Contents Traditional levodopa – strengths

Contents Traditional levodopa – strengths
Traditional levodopa – limitations of pulsatile delivery Suboptimal delivery with disease progression Optimization of levodopa delivery Stalevo and its benefits Benefits of earlier optimization of levodopa delivery Future directions Conclusions

Patients with severe disability and death (%)
Treatment with levodopa has dramatically reduced disability and mortality associated with PD 100 80 60 Untreated patients Patients with severe disability and death (%) Levodopa-treated patients 40 20 This graph demonstrates the dramatic impact levodopa has had in the treatment of Parkinson’s disease (PD) since its introduction in the 1960’s Compared with the pre-levodopa era (untreated patients), levodopa treatment has significantly reduced the amount of severe disability and mortality associated with PD These dramatic symptomatic benefits have led to an increase in the duration of time that PD patients can independently enjoy daily life and employment Hoehn (1992) Neurol Clin 10(2): 331–339 Olanow et al. (2004) Mov Disord 19(9): 997–1005 1–5 6–10 11–15 Years since diagnosis PD=Parkinson’s disease Hoehn and Yahr, 1967; Hoehn, 1983

Levodopa versus pramipexole
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 Pramipexole Levodopa p=0.003 –4 –2 2 4 10 20 30 40 50 Change in UPDRS score –16 –14 –12 –10 –8 –6 Time (months) Levodopa versus pramipexole Improvement Initiation of levodopa therapy in patients with PD is associated with better patient function than those initiated with a dopamine agonist The 4-year CALM-PD study evaluated the initiation of therapy with either traditional levodopa/carbidopa (100/25 mg three-times daily), or pramipexole (0.5 mg three-times daily) in patients with early PD In this study, the mean improvement in total United Parkinson’s Disease Rating Scale (UPDRS) score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (adjusted treatment difference) Despite the option of open-label levodopa, the group differences observed in the motor and activities of daily living components remained relatively uniform throughout the 4 years, with a parallel decay in UPDRS scores across time The 5-year 056 study compared the safety and efficacy of ropinirole with traditional levodopa. In those patients who completed the study, there was a slight improvement from baseline of 0.8 ± 10.1 points in UPDRS motor scores in the ropinirole group, compared with an improvement of 4.8 ± 8.3 points in the levodopa group (adjusted treatment difference of 4.48 points). In this study, ropinirole was initiated at 0.25 mg three-times daily and increased weekly, as necessary, up to a maximum dose of 8 mg three-times daily. Levodopa was initiated at a dose of 50 mg once daily and increased weekly, as necessary, to a maximum of 400 mg three-times daily Similar results confirming the superior efficacy (UPDRS motor scores) of levodopa, were again found in the 3–5-year trial comparing levodopa with cabergoline Holloway et al. (2004) Arch Neurol 61(7): 1044–1053 Rascol et al. (2000) N Engl J Med 342(20): 1484–1491 Bracco et al. (2004) CNS Drugs 18(11): 733–746 Holloway et al, 2004; Rascol et al, 2000; Bracco et al, 2004 UPDRS=United Parkinson’s Disease Rating Scale

All patients eventually require the superior efficacy of levodopa for symptom control
Need for levodopa in patients initiated with a dopamine agonist (pramipexole) Need for levodopa in patients initiated with a monoamine oxidase inhibitor (selegiline) 70 60 40 20 6 12 18 24 60 59% 50 Probability of requiring levodopa therapy (%) supplemental levodopa (%) Patients requiring 40 46% 30 20 23% Although dopamine agonists have been shown to have moderate–good efficacy as monotherapy in early PD, it is clear that they are less efficacious than levodopa. Therefore, in practice, the majority of patients initiated on dopamine agonist therapy require levodopa within the first 2 years of treatment for symptomatic efficacy In the CALM-PD trial of pramipexole as initial therapy, the majority of pramipexole patients required supplemental open-label levodopa therapy by study end Interestingly, the UPDRS scores of the pramipexole group never caught up with the levodopa group despite the option of open-label levodopa and other antiparkinsonian therapies. This might be related to the lower dose of levodopa used in the supplemented pramipexole patients (434 ± 498 mg/day) compared with those on levodopa monotherapy (702 ± 461 mg/day) The DATATOP study found that selegiline monotherapy provided adequate motor control for an average of 9 months before the symptomatic efficacy of levodopa was required Holloway et al. (2004) Arch Neurol 61(7): 1044–1053 10 16% 1 2 3 4 Years after randomization Months after randomization PSG, 1997; Holloway et al, 2004

Levodopa provides better overall short-term tolerability vs dopamine agonists
Dopaminergic adverse event Pergolide vs levodopa (%) Pramipexole vs levodopa (%) Ropinirole vs levodopa (%) Nausea 41 vs 21* 36 vs 37 49 vs 49 Somnolence 10 vs 5 32 vs 17* 27 vs 19 Oedema 5 vs 1* 18 vs 8* 14 vs 6 Hallucinations 3 vs 0* 9 vs 3* 17 vs 6 * Significantly less with levodopa vs dopamine agonist (p<0.05) Data included in the table are from the PELMOPET (pergolide), CALM-PD (pramipexole) and 056 (ropinirole) studies The PELMOPET study employed a pergolide (0.75–5.0 mg/day) and levodopa (150–1200 mg/day) monotherapy design In the 056 study, ropinirole was initiated at 0.25 mg three-times daily and increased weekly, as necessary, up to a maximum dose of 8 mg three-times daily. Levodopa was initiated at a dose of 50 mg once daily and increased weekly, as necessary, to a maximum of 400 mg three-times daily The 4-year randomized CALM-PD trial compared initial treatment with pramipexole (0.5 mg three-times daily) versus levodopa/carbidopa (100/25 mg three-times daily), followed by open-label levodopa supplementation as required The 056 ropinirole study did not report whether there was a significant difference in adverse events between groups Adverse events seen with levodopa are usually the result of increased levels of dopamine in the body, and are usually mild and transient The most common adverse events with both levodopa and dopamine agonists include nausea and vomiting Hallucinations and psychosis are more common with the directly acting dopamine agonists than with levodopa, and are particularly prone to occur in the elderly or patients with cognitive difficulties Other adverse events such as impulse control disorders, oedema and fibrosis have been associated with dopamine agonist use, however these are relatively rare PSG (2000) JAMA 284(15): 1931–1938 Oertel et al. (2006) Mov Disord 21(3): 343–353 Rascol et al. (2000) N Engl J Med 342(42): 1484–1491 Weintraub et al. (2006) Arch Neurol 63 (7): 969–973 Increased incidence of impulse control disorders (e.g. hyperphagia, hypersexuality and gambling) and fibrosis (ergot-derived) have been associated with dopamine agonist use PSG, 2000; Oertel et al, 2006; Rascol et al, 2000; Weintraub et al, 2006

