PD ExpertBriefings: Parkinson s Medications: Today and Tomorrow Led By: Cynthia L. Comella, M.D., F.A.A.N.

Transcription

1 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) and enter the passcode #. To learn more, please visit: If you have any questions, please contact webcast@pdf.org or at (212) Please note: These slides are accurate as of April 9. The presenter might make slight changes before the live session.

2 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

3 Welcoming Remarks Robin Elliott Executive Director Parkinson s Disease Foundation

4 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

5 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

6 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 )

7 Motor Fluctuations and Dyskinesias Related to L-Dopa Therapy On Dyskinesia 6-8 Hours 3-5 Hours Hours Off Bradykinesia Early Moderate Advanced Parkinson s Disease

8 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

9 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

10 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

11 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

12 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?

13 Progression of PD and effects of treatment Obstacle to disease modifying studies Rating scales (UPDRS) good inter-rater reliability motor scale measures key features rest tremor 40 rigidity bradykinesia gait/axial function 5 Confounded by 0 symptomatic therapies No brain imaging for direct measure of degenerative process time 0 1y 2y 3y 4y 5y 6y 7y start ldopa

14 The Adagio study Does rasagiline slow progression of PD? Olanow et al. NEJM 2009

15 The Adagio study Does rasagiline slow progression of PD? NOT approved by FDA for neuroprotection Olanow et al. NEJM 2009

16 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

17 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

18 Pipeline Non-motor symptoms Motor symptoms Primary PD symptoms Motor fluctuations Dyskinesias Neuroprotective

19 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

20 MAO-B inhibitors Safinamide Pipeline Motor symptoms MAO-B inhibitor, Glutamate inhibitor Modest improvement as monotherapy at higher doses May improve off time in patients with motor fluctuations May reduce dyskinesias

21 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

22 Pipeline Motor symptoms New formulations of levodopa Duodopa: levodopa gel Continuous infusions into the upper intestines (duodenum) Follow vitamin B12

23 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

24 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.

25 Pipeline Motor symptoms/dyskinesia Drugs to treat levodopa induced abnormal movements (dyskinesia) Amantadine extended release (Eased Study) Fipamezole (alpha-2 adrenergic antagonist) Levetiracetam (Kepra)

26 Pipeline Motor symptoms Repetitive Transcranial magnetic stimulation (rtms) Non-invasive Alters neuronal excitability Phase 2/3 multicenter study in 160 PD patients ongoing

27 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

28 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

29 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

30 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 /74 studies on pdtrials.org Improves PD severity, balance, gait Improves cognition, memory, depression Increases neurotrophic factors in animal models

31 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

32 Exercise in PD: Tandem cycling Alberts et al, 2009

33 UPDRS motor scores FE VE 10 0 baseline End train 1 month a7er stop Improvement in bradykinesia and rigidity (trends) Alberts et al, 2009

34 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

35 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

36 Motor UPDRS Scores Corcos et al, submitted 2012

37 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

38 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

39 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

40 Defining the problem Developing the hypothesis Getting the study sites for phase 3 Regulatory, IRB Finding the treatment Enrolling the appropriate patients Less than 1% will agree Finding the optimal dose(s) Running the study Proof of concept Analyzing the results Safety and efficacy Initiating the study Phase 1 Phase 2 About 10 years from phase 1 to FDA approval Most drugs do not make it FDA process

41 Websites: Research in PD Pdtrials.org Clinicaltrials.gov Foxtrialfinder.org

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43 Questions and Answers