Optimizing Outcomes: Balancing Disease-Modifying and Symptomatic Therapy in Multiple Sclerosis

1. Optimizing Outcomes: Balancing Disease-Modifying and Symptomatic Therapy in Multiple Sclerosis James D. Bowen, MD Medical Director Multiple Sclerosis Center Swedish Neuroscience Institute Seattle, Washington

2. Introduction and Case Presentation

3. Case—History • 52-year-old male • 1996 at age 36 • Right-hand numbness and weakness spreading to entire right body over 2 days • Told it was a “demyelinating event” but no other diagnosis or treatment given • Mild residual right tingling/heaviness • Early 2000s • Diplopia • Urinary urgency • Erectile dysfunction

4. Case—History • 2007 • Pain/burning in arms/legs • Diplopia • Weakness • Diagnosis uncertain • MRI interpreted as possible strokes

5. Case—History • December 2008 • Brain MRI • Improvement in left cerebral peduncle lesion • New right frontal lesion • C-spine MRI normal • Visual evoked potential and lumbar puncture normal • December 2009 • Saw an MS specialist • Diagnosed with MS • April 2010 • Started treatment with glatiramer acetate

6. Case—Current Presentation • Patient transfers to our clinic, February 2011 • Reports tolerating treatment well • Admits incomplete adherence • Has had occasional MS attacks

7. Efficacy of First-Line Disease-Modifying Therapies (DMTs) in Early MS

8. BENEFIT—IFN Beta-1b SC in Early MS • IFN beta-1b 250 µg vs placebo for 2 years • 468 patients with clinically isolated syndrome and abnormal MRI • Primary outcome: development of clinically definite MS (CDMS) Kappos L, et al. Neurology. 2006;67:1242-1249.

9. REFLEX—IFN Beta-1a SQ in Early MS • IFN beta-1a SQ 44 µg TIW vs QW vs placebo for 2 years • 517 patients with CIS and abnormal MRI • Primary outcome: time to MS diagnosis by McDonald criteria Abbreviations: CIS, clinically isolated syndrome; RR, rate ratio. Comi G, et al. Lancet Neurol. 2012;11:33-41.

10. PreCISe—Glatiramer Acetate in Early MS • GA 20 mg/day vs placebo for 3 years • 481 patients with CIS and abnormal MRI • Primary outcome: time to CDMS Abbreviations: CDMS, clinically definite MS, CIS, clinically isolated syndrome; GA, glatiramer acetate. Comi G, et al. Lancet. 2009;374:1503-1511.

11. PreCISe Open-Label Extension—Glatiramer Acetate in Early MS • 2-year open-label phase following initial 3-year trial of GA vs placebo • Early vs delayed GA treatment • Early cohort = patients initially randomized to GA • Delayed cohort = patients initially randomized to placebo Abbreviations: CDMS, clinically definite MS; NA, not available. Martinelli V, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.006.

12. Fingolimod 0.5 mg or 1.25 mg vs placebo for 2 years N = 1272 with RRMS Mean EDSS: 2.3, fingolimod 0.5 mg; 2.5, placebo Primary outcome: annualized relapse rate FREEDOMS—Fingolimod in Relapsing-Remitting MS (RRMS) Kappos L, et al. N Engl J Med. 2010;362:387-401.

13. Fingolimod 0.5 mg or 1.25 mg vs IFN beta-1a 30 µg IM for 1 year N = 1292 with RRMS Mean EDSS: 2.24, fingolimod 0.5 mg; 2.19, IFN Primary outcome: annualized relapse rate TRANSFORMS—Fingolimod vs IFN Beta-1a in RRMS • No trials under way for fingolimod in CIS Cohen JA, et al. N Engl J Med. 2010;362:402-415.

14. Teriflunomide (TFN) 7 mg and 14 mg vs placebo for 2 years N = 1086 with relapsing MS, mean EDSS 2.68 Primary outcome: annualized relapse rate TEMSO—Teriflunomide in Relapsing MS O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.

