2. Stalevo ® (levodopa / carbidopa / entacapone) Stalevo ® prescribing information is available at this meeting Information about adverse event reporting can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Orion Pharma (UK) Ltd on 01635 520300.

3. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

4. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

5. Treatment with levodopa has dramatically reduced disability and mortality associated with PD Years since diagnosis Patients with severe disability and death (%) 0 20 40 60 80 100 1–56–1011–15 Untreated patients Levodopa-treated patients Hoehn and Yahr, 1967; Hoehn, 1983 PD=Parkinson’s disease

6. Levodopa consistently provides better symptom control compared with dopamine agonists Improvement with levodopa: 5.9 points vs pramipexole* (p=0.003) on total UPDRS at 4 years 4.48 points vs ropinirole** (p=0.008) on UPDRS motor subscale at 5 years 2.9 points vs cabergoline*** (p<0.001) on UPDRS motor subscale at 5 years **Rascol et al, 2000; ***Bracco et al, 2004; *Figure adapted from Holloway et al, 2004 UPDRS=United Parkinson’s Disease Rating Scale Improvement

7. Most patients eventually require the superior efficacy of levodopa for symptom control Need for levodopa in patients initiated with a dopamine agonist (pramipexole)* 16% 23% 59% 46% Patients requiring supplemental levodopa (%) 0 10 20 30 40 50 60 70 12 3 4 *Figure adapted from PSG, 1997; **Figure adapted from Holloway et al, 2004 Need for levodopa in patients initiated with a monoamine oxidase inhibitor (selegiline)** Years after randomization Probability of requiring levodopa therapy (%) Months after randomization 60 40 20 0 0 6121824

8. Levodopa provides better overall short-term tolerability vs dopamine agonists Dopaminergic adverse event Pergolide vs levodopa (%) Pramipexole vs levodopa (%) Ropinirole vs levodopa (%) Nausea41 vs 21*36 vs 3749 vs 49 Somnolence10 vs 532 vs 17*27 vs 19 Oedema5 vs 1*18 vs 8*14 vs 6 Hallucinations3 vs 0*9 vs 3*17 vs 6 PSG, 2000; Oertel et al, 2006; Rascol et al, 2000; Weintraub et al, 2006 * Significantly less with levodopa vs dopamine agonist (p<0.05)

9. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

10. Traditional levodopa therapy is associated with the development of motor complications Figure adapted from Obeso et al, 2000 Early disease Smooth, long duration of clinical benefit Low incidence of dyskinesias Mid-stage disease Diminished duration of clinical benefit Increased incidence of dyskinesias Advanced disease Clinical response mirrors levodopa plasma pharmacokinetic profile ‘On’ time is associated with dyskinesias Time (hours) Levodopa 246 Clinical effect Levodopa 246 Clinical effect Levodopa 246 Clinical effect On Off Response threshold Dyskinesia threshold

11. In PD, traditional levodopa delivery leads to pulsatile dopamine levels in the brain The short half-life (60–90 min) of traditional levodopa leads to peaks and profound troughs in plasma levodopa levels which are further worsened by intermittent dosing Pulsatile plasma levodopa levels leads to pulsatile levels of dopamine in the brain In PD, the ability to regulate and maintain steady levels of dopamine in the brain is reduced due to progressing neuronal loss

12. The first manifestation of pulsatile levodopa delivery in the brain is often wearing-off Pulsatile levels of dopamine in the brain translate into fluctuations in clinical response Often the first complaint patients have is that the duration of symptom control provided by their traditional levodopa becomes shorter (‘wears-off’) and their symptoms re-emerge before the next scheduled dose Traditional levodopa Time Symptom re-emergence Symptoms controlled Figure adapted from Stacy et al, 2005

13. The long-term consequence of pulsatile levodopa delivery in the brain is often dyskinesia In PD, pulsatile plasma levodopa levels translates into pulsatile levels of dopamine in the brain Pulsatile stimulation of striatal dopamine receptors Further destabilization of an already unstable basal ganglia Dyskinesia

14. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

15. Constant levels of dopamine are vital for normal movement In the brain, constant levels of dopamine are required to Regulate cortical excitation of striatal neurons Stabilize the firing rate and excitability of striatal neurons Modulate plasticity of striatal neurons (long-term potentiation) Olanow et al, 2006 Striatum Substantia nigra Excitatory cortical input Normal motor function Dopaminergic regulatory input Basal ganglia

