Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: https://www.tandfonline.com/loi/iern20

Treatment of motor fluctuations in Parkinson’s disease: recent developments and future directions Adolfo Ramirez-Zamora & Eric Molho To cite this article: Adolfo Ramirez-Zamora & Eric Molho (2014) Treatment of motor fluctuations in Parkinson’s disease: recent developments and future directions, Expert Review of Neurotherapeutics, 14:1, 93-103, DOI: 10.1586/14737175.2014.868306 To link to this article: https://doi.org/10.1586/14737175.2014.868306

Published online: 13 Dec 2013.

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Review

Treatment of motor fluctuations in Parkinson’s disease: recent developments and future directions Expert Rev. Neurother. 14(1), 93–103 (2014)

Adolfo RamirezZamora* and Eric Molho Department of Neurology, Parkinson’s Disease and Movement Disorders Center of Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA *Author for correspondence: Tel.: +1 518 262 6611 Fax: +1 518 262 6612 [email protected]

Parkinson’s disease (PD) is characterized clinically by rest tremor, rigidity, bradykinesia and pathologically by degeneration of nigrostriatal dopamine neurons. Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of PD. Ongoing clinical and preclinical research has led to the discovery of promising new therapeutic targets that might prevent or reduce motor complications. Newer approaches modulating non-dopaminergic systems including adenosine A2A antagonists, monoamine oxidase-B inhibitors, glutamatergic antagonists, adrenergic receptor antagonists and serotonergic agents are encouraging strategies for management of advanced PD. Recent developments in levodopa delivery formulations include duodenal infusion of a levodopa/ carbidopa, new extended-release levodopa and oral pro-levodopa forms. Recent clinical trials revealed diverse but promising results raising the possibility of new therapeutic modalities for PD in the near future. KEYWORDS: deep brain stimulation • dopaminergic treatment • dyskinesias • Parkinson’s disease • wearing off

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder with well-characterized neurological symptoms. The pathological hallmark is loss of dopaminergic neurons in the midbrain, which leads to the classical symptoms of bradykinesia, rigidity, abnormal posture and tremor. Although initially effective for management of motor symptoms, dopaminergic therapies are eventually complicated by motor fluctuations including predictable or unpredictable ‘off’ times (periods of recurrence of PD symptoms when medication effect wears off). Another motor phenomenon observed with long-term use of dopaminergic therapy is the emergence of abnormal involuntary movements (typically choreiform, dystonic and rarely ballistic or myoclonic) commonly affecting the facial muscles, neck, upper and lower limbs and body axis, termed levodopa-induced dyskinesia (LID). The pathophysiology of LID is still not fully understood, but several factors including progressive neuronal loss in the substantia nigra, changes in neuronal plasticity of dopaminergic and non-dopaminergic systems,

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10.1586/14737175.2014.868306

glutamatergic overabundance and the pulsatile, chronic dopaminergic stimulation from levodopa are the critical factors not only for the appearance but for the severity of LID as well. Several risk factors for development of motor complications have been recognized and include younger age at onset of PD, higher levodopa dosage, disease severity and longer disease duration [1]. Motor complications occur in up to 50% of patients taking levodopa for >5 years, and prevalence increases with longer disease duration. Motor complications can be an important cause of disability in patients with PD [2]. At first, symptoms associated with motor fluctuations are mild and predictable. The most common manifestations, at this stage, are non-disabling dyskinesias and endof-dose wearing off of medication. Strategies such as adjusting the timing and size of levodopa doses or the addition of adjunctive medications are generally effective and well tolerated. Extending the duration of benefit of levodopa doses by using catechol-O-methyl transferase (COMT) inhibitors (entacapone,