Traditional levodopa therapy is associated with the development of motor complications
Clinical effect Clinical effect Clinical effect Off 2 4 6 2 4 6 2 4 6 Levodopa Levodopa Levodopa Time (hours) 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 In the early stages of PD, the response to levodopa is excellent. At this stage the antiparkinsonian benefits are associated with a low incidence of dyskinesia As the disease progresses, even in moderate disease, the duration of response to levodopa diminishes and begins to more closely reflect its short half-life (~1.5 hours). Symptom control becomes increasingly governed by fluctuations in plasma levodopa levels In more advanced PD, the short-duration response to levodopa predominates. The therapeutic window narrows, and adequate control of symptoms becomes increasingly difficult Initially this is manifested by an end-of-dose deterioration, where PD symptoms return before the next scheduled medication dose Patients are often either 'off', or 'on' with dyskinesia and other complications Obeso et al. (2000) Neurology 55(4 Suppl): S13–S20 Response threshold Dyskinesia threshold Obeso et al, 2000

In PD, traditional levodopa delivery leads to pulsatile dopamine levels 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 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 In PD, the progressive loss of dopaminergic neurons impairs the capacity of dopamine terminals to buffer fluctuations in plasma levodopa concentrations, therefore, striatal dopamine concentrations are increasingly dependent on the peripheral availability of levodopa Thus, the variability in plasma levodopa concentrations associated with traditional levodopa is reflected by variability in striatal dopamine concentrations and pulsatile stimulation of striatal dopamine receptors This leads to a change from the normal situation in which dopamine receptors are continuously exposed to dopamine, to one in which they are exposed to abnormally high or abnormally low dopamine concentrations This pulsatile stimulation destabilizes the already unstable basal ganglia Olanow et al. (2006) Lancet Neurol 5(8): 677–687 Pulsatile plasma levodopa levels leads to pulsatile levels of dopamine in the brain

The first manifestation of pulsatile levodopa delivery in the brain is often wearing-off
Symptoms controlled Time Symptom re-emergence Traditional levodopa 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 With disease progression, most patients with PD (up to 50% after 2-3 years of traditional levodopa therapy) develop motor complications, i.e. motor fluctuations and dyskinesia The most common and usually the first type of motor fluctuation to develop is ‘wearing-off’ As the name implies, the patient develops a decrease/loss of response to a dose of medication before taking the next dose. Patients commonly show a good response 30–60 minutes after taking an individual dose of levodopa, but their parkinsonian symptoms re-emerge before their next scheduled dose because the benefit of the last dose ‘wears-off’ The pathophysiology of the wearing-off response is probably multifactorial, although it is generally thought to reflect the degeneration of presynaptic dopaminergic neurons, resulting in a lack of storage for levodopa and a resultant inability to buffer variations in levodopa availability It is thought that wearing-off also involves centrally mediated mechanisms, which include alterations in receptor responsiveness and changes in the pharmacodynamic response. In support of this, the wearing-off phenomenon has also been reported with dopamine agonists, which are not stored in the presynaptic compartment Stacy et al. (2005) Mov Disord 20(6): 726–733 Stacy et al, 2005

Pulsatile stimulation of striatal dopamine receptors
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 Dopamine replacement with standard doses of traditional levodopa does not restore the basal ganglia function to normality Administration of repeated doses of levodopa (half-life of 60–90 min) leads to large and uncontrolled oscillations in striatal and synaptic dopamine concentrations, due to the loss of dopamine terminals and their capacity to buffer fluctuations in striatal dopamine concentrations This leads to a change from the normal situation in which dopamine receptors are continuously exposed to dopamine, to one in which they are exposed to abnormally high or abnormally low concentrations of the neurotransmitter It is believed that this pulsatile stimulation of striatal dopamine receptors leads to a sequence of molecular and physiological events that underlie the development of motor complications Pulsatility can be neatly described by an analogy of a Ferrari which requires high grade fuel in order for its engine to function at the required high revs. If the fuel is substituted with a low grade octane fuel, the engine will splutter, cut out intermittently and no longer function at its optimum capacity (i.e. You have to put the right fuel in the tank to get good motor function) Olanow et al. (2006) Lancet Neurol 5(8): 677–687 Dyskinesia

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) Excitatory cortical input Dopaminergic regulatory input Substantia nigra Striatum Dopamine exerts presynaptic modulation (in both up and down directions) on the glutamate-mediated excitation of striatal medium spiny neurons Most striatal neurons are medium spiny neurons that receive massive glutamatergic inputs from the cortex and thalamus Regulation of this neuronal activity requires a precise selection mechanism (i.e. dopamine modulation) to filter incoming and outgoing signals associated with movement Dopamine also acts postsynaptically to stabilize the firing rate and excitability of striatal neurons It has also been recently shown that a key function of dopamine is to modulate glutamate-mediated long-term potentiation and long-term depression, thereby regulating plasticity of striatal neurons Olanow et al. (2006) Lancet Neurol 5(8): 677–687- Basal ganglia Normal motor function Olanow et al, 2006

Dopamine receptor state
In PD, pulsatile delivery of traditional levodopa leads to pulsatile stimulation of dopamine receptors Dopamine receptor state Normal Activated Unactivated Striatum PD (untreated) Activated Substantia nigra Nigrostriatal neurons degenerate Unactivated Traditional levodopa With continued neuronal degeneration, plasma levodopa concentrations cannot be buffered and result in fluctuations in striatal dopamine levels Under normal circumstances, dopamine neurons fire continuously, therefore, striatal dopamine receptors are normally exposed to relatively constant levels of dopamine and are in a constant state of activation In PD, there is a progressive degeneration of nigral dopaminergic neurons and striatal dopamine levels become increasingly dependent on plasma levodopa concentrations However, levodopa has a short plasma half-life and does not provide dopamine to striatal receptors in a continuous and physiological manner With continued neuronal degeneration, fluctuations in plasma levodopa concentrations are translated into fluctuations in striatal dopamine levels and striatal dopamine receptors now become exposed to alternating high and low levels of dopamine resulting in ‘pulsatile stimulation’ Olanow et al. (2006) Lancet Neurol 5(8): 677–687 Traditional levodopa Activated Unactivated

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

Normal Movement Please note that you will require Adobe® Flash® Player 9 installed on your computer in order to run the following animation; you can download this software free of charge from the following link:

Parkinsonian State

Parkinsonian State with Intermittent Levodopa

Parkinsonian State with Continuous Levodopa

Increasing synaptic dopamine levels
In PD patients with motor complications, fluctuations in brain dopamine levels correspond to levels of levodopa Increasing synaptic dopamine levels Putamen raclopride binding potential (response to levodopa) This study was the first to show motor fluctuations are correlated with changes in the synaptic levels of dopamine Patients were prospectively studied in the early stages of PD with a follow-up after at least 3 years of levodopa treatment At baseline, three PET scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient [11C]raclopride is used as an indicator of striatal dopamine levels, based on its ability to compete with striatal dopamine for binding to D2/D3 receptors Patients who developed ‘wearing-off’ fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding potential from that observed in patients who were still stable by the end of the follow-up In fluctuating patients, the estimated increase in the synaptic level of dopamine 1 hour post-levodopa administration was three times higher in fluctuators than in stable responders These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent wearing-off phenomena The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in motor complications De la Fuente Fernandez et al. (2001) Ann Neurol 49(3): 298–303 Baseline 1 hour after oral levodopa 4 hours after oral levodopa De la Fuente-Fernández et al, 2001

