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Management of High Disease Activity in Multiple Sclerosis (MS)
- 1. Management of HighDisease Activity RRMS Patients DR SUDHIR KUMAR MD DM CONSULTANT NEUROLOGIST Apollo Hospitals, Hyderabad
- 2. Inflammation Regeneration Destruction Time since onsetof 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 inMS 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 diseaseduration 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 Therapyin 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 Pointsin 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 Patientswith 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 Highdisease 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 forRRMS 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 haveguidelines 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 couldbe a right therapy to start for HDA patients?
- 13. Natalizumab Provides MorePatients 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 Outcomesfrom 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 firstline 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 identifyTreatment Failure or Suboptimal Response ?? 16
- 17. We have differenttools 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 couldbe right option than cycling within IFNs and GA?
- 19. Escalation to NatalizumabIs 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 NatalizumabIs 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 WalkingPerformance 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 ImmunosuppressantUse 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 ofPML 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
- 24.