1. A Practical Approach to Current and Emerging Therapies for the Community Neurologist

2. Daniel Kantor, MD Ponte Vedra, FL Ramon Gil, MD Port Charlotte, FL Achraf Makki, MD Panama City, FL Daniel Kantor, MD Ponte Vedra, FL Ramon Gil, MD Port Charlotte, FL Achraf Makki, MD Panama City, FL Faculty

3. Case 1 Chief Complaint Numbness/tingling and weakness - I have never been to a neurologist before Chief Complaint Numbness/tingling and weakness - I have never been to a neurologist before

4. History of Present Illness 33 year old RH WW 5 week history of intermittent numbness in both arms and legs 1.5 week history of weakness in left arm/leg 33 year old RH WW 5 week history of intermittent numbness in both arms and legs 1.5 week history of weakness in left arm/leg

5. Past Medical History Childhood asthma Lupus (cousin) No MS Oral birth control Family History Medications

6. Social History Tobacco – None Alcohol – Social Drugs – None Single, no children Currently looking for a job in technology Tobacco – None Alcohol – Social Drugs – None Single, no children Currently looking for a job in technology

7. Exam General Exam: Normal Mental status / higher cognitive function / Speech / language: normal CN: II-XII – Normal Motor: (L) deltoid and iliopsoas 4/5, otherwise 5/5; no spasticity Sensory: Normal Reflexes: 2+ -(L) plantar response extensor (upgoing toe) Coordination: Normal Gait: Slightly wide-based General Exam: Normal Mental status / higher cognitive function / Speech / language: normal CN: II-XII – Normal Motor: (L) deltoid and iliopsoas 4/5, otherwise 5/5; no spasticity Sensory: Normal Reflexes: 2+ -(L) plantar response extensor (upgoing toe) Coordination: Normal Gait: Slightly wide-based

8. Question What other testing is needed?

9. Labs ANA – negative Vitamin B12 – normal TSH – normal ESR – normal Hepatitis B – negative Hepatitis C – negative Lyme - negative ANA – negative Vitamin B12 – normal TSH – normal ESR – normal Hepatitis B – negative Hepatitis C – negative Lyme - negative

10. Question If an MRI is going to be performed, which body part(s) should be scanned?

11. MRI ? Brain (with special orbital cuts) Cervical Thoracic Lumbar (outside central nervous system) With and without gadolinium Enhancement depends on -Dose of gadolinium -Delay between administration and scanning Closed MRI  higher Tesla (magnetic strength) Brain (with special orbital cuts) Cervical Thoracic Lumbar (outside central nervous system) With and without gadolinium Enhancement depends on -Dose of gadolinium -Delay between administration and scanning Closed MRI  higher Tesla (magnetic strength)

12. MRI Brain Two 4-5 cm lesions - Left juxtacortical gadolinium enhancing lesion -Right periventricular non-enhancing lesion MRI of spine is negative Two 4-5 cm lesions - Left juxtacortical gadolinium enhancing lesion -Right periventricular non-enhancing lesion MRI of spine is negative

13. Question Should a lumbar puncture be performed?

14. Role of CSF in Diagnosis Presence of oligoclonal bands or an elevated IgG/albumin index is evidence of intrathecal antibody production, presumably from resident plasma cells with the CNS Has a very important role in the diagnostic criteria for PPMS Interestingly, in patients with MRIs that are consistent with demyelination disseminated in time and space, only 16% of directors of MS centers would examine the CSF Presence of oligoclonal bands or an elevated IgG/albumin index is evidence of intrathecal antibody production, presumably from resident plasma cells with the CNS Has a very important role in the diagnostic criteria for PPMS Interestingly, in patients with MRIs that are consistent with demyelination disseminated in time and space, only 16% of directors of MS centers would examine the CSF Tornatore,C, et al. Neurol Clin Pract. 2012;2 (1): 48-57.