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 Pulsatile stimulation results in a variety of changes in gene expression in the basal ganglia. These changes are associated with alterations in the normal function of the basal ganglia and are thought to be partly responsible for the emergence of motor complications The images on this slide are from a study of the brains of patients with PD and age-matched controls (who died of non-neurological disease) An example of gene changes in the striatum include an increased expression of the opioid peptide-derived pre-proenkephalin B (PPE-B) pathway, which is highlighted in this slide. Thus, PPE-B is considered a marker for dyskinesia Henry et al. (2003) Exp Neurol 183(2): 458–468 Non-parkinsonian patient PD patient with dyskinesia Henry et al, 2003

Pulsatile stimulation leads to gene changes in the basal ganglia of MPTP primates whereas continuous stimulation does not Pre-proenkephalin-B (PPE-B; marker for dyskinesia) mRNA expression in the striatum High Pulsatile stimulation results in a variety of changes in gene expression in the basal ganglia. These changes are associated with alterations in the normal function of the basal ganglia and are thought to be partly responsible for the emergence of motor complications The images on this slide are from a study of brains of: Normal primates MPTP-treated primates given traditional levodopa intermittently to simulate pulsatile stimulation MPTP-treated primates given a long-acting agonist to simulate continuous stimulation This slide shows that pulsatile stimulation is associated with higher levels of the peptide PPE-B (a marker for dyskinesia) whereas the levels of PPE-B with continuous stimulation are more like the normal physiological state Normal Pulsatile stimulation Continuous stimulation Low Reproduced with permission from Peter Jenner

Traditional levodopa – limitations of pulsatile delivery Suboptimal levodopa delivery with disease progression Optimization of levodopa delivery Stalevo and its benefits Benefits of earlier optimization of levodopa delivery The patient’s perspective Conclusions

Plasma levodopa concentration (ng/ml) Dyskinesia score (AIMS)
Continuous delivery of levodopa by infusion reverses motor complications Oral levodopa After 6 months’ levodopa infusion 9 p<0.001 1000 2000 3000 4000 5000 09.00 11.00 13.00 15.00 17.00 19.00 Time of day 8 7 6 p<0.001 5 Plasma levodopa concentration (ng/ml) 4 3 The use of infusion achieves a stable plasma levodopa profile in patients with advanced PD and is associated with reduced motor complications A 6-month, prospective, open-label study evaluated the effects of an intraintestinal infusion of levodopa compared with traditional levodopa in patients with advanced PD Compared with treatment with intermittent doses of a standard oral formulation of levodopa, continuous infusion provided significant improvements in both ‘off periods’ and dyskinesia Plasma pharmacokinetic studies demonstrated that compared with oral administration, continuous levodopa infusion was associated with a significant increase in the levodopa bioavailability (area under the curve) and avoided the low plasma trough levels seen with oral drug administration Stocchi et al. (2005) Arch Neurol 62(6): 905–910 2 1 Off-time (h/day) Dyskinesia score (AIMS) AIMS=Abnormal Involuntary Movement Score Stocchi et al, 2005

But infusion is impractical
The use of infusion achieves a stable plasma levodopa profile in patients with PD and is associated with reduced motor complications However in practice, the use of levodopa pumps may be impractical for most patients

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 (Cmin), bioavailability (area under the curve) and plasma concentrations with infusion No significant differences in plasma variability (Cmax – Cmin) Therefore, maintaining completely smooth plasma levodopa levels may not be as important as avoidance of deep trough levels (minimum threshold level) Significant increases in the minimal plasma levodopa trough levels are observed in patients treated with continuous levodopa infusion Low trough levels seen with intermittent administration of standard oral formulations of levodopa are postulated to intermittently deprive striatal dopamine receptors of stimulation, with consequent plastic changes in intracellular signals and neuronal firing patterns leading to motor complications Therefore, levodopa infusion which avoids low plasma trough levels, may result in more constant activation of brain dopamine receptors with a reduced risk of motor complications Importantly, this suggests that it may not be necessary to maintain the plasma levodopa concentration at an absolutely constant level to minimize the risk of motor complications. Rather, the reduced motor complications associated with continuous levodopa infusion appear to be related primarily to avoiding low trough levels and maintaining the levodopa concentration above a minimal threshold level that is sufficient to provide continuous activation of dopamine receptors This plasma pharmacokinetic profile may be easier to replicate with oral dopaminergic strategies than the constant level that has previously been considered necessary to provide continuous dopaminergic stimulation Stocchi et al. (2005) Arch Neurol 62(6): 905–910 Stocchi et al, 2005

Levodopa plasma levels (ng/ml)
Increasing traditional levodopa dose frequency does not address pulsatility 500 1000 1500 2000 2500 3000 8 10 12 14 16 18 20 Levodopa plasma levels (ng/ml) Levodopa administration 7 9 11 13 15 17 19 21 5-hour intervals 3-hour intervals Trough Time of day An important question for achieving continuous dopaminergic stimulation with oral levodopa is how many daily doses are required to achieve a more continuous stimulation, and more constant blood levels with fewer troughs during the day Increasing the frequency of traditional levodopa, as a strategy to provide more continuous dopaminergic stimulation, has been attempted These data from separate patients depicts two typical examples from clinical practice With three doses of traditional levodopa a day, it is possible to achieve a stable clinical effect; however, the plasma levels fluctuate, with deep troughs during the day With a dosage regimen of traditional levodopa 100 mg every 3 hours (a strategy commonly used to treat patients with wearing-off), deep trough levodopa levels still occur in the middle of the day Stocchi (2006) Expert Opin Pharmacother 7(10): 1399–1407 Stocchi, 2006

% patient compliance with levodopa regimen
Adherence is an important issue in PD and may contribute to pulsatile stimulation “Poor timing compliance was universal… suggesting that erratic drug-taking is the norm rather than the exception in PD” 100 80 “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” 60 % patient compliance with levodopa regimen 40 20 This single-centre, observation study of adherence to therapy in 68 patients over 3 months has concluded that medication timing adherence was poor in patients with PD. This may contribute to the pulsatile delivery of traditional levodopa in PD and is likely to become more of a concern with dose fractionation strategies Of the 54 evaluable patients, 11 (20%) were underusers, while 43 (80%) taking a total of 91 PD preparations showed satisfactory adherence Timing adherence (number of doses taken in the correct time interval) was universally poor, in both underusers and those with satisfactory total adherence Increased age was associated with better total adherence (p<0.007), daily adherence (p<0.05) and timing adherence (p<0.04). Patients taking more medication had poorer adherence, considering PD medication alone (p<0.007) and all medication (for PD and other disorders; p<0.01). Poor total adherence was associated with depression (p<0.02) and with worse quality of life (p<0.002) Grosset et al. (2005) Mov Disord 20(11): 1502–1507 Total Daily Timing of medication Grosset et al, 2005