16. In PD, pulsatile delivery of traditional levodopa leads to pulsatile stimulation of dopamine receptors Traditional levodopa Activated Unactivated Normal PD (untreated) Traditional levodopa Substantia nigra Striatum Dopamine receptor state Nigrostriatal neurons degenerate Activated Unactivated Activated Unactivated

17. In PD, pulsatile delivery of traditional levodopa leads to pulsatile stimulation of the dopamine receptors Olanow et al, 2006

18. Normal Movement

20. Parkinsonian State

22. Parkinsonian State with Intermittent Levodopa

24. Parkinsonian State with Continuous Levodopa

26. In PD patients with motor complications, fluctuations in brain dopamine levels correspond to levels of levodopa Baseline1 hour after oral levodopa 4 hours after oral levodopa De la Fuente-Fernández, et al. 2001 Putamen raclopride binding potential (response to levodopa) Increasing synaptic dopamine levels

27. In PD, pulsatile stimulation causes further changes in gene expression in the already unstable basal ganglia Pre-proenkephalin B (marker for dyskinesia) mRNA expression in the caudate-putamen Henry et al, 2003 Non-parkinsonian patient PD patient with dyskinesia

28. Pulsatile stimulation leads to gene changes in the basal ganglia of MPTP primates whereas continuous stimulation does not NormalPulsatile stimulationContinuous stimulation Pre-proenkephalin-B (PPE-B; marker for dyskinesia) mRNA expression in the striatum High Low Reproduced with permission from Peter Jenner

29. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery The patient’s perspective Conclusions

30. Oral levodopa After 6 months levodopa infusion Plasma levodopa concentration (ng/ml) 0 1000 2000 3000 4000 5000 09.0011.0013.0015.0017.00 19.00 Time of day Continuous delivery of levodopa by infusion reverses motor complications Figure adapted from Stocchi et al, 2005 p<0.001 0 1 2 3 4 5 6 7 8 9 Off-time (h/day) Dyskinesia score (AIMS) p<0.001 AIMS=Abnormal Involuntary Movement Score

31. But infusion is impractical

32. Avoiding deep troughs in levodopa plasma levels may be more important than providing smooth delivery Pharmacokinetic analysis of levodopa infusion versus traditional oral therapy found: Significantly higher trough levels (C min ), bioavailability (area under the curve) and plasma concentrations with infusion No significant differences in plasma variability (C max – C min ) Therefore, maintaining completely smooth plasma levodopa levels may not be as important as avoidance of deep trough levels (minimum threshold level) Stocchi et al, 2005

33. Increasing traditional levodopa dose frequency does not address pulsatility Stocchi, 2006

34. Adherence is an important issue in PD and may contribute to pulsatile stimulation % patient compliance with levodopa regimen “Poor timing compliance was universal…suggesting that erratic drug-taking is the norm rather than the exception in PD.” “Given the significance attached to pulsatile stimulation of dopamine receptors…this suggests that irregular medication maybe... as significant as variable absorption in day- to-day and longer-term fluctuations” Figure adapted from Grosset et al, 2005 Timing of medication TotalDaily 100 80 60 40 20 0

35. Therefore, increasing the frequency of traditional levodopa dosing leads to variable control and increased risk of peak dose dyskinesia Decrease interdose interval May work in earlier stages Variable/short-term control Increase dosing frequency Limited utility and complicated dosing schedule beyond five doses per day ‘On’ dyskinesias Traditional levodopa Therapeutic window ‘Wearing-off’ Levodopa plasma concentrations (ng/ml) 135791113 Time (h) Figure adapted from Stocchi, 2006

36. Increasing the dose of traditional levodopa does not prevent pulsatility Figure adapted from Stocchi et al, 2004 0 500 1000 1500 07.0009.0011.0013.0015.00 100 mg levodopa Trough Levodopa plasma levels (ng/ml) Time of day 100 mg; 3-hour intervals150 mg; 3-hour intervals 150 mg levodopa 0 500 1000 1500 07.0009.0011.0013.0015.00 Trough

37. Therefore increasing the dose of traditional levodopa leads to variable control Increase dose Peak–dose dyskinesias Variable/short-term control Higher peak concentrations Traditional levodopa Therapeutic window ‘Wearing-off’ Peak–dose dyskinesias Levodopa plasma concentrations (ng/ml) 135791113 Time (h) Figure adapted from Stocchi, 2006

