CMSC, June 2004 SYMPTOM MANAGEMENT: PHARMACOLOGICTHERAPY Christopher T. Bever, Jr., M.D. Director, MS CoE - East June 5, 2004

CMSC, June 2004 Symptoms in Progressive MS RelapsingPreclinical Progressive Hartung HP et al. The Lancet. 2002;360: Time

CMSC, June 2004 Symptoms of MS Ataxia and tremor Ataxia and tremor Bladder and bowel dysfunction Bladder and bowel dysfunction Cognitive Impairment Cognitive Impairment Depression Depression Fatigue Fatigue Pain Pain Sexual dysfunction Sexual dysfunction Spasticity and weakness Spasticity and weakness Visual disturbances Visual disturbances IOM Report, 2001

CMSC, June 2004 Symptom Classifications Primary vs. secondary vs. tertiary Primary vs. secondary vs. tertiary Neurological vs. non-neurological Neurological vs. non-neurological Negative vs. positive Negative vs. positive Fixed vs. paroxysmal Fixed vs. paroxysmal A. Miller, 2000

CMSC, June 2004 Treatable Symptoms of MS Ataxia and tremor Ataxia and tremor Bladder and bowel dysfunction Bladder and bowel dysfunction Cognitive impairment Cognitive impairment Depression Depression Fatigue Fatigue Paroxysmal symptoms Paroxysmal symptoms Sexual dysfunction Sexual dysfunction Spasticity Spasticity Weakness Weakness

CMSC, June 2004 Treatable Symptoms of MS Ataxia and tremor Ataxia and tremor Bladder and bowel dysfunction Bladder and bowel dysfunction Cognitive impairment Cognitive impairment Depression Depression Fatigue Fatigue Paroxysmal symptoms Paroxysmal symptoms Sexual dysfunction Sexual dysfunction Spasticity Spasticity Weakness Weakness

CMSC, June 2004 Treatable Symptoms of MS Ataxia and tremor Ataxia and tremor Bladder and bowel dysfunction Bladder and bowel dysfunction Cognitive impairment Cognitive impairment Depression Depression Fatigue Fatigue Paroxysmal symptoms Paroxysmal symptoms Sexual dysfunction Sexual dysfunction Spasticity Spasticity Weakness Weakness

CMSC, June 2004 Fatigue in MS Subjective lack of physical or mental energy to carry out usual activities Subjective lack of physical or mental energy to carry out usual activities Present at some time in 75%-90% of patients with MS Present at some time in 75%-90% of patients with MS Present daily in 46%-66% Present daily in 46%-66%

CMSC, June 2004 Fatigue: Proposed Treatments Amantadine Amantadine Pemoline Pemoline SSRI’s SSRI’s Amphetamines Amphetamines Aminopyridines Aminopyridines Modafanil Modafanil Behavior modification Behavior modification

CMSC, June 2004 Amantadine Developed as an anti-viral agent Developed as an anti-viral agent Identified by a chance observation as improving MS fatigue Identified by a chance observation as improving MS fatigue Class I evidence from four trials supports its use in MS patients Class I evidence from four trials supports its use in MS patients Response rates of 20% to 40% at 100 mg bid Response rates of 20% to 40% at 100 mg bid

CMSC, June 2004 Modafanil Novel wakefulness-promoting agent Novel wakefulness-promoting agent Mechanism of action unknown Mechanism of action unknown Low abuse potential (Schedule IV) Low abuse potential (Schedule IV) FDA approval for narcolepsy FDA approval for narcolepsy

CMSC, June 2004 Phase II Trial in MS Randomized, patient-blind, placebo-controlled crossover design phase II trial Randomized, patient-blind, placebo-controlled crossover design phase II trial 72 patients enrolled at two sites 72 patients enrolled at two sites Outcome measures: Outcome measures:  FSS (primary)  MFIS  VAS-F  Epworth sleepiness scale

CMSC, June 2004 Results: FSS *p<0.001, Placebo run in vs Modafanil 200mg *

CMSC, June 2004 Results: MFIS *p<0.001, Placebo run in vs Modafanil 200mg *

CMSC, June 2004 Results: 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:  Nausea  Anxiety, nervousness  Dry mouth  Insomnia  Diarrhea  Asthenia

CMSC, June 2004 Conclusions Fatigue is one of the most common symptoms in MS patients Fatigue is one of the most common symptoms in MS patients Pharmacological treatments are an important part of fatigue management Pharmacological treatments are an important part of fatigue management Amantadine is effective, cheap and well tolerated Amantadine is effective, cheap and well tolerated Modafanil is effective and well tolerated Modafanil is effective and well tolerated

CMSC, June 2004 Treatable Symptoms of MS Ataxia and tremor Ataxia and tremor Bladder and bowel dysfunction Bladder and bowel dysfunction Cognitive impairment Cognitive impairment Depression Depression Fatigue Fatigue Paroxysmal symptoms Paroxysmal symptoms Sexual dysfunction Sexual dysfunction Spasticity Spasticity Weakness Weakness

CMSC, June 2004 Weakness One of the most common and disabling symptoms in MS One of the most common and disabling symptoms in MS Usually due to upper motor neuron dysfunction Usually due to upper motor neuron dysfunction Loss of voluntary control exacerbated by de-conditioning Loss of voluntary control exacerbated by de-conditioning Primary therapy is exercise Primary therapy is exercise