Therefore, increasing the frequency of traditional levodopa dosing leads to variable control and increased risk of peak dose dyskinesia Decrease interdose interval ‘On’ dyskinesias Increase dosing frequency May work in earlier stages Levodopa plasma concentrations (ng/ml) Therapeutic window Limited utility and complicated dosing schedule beyond five doses per day ‘Wearing-off’ With advancing disease, PD patients are often prescribed increasingly higher and more frequent levodopa doses to provide them with sustained levodopa bioavailability to maintain symptom control over the course of the day However, although these modification strategies can be useful in the short-term, there is general agreement that they are insufficient in the long-term For example, dose fractionation is often associated with intermittent re-emergence of symptoms due to suboptimal levodopa exposure Moreover, these constant changes to the drug regimen are often confusing and very frequent dosing regimens are associated with poor patient compliance – particularly in relation to the timing of medication Stocchi (2006) Expert Opin Pharmacother 7(10): 1399–1407 Grosset (2005) Mov Disord 20(11): 1397–1404 1 3 5 7 9 11 13 Time (h) Variable/short-term control Traditional levodopa Stocchi, 2006

Increasing the dose of traditional levodopa does not prevent pulsatility
100 mg; 3-hour intervals 150 mg; 3-hour intervals 1500 1500 Trough Trough 1000 1000 Trough Trough Levodopa plasma levels (ng/ml) 500 500 A common strategy in the management of wearing-off, to improve the delivery of traditional levodopa without the development of motor complications, is to increase the dose of traditional levodopa Notice that both the levodopa 100 and 150 mg regimens were associated with troughs in the levodopa plasma levels Stocchi et al. (2004) MDS Rome 07.00 09.00 11.00 13.00 15.00 07.00 09.00 11.00 13.00 15.00 100 mg levodopa 150 mg levodopa Time of day Stocchi et al, 2004

Therefore increasing the dose of traditional levodopa leads to variable control
Peak–dose dyskinesias Increase dose Higher peak concentrations Levodopa plasma concentrations (ng/ml) Therapeutic window Peak–dose dyskinesias ‘Wearing-off’ Increasing the total daily dose of traditional levodopa results in a more pulsatile plasma profile with higher peak concentrations and a slightly broader therapeutic window. However, studies have shown this approach is associated with a higher incidence and an increased severity of dyskinesia without a marked prolongation of the benefit of levodopa Moreover, in fluctuating patients, an increase in the dose of levodopa does not lead to further improvement in antiparkinsonian efficacy Stocchi (2006) Expert Opin Pharmacother 7(10): 1399–1407 Variable/short-term control 1 3 5 7 9 11 13 Time (h) Traditional levodopa Stocchi, 2006

% patients with motor complications Levodopa plasma levels (ng/ml)
Controlled-release levodopa does not prevent pulsatility or motor complications 20 15 10 5 1 2 3 4 Year Traditional levodopa Controlled-release levodopa 2500 % patients with motor complications 2000 Delayed ‘on’ due to erratic absorption 1500 Levodopa plasma levels (ng/ml) 1000 Controlled-release (CR) preparations were designed to provide smoother, more ‘physiologic’ circulating levels of levodopa and less frequent dosing regimes Dose failures and a ‘delay to on time’, which is commonly attributed to poor absorption of the drug formulation, are experienced following administration of CR levodopa over a 20-hour period After 5 years, in studies comparing traditional levodopa with CR levodopa, the traditional and the CR groups have similar levels of dyskinesia or motor fluctuations (20.6% and 21.8%, respectively) In an evidence-based review of PD treatments, the Movement Disorders Society (MDS) concluded that ‘CR levodopa preparations are not efficacious in reducing the incidence of motor fluctuations and/or dyskinesia’ Koller et al. (1999) Neurology 53(5): 1012–1019 Stocchi (2006) Expert Opin Pharmacother 7(10): 1399–1407 Trough 500 07.00 09.00 11.00 13.00 15.00 17.00 19.00 Time of day Stocchi, 2006; Figure adapted from Koller et al, 1999 200 mg

Variable/short-term control
Therefore, use of controlled-release formulations leads to unpredictable absorption and variable control ‘On’ dyskinesias Controlled-release formulations Unpredictable drug absorption Levodopa plasma concentrations (ng/ml) Therapeutic window Delayed ‘on’ or occasional lack of ‘on’ response with advancing disease ‘Wearing-off’ Although they can be a useful additional levodopa therapy (especially at night), CR preparations are associated with erratic absorption and unstable plasma levels No therapeutic benefit of CR levodopa over traditional immediate-release (IR) formulations, with no significant differences in the proportion of patients experiencing motor fluctuations or dyskinesia between treatment groups, has been found from clinical studies evaluating the effects of IR and CR levodopa/carbidopa and CR levodopa/benserazide in levodopa-naïve patients Based on these studies, the MDS concluded that ‘controlled-release levodopa preparations are not efficacious in reducing the incidence of motor fluctuations and/or dyskinesias’ If it is indeed avoidance of low trough plasma levodopa levels that are important in reducing motor complications, it may be that the low-dose frequency and erratic absorption of CR levodopa formulations do not provide the pharmacokinetic profile of levodopa required to provide continuous activation of dopamine Stocchi (2006) Expert Opin Pharmacother 7(10): 1399–1407 Variable/short-term control 1 3 5 7 9 11 13 Time (h) Traditional levodopa Stocchi, 2006

Dopamine agonists do not alter the pharmacokinetic profile of levodopa
1.2 Levodopa 1.0 Levodopa + cabergoline 0.8 Plasma concentrations of levodopa (mg/l) 0.6 0.4 0.2 One of the most common clinical scenarios is the introduction of levodopa following 1–2 years of monotherapy with a dopamine agonist. However, there has been little research to determine optimal dosing regimens when co-prescribing levodopa and dopamine agonist therapies Studies have shown that co-administration of dopamine agonists does not affect the peripheral pharmacokinetics of levodopa Other studies have shown that fluctuations in motor performance are related to changes in the plasma concentrations of levodopa, even when given in combination. Thus, it is always important to optimize levodopa delivery, even in the presence of a dopamine agonist Fariello (1998) Drugs 55(1 Suppl): 10–16 Nyholm (2002) Clinical Neuropharmacology 25(2): 89–96 0.0 60 120 180 240 300 360 420 480 Time (min) Fariello, 1998 5

How can we mimic infusion with oral therapy?

Traditional levodopa – limitations of pulsatile delivery Suboptimal delivery with disease progression Optimization of levodopa delivery Stalevo and its benefits Benefits of earlier optimization of levodopa delivery The patient’s perspective Conclusions

Compared with traditional levodopa, Stalevo has a longer levodopa plasma half-life with increased levodopa uptake to the brain When administered alone, levodopa is rapidly decarboxylated to dopamine in the body with only 1% passing into the brain where it is required By inhibiting the peripheral decarboxylation of levodopa, a DDC inhibitor (DDCI; carbidopa or benserazide) prolongs the plasma half-life of levodopa from 50 minutes to 1.5 hours, without increasing Tmax. Even with this DDC inhibition, only about 10% reaches the brain Compared with traditional levodopa/DDCI therapy, the pharmacokinetic profile of Stalevo is significantly improved. Studies comparing single doses with traditional levodopa/DDCI therapy report up to 75% increases in levodopa half-life Moreover, recent pharmacokinetic studies with multiple doses have demonstrated that Stalevo provides higher and more stable plasma levels of levodopa when compared with traditional formulations Gordin (2004) J Neural Transm 111(10–11): 1343–1363 Muller (2006) Mov Disord 21(3): 332–336 DDC=dopa decarboxylase COMT=catechol-O-methyltransferase Gordin et al, 2004

