta; IM=intramuscular; SC=subcutaneous; GA=glatiramer acetate; RRMS=relapsing-remitting MS; EU=European Union. 1. Kurtzke J. Neurology. 1983;33:1444-1452; 2. Whitaker J et al. Mult Scler. 1995;1:37-47; 3. Havrdova E et al. Lancet Neurol. 2009;8:254-260; 4. Phillips J et al. Mult Scler. 2011;17:970-979. Mitoxantrone 2000 Molecules currently in studies •Daclizumab* •Laquinimod* Teriflunomide* 2012 Dimethyl Fumarate, PEG-IFNβ-1a Alemtuzumab* 2015 * Not Approved In India
  • 6. 1. Inhibition 2. Stabilization 3. Improvement 4. Cure Goals of Therapy in MS Have Evolved as Treatment Options Have Increased
  • 7. Key Decision Points in the Treatment of MS Are Also Evolving as Goals Change 7 Disease progression Initiating therapy • When to start • Choice of first-line therapy Escalating therapy/efficacy • Persisting clinical/MRI activity • Choice of second-line therapy
  • 8. High Disease Activity Patients with high disease activity despite treatment with a beta-interferon. Patients who have failed to respond to a full and adequate course* of beta- interferon. At least 1 relapse in previous year on therapy and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd- enhancing lesion Patients with rapidly evolving, severe relapsing remitting MS 2 or more disabling relapses in one year and 1 or more Gd-enhancing lesion on brain MRI or a significant increase of T2 burden as compared to a previous recent MRI
  • 9. Management of High disease activity Patients with rapidly evolving, severe relapsing remitting MS 2 or more disabling relapses in one year and 1 or more Gd-enhancing lesion on brain MRI or a significant increase of T2 burden as compared to a previous recent MRI
  • 10. Therapeutic Recommendations for RRMS Gold, Hemmer, Wiendl, DGN Leitlinien zur MS Therapie, 2016 (Highly) active disease course • Natalizumab mild/moderate disease course relapse therapy • Teriflunomide • Interferon-ß • Glatiramer acetate • Dimethyl fumarate • Methylprednisolone pulse • Plasma separation
  • 11. Do we have guidelines which medication fits best? Not at all!  Individual decision Advantages Disadvantages Interferon/GA • long-lasting experience • no significant long-term side effects • PEG-IFN: only every second week • to be injected Dimethyl fumarate • oral • efficacy (ARR) • twice daily Natalizumab • High Efficacy • Once in month therapy • Iv infusion • PML risk
  • 12. Why Natalizumab could be a right therapy to start for HDA patients?
  • 13. Natalizumab Provides More Patients with Freedom from Disease Activity Post hoc analysis of AFFIRM. Natalizumab vs placebo for both overall and highly active patients. *Patients with ≥2 relapses in prior year and ≥1 Gd+ lesion at baseline. Havrdova E et al. Lancet Neurol. 2009;8:254-260. ProportionofDisease-FreePatients(%) n=304 n=600 n=59 n=146 Overall Population P<0.0001 Highly Active Patients* P<0.0001 7.2 1.7 36.7 27.4 0 10 20 30 40 50 Placebo Natalizumab 5 vs placebo 16 vs placebo
  • 14. Natalizumab: Efficacy Outcomes from AFFIRM 5× more than placebo 42%–54% reduction of disability progression 68% reduction in relapse rate 53%–64% reduction of disability progression 81% reduction in relapse rate 27% vs 2% free of disease activity 36% vs 15% improve in sustained disability 16× more than placebo 143% more than placebo (HR=2.43) Highly Active Patients*Overall Population 30% vs 19% improve in sustained disability 37% vs 7% free of disease activity 69% more than placebo (HR=1.69) *≥2 relapses reported in the year before study entry and ≥1 Gd+ lesion at the time of study entry. Polman CH et al. N Engl J Med. 2006;354:899-910; Havrdová E et al. Lancet Neurol. 2009;8:254-260; Munschauer F et al. Presented at ECTRIMS; September 17–20, 2008; Montréal, Quebec, Canada. Abstract P474; Hutchinson M et al. J Neurol. 2009;256:405-415, 1035-1037.
