parkinson’s medications: today and tomorrow led by · pluripotent stem cells and their potential...
TRANSCRIPT
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PD ExpertBriefings:
Parkinson’s Medications: Today and Tomorrow Led By: Cynthia L. Comella, M.D., F.A.A.N.
To hear the session live on:
Tuesday, April 17, 2012 at 1:00 PM ET.
DIAL: 1 (888) 272-8710 and enter the passcode 6323567#.
To learn more, please visit:
http://www.pdf.org/parkinson_briefing_medications
If you have any questions, please contact [email protected] or at (212) 923-4700
Please note: These slides are accurate as of
April 9. The presenter might make slight changes before the live session.
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PD ExpertBriefings: Parkinson’s Medications:
Today and Tomorrow
Presented By: Cynthia L. Comella, M.D., F.A.A.N
Rush University Medical Center
Chicago, IL
Tuesday, April 17, 2012 at 1:00 PM ET
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Welcoming Remarks
Robin Elliott Executive Director
Parkinson’s Disease Foundation
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Goals for PD treatment
• Restorative treatments – Reverse the process
• Disease modifying – Neuroprotective
• Symptomatic treatments for PD motor symptoms – Related to PD – Complications of therapy
• Treatment of non-motor features of PD
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Objectives
• Current treatments for PD • Slowing progression of PD • New treatments in clinical trials • New focus on exercise in PD • Challenge of clinical trials for PD
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Currently available treatments • Treatment of PD motor symptoms
– Amantadine – MAO-B inhibitors (selegiline (Eldepryl®), rasagiline
(Azilect®)) – Dopaminergic medications
• Carbidopa/levodopa (Sinemet®) • Pramipexole (Mirapex®) • Ropinirole (Requip®) • Apomorphine (Apokyn ®)
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Motor Fluctuations and Dyskinesias Related to L-Dopa Therapy
OnDyskinesia
OffBradykinesia6 - 8
Hours3 - 5
Hours0.5 - 2Hours
Early Moderate Advanced
Parkinson’s Disease
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Treatment of motor complications
• Wearing off and dyskinesia – Slow the metabolism of levodopa
• MAO-B inhibitors (selegiline (Eldepryl®), rasagiline (Azilect®))
• COMT inhibitors with levodopa – Entacapone (Comtan®), tolcapone
(Tasmar®) – Shorten the interval between doses – Amantadine for dyskinesia – DBS
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Problems with current treatments
• Treat symptoms not the cause of PD • None approved shown to slow progression of PD • Mostly directed toward motor symptoms • With advancing disease, lose efficacy • Side effects
– Sleepiness, nausea, lowered blood pressure, dizziness, dyskinesia, swelling in ankles, hallucinations etc.
• Do not adequately address non-motor features of PD
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Objectives
• Current treatments for PD • Slowing progression of PD • New treatments in clinical trials • New focus on exercise in PD • Challenge of clinical trials for PD
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Vitamins in PD
• Oral vitamin E: not effective • Other vitamins not adequately studied
• Approximately 60% PD vitamin D insufficient or deficient by serum 25(OH)D) – ? Primary or secondary – Bone loss, aching, other organ systems – Vit D replacement
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Trials of Putative Neuroprotective Agents
Agent MoA End Point Result Riluzole NMDA antag. Time to L-dopa Negative Immunophilin Neurotrophic Time to L-dopa Negative Remacemide NMDA antag. Time to L-dopa Negative TCH346 Antiapoptotic Time to L-dopa Negative CEP1347 Kinase inhib. Time to L-dopa Negative Selegiline MAO-B Time to L-dopa Negative?
Selegiline MAO-B Wash Out Negative?
Co-Q10 Bioenergetic Δ UPDRS Negative
Ropinirole Antiapoptotic CIT-SPECT ?
Pramipexole Antiapoptotic F-DOPA PET ?
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• Rating scales (UPDRS) – good inter-rater reliability – motor scale measures key features
• rest tremor • rigidity • bradykinesia • gait/axial function
– Confounded by symptomatic therapies
• No brain imaging for direct measure of degenerative process
0
5
10
15
20
25
30
35
40
time 0 1y 2y 3y 4y 5y 6y 7y
start ldopa
Progression of PD and effects of treatment Obstacle to disease modifying studies
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Olanow et al. NEJM 2009
The Adagio study Does rasagiline slow progression of PD?
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Olanow et al. NEJM 2009
The Adagio study Does rasagiline slow progression of PD?
