CMSC, June 2004

SYMPTOM MANAGEMENT:SYMPTOM MANAGEMENT:

PHARMACOLOGICPHARMACOLOGIC

THERAPYTHERAPY

Christopher T. Bever, Jr., M.D.Christopher T. Bever, Jr., M.D.

Director, MS CoE - EastDirector, MS CoE - East

June 5, 2004June 5, 2004

CMSC, June 2004

Symptoms in Progressive MS

RelapsingRelapsingPreclinicalPreclinical ProgressiveProgressive

Hartung HP et al. Hartung HP et al. The Lancet.The Lancet. 2002;360:2018-2025. 2002;360:2018-2025.

TimeTime

CMSC, June 2004

Symptoms of MS Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive ImpairmentCognitive Impairment DepressionDepression FatigueFatigue PainPain Sexual dysfunctionSexual dysfunction Spasticity and weaknessSpasticity and weakness Visual disturbancesVisual disturbances

IOM Report, 2001

CMSC, June 2004

Symptom Classifications

Primary vs. secondary vs. tertiaryPrimary vs. secondary vs. tertiary Neurological vs. non-neurologicalNeurological vs. non-neurological Negative vs. positiveNegative vs. positive Fixed vs. paroxysmalFixed vs. paroxysmal

A. Miller, 2000

CMSC, June 2004

Treatable Symptoms of MS

Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness

CMSC, June 2004

Treatable Symptoms of MS

Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness

CMSC, June 2004

Treatable Symptoms of MS

Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness

CMSC, June 2004

Fatigue in MS

Subjective lack of physical or Subjective lack of physical or mental energy to carry out usual mental energy to carry out usual activitiesactivities

Present at some time in 75%-90% Present at some time in 75%-90% of patients with MSof patients with MS

Present daily in 46%-66% Present daily in 46%-66%

CMSC, June 2004

Fatigue: Proposed Treatments AmantadineAmantadine PemolinePemoline SSRI’sSSRI’s AmphetaminesAmphetamines AminopyridinesAminopyridines ModafanilModafanil Behavior modificationBehavior modification

CMSC, June 2004

Amantadine

Developed as an anti-viral agentDeveloped as an anti-viral agent Identified by a chance observation Identified by a chance observation

as improving MS fatigueas improving MS fatigue Class I evidence from four trials Class I evidence from four trials

supports its use in MS patientssupports its use in MS patients Response rates of 20% to 40% at Response rates of 20% to 40% at

100 mg bid100 mg bid

CMSC, June 2004

Modafanil

Novel wakefulness-promoting agentNovel wakefulness-promoting agent Mechanism of action unknownMechanism of action unknown Low abuse potential (Schedule IV)Low abuse potential (Schedule IV) FDA approval for narcolepsyFDA approval for narcolepsy

CMSC, June 2004

Phase II Trial in MS

Randomized, patient-blind, placebo-Randomized, patient-blind, placebo-controlled crossover design phase II trialcontrolled crossover design phase II trial

72 patients enrolled at two sites72 patients enrolled at two sites Outcome measures:Outcome measures:

FSS (primary)FSS (primary) MFISMFIS VAS-FVAS-F Epworth sleepiness scaleEpworth sleepiness scale

CMSC, June 2004

Results: FSS

4.2

4.4

4.6

4.8

5

5.2

5.4

5.6

Placeborun in

Modafanil200mg

Modafanil400mg

Placebowashout

FSS

*p<0.001, Placebo run in vs Modafanil 200mg

*

CMSC, June 2004

Results: MFIS

3.4

3.6

3.8

4

4.2

4.4

4.6

Placeborun in

Modafanil200mg

Modafanil400mg

Placebowashout

MFIS

*p<0.001, Placebo run in vs Modafanil 200mg

*

CMSC, June 2004

Results: VAS-F

0

1

2

3

4

5

6

Placeborun in

Modafanil200mg

Modafanil400mg

Placebowashout

VAS-F

*p<0.003, Placebo run in vs Modafanil 200mg

*

CMSC, June 2004

Adverse Events

< 10% of patients< 10% of patients More common during treatment:More common during treatment:

NauseaNausea Anxiety, nervousnessAnxiety, nervousness Dry mouthDry mouth InsomniaInsomnia DiarrheaDiarrhea AstheniaAsthenia