Stalevo enhances the pharmacokinetics of levodopa
2.5 Time by which the half-life of levodopa is extended 2.0 Stalevo Plasma levodopa (µg/ml) 1.5 1.0 Traditional levodopa By inhibiting the peripheral decarboxylation of levodopa, a DDCI (carbidopa or benserazide) prolongs the plasma half-life of levodopa from 50 minutes to 1.5 hours, without increasing Tmax. However, even with this inhibition, still only about 10% of a given levodopa dose enters the brain Compared with traditional levodopa/DDCI therapy, the pharmacokinetic profile of Stalevo is significantly improved Studies comparing single doses with traditional levodopa/DDCI therapy report up to: 75% increases in levodopa half-life 75% decreases in plasma levels of the levodopa metabolite 3-O-methyl dopa (3-OMD) 50% increases in levodopa bioavailability (area under the curve [AUC]) Gordin et al. (2004) J Neural Transm 111(10–11): 1343–1363 0.5 0.5 1 2 3 4 Time (h) Gordin et al, 2004

Dual DDC/COMT inhibition increases levodopa uptake into the brain
Carbidopa Carbidopa/entacapone Stalevo (levodopa/carbidopa/entacapone [LCE]) therapy increases central levodopa levels considerably in the brains of patients with PD, compared with traditional levodopa Positron emission tomography (PET) studies using 18F-dopa (positron-emitting analogue of levodopa), show that dual enzyme inhibition of COMT and DDC significantly increases the half-life of 18F-dopa and therefore the central dopa availability, in both healthy subjects and patients with PD (p<0.0001) Sawle (1994) Neurology 44(7): 1292–1297 DDC=dopa decarboxylase COMT=catechol-O-methyltransferase Sawle et al, 1994

Stalevo delivery mimics infusion
Traditional levodopa Traditional levodopa After 6 months’ levodopa infusion Stalevo ON OFF 5000 5000 4000 4000 3000 3000 Plasma levodopa concentration (ng/ml) 2000 2000 The use of levodopa infusion achieves a stable plasma levodopa profile compared with traditional levodopa in patients with PD and is associated with reduced motor complications Data from PK studies show that the administration of Stalevo at 3-hour intervals provides a more stable plasma profile that most closely mimics the profile obtained with levodopa infusion. In contrast, traditional levodopa/DDCI therapy produces pulsatile levels of plasma levodopa, despite regular dosing Stocchi et al. (2005) Arch Neurol 62(6): 905–910 Stocchi (2006) Expert Opin Pharmacother 7(10): 1399–1407 1000 1000 09.00 11.00 13.00 15.00 17.00 19.00 08.00 10.00 12.00 14.00 16.00 18.00 20.00 Time of day * 200 mg †100mg * † † † † Stocchi et al, 2005; Stocchi, 2006

Immediate benefits versus traditional levodopa: more time without symptoms
Stalevo/LCE Traditional levodopa plus placebo 2.0 p<0.001 p<0.001 1.5 Change in daily ‘on’ time (h) 1.0 0.5 The efficacy and safety of Stalevo/LCE therapy has been proven in four prospective, randomized, double-blind, placebo-controlled Phase III studies performed in over 1000 PD patients worldwide In these studies, Stalevo/LCE therapy increased daily ‘on’ time by an average of 1–1.7 hours and decreased daily ‘off’ time by an average of 1.1–1.5 hours during waking hours On this slide, the results of the NOMECOMT study are shown demonstrating a significant increase in ‘on’ time with Stalevo/LCE therapy compared with traditional levodopa/DDCI therapy plus placebo In this study, mean daily ‘on’ time was assessed by home diaries. At 6 months, the mean daily ‘on’ time was increased by 1.4 hours compared with placebo and the mean increase in the duration of ‘on’ time after the first morning dose of levodopa was increased over placebo by 0.24 hours Rinne (1998) Neurology 51(5): 1309–1314 Poewe (2004) Neurology 62(1 Suppl): S31–S38 –0.5 B 2 4 8 16 24 Withdrawal Time (weeks) Mean daily time without symptoms (‘on’ time) increased by up to 1.7 hours versus baseline Rinne et al, 1998

Immediate benefits versus traditional levodopa: improved motor scores
5 4 Worsening 3 2 1 Stalevo/LCE Change in motor scores Traditional levodopa plus placebo –1 Improvement –2 Significant improvements in patient function have been observed with Stalevo/LCE versus traditional levodopa/DDCI therapy In the NOMECOMT study, motor scores decreased (i.e. improved) in the patients treated with Stalevo/LCE from 25.5 to 22.5 points and increased (i.e. deteriorated) with traditional levodopa plus placebo from 24.6 to 28.8 points. This difference between the groups was statistically significant (p<0.05) Rinne et al. (1998) Neurology 51(5): 1309–1314 –3 –4 Rinne et al, 1998

Mean change in PDQ-8 score at week 12
Immediate benefits versus traditional levodopa: improved quality of life Q1. Had difficulty getting around in public? Q2. Had difficulty dressing? Q3. Felt depressed? Q4. Had problems with close personal relationships? Q5. Felt unable to concentrate? Q6. Felt unable to communicate? Q7. Had painful muscle cramps or spasms? Q8. Felt embarrassed? Stalevo Traditional levodopa 0.3 NS p=0.037 p=0.007 0.2 p=0.056 p=0.025 p=0.033 Worsening 0.1 NS NS Mean change in PDQ-8 score at week 12 0.0 -0.1 Improvement This slide represents data from the QUEST study comparing Stalevo with traditional levodopa on quality of life (QoL) in PD patients with no or minimal non-disabling motor fluctuations Results from the study suggest that in patients with PD, prior to the physically debilitating motor complications becoming more dominant, Stalevo may offer significant improvements in emotional wellbeing, social relationships, communication and stigma The PDQ-8 questionnaire was used to assess changes in the patient’s QoL for a period of up to 12 weeks. PDQ-8 is a validated assessment scale completed by the patient The significant mean change in PDQ-8 score of –1.4 points in Stalevo-treated patients, relative to traditional levodopa, indicates that as early as 12 weeks, Stalevo confers QoL improvement in PD patients with no or minimal, non-disabling motor fluctuations MDSCRTG (Movement disorder society of Australia clinical research and trial group) and the QUEST-AP study group (2006) Mov Disord 12(15 Suppl): S446 -0.2 Q1 Q2 Q3 Q4 Q6 Q7 Q8 Q5 -0.3 PDQ-8: Parkinson’s Disease Questionnaire, 8 item MDSCRTG and QUEST-AP study group, 2006

