Parkinson’s Medications: Today and Tomorrow Led By · Pluripotent Stem cells and their potential in PD • Stem cells promising • Not ready for PD • Only dopaminergic neurons

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

April 9. The presenter might make slight changes before the live session.

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

•  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

OnDyskinesia

OffBradykinesia6 - 8

Hours3 - 5

Hours0.5 - 2Hours

Early Moderate Advanced

Parkinson’s Disease

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

Objectives


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 ?

•  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

Olanow et al. NEJM 2009

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

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


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


•  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


•  New formulations of levodopa –  Duodopa: levodopa gel

•  Continuous infusions into the upper intestines (duodenum)

Follow vitamin B12


•  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)


•  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


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

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

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


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

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

Websites: Research in PD

Pdtrials.org Clinicaltrials.gov Foxtrialfinder.org

Questions and Answers

Documents

Parkinson’s Medications: Today and Tomorrow Led By · Pluripotent Stem cells and their potential in PD • Stem cells promising • Not ready for PD • Only dopaminergic neurons