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Optimizing Outcomes: Balancing Disease-Modifying and Symptomatic Therapy in

Multiple SclerosisJames D. Bowen, MD

Medical DirectorMultiple Sclerosis Center

Swedish Neuroscience Institute Seattle, Washington

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Introduction and Case Presentation

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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

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Case—History 2007

– Pain/burning in arms/legs– Diplopia– Weakness– Diagnosis uncertain

MRI interpreted as possible strokes

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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

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

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Efficacy of First-Line Disease-Modifying Therapies

(DMTs) in Early MS

8Kappos L, et al. Neurology. 2006;67:1242-1249.

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)

Outcome IFN Beta-1b(n = 292)

Placebo(n = 176) P-Value

CDMS at 2 years 28% 45% <.0001

Time to CDMS (25%) 618 days 255 days ––McDonald at 2 years 69% 85% <.00001

McDonald at 6 months 28% 51% ––

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Outcome at 2 YearsIFN Beta-

1a TIW(n = 171)

IFN Beta-1a QW

(n = 175)Placebo(n = 171) P-Value

2-year probability of MS (McDonald) 62.5% 75.5% 85.8%

<.0001 TIW

.008 QW

2-year probability of CDMS 20.6% 21.6% 37.5% .004 TIW

.0023 QW

Combined unique active MRI lesions/person/scan, mean

0.6RR 0.19

1.23RR 0.37 2.70

<.0001 TIW

<.0001 QW

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.

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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

Outcome at 3 Years GA(n = 243)

Placebo(n = 238) P-Value

Time to CDMS (25%) 722 days 336 days .0005

CDMS 25% 43% <.0001New T2 lesions, last observed value 0.7 1.8 <.0001

Abbreviations: CDMS, clinically definite MS, CIS, clinically isolated syndrome; GA, glatiramer acetate.Comi G, et al. Lancet. 2009;374:1503-1511.

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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

Outcome at 5 Years Early GA(n = 243)

Delayed GA(n = 238) P-Value

CDMS 33% 49.5% .0005Annualized relapse rate 0.22 0.29 NABrain volume change -0.99% -1.27% .021

Abbreviations: CDMS, clinically definite MS; NA, not available.Martinelli V, et al. 63rd AAN; April 9-16, 2011; Honolulu, Hawaii. Abstract PD6.006.

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FREEDOMS—Fingolimod in Relapsing-Remitting MS (RRMS)

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

Outcome at 2 YearsFingolimod

0.5 mg(n = 425)

Placebo(n = 418) P-Value

Annualized relapse rate 0.18 0.40 <.001

Free of sustained progression 82.3% 75.9% .03

Mean new/enlarging T2 lesions 2.5 9.8 <.001

Kappos L, et al. N Engl J Med. 2010;362:387-401.

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TRANSFORMS—Fingolimod vs IFN Beta-1a in RRMS

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

Outcome at 1 yearFingolimod

0.5 mg(n = 429)

IFN(n = 431) P-Value

Annualized relapse rate 0.16 0.33 <.001

Free of sustained progression 94.1% 92.1% .25Mean new/enlarging T2 lesions 1.7 2.6 .004

Cohen JA, et al. N Engl J Med. 2010;362:402-415.

No trials under way for fingolimod in CIS

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TEMSO—Teriflunomide in Relapsing MS

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

Outcome at 2 YearsTFN 7 mg

(n = 365)

TFN 14 mg

(n = 358)Placebo(n =363)

P-Value7 mg/14 mg

Annualized relapse rate 0.37 0.37 0.54 <.001/<.001

Sustained progression 21.7% 20.2% 27.3% .08/.03Change in T2 lesion volume from baseline 1.31 mL 0.72 mL 2.21 mL .03/

<.001

O'Connor P, et al. N Engl J Med. 2011;365:1293-1303.

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TOWER—Teriflunomide Multiple Sclerosis Oral

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

Outcome at 2 YearsTFN 7 mg

(n = 407)

TFN 14 mg

(n = 370)Placebo(n = 388)

P-Value7 mg/14 mg

Annualized relapse rate 0.389 0.319 0.50 .018/ .0001

Sustained progression 21.0% 22.2% 15.8% .76/.04

Kappos L, et al. Paper presented at: ECTRIMS 2012; October 10-13, 2012; Lyon, France. Abstract 153.

CIS trial under way—TOPIC (NCT00622700)

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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

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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

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Case—MRI Findings

T2 FLAIR weighted MRI showing lesions typical for MS

Graphic courtesy of James D. Bowen, MD.