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tolcapone) or monamine oxidase B inhibitors (selegiline, rasagiline) or by using synthetic, longer-acting dopamine agonists (pramipexole, ropinirole, rotigotine) to smooth out the response to medication will generally work well in these patients. Accurate assessment of motor fluctuations might be challenging. In clinical practice and research trials involving patients with motor fluctuations, the most common screening instrument used to evaluate motor function is the section III and IV of the Unified Parkinson’s Disease Rating Scale (UPDRS). When used properly, this scale can address the occurrence of off periods including dystonia, freezing of gait, wearing off and dyskinesias providing motor evaluations at single time points using a standardized examination. Another common instrument utilized to judge motor function is PD diaries. Early PD diaries assessed time when the patient was asleep, ‘on’ or ‘off’. However, in an effort to better determine the functional impact of dyskinesias during on time, current PD diaries consistently include the categories asleep, off, on without dyskinesia, on with non-troublesome dyskinesia and on with troublesome dyskinesia [3]. Over time, motor fluctuations become more difficult to treat satisfactorily as PD progresses, for several reasons. Peripheral mechanisms such as slowed gastrointestinal motility and erratic absorption of levodopa become more important factors. Central mechanisms also play an important role, including the progressively limited ability of surviving dopaminergic neurons to store and release dopamine in a physiological fashion and postsynaptic changes in dopamine receptors and basal ganglia circuitry. These changes lead to chaotic responses to medication and striking differences between ‘on’ and ‘off’ functioning, including severe disabling dyskinesia and disabling ‘off’ periods. Additionally, as patients become more impaired cognitively, vulnerability to medication side effects limits the use of strategies that would have been well tolerated in earlier stages of PD. Although deep brain stimulation (DBS) has emerged as an effective treatment to minimize motor fluctuations, only a limited number of patients qualify for the procedure, and other patients are unwilling to expose themselves to the risks of brain surgery. As a result, there has been increasing interest in developing strategies to treat existing motor fluctuations. These include targeting non-dopaminergic aspects of basal ganglia circuitry and developing continuous delivery systems for dopaminergic medications. To this end, several dopaminergic and non-dopaminergic strategies have emerged over recent years targeting motor complications, and numerous clinical trial results have been published evaluating these novel alternatives for treatment of wearing off and dyskinesias. In this article, the authors critically review the evidence of newer treatments for management of motor fluctuations in PD and address future needs and areas of development. Non-dopaminergic therapies

It is now well recognized that the pathological changes in PD also involve several neurotransmitter systems other than the 94

nigrostriatal dopaminergic system. Glutamate, adenosine, norepinephrine and serotonin are also involved in control of motor function. Multiple non-dopaminergic neurotransmitters and neuromodulators have also been implicated in the neural mechanisms underlying the motor symptoms of PD as well as the development of motor fluctuations and dyskinesia following long-term levodopa therapy [4]. Adenosine A2A antagonists

Adenosine A2A receptors are selectively located on the gabaergic cell bodies and terminals of the indirect striatopallidal pathway, and their activation enhances GABA release in the external globus pallidus, a mechanism that is thought to contribute to the overactivity of the indirect pathway in PD with consequent increased activation of inhibitory motor pathways [5]. The theoretical action is that A2A antagonists may reduce PD symptoms via modulation of the indirect pathway with a decrease in excessive activation of the striatopallidal output pathway, restoring the balance in the basal ganglia-thalamocortical circuit facilitating generation of movement. Istradefylline is a selective adenosine A2A antagonist that has been shown to improve motor disability without inducing dyskinesia in animal models of PD [6,7]. Based on encouraging preliminary data including a small, open-label clinical trial [8], a subsequent randomized, double-blind, 12-week trial of istradefylline (40 mg/day) was conducted in 196 levodopa-treated PD subjects experiencing prominent wearing off [9]. The primary efficacy end point was the change from baseline in the percentage of daily awake time spent in the ‘off’ state, based on the 24-h home PD diary. Istradefylline was well tolerated and reduced end-of-dose wearing off by approximately 18% (1.2 h) compared with placebo. Importantly, the reduction in ‘off’ time occurred without an increase in ‘troublesome’ dyskinesia. A subsequent Phase III double-blind, 12-week, placebocontrolled study was conducted evaluating the efficacy and tolerability of istradefylline (20 mg/day) versus placebo in PD subjects with motor fluctuations [10]. Istradefylline significantly improved ‘off’ time compared with placebo, with a reduction in ‘off’ time of 0.7 h from baseline. Increased dyskinesia was reported in the above trials, but this was generally nondisabling, and overall istradefylline tolerability was adequate. Another study evaluated the efficacy of istradefylline in treatment of wearing off in a Japanese cohort [11]. A total of 363 subjects were randomized to receive placebo or istradefylline (20 or 40 mg/day) in a 12-week, randomized, doubleblind fashion. The primary outcome was the change in the daily ‘off’ time, based on the patient’s diary. Istradefylline reduced ‘off’ time from baseline by 1.3–1.5 h in the active group. The drug was well tolerated, and the most common adverse effect was development of dyskinesias in 6–8% of patients receiving the drug. The same Japanese group recently published the results of a subsequent multicenter, placebocontrolled, randomized, double-blind, parallel-group study to confirm the results of their initial trial [12]. The authors reported a reduction in daily ‘off’ time with increases in daily Expert Rev. Neurother. 14(1), (2014)