CMSC, June 2004

Conclusions

Fatigue is one of the most common Fatigue is one of the most common symptoms in MS patientssymptoms in MS patients

Pharmacological treatments are an Pharmacological treatments are an important part of fatigue managementimportant part of fatigue management

Amantadine is effective, cheap and Amantadine is effective, cheap and well toleratedwell tolerated

Modafanil is effective and well Modafanil is effective and well toleratedtolerated

CMSC, June 2004

Treatable Symptoms of MS

Ataxia and tremorAtaxia and tremor Bladder and bowel dysfunctionBladder and bowel dysfunction Cognitive impairmentCognitive impairment DepressionDepression FatigueFatigue Paroxysmal symptomsParoxysmal symptoms Sexual dysfunctionSexual dysfunction SpasticitySpasticity WeaknessWeakness

CMSC, June 2004

Weakness

One of the most common and One of the most common and disabling symptoms in MSdisabling symptoms in MS

Usually due to upper motor neuron Usually due to upper motor neuron dysfunctiondysfunction

Loss of voluntary control Loss of voluntary control exacerbated by de-conditioningexacerbated by de-conditioning

Primary therapy is exercisePrimary therapy is exercise

CMSC, June 2004

Aminopyridine Potassium Channel Blockers Nonspecific blockers of voltage Nonspecific blockers of voltage

sensitive potassium channelssensitive potassium channels Improve action potential Improve action potential

propagation in demyelinated axonspropagation in demyelinated axons Increase transmitter release at Increase transmitter release at

synaptic endingssynaptic endings

CMSC, June 2004

3,4 Diaminopyridine

Orally activeOrally active Short serum half-lifeShort serum half-life Crosses blood brain barrier poorlyCrosses blood brain barrier poorly Available for the treatment of Available for the treatment of

Lambert-Eaton Myasthenic Lambert-Eaton Myasthenic SyndromeSyndrome

CMSC, June 2004

Phase II Trial of DAP in MS Double-blind, placebo-controlled, Double-blind, placebo-controlled,

crossover trialcrossover trial 22 MS patients with leg weakness22 MS patients with leg weakness One month treatment periods with up to One month treatment periods with up to

100 mg per day100 mg per day Outcome measures:Outcome measures:

Patient and physician impressions of Patient and physician impressions of changechange

Manual motor testingManual motor testing Quantitative motor testingQuantitative motor testing Ambulation indexAmbulation index

CMSC, June 2004

Results: # Improved

OutcomeOutcome DAPDAP PlaceboPlacebo pp

Physician IC Physician IC 2121 11 0.0050.005Patient ICPatient IC 1414 22 0.0080.008MMTMMT 1616 33 0.0020.002QMT-HSQMT-HS 1616 99 0.0010.001QMT-QQMT-Q 1515 88 0.040.04AIAI 55 00 0.020.02

CMSC, June 2004

Results: Mean scores

OutcomeOutcome DAPDAP PlaceboPlacebo pp

MMTMMT 41.641.6 39.939.9 0.0020.002QMTQMT -HS-HS 130130 123123 0.0010.001QMT-QQMT-Q 231231 206206 0.040.04

CMSC, June 2004

Results: Mean Strength Scores

30

32

34

36

38

40

42

44

0 4 8 12 16

Week

Mean M

MT s

core

Placebo-DAPDAP-Placebo

CMSC, June 2004

Results: Mean AI Scores

3.8

4.8

5.8

6.8

0 4 8 12 16Week

Mean A

I sc

ore

Placebo-DAPDAP-Placebo

CMSC, June 2004

Conclusions

3,4 DAP treatment can improve leg 3,4 DAP treatment can improve leg strength in selected patientsstrength in selected patients

3,4 DAP treatment can improve 3,4 DAP treatment can improve ambulation times in a subset of ambulation times in a subset of patientspatients

3,4 DAP treatment causes 3,4 DAP treatment causes paresthesias and gastrointestinal paresthesias and gastrointestinal adverse events that limit its useadverse events that limit its use

Rarely 3,4 DAP treatment can cause Rarely 3,4 DAP treatment can cause seizuresseizures