Immediate benefits vs traditional levodopa in stable patients
Stalevo/LCE provides: Improvements in activities of daily living (ADL) scores of 0.9–2.2 points versus traditional levodopa US-01 study: significant improvements in QoL versus traditional levodopa PDQ-39 Total Score (P=<0.001) SF-36 Physical Component Score (P=0.009) Celomen UK–Irish 2 1.5 Worsening 1 0.5 ADL Score -0.5 Improvement -1 This slide describes the results of two trials (Celomen and UK–Irish) which investigated the benefits of Stalevo/LCE compared with traditional levodopa in a sub-group of stable patients (<4.5 hours of ‘off’ time over 3 home-diary days) In the UK–Irish study, ADL scores decreased (i.e. improved) from 10.6 to 10.0 in the Stalevo/LCE group compared with an increase (i.e. worsening) of 0.1 points in the traditional levodopa/DDCI group In the Celomen study, ADL scores improved from 11.3 to 10.3 points in the Stalevo/LCE group. Whereas a worsening of disability occurred in the traditional levodopa group, with changes from 9.8 to 11.3 points. However, the differences between the groups were not statistically significant due to the small sample size (25 patients for Stalevo/LCE and 16 for traditional levodopa) The US-01 study was specifically designed to assess the effect of Stalevo/LCE in levodopa-treated PD patients who did not experience motor fluctuations. In comparison to levodopa plus placebo-treated patients, those randomized to Stalevo/LCE were significantly improved on a variety of measures of QoL, including the PDQ-39, the SF-36 and the Problem-Solving Inventory (PSI) Poewe (2002) Acta Neuro Scand 105(4): 245–255 Brooks (2003) J Neurol Neurosurg Psychiatry 74(8): 1071–1079 Olanow et al. (2004) Arch Neurol 61(10): 1563–1568 -1.5 Stalevo/LCE Levodopa/DDCI plus placebo Poewe et al 2002; Brooks et al 2003; Olanow et al 2004

Long-term benefits: sustained patient function for at least 3 years
Baseline 45 41.7 40.8 After 3 years Stalevo/LCE 40 35 28.4 29.0 30 25 UPDRS 20 15 10.5 10.8 10 This slide describes the results of the long-term NOMESAFE study which investigated the long-term benefits of Stalevo/LCE The NOMESAFE trial was an open-label extension study of the 6-month, Nordic, multicentre NOMECOMT trial. All patients received open-label Stalevo/LCE. Efficacy measurements were taken for up to 3 years during ‘best-on’ periods The NOMESAFE study indicated that with Stalevo/LCE, there was no significant deterioration in UPDRS scores (total, ADL and motor scores), indicating that Stalevo preserves patient function for at least 3 years By contrast, studies in similar patients by Goetz et al. treated with traditional levodopa therapy have reported a significant decline in UPDRS motor scores (approximately 1 point per year) Larsen et al. (2003) Eur J Neurol 10(2): 137–146 Goetz et al. (2000) Mov Disord 15(3): 479–484 5 Total score ADL score Motor score Larsen et al, 2003

Long-term benefits: sustained efficacy versus baseline for at least 5 years
1 Change from baseline in duration of benefit of morning dose (hrs) Stalevo/LCE 5-year data from the NOMESAFE study show that compared with baseline, the duration of benefit of the first morning dose of Stalevo/LCE therapy was consistently increased compared with baseline throughout the 56-month follow-up period Nissinen (2006) Mov Disord 21(suppl 15): S468 B 3 6 9 12 16 20 24 28 32 36 40 44 48 52 56 Month Nissinen et al, 2006

Long-term benefits: no need to increase the levodopa dose for at least 3 years
Double-blind (NOMECOMT) Open-label (NOMESAFE) 1000 800 Stalevo/LCE Levodopa dose (mg) 600 In the NOMESAFE study, initiation of Stalevo/LCE, in patients with PD experiencing motor fluctuations, allowed a reduction in the mean daily levodopa dose from an average of 737 mg at baseline (following washout from NOMECOMT study) to 649 mg at Month 18. This then increased gradually over time to 696 mg at Month 42, but was still significantly lower (41 mg, p<0.01) at the end of the study compared with baseline (end of NOMECOMT study) This indicates that with Stalevo/LCE therapy, there is no need to increase the levodopa dose for at least 3 years Larsen et al. (2003) Eur J Neurol 10(2): 137–146 400 6 18 42 Washout Months Larsen et al, 2003

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 Significant improvements in QoL domains Long-term benefits Sustained patient function through 5 years No need to increase the levodopa dose for at least 3 years 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

QUALY: quality-adjusted life-years
Stalevo provides significantly improved QoL compared with standard of care Societal perspective Cost (£) QALYs Stalevo 59,563 2.571 Standard of care 69,761 1.529 Difference: Stalevo  standard of care 10,198 1.042 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 A Markov model was used to evaluate the cost-effectiveness of Stalevo in the treatment of patients with PD and motor fluctuations Stalevo, with or without other antiparkinsonian medications, was compared with UK standard care, comprising traditional levodopa/DDCI with other antiparkinsonian medications (e.g. selegiline or dopamine agonists) added as needed. The costs and outcomes of both treatments were projected over a period of 10 years from the perspective (a) of society as a whole and (b) of the UK National Health Service (NHS) Treatment with Stalevo produced an average gain of quality-adjusted life-years (QALYs) per patient (2.57 vs 1.53). This gain was accompanied by a reduction in the total 10-year direct cost of care to society of £10,198 per patient From the societal perspective, therefore, Stalevo was dominant, producing better clinical outcomes with lower costs Although treatment with Stalevo resulted in an increase in direct costs per patient of £3239 (£25,756 vs £22,517) to the NHS over the 10-year period, the incremental cost-effectiveness ratio (ICER) of LCE was only £3105 per QALY gained. This ICER is within the range usually considered to indicate acceptable or highly acceptable cost-effectiveness (defined as < £30,000 per QALY gained) Thus overall, the use of Stalevo to treat PD patients with wearing-off was considered beneficial to individual patients and likely to offer money savings to society as a whole, compared with UK standard therapy. The added cost of the medication itself was exceeded by the savings made in other direct costs of PD, mainly those relating to social care or PD-related private expenditures Findley et al. (2005) Curr Med Res Opin 21(7): 1005–1014 QUALY: quality-adjusted life-years Findley et al, 2005

Patients can require optimization 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 In the ELLDOPA study, the incidence of dyskinesia with traditional levodopa therapy was: 3.3% for 150 mg/day 2.3% for 300 mg/day 16.5% for 600 mg/day The incidence of wearing-off with traditional levodopa therapy was: 16.3% for 150 mg/day 18.2% for 300 mg/day 29.7% for 600 mg/day The time of onset of the motor complications in ELLDOPA was 5–6 months after starting traditional levodopa therapy Fahn et al. (2004) N Engl J Med 351(24): 2498–2508 Fahn (2005) J Neurol 252(4 Suppl): IV37–IV42 Fahn et al, 2004; Fahn, 2005

Mean % change in total UPDRS
In de novo disease, early initiation of effective therapy provides long-term benefits versus 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 Levodopa Years 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 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 12 12 10 10 8 8 Placebo Placebo 6 6 Change in total UPDRS score (units) 4 4 2 2 150 mg 150 mg In the ELLDOPA (levodopa) and TEMPO (rasagiline) studies, those patients who received effective symptomatic treatment earlier in the course of their disease fared significantly better clinically than those initiated on placebo even when, as in the case of TEMPO, they were switched to the active drug after only 6 months It has been suggested that ‘normalization’ of basal ganglia function by early dopaminergic therapy therefore would have benefits in terms of symptomatic improvements and longer-term effects in delaying clinical progression Fahn et al. (2004) N Engl J Med 351(24): 2498–2508 PSG (2004) Arch Neurol 61(4): 561–566 Schapira and Obeso (2006) Ann Neurol 59(3): 559–562 300 mg 300 mg – – 2 2 – – 4 4 600 mg 600 mg – – 6 6 – – 8 8 2 2 6 6 10 10 14 14 18 18 22 22 26 26 30 30 34 34 38 38 42 42 46 46 Baseline Withdrawal of study drug Week Fahn et al, 2004; PSG, 2004; Schapira and Obeso 2005