  • 15. Management after first line therapy failure active MS Patients Patients with high disease activity despite treatment with a beta-interferon or GA Patients who have failed to respond to a full and adequate course* of beta- interferon or GA At least 1 relapse in previous year on therapy and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd- enhancing lesion
  • 16. How to identify Treatment Failure or Suboptimal Response ?? 16
  • 17. We have different tools to identify treatment failure… 17 Rio J et al. Mult Scler. 2009; 15: 848–853; Sormani MP et al. Mult Scler. 2013;19:605-612.
  • 18. Why Natalizumab could be right option than cycling within IFNs and GA?
  • 19. Escalation to Natalizumab Is More Effective Than Continuing on Prior IFNβ/GA or Switching Within this Group *Annualized relapse rate by treatment arm for the first event in the first 12 months. IFN=interferon; GA=glatiramer acetate; TOP=Tysabri® Observational Program. Spelman T et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P01.211. Natalizumab treatment in TOP was associated with a significant reduction in risk of relapse, compared with a prospective outcome registry of RRMS patients experiencing at least one relapse on treatment with IFN-GA (MS-COMET). 0.54 0.25 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Unmatched, Unadjusted n=694 n=3976 AnnualizedRelapseRate* 54% IFN-GA (MS-COMET) Natalizumab (TOP) P<0.0001 0.66 0.11 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Propensity Matched n=569 n=569 83% P<0.0001 AnnualizedRelapseRate*
  • 20. Escalation to Natalizumab Is More Effective Than Switching Among IFN/GA 0 25 50 75 100 %Patients Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161 Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. IFN=interferon beta. Prosperini L et al. Mult Scler. 2012;18:64-71. No EDSS Progression No MRI Activity Disease Activity Free P<0.0001 P=0.0003 P<0.0001 51 36 51 21 83 67 72 59 No Relapses P<0.0045 Over 24 months*
  • 21. Natalizumab Improves Walking Performance in RRMS Patients After Previous Therapy Failure Belachew S et al. Eur J Neurol. 2011;18:240-245. 33.3 38.1 28.6 23.8 0 10 20 30 40 Patientswith3-MonthSustained >20%Improvement(%) Treatment Duration 20 Weeks Dose 6 44 Weeks Dose 12 Prior Treatment IFNβ GA
  • 22. Anti-JCV Antibody Status Prior Immunosuppressant Use Positive Treatment Duration >2 years Treatment Duration ≤2 years Negative No Prior Immunosuppressant Use Low Index High Index • Yearly brain MRI • Anti-JCV antibody testing every 6 months • Yearly brain MRI • Yearly brain MRI • Abbreviated brain MRI protocol (T2, FLAIR and DWI) every 3-6 months • Yearly brain MRI • Anti-JCV antibody testing every 6 months with Index Summary of the Recommended Monitoring http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Tysabri_20/Opinion_provided_by_Committee_fo Use/WC500203426.pdf
  • 23. Early Detection of PML and Clinical Outcome • Detection of PML on routine MRI (confirmed by CSF analysis) has been demonstrated in asymptomatic patients1–5 – Asymptomatic PML patients have improved survival and less functional disability compared with symptomatic patients6 FLAIR=fluid-attenuated inversion recovery. 1. Vermersch P et al. Neurology. 2011;76:1697-1704; 2. Phan-Ba R et al. Neurology. 2012;79:1067-1069; 3. Blair NF et al. Neurology. 2012;78:507-508; 4. Ayzenberg I et al. J Neurol. 2012;259:1732-1733; 5. Yousry TA et al. Ann Neurol. 2012;72:779-787; 6. Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271. Months from PML Diagnosis