CMSC, June 2004 Aminopyridine Potassium Channel Blockers Nonspecific blockers of voltage sensitive potassium channels Nonspecific blockers of voltage sensitive potassium channels Improve action potential propagation in demyelinated axons Improve action potential propagation in demyelinated axons Increase transmitter release at synaptic endings Increase transmitter release at synaptic endings

CMSC, June ,4 Diaminopyridine Orally active Orally active Short serum half-life Short serum half-life Crosses blood brain barrier poorly Crosses blood brain barrier poorly Available for the treatment of Lambert- Eaton Myasthenic Syndrome Available for the treatment of Lambert- Eaton Myasthenic Syndrome

CMSC, June 2004 Phase II Trial of DAP in MS Double-blind, placebo-controlled, crossover trial Double-blind, placebo-controlled, crossover trial 22 MS patients with leg weakness 22 MS patients with leg weakness One month treatment periods with up to 100 mg per day One month treatment periods with up to 100 mg per day Outcome measures: Outcome measures:  Patient and physician impressions of change  Manual motor testing  Quantitative motor testing  Ambulation index

CMSC, June 2004 Results: # Improved OutcomeDAPPlacebop Physician IC Patient IC MMT QMT-HS QMT-Q AI500.02

CMSC, June 2004 Results: Mean scores OutcomeDAPPlacebop MMT QMT-HS QMT-Q

CMSC, June 2004 Results: Mean Strength Scores

CMSC, June 2004 Results: Mean AI Scores

CMSC, June 2004 Conclusions 3,4 DAP treatment can improve leg strength in selected patients 3,4 DAP treatment can improve leg strength in selected patients 3,4 DAP treatment can improve ambulation times in a subset of patients 3,4 DAP treatment can improve ambulation times in a subset of patients 3,4 DAP treatment causes paresthesias and gastrointestinal adverse events that limit its use 3,4 DAP treatment causes paresthesias and gastrointestinal adverse events that limit its use Rarely 3,4 DAP treatment can cause seizures Rarely 3,4 DAP treatment can cause seizures

CMSC, June Aminopyridine Orally active Orally active Crosses blood brain barrier readily Crosses blood brain barrier readily Longer half-life than DAP Longer half-life than DAP Used to reverse neuromuscular blockade after surgery Used to reverse neuromuscular blockade after surgery

CMSC, June 2004 Trials of 4-Aminopyridine in MS Jones et al: Open label pilot Jones et al: Open label pilot Davis & Stefoski: Controlled crossover Davis & Stefoski: Controlled crossover Van Diemen, et al: Randomized, controlled, crossover Van Diemen, et al: Randomized, controlled, crossover Bever et al: Randomized, controlled, crossover Bever et al: Randomized, controlled, crossover Schwid et al: Randomized, controlled, crossover Schwid et al: Randomized, controlled, crossover Goodman et al: Randomized, DB, PC parallel group Goodman et al: Randomized, DB, PC parallel group

CMSC, June 2004 Objectives Primary: Determine safety of multiple doses of fampridine-SR (one week each of 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day and 80 mg/day). Primary: Determine safety of multiple doses of fampridine-SR (one week each of 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day and 80 mg/day). Secondary: Obtain evidence of efficacy and dose- response using several outcome measures Secondary: Obtain evidence of efficacy and dose- response using several outcome measures  Standard MS measurements, including timed walk, lower extremity muscle strength, PASAT, 9-hole peg test  Daily Fatigue Diary – Brief Fatigue Inventory Goodman, A, 2002

CMSC, June 2004

Dose Response- 25 ft Walk

CMSC, June 2004 Leg strength 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 AEs25 (100%)10 (90.9%) Most Frequently Reported AEs Dizziness9 (36.0%)2 (19.2%) Insomnia9 (36.0%)1 (9.1%) Paresthesia8 (32.0%)1 (9.1%) Nausea7 (28.0%)1 (9.1%) Asthenia7 (28.0%)1 (9.1%) Headache6 (24.0%)1 (9.1%) Tremor6 (24.0%)0 Pain5 (20.0%)0 Back Pain5 (20.0%)0 Anxiety3 (12.0%)0 Hypertonia1 (4.0%)3 (27.3%)

CMSC, June 2004 Safety Summary The most common adverse events in the fampridine treated group were consistent with the findings of previous studies The most common adverse events in the fampridine treated group were consistent with the findings of previous studies  Dizziness, Insomnia, Parasthesia, Nausea, Asthenia, Headache, Tremor At doses above 40 mg/day, more severe adverse events were reported, including two cases of seizure (at 60 and 70 mg/day) At doses above 40 mg/day, more severe adverse events were reported, including two cases of seizure (at 60 and 70 mg/day) As anticipated, the risk of seizure requires further study and characterization particularly in the anticipated dose range As anticipated, the risk of seizure requires further study and characterization particularly in the anticipated dose range

CMSC, June 2004 Summary Safety profile consistent with previous experience Safety 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 (p=0.01) Significant* benefit on lower extremity strength (p=0.01) Evidence of dose-response in mg/day range Evidence of dose-response in 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 above 50 mg/day Little added benefit, and increased AEs at doses above 50 mg/day *repeated measure ANOVA (weeks 1-7)