Tactics and techniques in management of Multiple sclerosis
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This document discusses key decision making points in the treatment of multiple sclerosis. It begins with the author's disclosure statement noting they have received honoraria from various pharmaceutical companies. It then outlines the process for diagnosing MS and distinguishing it from other conditions. Several factors that influence the choice of first-line therapy are discussed, including adherence, patient preferences, prognostic factors, disease activity, comorbidities, safety, tolerability, efficacy, and pregnancy plans. Strategies for improving adherence are presented. The risks and categories of various disease-modifying therapies during pregnancy are shown. Methods for stratifying individual patient risk are provided. Definitions of highly active MS are outlined. The document concludes with recommendations on escalating versus inducing therapy based
![– Male (vs female) sex and all age groups older than the
18-to-34-year group were significantly associated with a
higher probability of adherence to the index DMD type
(odds ratios [ORs] for nonadherence: 0.812 and 0.696–
0.812, respectively; p,0.05 for all comparisons).
– The presence of depression was associated with a
significantly higher likelihood of being nonadherent to
therapy (OR: 1.722; p,0.0001).
– Index DMD type was not a significant predictor of DMD
nonadherence (OR: 1.144; p=0.1821).
Factors predictive of DMD nonadherence](https://image.slidesharecdn.com/tacticsandtechniquesinmanagementofms-180518154815/85/Tactics-and-techniques-in-management-of-Multiple-sclerosis-25-320.jpg)
Tactics and techniques in management of Multiple sclerosis
- 1. Amr Hassan MD,FEBN Associate professor of Neurology Cairo University 2018 Tactics and techniques in Management of Multiple Sclerosis
- 2. Disclosure Received honoria or travel/registration coverage of international congresses and symposia from Novartis, Merck, Biologix, Roche, Sanofi GENZYME, Bayer, HIKMA pharma, Al Andalus.
- 3. Key decision making points in Treatment of MS
- 4. Key decision making points in Treatment of MS
- 5. Key decision making points in Treatment of MS
- 6. Key decision making points in Treatment of MS
- 7. 7 Clinical/Paraclinical/Imaging suggestive of inflammatory demyelinating disease Fulfills Criteria of DIT and DIS (McDonald’s criteria) Atypical presentation for MS (Red Flags Present) ** Work Up for Alternative Diagnoses Clinical/Imaging Follow Up Alternative Diagnosis Established (DIT and/or +ve OCB) and DIS are fulfilled (McDonald’s criteria) or CDMSMS Diagnosis Typical for MS not Fulfilling Criteria of DIT and DIS (McDonald’s criteria) =CIS Clinical/Imaging Follow Up every 6 months for 2 years Stratify risk of conversion to MS (Demographics,Number and location of MRI lesions,) high low yes Start DMT No Exclude non demyelinating syndromes* and demyelinating syndromes other than MS (NMO,ADEM) Clinical/Imaging Follow Up every year for 3 years
- 8. Effect of baseline clinical, biological and MRI characteristics on the conversion to CDMS
- 9. 9 Effect of baseline clinical, biological and MRI characteristics on the conversion to CDMS
- 10. Key decision making points in Treatment of MS
- 11. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 12. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 13. Gold et al, NEJM 2012, Comi et al, NEJM 2012, Kappos et al, NEJM 2010, O’Connor et al, NEJM 2011, Kappos et al, Neurology 2006 13 Completers on study drug Study Completers in Recent Clinical Trials
- 14. *No information whether these patients are still taking the medication provided. Gold et al, NEJM 2012, Comi et al, NEJM 2012, Kappos et al, NEJM 2010, O’Connor et al, NEJM 2011, Kappos et al, Neurology 2006 14 Study completers* Study completers* Study Drug Adherence Rates in Recent Clinical Trials
- 15. Route of administration Short courses/ Low frequency Low monitoring requirements Durable efficacy /Well tolerated treatment Improving patient adherence
- 16. Begus-Nahrmann Y et al. Presented at ECTRIMS; September 14–17, 2016; London, UK, P1214. Individualized Patient Coaching: Reasons for Therapy Discontinuation and Dropout
