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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.
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Please note: These slides are accurate as of
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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
Welcoming Remarks
Robin Elliott
Executive Director
Parkinson’s Disease Foundation
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
Objectives
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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
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 ®)
Motor Fluctuations and Dyskinesias
Related to L-Dopa Therapy
On
Dyskinesia
6-8
Hours
3-5
Hours
0.5 - 2
Hours
Early
Moderate
Advanced
Parkinson’s Disease
Off
Bradykinesia
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
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
• 
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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
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
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
?
Progression of PD and effects of treatment
Obstacle to disease modifying studies
•  Rating scales (UPDRS)
–  good inter-rater reliability
–  motor scale measures key features
40
•  rest tremor
35
30
•  rigidity
25
•  bradykinesia
20
15
•  gait/axial function
10
5
–  Confounded by
0
time 0
1y
2y
3y
4y
5y
symptomatic therapies
•  No brain imaging for direct measure of
start ldopa
degenerative process
6y
7y
The Adagio study
Does rasagiline slow
progression of PD?
Olanow et al. NEJM 2009
The Adagio study
Does rasagiline slow
progression of PD?
NOT approved by FDA
for neuroprotection
Olanow et al. NEJM 2009
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
Objectives
• 
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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
Pipeline
•  Non-motor symptoms
•  Motor symptoms
–  Primary PD
symptoms
–  Motor fluctuations
–  Dyskinesias
•  Neuroprotective
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
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
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
Pipeline
Motor symptoms
•  New formulations of levodopa
–  Duodopa: levodopa gel
•  Continuous infusions into the upper intestines
(duodenum)
Follow vitamin B12
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
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.
Pipeline
Motor symptoms/dyskinesia
•  Drugs to treat levodopa induced abnormal
movements (dyskinesia)
–  Amantadine extended release (Eased Study)
–  Fipamezole (alpha-2 adrenergic antagonist)
–  Levetiracetam (Kepra)
Pipeline
Motor symptoms
•  Repetitive Transcranial
magnetic stimulation
(rTMS)
–  Non-invasive
–  Alters neuronal
excitability
–  Phase 2/3 multicenter
study in 160 PD
patients ongoing
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
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
Objectives
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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
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
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
Exercise in PD:
Tandem cycling
Alberts et al, 2009
UPDRS motor scores
60 50 40 FE 30 VE 20 10 0 baseline End train 1 month a7er stop Improvement in bradykinesia and rigidity (trends)
Alberts et al, 2009
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
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
Motor UPDRS Scores
Corcos et al, submitted 2012
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
Objectives
• 
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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
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
Defining the problem
Developing the hypothesis
Getting the study sites for phase 3
Regulatory, IRB
Enrolling the
appropriate patients
Less than 1% will agree
Finding the treatment
Finding the
optimal dose(s)
Running the study
Proof of concept
Analyzing the results
Safety and efficacy
Initiating the study
Phase 1
Phase 2
FDA process
About 10 years from phase 1
to FDA approval
Most drugs do not make it
Websites:
Research in PD
Pdtrials.org
Clinicaltrials.gov
Foxtrialfinder.org
Questions and
Answers