1. Adjunctive Drug Therapy for Advanced Parkinson’s Disease Combination Strategies and Sequencing Pharmacotherapy Lawrence Elmer, MD, PhD Program Chairman Associate Professor Department of Neurology University of Toledo College of Medicine Lawrence Elmer, MD, PhD Program Chairman Associate Professor Department of Neurology University of Toledo College of Medicine The Science and Medicine of Parkinson’s Disease

2. Stages of Parkinson’s Disease ► Mild symptoms, no disability ► Non-pharmacological approaches ► Moderate symptoms with some disability ► Multiple treatments available including l-dopa ► Progression of symptoms ► Levodopa required +/- other meds Early ModerateAdvanced ► Disease progresses ► Non-motor complications may outweigh motor disturbances Adjunctive Drug Therapy for Advanced PD Report of the Quality Standards Subcommittee of the American Academy of Neurology 2006

3. Early or Moderate Stage Management of PD ► Level A – MAO-B inhibitors – selegiline, rasagiline ► Level A – Dopamine agonists – pramipexole, ropinirole, rotigotine – caution in elderly, cognitive impairment, young males (?) ► Level A - Carbidopa/levodopa – immediate release ► Level B - Carbidopa/levodopa – controlled release Recommended Years 1-5 (possibly more?) Questionable ► Co-enzyme Q10 ► Amantadine Therapeutic Agents Adjunctive Drug Therapy for Advanced PD Miyasaki, JM, et al., Neurology 2002;58:11–17 O. Suchowersky, et al., Neurology 2006; 66: 976-982

4. Long-term Treatment of Parkinson’s Disease Associated with Motor Complications Adjunctive Drug Therapy for Advanced PD

5. Goals of Current Therapeutic Strategies Adjunctive Drug Therapy for Advanced PD

6. DA GABA ACh Striatum Substantia Nigra LevodopaLevodopa Anticholinergics Sites of Action of PD Drugs: 1960’s Adjunctive Drug Therapy for Advanced PD

7. DA GABA ACh Striatum Levodopa Amantadine Selegiline Dopamine agonists Bromocriptine Bromocriptine Pergolide Pergolide Anticholinergics BBB Carbidopa Carbidopa Benserazide Benserazide MAO-B Sites of Action of PD Drugs: 1990’s Adjunctive Drug Therapy for Advanced PD

8. DA GABA ACh Striatum Substantia Nigra Levodopa Amantadine Selegiline Dopamine agonists Bromocriptine Bromocriptine Pergolide Pergolide Pramipexole Pramipexole Popinirole Popinirole Baclofen Anticholinergics BBB Carbidopa Carbidopa Benserazide Benserazide Tolcapone Tolcapone Entacapone Entacapone MAO-B Sites of Action of PD Drugs: 2000 Adjunctive Drug Therapy for Advanced PD

9. DA GABA ACh Striatum Substantia Nigra Levodopa Amantadine Selegiline Zydis selegiline Rasagiline Dopamine agonists Apomorphine Apomorphine Bromocriptine Bromocriptine Pergolide Pergolide Pramipexole Pramipexole Ropinirole Ropinirole Rotigotine Rotigotine Baclofen Anticholinergics BBB Carbidopa Carbidopa Benserazide Benserazide Tolcapone Tolcapone Entacapone Entacapone MAO-B Stalevo®(carbidopa/levodopa/entacapone) Parcopa® Sites of Action of PD Drugs: 2008 Adjunctive Drug Therapy for Advanced PD

10. Singh, et al, Progress in Neurobiology, 81:29-44 (2007). Sites of Action of Pharmacological Therapies Currently Prescribed for PD

11. Sites of Action of PD Drug Treatment: Emerging Adjunctive Drug Therapy for Advanced PD DA GABA ACh Striatum Substantia Nigra Other Receptor Targets Serotonergic Antagonists Adenosine Antagonists AMPA Antagonists Adrenergic Antagonists Dopamine agonists Controlled-release Novel DA’s Nasal sprays Other transdermal MAO-B Extended levodopa delivery systems

12. Advanced Management of PD Treating Motor Fluctuations ► Level A – entacapone, rasagiline ► Level B – pramipexole, ropinirole, tolcapone - caution hepatotoxicity ► Level C – apomorphine, cabergoline, and selegiline ► Level C (surgical) – STN deep brain stimulation ► Level C (dyskinesias) - amantadine ► Disregarded – bromocriptine, sustained release carbidopa/levodopa Evidence Years 1-3 and following Adjunctive Drug Therapy for Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995