Starting Stalevo/LCE earlier provides superior motor scores at 1 year
2.0 Traditional levodopa plus placebo Stalevo/LCE 0.0 Change in UPDRS III scores Improvement –2.0 –4.0 Baseline (n=484) 3 (n=476) 6 (n=479) 9 (n=445) 12 (n=410) This study aimed to evaluate the effect of early versus delayed initiation of Stalevo/LCE on efficacy in PD patients initially receiving traditional levodopa/DDCI therapy This is a retrospective pooled analysis of three double-blind, placebo-controlled Phase III studies and their long-term open-label extensions conducted in PD patients with wearing-off symptoms In all three studies, patients were initiated on either Stalevo/LCE (early start group) or traditional levodopa/DDCI plus placebo (delayed start group) At baseline of the double-blind phase, the mean age in the early and delayed start groups, respectively, was 61.6 vs 62.2 years, the duration of PD 9.1 vs 10.9 years, the duration of levodopa treatment 7.7 vs 8.8 years, the mean daily levodopa dose 673 vs 692 mg and the mean UPDRS III score 24.2 vs 24.3 Analysis revealed a statistically significant benefit of early initiation of Stalevo/LCE at 1 year with a reduction in UPDRS III of –1.33 points compared with the delayed start treatment group (95% CI [–2.50, –0.17]; repeated measures analysis of variance p<0.05) This study is the first to indicate that earlier optimization of levodopa therapy has clinically meaningful benefits in patients already on levodopa and experiencing the symptoms of wearing-off. Moreover, the study suggests that optimizing levodopa therapy earlier, even by 6 months (e.g. only one office visit), can have clinically significant benefits for the patient Nissinen et al. (2006) Mov Disord 21(13 Suppl): S111–S112 Months At 1 year, early initiation of Stalevo/LCE provided significantly better motor function compared with a 6-month delay (treatment difference –1.33 points, p<0.05) Nissinen et al, 2006

The benefit of starting Stalevo/LCE earlier is sustained over 5 years
18.0 Traditional levodopa plus placebo 12.0 Stalevo/LCE Change in UPDRS III scores 6.0 0.0 Improvement –6.0 Baseline 1 2 3 4 5 (n=484) (n=410) (n=101) (n=90) (n=44) (n=37) This study aimed to evaluate the effect of early versus delayed initiation of Stalevo/LCE on long-term (5-year) efficacy in PD patients initially receiving traditional levodopa/DDCI therapy This is a retrospective pooled analysis of three double-blind, placebo-controlled Phase III studies and their long-term open-label extensions conducted in PD patients with wearing-off symptoms In all three studies, patients were initiated on either Stalevo/LCE (early start group) or traditional levodopa/DDCI plus placebo (delayed start group) UPDRS III assessments were analysed until fewer than 10 patients in either group remained in the study At baseline of the double-blind phase, the mean age in the early and delayed start groups, respectively, was 61.6 vs 62.2 years, the duration of PD 9.1 vs 10.9 years, the duration of levodopa treatment 7.7 vs 8.8 years, the mean daily levodopa dose 673 vs 692 mg and the mean UPDRS III score 24.2 vs 24.3 There was a benefit of early start Stalevo/LCE over 5 years with a mean difference in UPDRS III between the early and delayed start treatment groups of −1.66 points (95% CI [−3.01, −0.31]; RMANCOVA p<0.05) This study is the first to indicate that earlier optimization of levodopa therapy has clinically meaningful benefits in patients already on levodopa and experiencing the symptoms of wearing-off. Moreover, the study suggests that optimizing levodopa therapy earlier, even by 6 months (e.g. only one office visit), can have clinically significant long-term benefits for the patient Nissinen et al. (2006) Mov Disord 21(13 Suppl): S111–S112 Years The significant difference in UPDRS III scores between the early and delayed start groups was maintained through the study period This suggests that optimizing levodopa therapy earlier, even by 6 months (e.g. only one office visit), can have clinically significant long-term benefits Nissinen et al, 2006

Survival distribution function
The MPTP primate model of PD has been very predictive of clinical outcomes in idiopathic PD MPTP model Idiopathic PD 1.0 4 0.8 3 0.6 Survival distribution function Dyskinesia score 2 0.4 1 0.2 To date, there are no discrepancies between the effects of specific drug treatments in the MPTP-treated primate model of PD and in patients with idiopathic PD In the MPTP primate model, initiation of traditional levodopa induced marked dyskinesia over the period of treatment, in contrast to ropinirole which produced a low intensity of involuntary movements This observation predicted the low level of dyskinesia with ropinirole versus traditional levodopa therapy observed in the 5-year clinical study of ropinirole monotherapy in early PD patients Rascol et al. (2000) N Engl J Med 342(20): 1484–1491 Maratos et al. (2001) Mov Disord 16(4): 631–641 0.0 1 8 15 22 1 2 3 4 5 Days Years Ropinirole Traditional levodopa Rascol et al, 2000; Maratos et al, 2001 MPTP: 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine

Studies in MPTP primates show the potential of early initiation of Stalevo/LCE to avoid dyskinesia induction Stalevo/LCE (4x/day) Traditional levodopa (4x/day) 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 4 3 Peak dyskinesia 2 †p<0.05 1 † † In this study conducted in MPTP-treated primates, treatment with levodopa/carbidopa four-times daily reversed motor disability and rapidly induced dyskinesia However, initiation of Stalevo/LCE produced more continuous improvement in locomotor activity with less dyskinesia than animals treated with traditional levodopa/carbidopa four-times daily Smith et al. (2005) Mov Disord 20(3): 306–314 1 4 7 10 13 16 Smith et al, 2005

Stalevo/LCE has a lower risk of dyskinesia induction versus traditional levodopa, regardless of parkinsonian severity in the MPTP primate model of PD 50% MPTP-induced lesion 75% MPTP-induced lesion 4 4x/day dosing 4 4x/day dosing 3 3 Peak dyskinesia Peak dyskinesia 2 2 1 1 Trad levodopa Stalevo/LCE Trad levodopa Stalevo/LCE 100 90% MPTP-induced lesion 4x/day dosing 4 In this study, the antiparkinsonian activity and risk of dyskinesia induction with Stalevo/LCE versus traditional levodopa therapy was compared in primates with MPTP-induced lesions of varying severity A common criticism of the 90% MPTP-lesioned model is the rapidity of the development of dyskinesias with levodopa treatment, which is thought to reflect the high degree of nigrostriatal degeneration observed in these animals. The 90% lesioned model is considered to be a better model for advanced PD Jenner et al. varied MPTP treatment to approximate 50% and 75% lesions of nigral dopaminergic neurons to approximate the earlier stages of the disease Marmosets with full (>90%) or partial (50% and 75%) MPTP lesions of the substantia nigra received traditional levodopa therapy or Stalevo/LCE for up to 30 days In the 50%-lesioned primates, traditional levodopa therapy produced an antiparkinsonian response with no dyskinesia. In this model of early PD, initiation of Stalevo/LCE enhanced the response, improving motor disability scores, with no induction of dyskinesia In the 75%-lesion group, traditional levodopa therapy produced an antiparkinsonian response with a gradual development of dyskinesia. By contrast, initiation of Stalevo/LCE enhanced the duration of the levodopa response and indicated lower peak dyskinesia scores In the >90%-lesion group, traditional levodopa therapy resulted in a pulsatile antiparkinsonian response and a rapid induction of severe dyskinesia. In this model, initiation of Stalevo/LCE enhanced the antiparkinsonian response and also significantly reduced the occurrence and severity of dyskinesia This study indicates that the risk of developing dyskinesia with traditional levodopa increases with the size of lesion. Since it is not possible to monitor lesion size or rate of PD progression in individual patients, early initiation of Stalevo/LCE may lessen the risk of motor complications Jenner et al. (2006) Mov Disord 21(13 Suppl): S73 3 p<0.05 % nigral neurons remaining 50 Peak dyskinesia 2 1 25 Trad levodopa Stalevo/LCE 10 Jenner et al, 2006