15. Teriflunomide (TFN) 7 mg and 14 mg vs placebo for 48 wks+ ≤18 months extension N = 1165 with relapsing MS, mean EDSS 2.7 Primary outcome: annualized relapse rate TOWER—Teriflunomide Multiple Sclerosis Oral • CIS trial under way—TOPIC (NCT00622700) Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.

16. Importance of Early Treatment • Studies of injectable first-line DMTs(IFN betas and GA) approved for RRMS have shown benefit in clinically isolated syndrome (CIS) • These often have a greater magnitude of benefit than the RRMS study • Different populations studied, however • No data yet on newer oral first-line DMTs • No CIS trial under way for fingolimod • TOPIC trial under way for teriflunomide in CIS

17. Case Continues—Findings at Presentation • Occasional attacks, adherence poor • Timed 25-Foot Walk – 14.2 sec • Internuclear ophthalmoplegia (INO) on right gaze • Motor: 4/5 throughout, spasticity right > left • Decreased light touch/pin prick all 4 limbs, pain • Gait: right >left hemiparetic • Reflexes: 4+, right >left with clonus • Urinary urgency/frequency, cognitive impairment, fatigue

18. Case—MRI Findings T2 FLAIR weighted MRI showing lesions typical for MS Graphic courtesy of James D. Bowen, MD.

19. Case—Issues to Address • Issues with greatest impact for this patient • Nonadherence • Cognitive impairment • Mobility impairment • Additional issues • Urinary urgency • Fatigue

20. Nonadherence

21. Case Continues—Assessment of Poor Adherence • First priority = improve adherence • Nurse discussed poor adherence with patient • Identified reasons • Insurance lapses • Pharmacy refill interruptions • Cognitive impairment

22. Barriers to Adherence • Financial • Insurance/pharmacy • Perceived lack of benefit • Intolerance of injections • Intolerance of side effects • Laboratory abnormalities • Treatment failure For more information on adherence, participate in a recent MS MedImage case by Dr. James D. Bowen: “Switching Disease-Modifying Therapy Due to Adherence Issues.” Find it at: http://mic.projectsinknowledge.com/neurology/multiple-sclerosis/Switching-Disease-Modifying-Therapy-Due-to-Adherence-Issues.cfm?jn=2022.29

23. Financial Support • Manufacturer support programs • Contact manufacturer for support for individual medication • National Multiple Sclerosis Society Financial Assistance Program • http://www.nationalmssociety.org/living-with-multiple-sclerosis/society-programs-and-services/financial-assistance-program/index.aspx

24. Case Continues—Addressing Nonadherence • Nurse put into place a system to remind patient about GA injections • Smart phone alarm • Social worker stabilized insurance and worked with pharmacy to ensure refills • Patient has remained adherent since

25. Cognitive Impairment

26. Cognitive Impairment in MS • About 60% of MS patients have cognitive impairment • About 35% of those with low-disability relapsing-remitting MS • May be subtle and difficult to recognize in clinic • Most common − processing speed and episodic memory Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342.

27. Cognitive Screening Tests • Paced Auditory Serial Addition Test (PASAT)1 • Takes 2 or 3 minutes 1 5 3 7 6 8 10 • Symbol Digit Modality Test (SDMT)2 • Takes about 90 seconds1 2 3 X ∧ 1. National MS Society. Multiple Sclerosis Functional Composite (MSFC) Administration and Scoring Manual. 2001. Accessed 10/1/12 at: http://www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/msfc/index.aspx. 2. Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342. Graphics courtesy of Dr. James D. Bowen.

28. Medications for Cognitive Impairment in MS • Disease-modifying therapies • Other1 • Potassium-channel blockers • 3,4-diaminopyridine, 4-aminopyridine • Dopaminergic antiparkinsonism agents • Amantadine • Stimulants • Modafinil, methylphenidate, L-amphetamine • Acetylcholinesterase inhibitors • Donepezil, rivastigmine Benedict RH, et al. Nat Rev Neurol. 2011;7:332-342.