CMSC, June 2004

4-Aminopyridine

Orally activeOrally active Crosses blood brain barrier readilyCrosses blood brain barrier readily Longer half-life than DAPLonger half-life than DAP Used to reverse neuromuscular Used to reverse neuromuscular

blockade after surgeryblockade after surgery

CMSC, June 2004

Trials of 4-Aminopyridine in MS Jones et al: Open label pilotJones et al: Open label pilot Davis & Stefoski: Controlled crossoverDavis & Stefoski: Controlled crossover Van Diemen, et al: Randomized, Van Diemen, et al: Randomized,

controlled, crossovercontrolled, crossover Bever et al: Randomized, controlled, Bever et al: Randomized, controlled,

crossovercrossover Schwid et al: Randomized, controlled, Schwid et al: Randomized, controlled,

crossovercrossover Goodman et al: Randomized, DB, PC Goodman et al: Randomized, DB, PC

parallel groupparallel group

CMSC, June 2004

Objectives Primary: Determine safety of multiple doses of Primary: Determine safety of multiple doses of

fampridine-SR (one week each of 20 mg/day, 30 fampridine-SR (one week each of 20 mg/day, 30

mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70

mg/day and 80 mg/day).mg/day and 80 mg/day).

Secondary: Obtain evidence of efficacy and dose-Secondary: Obtain evidence of efficacy and dose-

response using several outcome measuresresponse using several outcome measures Standard MS measurements, including timed walk, Standard MS measurements, including timed walk,

lower extremity muscle strength, PASAT, 9-hole peg lower extremity muscle strength, PASAT, 9-hole peg

testtest Daily Fatigue Diary – Brief Fatigue InventoryDaily Fatigue Diary – Brief Fatigue Inventory

Goodman, A, 2002

CMSC, June 2004

CMSC, June 2004

Dose Response- 25 ft Walk

10

11

12

13

14

15

16

17

18

scre

en

base

1

base

2

base

3ru

n-in

20m

g30

mg

40m

g50

mg

60m

g70

mg

80m

g

Tim

e (s

ecs)

All subjects (n=25)

Completers (n=20)

CMSC, June 2004

Leg strength

-20 0 20 40 60 80

1

4

7

10

13

16

19

22

25

Change in LEMMT (%)

-20 0 20 40 60 80

1

3

5

7

9

11

Change in LEMMT (%)

Fampridine-SR(20-50 mg/day)

Placebo

BetterWorse

CMSC, June 2004

Treatment emergent adverse events Fampridine-SR

(N=25)Placebo(N=11)

No. with AEs All AEs 25 (100%) 10 (90.9%) Most Frequently Reported AEs Dizziness 9 (36.0%) 2 (19.2%)Insomnia 9 (36.0%) 1 (9.1%)Paresthesia 8 (32.0%) 1 (9.1%)Nausea 7 (28.0%) 1 (9.1%)Asthenia 7 (28.0%) 1 (9.1%)Headache 6 (24.0%) 1 (9.1%)Tremor 6 (24.0%) 0Pain 5 (20.0%) 0Back Pain 5 (20.0%) 0Anxiety 3 (12.0%) 0Hypertonia 1 (4.0%) 3 (27.3%)

CMSC, June 2004

Safety Summary The most common adverse events in the The most common adverse events in the

fampridine treated group were consistent fampridine treated group were consistent with the findings of previous studieswith the findings of previous studies Dizziness, Insomnia, Parasthesia, Nausea, Asthenia, Dizziness, Insomnia, Parasthesia, Nausea, Asthenia,

Headache, TremorHeadache, Tremor

At doses above 40 mg/day, more severe At doses above 40 mg/day, more severe adverse events were reported, including adverse events were reported, including two cases of seizure (at 60 and 70 two cases of seizure (at 60 and 70 mg/day)mg/day)

As anticipated, the risk of seizure requires As anticipated, the risk of seizure requires further study and characterization further study and characterization particularly in the anticipated dose rangeparticularly in the anticipated dose range

CMSC, June 2004

Summary Safety profile consistent with previous experienceSafety profile consistent with previous experience

Significant* benefit on timed walking (p=0.04)Significant* benefit on timed walking (p=0.04)

Significant* benefit on lower extremity strength Significant* benefit on lower extremity strength

(p=0.01)(p=0.01)

Evidence of dose-response in 20-40 mg/day rangeEvidence of dose-response in 20-40 mg/day range

No evidence of benefit on overall fatigue No evidence of benefit on overall fatigue

Little added benefit, and increased AEs at doses Little added benefit, and increased AEs at doses

above 50 mg/dayabove 50 mg/day

*repeated measure ANOVA (weeks 1-7)