NOT approved by FDA for neuroprotection
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Neuroprotection study underway
• Pioglitazone for slowing clinical progression in early PD (FS-Zone)
• Glucose lowering drug used in diabetes • Antioxidant properties • Regulate inflammatory pathways • Promising results in rotenone and MPTP animal
models of PD – Phase 2 study in progress in PD
• 216 patients on MAO-B Inhibitor < 5 years PD • 44 week study placebo, 2 doses pioglitazone
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Objectives
• Current treatments for PD • Slowing progression of PD • New treatments in clinical trials • New focus on exercise in PD • Challenge of clinical trials for PD
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Pipeline
• Non-motor symptoms • Motor symptoms
– Primary PD symptoms
– Motor fluctuations – Dyskinesias
• Neuroprotective
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Pipeline Non motor symptoms
• Orthostatic hypotension – Droxidopa
• Sialorrhea (drooling) – Botulinum toxin, oxybutynin-clonidine syrup
• Gait and balance – Varenicline (Chantix)
• Psychosis – Pimavanserin
• Impulse control disorders – naltrexone
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Pipeline Motor symptoms
• MAO-B inhibitors – Safinamide
• MAO-B inhibitor, Glutamate inhibitor • Modest improvement as monotherapy at
higher doses • May improve off time in patients with motor
fluctuations • May reduce dyskinesias
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Pipeline Motor symptoms
• New formulations of levodopa – Impax (IPX066)
• Rapid absorbing and extended release levodopa • Provides both effects of carbidopa-levodopa regular
formulation with that of sustained release formulations
– XP21279 • Levodopa prodrug with sustained release
– Absorbed in upper and lower GI tract • Phase 1, 1b studies:
– Less variability in plasma levodopa levels – Reduced off time by 30% Hauser et al, 2011
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Pipeline Motor symptoms
• New formulations of levodopa – Duodopa: levodopa gel
• Continuous infusions into the upper intestines (duodenum)
Follow vitamin B12
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Pipeline Motor symptoms
• Patch therapy – Rotigotine patch (Neupro)
• Transdermal dopamine agonist • Withdrawn from the US market due to “snowflakes” • In preparation for another release
– Levodopa ethyl ester patch • Promising • Discontinued due to skin irritation
– ND0611 • Continuous carbidopa solution used with oral L-dopa • Administered under the skin using patch
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Pipeline Motor symptoms/fluctuations
• A2a antagonists for fluctuations • Involved in activity of pathways involved in PD • May avoid dopaminergic side effects
– Istradefylline • Not beneficial as monotherapy • Variable outcomes for improvement motor fluctuations • FDA: not approvable • No longer being developed in the US
– Preladenant • Currently phase 3 studies as adjunct to levodopa for
motor fluctuations.
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Pipeline Motor symptoms/dyskinesia
• Drugs to treat levodopa induced abnormal movements (dyskinesia) – Amantadine extended release (Eased Study) – Fipamezole (alpha-2 adrenergic antagonist) – Levetiracetam (Kepra)
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Pipeline Motor symptoms
• Repetitive Transcranial magnetic stimulation (rTMS) – Non-invasive – Alters neuronal
excitability – Phase 2/3 multicenter
study in 160 PD patients ongoing
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Pipeline protective or restorative
• Increase neurotrophic factors • Promote development and survival
of cells – Cogane
• Oral medication that induces neurotrophic factors in the brain
– Neurturin with viral vector (Ceregene) • Surgically injected into putamen and substantia nigra
– GDNF with viral vector • Surgically injected into putamen and substantia nigra
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Pluripotent Stem cells and their potential in PD
• Stem cells promising • Not ready for PD • Only dopaminergic
neurons – Does not address
non-motor • Establish methods to
modulate stem cell growth
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Objectives
• Current treatments for PD • Slowing progression of PD • New treatments in clinical trials • New focus on exercise in PD • Challenge of clinical trials for PD
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Role of exercise in PD
• 3 of 10 most cited studies in the Movement Disorders Journal relate to the effect of exercise for PD
• 227 citations in PUB MED since 2010 • 13/74 studies on pdtrials.org • Improves PD severity, balance, gait • Improves cognition, memory, depression • Increases neurotrophic factors in animal models
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How much physical activity do adults need: CDC recommendations 2008
• Per week – Moderate aerobic activity:
• 30 minutes 5 times per week – Muscle strengthening all major muscle groups at least 2
days OR – Vigorous activity :
• 15 minutes 5 times per week – Muscle strengthening all major muscle groups at least 2
days • For maximal benefit, double activity time • 10 minutes at a time is fine
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Exercise in PD: Tandem cycling
Alberts et al, 2009
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UPDRS motor scores
0
10
20
30
40
50
60
baseline End train 1 month a7er stop
FE
VE
Improvement in bradykinesia and rigidity (trends)
Alberts et al, 2009
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Tai Chi and Postural Stability in PD
• PD patients randomized to 3 groups – 65 in Tai Chi; 65 in resistance; 65 stretching
• Twice weekly for 24 weeks • Tai Chi associated with improvement for:
– Postural stability – Number of falls – Gait
• Improvement may be present 3 months after training completed.
Fuzhong et al, NEJM 2012
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Exercise in PD
• Comparing progressive resistance to flexibility and balance
• 24 patients randomized to each group • Exercise program 2-3 times per week • Personal trainer • Followed for 2 years
Corcos et al, submitted 2012
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Motor UPDRS Scores
Corcos et al, submitted 2012
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SPARX study: the NEXT step
• Progressive resistance exercise improves PD symptoms
• What “dose” of exercise is optimal? • Untreated PD patients • Exercise at different intensities
– 60% and 80% of maximal heart rate – 3 times per week for 1 year
Margaret Schenkman, PhD, PT
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Objectives
• Current treatments for PD • Slowing progression of PD • New treatments in clinical trials • New focus on exercise in PD • Challenge of clinical trials for PD
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Clinical trials in Parkinson disease?
• Cannot determine efficacy by anecdotal experience, case studies, trials without a control for comparison
• Placebo effects can be prominent in PD • Only those treatments whose effects are
superior to placebo should be approved for use in PD
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About 10 years from phase 1 to FDA approval
Most drugs do not make it
Finding the optimal dose(s)
Proof of concept
Defining the problem Developing the hypothesis
Getting the study sites for phase 3 Regulatory, IRB
Enrolling the appropriate patients
Less than 1% will agree
Running the study
Analyzing the results Safety and efficacy
FDA process Initiating the study
Phase 1 Phase 2
Finding the treatment
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Websites: Research in PD
Pdtrials.org Clinicaltrials.gov Foxtrialfinder.org
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Questions and Answers