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Case—Issues to Address Issues with greatest impact for this patient

– Nonadherence– Cognitive impairment– Mobility impairment

Additional issues– Urinary urgency– Fatigue

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Nonadherence

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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

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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

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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

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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

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Cognitive Impairment

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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.

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Cognitive Screening Tests Paced Auditory Serial Addition Test (PASAT)1

– Takes 2 or 3 minutes1 5 3 7

6 8 10 Symbol Digit Modality Test (SDMT)2

– Takes about 90 seconds

1 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.

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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.

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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.

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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 = .0341. Fischer JS, et al. Ann Neurol. 2000;48:885-892. 2. Patti F, et al. Ther Adv Neurol Disord. 2009;2:67-77.

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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 images1. Weinstein A, et al. Arch Neurol. 1999;56:319-324. 2. Mori F, et al. Neurology. 2012;78:P04.118.

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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.

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3,4-Diaminopyridine (DAP)

*Primary outcome – leg weakness in 34 patients, arm ataxia in 2.Bever CT, et al. Neurology. 1996;47:1457-1462.

Outcome 3,4-DAP NA P-Value

Improvement in defined deficit* 22 2 .0005

Selective Reminding Test, mean 37.5 36.9 NS10/36 Spatial Recall, mean 18.8 17.2 NS

Symbol Digit Modality Test, mean 34.2 34.5 NS

PASAT, mean 66.6 65.4 NS

Word List Generation, mean 28.6 27.7 NS

3,4-DAP up to 100 mg/day vs nicotinic acid (NA) 10 mg/day N = 36 with MS– Randomized, double-blind, crossover design

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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.

Test Outcome

PASAT Significant only for 45 mg

SDMT Significant only for 45 mg, trend 30 mg

TMT, Part A Significant only for 45 mg

TMT, Part B; RAVLT; BVMTR Not significant

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L-AmphetamineL-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.

Test Outcome

SDMT (primary outcome) No significant difference

CVLT2-TL No significant differenceCVLT2-DR Significantly betterBVMTR-TL Significantly betterBVMTR-DR Significantly betterPASAT No significant difference

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Donepezil

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.

Outcome, Mean Donepezil(n = 61)

Placebo(n = 59) P-Value

SRT (primary outcome) 1.6 1.7 NS

10/36 Spatial Recall -0.4 1.6 NS

SDMT 0.6 2.0 NS

PASAT 2 + 3 3.8 3.5 NS

COWA 1.0 0.6 NS

D-KEFS Sort 0.6 0.5 NS

JOLO 0.6 0.6 NS

Donepezil 10 mg/day vs placebo for 24 weeks– N = 120 with MS, memory deficit– Multi-center, double-blind, randomized trial

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Methylphenidate

*P = <.001; †P = NS.Harel Y, et al. J Neurol Sci. 2009;276:38-40.

Test

Methylphenidate(n = 14)

Placebo(n = 12)

Baseline 1 HourAfter Baseline 1 Hour

After

PASAT 3 33.3 40.9* 37.8 39.5†

PASAT 2 24.6 30.9* 28.0 28.3†

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

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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.

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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.

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Medications for Cognition in MS None proven effective Stimulants may have some benefit

– Perhaps nonspecific due to increased alertness, decreased fatigue

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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

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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

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Mobility Impairment

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Contributors to MS-Related Mobility Loss

Spasticity Proprioceptive deficits Balance deficit Psychological contributors

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

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Balance Deficit Loss of position sense Visual loss Vestibular loss Ataxia

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Oral Medications for Spasticity Baclofen Tizanidine Benzodiazepines Dantrolene Cannabis

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Physical Therapy for Mobility Stretching Strengthening Cardiovascular Balance

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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.

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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.

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Surgical Options Nerve blocks – phenol Neurectomy Rhizotomy Tenotomy

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Dalfampridine—Mechanism of Action

Demyelinated axons have excessive potassium channels that lead to – Potassium leakage out of the cell – Signal failure

Dalfampridine blocks these channels – Improving signal conduction

Jeffery DR, et al. Core Evid. 2010;5:107-112.