Treatment of motor fluctuations in Parkinson’s disease

‘on’ time without troublesome dyskinesia for istradefylline at 20 and 40 mg/day compared with placebo. No difference was observed between the 20 and 40 mg/day doses. A larger follow-up study with a similar experimental design (randomized, 12-week, double-blind, placebo-controlled, parallel group) evaluated the efficacy of 10, 20 and 40 mg/day of istradefylline in 610 PD patients with motor fluctuations [13]. The primary objective was reduction in the percentage of awake time/day spent in the ‘off’ state. Istradefylline did not provide significant improvement in ‘off’ time in contrast to previously published trials. A long-term, multicenter, open-label safety and tolerability follow-up study of patients participating in the Phase IIa and Phase III istradefylline trials has been reported [14]. Patients received open-label istradefylline (40 mg/day) for 2 weeks; thereafter, the dose could be increased to 60 mg/day or decreased to 20 mg/day. The data supported the long-term effectiveness of istradefylline in reducing ‘off’ time when administered as adjunctive therapy to levodopa for up to 1 year with adequate tolerance. However, these results should be interpreted carefully because the sponsor terminated the study prior to completion to investigate a finding of mineralization in the rodent brain associated with the drug and assess its impact on chronic istradefylline exposure in humans. Preladenant is another selective adenosine A2A receptor antagonist under investigation for treatment of PD. In a Phase II dose-finding trial, 253 patients with advanced PD and motor fluctuations were randomized to receive preladenant (1, 2, 5 or 10 mg) or placebo for 12 weeks [15]. Preladenant at doses of 5 and 10 mg twice daily was shown to reduce ‘off’ time, with a mean daily ‘off’ time reduction of 1.2 h in patients taking 10 mg and 1 h in those taking 5 mg. A subsequent multicenter, 36-week, open-label safety and tolerability extension study revealed that improvements in ‘off’ time were comparable with those of the randomized study [16]. A higher incidence of side effects and dyskinesias in the extension phase was reported, and most patients needed adjustments in dopaminergic medications to manage their symptoms during long-term follow-up.

Review

Phase III double-blind, randomized clinical trial (MOTION) over 24 weeks also evaluated safinamide (50 and 100 mg/day) as add-on to a dopamine agonist in 679 PD patients with early motor fluctuations. Preliminary results have been published in abstract form [18]. Safinamide at doses of 100 mg/day showed improvement in UPDRS III and quality-of-life PD questionnaire (PDQ-39) measures compared with placebo. A Phase III, 24-week, double-blind, placebo-controlled, randomized trial of safinimade (50–100 mg/day) as add-on therapy was conducted in 549 subjects with idiopathic PD and motor fluctuations with stable dopaminergic therapy (SETTLE) [19]. The primary outcome measure was change in daily ‘on’ time from baseline. Preliminary data revealed a significant benefit of safinamide (50–100 mg) versus placebo, with a mean change from baseline in daily ‘on’ time of 1 h. The investigators did not report an increase in troublesome dyskinesia or concerns about safety or tolerability. Additionally, in a recent article, safinamide demonstrated reduction in LIDs along with increased duration of the antiparkinsonian response in a primate model of PD [20]. Based on initial open-label and small trials suggesting a potential beneficial effect of zonisamide in PD, a multicenter, randomized, double-blind, parallel-treatment, placebo-controlled study of zonisamide as adjunctive treatment in 279 PD patients with motor fluctuations was conducted by Murata et al. [21]. The tentative mechanism of action of zonisamide is complex and includes dose-dependent MAO-B inhibition and inhibition of glutamate release by blockade of voltage-gated sodium channel. The therapeutic dose in PD is much lower than the dose used for epilepsy (200–400 mg/day), and patients were randomized to receive 25, 50 or 100 mg of zonisamide. There was reduction UPDRS III scores compared with placebo, with a mean decrease in total ‘off’ time from baseline at final assessment of 1.63 h in the 100 mg group. There are also other reports suggesting a role for the drug in the treatment of parkinsonian tremors [22]. Glutamate antagonists