- 17. Coached patients reported almost 100% fewer total discontinuations (29.2%) over 24 months compared with the control cohort (56.4%) *Data represent Kaplan-Meier estimates of discontinuation data. GI=gastrointestinal. Begus-Nahrmann Y et al. Presented at ECTRIMS; September 14–17, 2016; London, UK, P1214. Total Dropouts* GI-Specific Dropouts* Individualized Patient Coaching: Total Dropouts and GI-Specific Dropouts
- 18. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 19. Ruth Ann Marrie, Nature Reviews Neurology , 13,375–382 (2017) MS Comorbidities
- 20. Ruth Ann Marrie, Nature Reviews Neurology , 13,375–382 (2017) MS Comorbidities
- 21. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 22. Integrated GBP Summary • Templates • December 2014 • For Internal Use Only G.MKT.GN.09.2015.0091 €Billion Share within injectable subset MS market will grow due to multiple, new oral entrants, however, oral growth will eventually stabilize due to relatively small differences between compounds Betaferon needs to stay focused on the injectable segment – 1.5% market share represents more than €100mm revenue Source: 2010-2014 based on company reported sales (Q4-2014 estimated). 2016+ projected during Strako Page 22 • 16.7 14.6 12.2 11.0 16.1 17.5 18.1 Despite new oral entrants, injectables will still deliver 6 billion euros in 2018
- 23. Reported better adherence with injectables than orals MS center cohort evaluation, Lexington, MA, US 6.2% 11.9% 11.9% 11.3% 0% 10% 20% 30% 40% 50% Fingolimod (n=889) GA (n=1233) IFNB (n=1341) Natalizumab (n=287) %ofpatientswithMPR<80%duringthelastyear MPR: Medication possession ratio, Bergvall et al J Med Econ 2014 17 696-707, Dionne et al CMSC 2015 P DX19 N=30 N=89 N=90 in past 4 weeks 23 Reported better adherence with orals than injectables Data from PharMetrics Plus US administrative claims data all p <0.05 vs. fingolimod Real world: Is adherence with oral drugs better than with injectables?
- 24. Factors predictive of DMD nonadherence
- 25. – Male (vs female) sex and all age groups older than the 18-to-34-year group were significantly associated with a higher probability of adherence to the index DMD type (odds ratios [ORs] for nonadherence: 0.812 and 0.696– 0.812, respectively; p,0.05 for all comparisons). – The presence of depression was associated with a significantly higher likelihood of being nonadherent to therapy (OR: 1.722; p,0.0001). – Index DMD type was not a significant predictor of DMD nonadherence (OR: 1.144; p=0.1821). Factors predictive of DMD nonadherence
- 26. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 27. Category A Category B Glatiramer Acetate Category C Interferons, Tysabri, Gilenya, Tecfidera Category D Category X Aubagio *Description in Notes Section Depicted from http://depts.washington.edu/druginfo/Formulary/Pregnancy.pdf accessed March 14 2012, Category allocation according to US prescribing information of the respective products as of Nov 2012. Category X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Risk For Fetus Pregnancy Categories – US* 27 Pregnancy plans
- 28. • Try to stabilize patient 6 months -1 year prior to trials of pregnancy (attack free + stable MRI). • Stop DMDs before conception attempts 28 6 months 1 month GA DMF 2 months 3 months Immuran Mitoxantrone Methotrexate: (either parent) 4 months Alemutuzumab 12 months Rituximab Precautions before pregnancy. INF fingolimode Natalzumab Pregnancy plans
- 29. 29 GAAlemutuzumab INF Natalzumab DMTs that can be used during pregnancy
- 30. Pregnancy plans
- 31. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 32. 32 GOOD Epideiological factors BAD Female Sex Male < 40 y Age > 40 y Stratify individual patients based on risk of MS disability progression Freedman et al., 2016
- 33. 33 GOOD RELAPSES BAD Mild, monofocal 1st relapse Severe , multifocal Sensory, ON Clinical presentation Motor, cerebellar Full recovery Response to ttt Residual Long Time to 2nd relapse Short Low Relapse rate High Stratify individual patients based on risk of MS disability progression Freedman et al., 2016
- 34. 34 GOOD DISABILITY BAD Long Time to EDSS 4-5 Short GOOD MRI BAD Low T2 Lesion load High Absent CEL Present Absent Black holes Present Absent Infratentorial lesions Present Stratify individual patients based on risk of MS disability progression Freedman et al., 2016