15. CSF (cerebrospinal fluid) IgG index elevated Oligoclonal bands - positive IgG index elevated Oligoclonal bands - positive

16. Question Does this patient meet criteria for MS?

17. Criteria for Diagnosis of MS Dissemination in Space (DIS) Dissemination in Time (DIT)

18. 2010 McDonald MRI Criteria for Demonstration of DIS Polman CH, et al. Ann Neurol. 2011;69:292-302. DIS can be demonstrated by ≥1 T2 Lesion a in at Least 2 of 4 areas of the CNS: - Periventricular - Juxtacortical - Infratentorial - Spinal Cord b a Gadolinium enhancement of lesions is not required DIS b If a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the Criteria and do not contribute to lesion count

19. Polman CH, et al. Ann Neurol. 2011;69:292-302. DIT can be demonstrated by: A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan irrespective of the timing of the baseline MRI Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time 2010 McDonald MRI Criteria for Demonstration of DIT

20. The 2010 McDonald Criteria for Diagnosis of MS Polman CH, et al. Ann Neurol. 2011;69:292-302. Clinical PresentationAdditional Data Needed for MS Diagnosis ≥2 attacks; objective clinical evidence of ≥2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack None ≥2 attacks; objective clinical evidence of 1 lesion Dissemination in space, demonstrated by: ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord); or Await a further clinical attack implicating a different CNS site 1 attack; objective clinical evidence of ≥2 lesions Dissemination in time demonstrated by: Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time, or A new T2 and/or gladolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack 1 attack; objective clinical evidence of 1 lesion (clinically isolated syndrome) Dissemination in space and time, demonstrated by: For DIS: ≥1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord); or Await a further clinical attack implicating a different CNS site; and For DIT: A new T2 and/or gladolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or Await a second clinical attack

21. Prognostic Risk Factors in MS Six risk factors Completeness of recovery from initial attacks Attack frequency in first 2 years (relapse rate) Interval between first and second attack MRI status Symptoms at onset Age at onset Patient risk groups Low – 0 to 1 risk factor Medium – 2 to 3 risk factors High – 4 to 6 risk factors At diagnosis of CDMS Final follow-up (mean, 37.2 mo) LowMedium High 0 1 2 3 4 Risk Group Average EDSS An 8 yr retrospective chart review study of 98 MS patients P value shows significance for both the between-risk group final EDSS scores and change in EDSS scores. Scott, et al. Neurology. 2000;55:689.

22. Question What are our treatment options?

23. FDA Approved Medications 2012 NameDoseRouteFreq.Refrigerate Beta interferon 1a30 mcgIMQWY Beta interferon 1b250 mcgSCQODN Beta interferon 1a44 mcgSCTIWY Glatiramer Acetate20 mgSCDailyY Natalizumab300 mgIVMonthlyN/A Fingolimod0.5 mgPODailyN Teriflunomide7 or 14 mgPODailyN MitoxantroneVariableIVVariableN/A

24. Existing and Emerging MS Therapies Phase III completedIn Phase III Approved therapies 20092010 2011 200519952000 Fingolimod Alemtuzumab Dimethyl Fumarate (BG-12) Teriflunomide IFNβ-1b IM NatalizumabIFNβ-1b SC Glatiramer Acetate IFNβ-1a IM IFNβ-1a SC Mitoxantrone Laquinimod Approval date Estimated launch date Cladribine* 2012 *In March 2011, the FDA did not approve cladribine and requested an improved understanding of its safety risks and overall benefit- risk profile Daclizumab Ocrelizumab Ofatumumab Mastinib Dalfampridine Dextromehtorphan/ Quinidine Approved Sx Mgt Pending Safety Data

25. Treatment of the Newly Diagnosed MS Patient All of the immunomodulatory agents have a potential role in the treatment of the newly diagnosed MS patient

26. Beta Interferons and Glatiramer Phase III data from pivotal trials for all 3 interferons and glatiramer have been standard of care for the past 2 decades in newly diagnosed MS patients Jacobs, et al. Ann Neurol. 1996;39:285. Johnson, et al. Neurology. 1995;45:1268. IFNB MS Study Group. Neurology. 1993;43:655. Johnson, et al. Neurology. 1998;50:701. PRISMS Study Group. Lancet. 1998;352:1498.