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Dalfampridine Phase III Trials—Responder Analysis

Responder analysis = percentage of patients in each group who respond– Not mean differences between groups

Best means of capturing response when some individuals have a high level of response, while others have little or no response

Facilitates assessing patient-perceived value of response

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Dalfampridine-Extended Release (ER) Phase IIIb Trial

Oral dalfampridine 10 mg BID vs placebo for 9 weeks– N = 239, MS-related gait impairment– Relapsing-remitting MS, primary-progressive MS,

secondary-progressive MS, progressive-relapsing MS– Double-blind, randomized, controlled trial

Primary outcome = proportion of “timed walk responders”– Timed 25-Foot Walk

Timed walk responder = subject whose walking speed on at least 3 of the 4 “on-drug” visits is faster than the fastest speed during any of the 5 “off-drug” visits

Goodman AD, et al. Ann Neurol. 2010;68:494-502.

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Dalfampridine-ER Phase IIIb Trial Outcomes

Proportion of Timed Walk Responder (TWR)– Dalfampridine 42.9% vs placebo 9.3%; P <.0001

Walking speed, change from baseline– Dalfampridine TWRs 24.7% vs placebo 7.7%

12-Item MS Walking Scale, change from baseline– TWRs -6.04 vs nonresponders 0.85; P <.001

Leg strength improvement– Dalfampridine TWRs 0.145 U vs placebo 0.042 U; P = .028

Goodman AD, et al. Ann Neurol. 2010;68:494-502.

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Dalfampridine-ER in Clinical Practice

Approved to improve walking in MS patients1

– Only drug approved for this indication Benefit is seen in patients with progressive MS, as well

as RRMS2

Contraindication1

– Renal failure or seizure history Adverse effects3,4

– Urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, fatigue, back pain

In those patients who respond, dalfampridine results in a significant improvement in walking and quality of life

1. Jeffery DR, et al. Core Evid. 2010;5:107-112. 2. Pozzilli C, et al. Neurology. 2011;76(suppl 4):A73.3. Goodman AD, et al. Lancet. 2009;373:732-738. 4. Goodman AD, et al. Ann Neurol. 2010;68:494-502.

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Gait Aids Canes, staffs, trekking poles Forearm crutches Walkers Orthoses

– Ankle-foot orthoses, knee, Hip Flexion Assist Device

Functional electrical stimulation – Tibialis, quadricep

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Dalfampridine ER + Walking Aids

Dalfampridine improved walking speeds in phase III trials in patients already requiring walking aids (EDSS 6.0+)1-3

Clinical experience suggests synergy between physical therapy, exercise, walking devices, and pharmacotherapy with dalfampridine

1. Goodman AD, et al. Lancet. 2009;373:732-738. 2. Goodman AD, et al. Ann Neurol. 2010;68:494-502. 3. Brown T, et al. 62nd AAN; April 10–17, 2010; Toronto, Ontario, Canada. Abstract P07.164.

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Case Continues and Conclusion

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Case Continues—Addressing Mobility Impairment

Spasticity identified as a major source of symptoms

Physical therapy– Patient started doing leg stretching at home with

therapist oversight Gait aids

– Single point cane recommended Pathogenesis of imbalance due to sensory loss

described Patient resistant in past, but now will consider

– Ankle-foot orthoses recommended but patient refused

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Case Continues—Addressing Mobility Impairment

Botulinum toxin – Injected into gastrocnemius with excellent

results Baclofen

– Started baclofen 10 mg TID, but continued marked hyperreflexia

– Dose gradually increased to 20 mg TID with marked improvement in spasticity

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Case—Mobility Issue Follow-Up Spasticity under much better control Still having falls due to decreased balance

– Most likely due to sensory loss in legs After other issues addressed, patient still had

gait dysfunction Dalfampridine Extended Release trial

– Improvement in Timed 25-Foot Walk from 14.2 seconds to 10.1 seconds

– Patient reports that this led to an improvement in his daily function with better gait

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Case Continues—Other Issues Now that the issues with greatest impact on

patient have been addressed, focus can turn to other issues– Urinary urgency– Fatigue

Management strategies for each

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Practical Considerations of Balancing DMTs and Symptomatic Therapies

Generally add 1 medication at a time Increase dose to effectiveness or tolerability

limit Discontinue medications that fail Try to dose as few times a day as possible Use PRN when possible (fatigue, bladder) Review medications at each visit Emphasize nonmedical therapy (exercise)

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Conclusions Optimal patient care requires balance

between DMTs and symptomatic therapy– Patients often more concerned about symptoms

than disease modification– Must address both symptoms and DMT

Often intertwined: optimal DMT use requires that symptoms be addressed– Symptoms and DMT adherence often

interconnected– Prioritize those symptoms that interfere with

DMT adherence