- 35. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 36. • EDSS score of 4.0 within 5 years of onset • Poor response to at least 1 full year of therapy with one or more disease-modifying therapies, not because of intolerance • Breakthrough disease over at least 1 year of disease-modifying therapy consisting of: – Two or more disabling relapses with incomplete resolution – Two or more MRI studies showing new or enlarging T2 lesions or gadolinium-enhancing lesions Freedman et al., 2016 Definition of Highly active MS
- 39. Too aggressive for a mild disease Too mild for an aggressive disease Treatment decision making
- 40. New Real-World Results from the TYSABRI® Observational Program (TOP): In Treatment-Naïve RRMS Patients Initiating Natalizumab Earlier Is Associated with Greater Disability Improvement Than Delaying Treatment American Academy of Neurology 2017 - 69th Annual Meeting I April 22-28, 2017 I Boston, MA
- 41. TOP: Initiating Natalizumab Earlier in the Treatment Sequence was Associated with Less Disease Activity over 2 Years *Confirmed EDSS improvement was defined as a decrease, sustained for 24 weeks, of ≥1.0 point from a baseline EDSS score ≥2.0. MS=multiple sclerosis; DMT=disease-modifying treatment; EDSS=Expanded Disability Status Scale; ARR=annualized relapse rate; CI=confidence interval; BRACE=Betaferon®, Betaseron®, Rebif®, Avonex®, Copaxone® or Extavia®. Butzkueven H et al. Presented at AAN; April 15–21, 2016; Vancouver, Canada. P2.069. 0.0 0.5 1.0 1.5 2.0 2.5 BRACE Fingolimod Treatment naive Treatment Prior to Starting Natalizumab Pre-natalizumab (n=4688) (n=552) P<0.0001 P<0.0001P<0.0001 ARR Pre- and Post-Natalizumab by Prior Therapy Cumulative Probability of 24-Week Confirmed EDSS Improvement During the First 96 Weeks of Natalizumab Treatment* ARR(95%CI) 1.99 0.22 2.05 0.35 2.06 0.16 Number of Patients at Risk BRACE3975 3767 3588 3074 2863 2622 2457 2263 2107 Fingolimod 149 133 119 104 91 78 73 62 51 Treatment naive 443 412 389 331 297 263 244 207 186 0 12 24 4836 7260 84 96 CumulativeProbability BRACE Fingolimod Treatment naive Weeks from First Natalizumab Infusion 1.00 0.80 0.60 0.40 0.20 0 33.2% 21.4% 22.1%
- 42. TOP: Patients Who Remained on Natalizumab Therapy had Sustained and Potentially Enhanced Reductions in EDSS Progression Over Time EDSS=Expanded Disability Status Scale. Wiendl H et al. PLoS One. 2016;11:e0144834. 0.2 Months 0–24Months 25–48Months 1–48 Patients(%) 100 80 60 40 20 0 100 80 60 40 20 0 Only 3 of 496 patients (0.6%) experienced 6-month confirmed disability progression in both treatment epochs, and only 1 of 496 patients (0.2%) experienced 12-month confirmed disability progression in both treatment epochs 6-Month Confirmed 12-Month Confirmed 0.6 Months 1–24Months 25–48Months 1–48 Patients(%) No confirmed progression Confirmed progression in months 1–24 Confirmed progression in months 25–48 Confirmed progression in months 1–24 only Confirmed progression in months 25–48 only Confirmed progression in both epochs Proportion of Patients with Confirmed EDSS Progression in Different Treatment Epochs (4-year completers, n=496) 10.9 89.1 93.8 6.3 83.5 10.3 5.7 9.5 90.5 4.6 95.4 4.4 9.3 86.1
- 43. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 44. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 45. Patient Disease DMTs Factors governing Choice of the 1st line therapy Adherence Preference Prognostic factors Activity Comorbidities Safety Tolerability Efficacy Pregnancy plans
- 46. Comparative efficacy of oral therapies Fingolimod BG-12 Teriflunomide ARR FREEDOMS ↓ 54% * DEFINE ↓ 48% * TEMSO ↓ 31%* TRANSFORMS ↓ 52% * CONFIRM ↓ 50% * TOWER ↓ 36%* FREEDOMS II ↓ 48% * Confirmed disability progression FREEDOMS ↓ 30% * DEFINE ↓ 34% * TEMSO ↓ 30%* TRANSFORMS ↓ 29% CONFIRM ↓ 24% TOWER ↓31%*FREEDOMS II ↓ 17% * P< 0.05
- 47. Comparing DMF to Fingolimod :A single Center Experience Hersh et al. ECTRIMS 2016 A total of 775 patients treated with DMF and Fingolimod were identified from a single large academic MS center. Measures of disease activity were assessed using chi-square unadjusted comparisons and propensity score adjustment. Outcomes included proportions of patients with relapses and MRI activity within 12 months of DMT initiation.