29. DMTs in MS-Related Cognitive Impairment—Rationale • MS lesions and attacks likely contribute to cognitive impairment1 • Nonlesion damage may also contribute (atrophy, normal appearing white matter changes, gray matter changes)1,2 • DMTs alter exacerbations, MRI lesion activity, atrophy, and noncognitive disability 1. Calabrese M, et al. Arch Neurol. 2009;66:1144-1450. 2. Calabrese M, et al. Expert Rev Neurother. 2011;11:425-432.

30. DMTs in MS-Related Cognitive Impairment—Interferon Betas • IFN beta-1a IM vs placebo for 2 years1 • N = 166 with relapsing MS • Significant benefit for information processing/memory; P = .036 • Trend to benefit for visuospacial/executive;P = .005, corrected for baseline, P = .085 • No effect on verbal ability/attention span; P = .60 • Sustained PASAT deterioration: IFN 19.5%, placebo 36.6%; P = .023 • IFN beta-1a SQ 22 µg vs 44 µg TWI for 2 years, open label2 • N = 356 with RRMS • Proportion with ≥3 impaired cognitive tests:22 µg = 26.5%, 44 µg = 17.0%; P = .034 1. Fischer JS, et al. Ann Neurol. 2000;48:885-892. 2. Patti F, et al. Ther Adv Neurol Disord. 2009;2:67-77.

31. DMTs in MS-Related Cognitive Impairment—Glatiramer Acetate • GA vs placebo, phase III1 • N = 248 with relapsing-remitting MS • 5 cognitive domains • No difference between GA and placebo groups • However, no measurable decline in cognition in placebo group • Patients had little baseline impairment • GA for 3 months2 • N = 30 with MS • PASAT improved from 42.16 to 47.76, P <.05, in those with Gd+ MRI images 1. Weinstein A, et al. Arch Neurol. 1999;56:319-324. 2. Mori F, et al. Neurology. 2012;78:P04.118.

32. DMTs in MS-Related Cognitive Impairment—Natalizumab, Fingolimod, and Teriflunomide • Natalizumab • AFFIRM phase III trial – natalizumab vs placebo • 43% reduction in risk of PASAT-3 worsening, P = .013 • Fingolimod • Little data • Teriflunomide • Little data Weinstock-Guttman B, et al. J Neurol. 2012;259:898-905.

33. 3,4-Diaminopyridine (DAP) • 3,4-DAP up to 100 mg/day vs nicotinic acid (NA) 10 mg/day • N = 36 with MS • Randomized, double-blind, crossover design *Primary outcome – leg weakness in 34 patients, arm ataxia in 2. Bever CT, et al. Neurology. 1996;47:1457-1462.

34. L-Amphetamine • 4 doses: L-amphetamine 15, 30, and 45 mg or placebo • N = 19 with MS, suspected cognitive deficit • Counterbalanced within-subjects design • Outcome: neuropsychological testing 2 h after dose Abbreviations: BVMTR, Brief Visuospatial Memory Test – Revised; PASAT, Paced Auditory Serial Addition Test; RAVLT, Rey Auditory Verbal Learning Test; SDMT, Symbol Digit Modalities Test; TMT, Trail Making Test. Benedict RH, et al. J Neurol. 2008;255:848-852.

35. L-Amphetamine • L-amphetamine 30 mg vs placebo for 29 days • N = 151 with MS, cognitive deficit • Randomized, double-blind, controlled trial Abbreviations: Brief Visual Memory Test-Revised-Total Learning (BVMTR-TL); Brief Visual Memory Test-Revised-Delayed Recall (BVMTR-DR); California Verbal Learning Test, second edition-Delayed Recall (CVLT2-DR); California Verbal Learning Test, second edition-Total Learning (CVLT2-TL); Paced Auditory Serial Addition Test (PASAT); Symbol Digit Modalities Test (SDMT). Morrow SA, et al. J Neurol. 2009;256:1095-1102.

36. Donepezil • Donepezil 10 mg/day vs placebo for 24 weeks • N = 120 with MS, memory deficit • Multi-center, double-blind, randomized trial Abbreviations: COWA, Controlled Oral Word Association; D-KEFS Sort, Delis-Kaplan Executive Function System Sorting; JOLO, Judgment of Line Orientation; PASAT, Paced Auditory Serial Addition Test; SDMT, Symbol Digit Modalities Test; SRT, Selective Reminding Test. Krupp LB, et al. Neurology. 2011;76:1500-1507.