27. Newer Agents Different mechanisms of action Different modes of delivery (IV, PO) Potential for safety issues Different mechanisms of action Different modes of delivery (IV, PO) Potential for safety issues Polman CH, et al. N Engl J Med. 2006;354:899-910. Cohen J, et al. N Engl J Med. 2010;362:402-415.

28. Continuation of Our Case 5 years have elapsed When to consider switching - Relapses – how many? - Disability progression – how many EDSS points? Worsening cognition Worsening fatigue - MRI – how many new T2 hyperintensities? 5 years have elapsed When to consider switching - Relapses – how many? - Disability progression – how many EDSS points? Worsening cognition Worsening fatigue - MRI – how many new T2 hyperintensities?

29. Expanded Disability Status Scale Kurtzke JF. Neurology. 1983;33:1444-1452. 0 = Normal neurologic exam 1.0-1.5 = No impairment 2.0-2.5 = Impairment is minimal 3.0-3.5 = Impairment is mild to moderate 4.0-4.5 = Impairment is relatively severe 5.0-5.5 = Increasing limitation in ability to walk 6.0-6.5 = Walking assistance is needed 7.0-7.5 = Confined to wheelchair 8.0-8.5 = Confined to bed/chair; self-care with help 9.0-9.5 = Completely dependent 10.0 = Death due to MS

30. Disability Relapses Other Factors: Iron deposition Astrocytes Oligodensrocytes Underlying inflammation Neurodegeneration

31. Disease Freedom Bashir K, et al. J Neurol Sci. 2002:201(1-2):89-90.

32. Response to Therapy: Model #1 Frequency of Relapses Severity of Relapses Pre-Rx Post-Rx Benign MS  R NR Black and white All or none  Bad MS  Poor response Great  response

33. Response to Therapy: Model #2 Frequency of Relapses Severity of Relapses Post-Rx Pre-Rx Benign MS  Great  response  Bad MS  “Poor” response Gray zone Corollary— Is one attack bad?

34. Switch Studies vs. Direct Comparison Glatiramer switches - Switchers were worse, do worse, switched in past, use combo Rx - Remove confounders: same statistical trends % Relapse-free - IFN-beta 42%  glatiramer 53% - Glatiramer 12%  interferon 87% - IM IFN-b-1a 41%  SQ IFN-b 67% Clinical vs. MRI predictors - 0-2 T2+ on IM IFN-b-1a  no progression - 3+ T2+  0.8 progression, similar to PL, & 2+ Gd+ - 2 Clinical attacks = 1.0 progression in IFN and PL Glatiramer switches - Switchers were worse, do worse, switched in past, use combo Rx - Remove confounders: same statistical trends % Relapse-free - IFN-beta 42%  glatiramer 53% - Glatiramer 12%  interferon 87% - IM IFN-b-1a 41%  SQ IFN-b 67% Clinical vs. MRI predictors - 0-2 T2+ on IM IFN-b-1a  no progression - 3+ T2+  0.8 progression, similar to PL, & 2+ Gd+ - 2 Clinical attacks = 1.0 progression in IFN and PL

35. Switch Studies vs. Direct Comparison All drugs are partially effective, but: -some may be more effective than others, and -individual responses will vary Change will be to a partially effective DMD Side effects vary, and affect compliance All drugs are partially effective, but: -some may be more effective than others, and -individual responses will vary Change will be to a partially effective DMD Side effects vary, and affect compliance

36. Time to Stop Medications? Does MS “burn out?” Futility of Treatment? - Individual Patient Neurologist - General philosophy Does MS “burn out?” Futility of Treatment? - Individual Patient Neurologist - General philosophy

37. Personalized Medicine No lab biomarker - MRI - History - Physical Examination Neurologist - Neurological exam - Scales Patient perspective Treat each person as an individual  personalized medicine No lab biomarker - MRI - History - Physical Examination Neurologist - Neurological exam - Scales Patient perspective Treat each person as an individual  personalized medicine

38. Good News! More Research in MS Than Ever 300 250 200 150 100 50 0 1965197019751980198519901995 2010 No. of publications Year