- 48. DMT Efficacy Moderate Efficacy’High Efficacy Continuous Therapy Natalizumab Ocrelizumab Cladribine Non- continuous therapy Alemluzumab OralsInjectables Dimethy fumarate Teriflunomide Fingolimod IFNB PEG-INFB-1a Glatiramer acetate Daclizumab’ Classification of DMTS
- 49. Maintenance/Escalation Therapy (MET) Immune Reconstitution Therapy (IRT) Choroic Therapy that is maintained and/or escalated over time resulting in changes in immune function only during active treatment Short course therapy resulting in long-team Qulitative changes in immune function Immunomodulation …. Immunosuppression MET that results in continuous immunomodulation E.g.intreferon-B MET that results in continuous immunosuppression E.g.fingolimod Selective IRT (SIRT) Non-Selective IRT (NIRT) IRT that selectively affects the adaptive immune system IRT that affects both the innate & adaptive immune systems E.g. cladribine E.g. alemtuzumab A New Classification of Disease-Modifying Therapies for RMS
- 51. Unmet need Efficacy Vs Safety
- 55. • NEDA • MEDA Definition of suboptimal response
- 56. NEDA 3 NEDA
- 57. NF 5 Cognition 6 NEDA 3 NEDA 6 NEDA 5 NEDA 4 NEDA
- 58. MEDA
- 59. Definition of suboptimal response
- 67. NEDA-4/5 Brain atrophy and CSF neurofilament levels NZ/AZ/Fingo/DAC/Clad NEDA-3 Focal MRI activity NZ/AZ Fanigo/Dac/Clad IFNBeta/GA/ Teri/DMF NEDA-1 & 2 Focal MRI activity NZ/AZ Fingo/Dac/Clad IFNBeta/GA/ Teri/DMF MS Disease Acitivity Rapidly-evolving Severe Highly-active Active Inactive Conventional Step-care Rapid Escalation Early top-down “FLIPPING THE PYRAMID IN MS”
- 68. Evolving Paradigm: Individualized Treatment Based on projected Disease Course The Individual MS Paient • MS Prognosis • Patient Preferences • Treatment history • Potential to remain adherent Therapy Choice • Therapy Choice tailored to individual Patient profile, including MS Prognosis and Consideration of the context of MS disease progression when Evaluating risk of treatment Ongoing Assessment: • Clinical - Relapse - Disabiliity Progressiom • MRI - T2 lesions - T1 Gd-enhandng lesions • Bioarkers of reduced drug activity and/or safety - NAbs • Tolerability • Safety event • Adherece Define the individual MS Patient Profile Discuss therapy options With Patient/ Choose therapy Ongoing assessment Stable treatment? no Yes
- 70. MS treatment Algorithm 1 St-line TX IFH, GA, Terifiunomide, DMF Perceived level of disease Switch therapy Low Another 1 st-line HIGH 2 nd-line agent Fingo, NZ or Alemtuzumab Temporary Permanent 3rd-line agent Mx, Cy or cladrbine (sc,Iv) both temporary with exposure octated by dose Further suboptimal Tx response Experimental therapies Type of escalstion Monitor Tx response S1 year Switch therapy Monitor Tx response S1 year
- 71. Key decision making points in Treatment of MS