38. Controlled-release levodopa does not prevent pulsatility or motor complications 200 mg Time of day19.0017.0015.0013.0011.0009.0007.00 2500 2000 1500 1000 500 0 Levodopa plasma levels (ng/ml) Delayed ‘on’ due to erratic absorption Stocchi, 2006; Figure adapted from Koller et al, 1999 % patients with motor complications 20 15 10 5 0 01 2 345 Year Traditional levodopa Controlled-release levodopa Trough

39. Controlled-release formulations Delayed ‘on’ or occasional lack of ‘on’ response with advancing disease Variable/short-term control Unpredictable drug absorption Therefore, use of controlled-release formulations leads to unpredictable absorption and variable control ‘On’ dyskinesias Traditional levodopa Therapeutic window ‘Wearing-off’ Levodopa plasma concentrations (ng/ml) 135791113 Time (h) Stocchi, 2006

40. Fariello, 1998 Dopamine agonists do not alter the pharmacokinetic profile of levodopa Plasma concentrations of levodopa (mg/l) Time (min) 1.2 0 0.2 0.4 0.6 0.8 1.0 060120180240300360420480 Levodopa Levodopa + cabergoline

41. How can we try to mimic infusion with oral therapy?

42. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery The patient’s perspective Conclusions

43. Gordin et al, 2004 Compared with traditional levodopa, Stalevo has a longer levodopa plasma half-life with increased levodopa uptake to the brain DDC=dopa decarboxylase COMT=catechol-O-methyltransferase

44. Stalevo enhances the pharmacokinetics of levodopa 0 0.5 1.0 1.5 2.0 2.5 01234 Time (h) Plasma levodopa (µg/ml) Traditional levodopa Stalevo Time by which the half-life of levodopa is extended Gordin et al, 2004

45. Dual DDC/COMT inhibition increases levodopa uptake into the brain Sawle et al, 1994 DDC=dopa decarboxylase COMT=catechol-O-methyltransferase Carbidopa Carbidopa/entacapone

46. Stalevo delivery strives to mimic infusion 08.0010.0012.0014.0016.0018.0020.00 0 1000 2000 3000 4000 5000 Figure adapted from Stocchi et al, 2005; Figure adapted from Stocchi, 2006 0 1000 2000 3000 4000 5000 09.0011.0013.0015.0017.00 19.00 Plasma levodopa concentration (ng/ml) Time of day Traditional levodopa After 6 months levodopa infusion Traditional levodopa Stalevo ON OFF * * 200 mg † 100mg † † ††

47. Immediate benefits versus traditional levodopa: more time without symptoms Stalevo/LCE Traditional levodopa plus placebo Change in daily ‘on’ time (h) · · · · · · p<0.001 B2481624 Withdrawal Time (weeks) –0.5 0 0.5 1.0 1.5 2.0 Figure adapted from Rinne et al, 1998 Mean daily time without symptoms (‘on’ time) increased by up to 1.7 hours versus baseline

48. Immediate benefits versus traditional levodopa: improved activities of daily living Poewe et al, 2002 Time (months) 0 0123456 ADL score 11 12 13 14 10 9 8 7 6 5 4 2 1 3 Stalevo/LCE Traditional levodopa plus placebo Difference between the groups was p<0.05

49. Immediate benefits versus traditional levodopa: improved motor scores Rinne et al, 1998 –4–4 –3–3 –2–2 –1–1 0 1 2 3 4 5 Traditional levodopa plus placebo Stalevo/LCE Change in motor scores Worsening Improvement p<0.05

50. Long-term benefits: sustained patient function for at least 3 years UPDRS Larsen et al, 2003; Goetz et al, 2000 40.8 10.5 28.4 41.7 10.8 29.0 0 5 10 15 20 25 30 35 40 45 Total scoreADL score Motor score Baseline After 3 years Stalevo/LCE

51. Long-term benefits: sustained efficacy versus baseline for at least 5 years Nissinen et al, 2006 Poster Change from baseline in duration of benefit of morning dose (hrs) 0 1 B369121620242832364044485256 Month Stalevo/LCE

52. Long-term benefits: no need to increase the levodopa dose for at least 3 years 400 600 800 1000 061842 Months Levodopa dose (mg) Double-blind (NOMECOMT) Open-label (NOMESAFE) Washout Larsen et al, 2003 Stalevo/LCE