13. Published Reductions in “OFF” Time: Moderate to Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995 Appendix E-1 DrugDurationActivePlacebo Treatment Effect pramipexole 32 week 31%* (1.8 h) 7% (0.2 h) 24% (1.6 h) pramipexole 40 week 15%*3% 12% ropinirole 12 week 23%*4% 19% ropinirole 26 week 11.7%*5% 6.7% ODT selegiline 12 week 32% (2.2 h)* 9% (0.6 h) 23% (1.6 h) rasagiline (0.5mg) 26 week 23% (1.4h)* 15% (0.9 h) 8% (0.5 h) rasagiline (1.0mg) 26 week 29% (1.8h)* 15% (0.9 h) 14% (0.9 h) rasagiline 18 week 21% (1.2 hr)* 7% (0.4 h) 14% (0.8 h) tolcapone (100mg tid) 12 week 32% (2.3 h) 20% (1.4 h) 12% (0.9 h) tolcapone (200mg tid) 12 week 48% (3.2 h)* 20% (1.4 h) 28% (1.8 h) tolcapone (100mg tid) 12 week 31.5%*11% 20.5% entacapone 18 week 21% (1.2 h)* 7% (0.4 h) 14% (0.8 h) entacapone 24 week 25.8% (1.6 h)* 13.4% (0.9 h) 12.4% (0.7 h) entacapone 24 week 23.6% (1.3 h)* 1.9% (0.1 h) 21.7% (1.2 h)

14. Dopamine Agonists vs. Levodopa 45 20 34 23 Rascol et al. N Engl J Med 2000;342:1484-1491; Parkinson Study Group. Arch Neurol 2004; 61:1044-1053. (%)(%) 74 74 52 63 47 54 25 0 20 40 60 80 100 1st 1stComplication Wearing off Dyskinesia Levodopa (n=89) Ropinirole (n=179) Levodopa (n=150) Pramipexole (n=151) 0 20 40 60 80 100 Wearing off Dyskinesia Pergolide – time to onset of dyskinesia greater with pergolide; 16.3% of pergolide and 32.9% of levodopa group had dyskinesia at 3 years. Courtesy K. Lyons, PhD. 2006

15. Goals of Current Therapeutic Strategies Adjunctive Drug Therapy for Advanced PD

16. Plasma Levels – Rotigitine CDS Adjunctive Drug Therapy for Advanced PD

17. Adjunctive Transdermal System Adjunctive Drug Therapy for Advanced PD

18. UPDRS Motor Scores Following Intermittent SC Apomorphine R. Pfeiffer, L. Gutmann, K. Hull, Jr., P. Bottini, J. Sherry; Parkinsonism & Related Disorders, 13:93-100 (2007).

19. Effect Of Tolcapone On Levodopa- Induced Improvement In PD Motor score improvement Minutes Roberts et al, 1994. LD dose 4040 4242 4 4646 4848 410 412 414 416 4040460412041804240 4Tolcapone 4Placebo

20. Percentage Reduction in Off-time and Levodopa with COMT Inhibition Rajput, A. H. et al. Neurology. 1997 Oct;49(4):1066-71. 2 -20 -21 -32 -24 -48 -60 -50 -40 -30 -20 -10 0 10 % Reduction in off time % Reduction in Ldopa dose Placebo Tolcapone 100 mg tid Tolcapone 200 m tid

21. Adjunctive Drug Therapy for Advanced PD Lew M, Kricorian G., World Congress of Neurology 2005 Long-term Surveillance of Tolcapone Hepatotoxicity

22. ► Entacapone prolongs the half-life of levodopa by  85%, with no change in C max or T max ► Increases levodopa exposure by  35% Effect of Entacapone on Levodopa Pharmacokinetics Buottinen HM, et al. J Neurol Neurosurg Psychiatry. 1996. Diagnosis and Treatment of Parkinson’s Disease: Update 2004

23. Entacapone in Fluctuating PD ► Five (5) pivotal randomized, placebo- controlled, double blind studies ● Increase in “on” time of approximately 1 to 2 hours ● Reduction in “off” time 1 to 1.5 hours ● Reduction in daily levodopa dose of 33 to 140 mg 33 to 140 mg ● Improvement in UPDRS “on” score ► Five (5) pivotal randomized, placebo- controlled, double blind studies ● Increase in “on” time of approximately 1 to 2 hours ● Reduction in “off” time 1 to 1.5 hours ● Reduction in daily levodopa dose of 33 to 140 mg 33 to 140 mg ● Improvement in UPDRS “on” score Ruottinen 1996; PSG 1997; Rinne 1998; Poewe 2002; Brooks 2003.