37. Methylphenidate • Single dose: methylphenidate 10 mg vs placebo • N = 26 with MS, attention deficit (PASAT score <25th percentile) • Double-blind, placebo-controlled • All patients treated with IFN beta-1a ≥6 months *P = <.001; †P = NS.Harel Y, et al. J Neurol Sci. 2009;276:38-40.

38. Modafinil • IM IFN beta-1a vs IM IFN beta-1a + modafinil • N = 60 with RRMS, attention deficit • 49 completed study • Improvement in multiple cognitive outcomes • However: • No placebo control • High dropout • Multiple comparisons Wilken JA, et al. Int J MS Care. 2008;10:1-10.

39. Drugs with No Significant Cognitive Effects • 4-aminopyridine (AP) vs placebo1 • N = 20 with MS; randomized, double-blind, crossover • 4-AP 32 mg/d vs placebo for 6 mo2 • N = 54 with progressive MS; randomized, double-blind, crossover design • Amantadine vs pemoline vs placebo for 6 wk3 • N = 45 with MS and severe fatigue • Only written Symbol Digit Modalities Test showed significance for amantadine • Rivastigmine 3 mg BID vs placebo for 12 wk4 • N = 60 with MS and cognitive impairment; double-blind, randomized, controlled trial 1. Smits RC, et al. Neurology. 1994;44:1701-1705. 2. Rossini PM, et al. Mult Scler. 2001;7:354-358. 3. Geisler MW, et al. Arch Neurol. 1996;53:185-188.4. Shaygannejad V, et al. Can J Neurol Sci. 2008;35:476-481.

40. Medications for Cognition in MS • None proven effective • Stimulants may have some benefit • Perhaps nonspecific due to increased alertness, decreased fatigue

41. Cognitive Rehabilitation • Few studies • Psychology for stress reduction • Neuropsychology for identification of specific areas of deficit • Speech therapy for help with organizational skills • Occupational or physical therapy for energy conservation • Assistive technology

42. Case Continues—Addressing Cognitive Impairment • Neuropsychological testing offered to patient, but refused • Family recognized that cognitive loss was due to MS • Reminders put in place • Cell phone, memory book • With these, patient and family believe he is functioning adequately • If reminders fail, will consider further testing or cognitive rehabilitation with speech/language pathology and neuropsychology

43. Mobility Impairment

44. Contributors to MS-Related Mobility Loss • Spasticity • Proprioceptive deficits • Balance deficit • Psychological contributors

45. Spasticity • Weakness • Stiffness (clasp knife) • Spastic leg jumps • Hyperreflexia (clonus) • Babinski response

46. Balance Deficit • Loss of position sense • Visual loss • Vestibular loss • Ataxia

47. Oral Medications for Spasticity • Baclofen • Tizanidine • Benzodiazepines • Dantrolene • Cannabis

48. Physical Therapy for Mobility • Stretching • Strengthening • Cardiovascular • Balance

49. Botulinum Toxin • Prevents acetylcholine release at neuromuscular junction1 • Typically lasts about 3 months1 • Ideal for relatively localized muscle groups (eg, footdrop, hand flexors) Hyman N, et al. J Neurol Neurosurg Psychiatry. 2000;68:707-712.

50. Intrathecal Baclofen • Ideal patient is one in whom oral baclofen works but sedation is excessive1 • Also for patients with severe spasticity who require higher dose than can be delivered orally • Delivered directly into CSF by lumbar catheter1 • Typically, a test dose is given first1 • Complications/adverse effects2 • Mechanical pump/catheter failure, infection, sedation, dizziness, impaired vision, slurred speech 1. National MS Society. Intrathecal baclofen. Accessed 10/2/12 at: http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/treatments/medications/baclofen-intrahecal/index.aspx. 2. Beard S, et al. Health Technol Assess. 2003;7:1-111.