53. Stalevo/LCE and its benefits Immediate benefits More time without symptoms Mean daily ‘on’-time increased by up to 1.7 hours Better patient function Mean ADL scores improved by up to 1.7 points Mean motor scores improved by up to 3.2 points Long-term benefits Sustained patient function through 5 years No increase in mean levodopa dose over baseline Parkinson Study Group, 1997; Myllyla et al. 2001; Poewe et al. 2002; Rinne et al. 1998; Brooks et al. 2003; Larsen et al, 2003; Nissinen et al, 2006

54. Stalevo provides significantly improved QoL compared with standard of care The cost-effectiveness of Stalevo was compared with UK standard of care Patients on Stalevo had significantly improved QoL (+1.04 QALYs) The costs to society decreased by £10,200/patient/10 years This decrease was mainly due to savings in social service costs and secondary care Societal perspective Cost (£)QALYs Stalevo59,5632.571 Standard of care69,7611.529 Difference: Stalevo  standard of care  10,198  1.042 Findley et al, 2005 QUALY: quality-adjusted life-years

55. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

56. Patients can require enhancement of traditional levodopa therapy within only 6 months In the ELLDOPA study, patients initiated with traditional levodopa (150–600 mg) experienced: Wearing-off (16–30%) Dyskinesia (3–17%) The time of onset for these complications was only 5–6 months after initiation of traditional levodopa therapy Fahn et al, 2004; Fahn, 2005

57. In de novo disease, early initiation of effective therapy provides long-term benefits vs no treatment “We suggest that early restoration of basal ganglia physiology will support the compensatory events and delay the irreversible modification of circuitry that characterizes the clinical progression of PD” Schapira and Obeso 2006 Fahn et al, 2004; PSG, 2004; Schapira and Obeso, 2006 Levodopa Change in total UPDRS score (units) Week of study drug Baseline 2610141822263034384246 12 10 8 6 4 2 0 –2 –4 –6 –8 Placebo 150 mg 300 mg 600 mg Withdrawal 2610141822263034384246 12 10 8 6 4 2 0 –2 –4 –6 –8 Placebo 150 mg 300 mg 600 mg Years 0.00.51.01.52.02.53.03.54.04.55.05.56.0 0 10 20 30 40 50 60 70 80 90 0.00.51.01.52.02.53.03.54.04.55.05.56.0 0 10 20 30 40 50 60 70 80 90 0.00.51.01.52.02.53.03.54.04.55.05.56.00.00.51.01.52.02.53.03.54.04.55.05.56.00.00.51.01.52.02.53.03.54.04.55.05.56.0 0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90 Delayed start Early start * * * * * * NS (n=404)(n=324)(n=272)(n=237)(n=206)(n=164) Mean % change in total UPDRS Rasagiline

58. Starting Stalevo/LCE without delay provides superior motor scores at 1 year At 1 year, earlier initiation of Stalevo/LCE provided significantly better motor function compared with a 6-month delay (treatment difference –1.33 points, p<0.05) –4.0 –2.0 0.0 2.0 Baseline (n=484) 3 (n=476) 6 (n=479) 9 (n=445) 12 (n=410) Months Change in UPDRS III scores Stalevo/LCE Traditional levodopa plus placebo Nissinen et al, 2006 UPDRS III: Unified Parkinson’s Disease Rating Scale Improvement

59. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

60. The benefit of starting Stalevo/LCE without delay is sustained over 5 years The significant difference in UPDRS III scores between the early and delayed start groups was maintained through the study period This suggests that enhancing levodopa earlier, even by 6 months (e.g. only one office visit), can have clinically significant long-term benefits –6.0 0.0 6.0 12.0 18.0 Baseline (n=484) 1 (n=410) 2 (n=101) 3 (n=90) 4 (n=44) 5 (n=37) Years Change in UPDRS III scores Stalevo/LCE Traditional levodopa plus placebo Improvement Nissinen et al, 2006

61. The MPTP primate model of PD has been very predictive of clinical outcomes in idiopathic PD Years Proportion of patients remaining free of dyskinesia 0.0 0.2 0.4 0.6 0.8 1.0 012345 Ropinirole Traditional levodopa Dyskinesia score Days MPTP modelIdiopathic PD 0 1 2 3 4 181522 Rascol et al, 2000; Maratos et al, 2001 MPTP: 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine

62. Studies in MPTP primates show the potential of early initiation of Stalevo/LCE to avoid dyskinesia induction Studies conducted in the MPTP- treated primate model of PD Compared with traditional levodopa, Stalevo/LCE (4x/day) Significantly improves the antiparkinsonian response Significantly decreases in intensity and duration of peak dyskinesia † p<0.05 †† Peak dyskinesia Smith et al, 2005 0 1 2 3 4 147101316 Stalevo/LCE (4x/day) Traditional levodopa (4x/day) MPTP: 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine

63. 0 25 50 100 10 % nigral neurons remaining 0 1 2 3 4 Peak dyskinesia Trad levodopa LCE 90% MPTP-induced lesion 0 1 2 3 4 Peak dyskinesia Trad levodopa 4x/day dosing LCE 50% MPTP-induced lesion75% MPTP-induced lesion 0 1 2 3 4 Peak dyskinesia Trad levodopa LCE LCE has a lower risk of dyskinesia induction vs traditional levodopa, regardless of parkinsonian severity in the MPTP primate model of PD p<0.05 4x/day dosing MPTP: 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine Jenner et al, 2006

64. FIRST-STEP: an ongoing clinical study to confirm the efficacy of Stalevo in de novo* disease Aim: To evaluate the effect of Stalevo 100 (3x/day) versus traditional formulation levodopa/carbidopa 100/25 mg (3x/day) in PD patients requiring levodopa therapy Hauser, 2006 * De novo use of Stalevo is not currently licensed

65. STRIDE-PD: an ongoing clinical study to confirm the potential of Stalevo to avoid dyskinesia induction Aim: To demonstrate that when used as initial levodopa therapy*, Stalevo results in a significant prolongation in the time to onset of dyskinesia when compared with traditional formulation levodopa/carbidopa in PD With comparable symptom control With similar QoL * De novo use of Stalevo is not currently licensed Olanow, 2006

66. Contents Traditional levodopa – strengths Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Enhancing levodopa delivery Stalevo Benefits of earlier enhancement of levodopa delivery Future directions Conclusions

67. Conclusions I Compared with other antiparkinsonian therapies, levodopa has superior efficacy and short-term tolerability However, traditional levodopa therapy is often spared due to concerns about the development of motor complications The pulsatile stimulation of dopamine receptors caused by traditional levodopa is an important factor in the development of these complications Infusion data show that consistent delivery of levodopa reverses established complications, even though high doses are used Modification strategies fail to address the pulsatility of traditional levodopa and therefore frequent changes are often required

68. Conclusions II Stalevo provides oral levodopa in a manner which strives to mimic infusion In fluctuating patients, enhancing levodopa delivery with Stalevo significantly improves patient function This benefit is sustained for at least 5 years Initiating Stalevo 6 months earlier may lead to long-term benefits in patient function STA2456; Item date November 2006

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75. Stalevo ® (levodopa / carbidopa / entacapone) and its benefits I Brooks, D. J. and Sagar H. Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised, placebo controlled, double blind, six month study. J Neurol Neurosurg Psychiatry 2003; 74(8): 1071–1079. Findley, L. J., Lees A., Apajasalo M. et al. Cost-effectiveness of levodopa/carbidopa/entacapone (Stalevo) compared to standard care in UK Parkinson's disease patients with wearing-off. Curr Med Res Opin 2005; 21(7): 1005–1014. Goetz, C. G., Stebbins G. T. and Blasucci L. M. Differential progression of motor impairment in levodopa-treated Parkinson's disease. Mov Disord 2000; 15(3): 479–484. Gordin, A., Kaakkola S. and Teravainen H. Clinical advantages of COMT inhibition with entacapone - a review. J Neural Transm 2004; 111(10–11): 1343–1363.

76. Stalevo and its benefits II Larsen, J. P., Worm-Petersen J., Siden A. et al. The tolerability and efficacy of entacapone over 3 years in patients with Parkinson's disease. Eur J Neurol 2003; 10(2): 137–146. Muller, T., Erdmann C., Muhlack S. et al. Inhibition of catechol-O- methyltransferase contributes to more stable levodopa plasma levels. Mov Disord 2006; 21(3): 332–336. Myllyla, V., Kultalahti E. R. V., Haapaniemi H. et al. Twelve-month safety of entacapone in patients with Parkinson's disease. Eur J Neurol 2001; 8(1): 53–60. Nissinen, H., Kuoppamaki M. and Leinonen M.. Early initiation of entacapone leads to superior 5-year efficacy compared to delayed initiation in Parkinson’s disease patients receiving traditional levodopa/DDCI therapy. Mov Disord, 2006; 12(Suppl 15): S593.

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