Mixed monoamine oxidase-B inhibitors & glutamate release inhibition

Safinamide is an a-aminoamide with both dopaminergic and non-dopaminergic mechanisms of action, including monoamine oxidase-B (MAO-B), activity-dependent sodium channel antagonism, and inhibition of glutamate release in vitro. It has been tested in clinical trials as add-on therapy in early PD patients [17]. The study was a 24-week, randomized, doubleblind, placebo-controlled, parallel-group trial in 270 PD patients. Safinamide (200 mg/day) failed to demonstrate a change in UPDRS III (primary end point) total score from baseline to end point when compared with placebo. Additional data analysis indicated a significant improvement in UPDRS III and II (activities of daily living scale) and Clinical Global Impression-Change from baseline scores for safinamide (100 mg/day) versus placebo. The reason for the lack of efficacy of the higher dose of safinamide is unknown. A second www.expert-reviews.com

Recent clinical and experimental findings indicate that dyskinesia is associated with functionally related abnormalities in neurotransmitter systems which lead to abnormalities in the rate, pattern and synchronization of neuronal activity within and outside the basal ganglia [23]. There has been increasing interest in treatment of LIDs with glutamate antagonists. Increased glutamate transmission contributes to the striatal plasticity that underpins LID and to the progression of neurodegeneration through excitotoxic mechanisms. Glutamate receptors have therefore long been considered as potential targets for pharmacological intervention in PD, with emphasis on either blocking activation of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid, N-methyl-D-aspartate, or excitatory metabotropic glutamate (mGlu) 5 receptors or promoting the activation of group II/III mGlu receptors. Amantadine is currently the only glutamate antagonist recommended for treatment of dyskinesias in doses between 200 and 300 mg/day. The drug has 95

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demonstrated a 24% reduction in total dyskinesias and 17% decrease in maximal dyskinesia scores and time with dyskinesias in a class II single-center, double-masked, placebo-controlled, randomized, crossover trial [24]. Other studies have confirmed benefits of amantadine in dyskinesias, but the duration of beneficial effect is unknown after 1 year [25,26]. Although initial preclinical studies with ionotropic glutamate receptor antagonists showed antiparkinsonian and antidyskinetic activity, their clinical use was limited due to psychiatric adverse effects [27]. Several newer drugs with antiglutaminergic properties have been tested to determine the efficacy and safety in LID. Perampanel, a selective and non-competitive a-amino3-hydroxy-5-methylisoxazole propionic acid-type glutamate receptor antagonist, was well tolerated in clinical trials but failed to show improvement in motor symptoms in PD subjects with motor fluctuations [28,29]. Remacemide hydrochloride, a non-competitive N-methyl-D-aspartate glutamate receptor channel blocker, has been investigated in preclinical and clinical studies with conflicting results and limited clinical benefit in randomized controlled trials of PD patients with motor fluctuations [30,31]. Antagonists of mGlu receptor 5 have shown LID reduction in a rodent and primate models of PD [32,33]. AFQ056 is a selective antagonist of mGlu receptor 5 that has been investigated in a number of proof-of-concept, short-duration, randomized, placebo-controlled studies [34]. These were followed by a recent 13-week, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study of PD patients with peak-dose, moderate-to-severe intensity LID [35]. A total of 197 PD subjects were randomized to receive 1 of 5 different AFQ056 doses (20, 50, 100, 150 and 200 mg) or placebo. Twenty-four percent of patients withdrew from the trial due to adverse effects or unsatisfactory therapeutic effect. Significant improvements in dyskinesia severity, measured using the modified Abnormal Involuntary Movements Scale, were observed in patients randomized to receive AFQ056 at 200 mg daily. The most commonly reported adverse effects included dizziness, dyskinesias, fatigue and hallucinations. Adrenergic & serotonergic agents