24. Zydis Selegiline: Reduction in “Off” Time at 12 Weeks 32%* *p<0.001 Observation Period Adjunctive Drug Therapy for Advanced PDWaters CH, et al., Mov Disord 2004;19:426-32

25. Adjunctive Drug Therapy for Advanced PD Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363 Zydis Selegiline: Long-term Follow-up

26. Adjunctive Drug Therapy for Advanced PD Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363 Zydis Selegiline: Long-term Follow-up – Concomitant Meds Zydis Selegiline CharacteristicContinuing (n=171),n (%) Prior Placebo (n=83),n (%) All Patients (n=254) ),n (%) Dopamine agonists Anticholinergics 4 (2.3) 3 (1.8) 2 (2.4) 0 (0) 6 (2.4) 3 (1.2)

27. Rasagiline: Reduction in “OFF” Time Similar to Entacapone Change from Baseline Hours) Change from Baseline (Hours) -1.20 -1.18 -0.40 Rasagiline 1 mg Entacapone 200 mg Placebo-LD/DDIPlacebo-LD/DDI-0.2-0.2-0.7-0.7 -2.2-2.2 -1.2-1.2 P = 0.0001 P < 0.0001 Adjusted Means ±SE Rascol. Lancet. 2005; 365:947-54. All patients on LD/DDI Improvement Adjunctive Drug Therapy for Advanced PD

28. 2468101216202414182226 PRESTO: Change From Baseline in Total Daily “OFF” (Hours) by Visit 0.50.0 -0.5 -1.5 -2.0 -2.5 Week Rasagiline 0.5 mg Rasagiline 1 mg Placebo 0 Hours

29. Adjunctive Drug Therapy for Advanced PD Heinz Reichmann, Wolfgang Jost World Congress on Parkinson’s Disease and Related Disorders, 2007 Open Label Study of Rasagiline in Fluctuating Patients: Delayed Benefit? Baseline 4 weeks 4 months Median total daily OFF time (Diary) *** N=545 ***# *** p< 0.001 vs. baseline # p<0.001 vs. 4 weeks

30. Concomitant Medication Usage in PRESTO Rasagiline Characteristic Placebo (n=159) 0.5 mg/day (n=164) 1 mg/day (n=149) Dopamine agonists Entacapone Amantadine 111 (69.8) 61 (38.4) 38 (23.9) 113 (68.9) 55 (33.5) 34 (20.7) 106 (71.1) 49 (32.9) 26 (17.4) Data = N (%) Elmer, L and the Parkinson Study Group. MDS, 2005

31. Rasagiline 1.0 mg/day Rasagiline 0.5 mg/day Placebo Without COMT-I (n=307) With COMT-I (n=165) All patients on LD/CD *p<0.05; ***p<0.001 vs placebo Change from baseline in mean Total daily OFF time (hours) Rasagiline with and without Concomitant COMT-I Adjunctive Drug Therapy for Advanced PDElmer, L and the Parkinson Study Group. MDS, 2005 *** *

32. Rasagiline 1.0 mg/day Placebo All patients on LD/DDI Change from baseline in mean Total daily OFF time (hours) Without DAs (n=91) With DAs (n=217) ***p<0.001 vs placebo Rasagiline with and without Concomitant DA Adjunctive Drug Therapy for Advanced PDElmer, L and the Parkinson Study Group. MDS, 2005 ***

33. Cognitive and Behavioral Adverse Events Comparison of Rasagiline with Other Agents % Incidence of CBAE’s above placebo (from package inserts) % Incidence of CBAE’s above placebo (from TEMPO and PRESTO ) EntacaponePramipexoleRopiniroleRasagiline As Monotherapy Sleep disorder Sleep disorder5N/AN/A Somnolence Somnolence1334N/A Depression DepressionN/AN/A3 Abnormal dreams Abnormal dreamsN/AN/A>1 Hallucinations Hallucinations64N/A Confusion Confusion34N/A As Adjunctive Therapy Sleep disorder Sleep disorderN/A1N/A1 Somnolence Somnolence23121.6 Depression DepressionN/AN/AN/AN/A Abnormal dreams Abnormal dreamsN/A112.7 Hallucinations HallucinationsN/A1361 Confusion ConfusionN/A37>1 Elmer L, et al., J Neurol Sci 2006;248(1-2):78-83.

34. Deep Brain Stimulation: Reduction in “Off” Time The Deep-Brain Stimulation for Parkinson’s Disease Study Group. N Engl J Med 2001;345:956-963. Baseline Six Months 27% ON 50% OFF 23% ON w/dysk 74% ON 19% OFF 7% ON w/dysk All P values < 0.001

35. Conclusions: Advanced Treatment ► Combination therapy reasonable to consider before levodopa introduced ► Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well- tolerated ► Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for advanced management of Parkinson’s disease. ► Combination therapy reasonable to consider before levodopa introduced ► Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well- tolerated ► Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for advanced management of Parkinson’s disease.