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 STRIDE-PD is a multicentre, double-blind, parallel-group, placebo-controlled study in PD patients (diagnosis <5 years) who require initiation of levodopa therapy A total of 747 patients (based on power calculations) will be randomized to receive either Stalevo (LCE; 50/12.5/200 or 100/25/200 mg) or traditional levodopa/carbidopa (12.5/50 or 25/100 mg) four-times daily (3.5 hourly intervals) Patients will be stratified according to whether or not they are also receiving dopamine agonist therapy The study will continue until all patients have been treated for 2 years Patients will be evaluated at 1 and 3 months, and then every 3 months for the duration of the trial The presence of motor complications will be determined by a blinded-rater at each visit The primary endpoint is time to onset of dyskinesia Secondary efficacy measurements include frequency of dyskinesia at 2 years, time to onset of wearing-off, UPDRS (Parts I–VI) and PDQ-39 Olanow (2006) Eur J Neurol 13(2 Suppl):93 *De novo use of Stalevo is not currently licensed Olanow, 2006

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 FIRST-STEP is a US regulatory, multicentre, double-blind, parallel-group study in early PD patients requiring initiation of levodopa therapy 424 patients will be enrolled into the study Patients in need of levodopa will be randomized to receive either Stalevo (100/25/200 mg) or levodopa/carbidopa (100/25 mg) three times a day The primary outcome variable is change from baseline to Week 39 on UPDRS Parts II plus III Secondary outcomes are UPDRS subscale scores (Parts I–III, V, VI), the PDQ-39, Clinical Global Impression Scale and the incidence of motor complications UPDRS assessments and the presence of motor complications will be determined by a blinded-rater at each visit Hauser (2006) Eur J Neurol 13(2 Suppl):94 Hauser, 2006

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

Conclusions II Stalevo provides oral levodopa in a manner which closely mimics infusion In fluctuating patients, optimization of levodopa delivery with Stalevo significantly improves patient function This benefit is sustained for at least 5 years without the need to increase the levodopa dose Initiating Stalevo 6 months earlier may lead to long-term benefits in patient function

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Optimization of levodopa delivery II
Nyholm, D., Lennernas H., Gomes-Trolin C. et al. Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations. Clin Neuropharmacol 2002; 25(2): 89–96. Stocchi, F., Battaglia G., Vacca L. et al. Clinical models of continuous dopaminergic stimulation. Movement Disorders 2004; 19(Suppl 9): S435. Stocchi, F., Vacca L., Ruggieri S. et al. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 2005; 62(6): 905–910. Stocchi, F. The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006; 7(10): 1399–1407.

Stalevo 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.

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. Movement Disorder Society of Australia Clinical Research and Trial Group and QUEST-AP study group. A randomized, double-blind study to compare the effect on quality of life of levodopa/carbidopa/entacapone (Stalevo®) with levodopa/carbidopa in patients with Parkinson’s disease with no or minimal, nondisabling motor fluctuations. Mov Disord, 2006; 21(Suppl 15): S446. 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.

Stalevo and its benefits III
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. Olanow, C. W., Kieburtz K., Stern M. et al. Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease. Arch Neurol 2004b; 61(10): 1563–1568. Poewe, W. The role of COMT inhibition in the treatment of Parkinson's disease. Neurology 2004; 62(1 Suppl 1): S31–S38. Poewe, W. H., Deuschl G., Gordin A. et al. Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study). Acta Neurol Scand 2002; 105(4): 245–255.

Stalevo and its benefits IV
Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Ann Neurol 1997b; 42(5): 747–755. Rinne, U. K., Larsen J. P., Siden A. et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998; 51(5): 1309–1314. Sawle, G. V., Burn D. J., Morrish P. K. et al. The effect of entacapone (OR-611) on brain [18F]-6-L-fluorodopa metabolism: implications for levodopa therapy of Parkinson's disease. Neurology 1994; 44(7): 1292–1297. Stocchi, F. The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations. Expert Opin Pharmacother 2006; 7(10): 1399–1407. Stocchi, F., Vacca L., Ruggieri S. et al. Intermittent vs continuous levodopa administration in patients with advanced Parkinson disease: a clinical and pharmacokinetic study. Arch Neurol 2005; 62(6): 905–910.

Benefits of earlier optimization of levodopa delivery
Fahn, S. Does levodopa slow or hasten the rate of progression of Parkinson's disease? J Neurol 2005; 252(Suppl 4): iv37–iv42. Fahn, S., Oakes D., Shoulson I. et al. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004; 351(24): 2498–2508. 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; 21(Suppl13): S111. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61(4): 561–566. Schapira, A. H. and Obeso J. Timing of treatment initiation in Parkinson's disease: a need for reappraisal? Ann Neurol 2006; 59(3): 559–562.

Future directions I Hauser, R. The First-step study: a study to evaluate the effects of intitiating a fixed dose of Stalevo or levodopa/carbidopa t.i.d. in early PD patients requiring levodopa. Eur J Neurol 2006; 13(Suppl 2): 94. Jenner, P., Jackson M., Rose S. et al. Coadministration of levodopa/carbidopa/entacapone avoids dyskinesia induction in MPTP-treated primates with full or partial nigral lesions. Mov Disord 2006; 21 (Suppl 13): S73. Maratos, E. C., Jackson M. J., Pearce R. K. et al. Antiparkinsonian activity and dyskinesia risk of ropinirole and L-DOPA combination therapy in drug naive MPTP-lesioned common marmosets (Callithrix jacchus). Mov Disord 2001; 16(4): 631–641.

Future directions II Olanow, C. W. The STRIDE-PD (Stalevo Reduction In Dyskinesia Evaluation) Study: A Long-term, Controlled study to evaluate the effects of initiating Stalevo or carbidopa/levodopa in early PD. Eur J Neurol 2006; 13(Suppl 2): 93. Rascol, O., Brooks D. J., Korczyn A. D. et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000; 342(20): 1484–1491. Smith, L. A., Jackson M. J., Al-Barghouthy G. et al. Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naive primates. Mov Disord 2005; 20(3): 306–14.

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