Anatomically, there are distinctive noradrenergic and serotoninergic projections from the raphe nucleus and locus coeruleus to the neostriatum. In addition to substantia nigra compacta dopamine cell loss, norepinephrine neurons of the locus coeruleus degenerate, even preceding the death of dopaminergic neurons. The role of norepinephrine receptors in basal ganglia is not well defined, but possible suggestions include modulation of GABA release contributing to the overactivity of the direct striatopallidal pathway, resulting in dyskinesia [36,37]. Furthermore, there is also neuronal loss within the raphe nucleus of the brainstem, resulting in loss of serotoninergic (5-HT) input to the striatum [38]. It has been suggested that activation of a2adrenergic receptors can facilitate movements by activation of the direct pathway, thus highlighting the potential for enhanced a2-adrenergic stimulation to contribute to the generation of LID [39]. Idazoxan, a selective and potent a2-adrenergic 96

receptor antagonist, reduces LID in the 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine lesioned marmoset and rat models of PD [40,41]. Fipamezole, a selective a2-adrenergic antagonist, significantly reduced LID and prolonged the benefit of levodopa by 66% in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesioned monkeys [42]. A small double-blind, placebo-controlled clinical trial of fipamezole (up to 90 mg) in subjects with PD demonstrated good tolerability and LID suppression without exacerbating parkinsonism. A 4-week, Phase II, multicenter, randomized, placebo-controlled, double-blind and doseescalating study of fipamezole in patients with PD experiencing LID was conducted in the USA and India [43]. Patients needed to experience moderately disabling peak-effect LID for at least 25% of waking hours. A total of 180 patients were randomized to placebo or fipamezole at doses of 30, 60 or 90 mg. For the total study population, there was no significant difference compared with placebo for the total LID score, a measure calculated as the average LID value of assessments made while the subject is in the ‘on’ state at baseline and 0.5 and 1 h afterward. Fipamezole at 90 mg three-times a day showed modest reduction in LID in the US centers. The drug was safe and well tolerated and did not exacerbate parkinsonism as had been suggested by previous trials. There was no significant change in PD subjects recruited from India, possibly due to heterogeneity in patients in terms of body mass and levodopa dosage. Loss of 5-HT is less profound than dopamine loss affecting the nigrostriatal pathway, and consequently, levodopa is converted to dopamine in remaining serotonergic neurons. Nonphysiological release of dopamine by these serotonergic neurons can thus cause abnormal dopamine receptor stimulation within the striatum. This has been suggested as a potential cause of LID. Sarizotan is a compound with 5-HT1A agonist properties and additional high affinity for D3 and D4 receptors. An open-label study documented improvements in PD patients with LID [44]. A Phase IIIb, double-blind, randomized, placebo-controlled, 12-week, dose-finding trial of sarizotan in PD patients with motor fluctuations and dyskinesias was subsequently conducted [45]. A total of 398 PD subjects received placebo or sarizotan at doses of 2, 4 or 10 mg/day. No significant changes in dyskinesias were documented in sarizotan groups compared with placebo for any diary-based measure of dyskinesia or the Abnormal Involuntary Movements Scale score. Additionally, the drug was associated with increased ‘off’ times at higher doses, likely due to a dose-dependent dopaminergic blockade mechanism. Other 5-HT1A agonists have been investigated for treatment of dyskinesias in PD, including piclozotan and pardoprunox. However, the efficacy and applicability of these compounds remain unclear. Newer dopaminergic strategies to reduce motor fluctuations

Several new dopaminergic therapies for management of motor fluctuations in PD have emerged since the American Academy of Neurology published current evidence-based recommendations [46]. The concept of continuous dopaminergic ‘delivery’ Expert Rev. Neurother. 14(1), (2014)

Treatment of motor fluctuations in Parkinson’s disease

has evolved as a practical modification of the theoretical principle of continuous dopaminergic ‘stimulation’. This concept indicates that a non-physiological pulsatile stimulation of dopamine receptors using short-lasting oral dopaminergic drugs induces molecular and neurophysiological changes in striatal neurons and their efferents, manifesting clinically as motor fluctuations and dyskinesias [47]. Apomorphine is the oldest dopaminergic medication and the most potent dopamine receptor agonist exerting this effect on D1 and D2 receptors. The drug has been used as a ‘rescue’ medication in patients with severe or sudden ‘off’ periods in the USA. Several small, single-center clinical studies of continuous apomorphine delivery utilizing subcutaneous pumps have been conducted in PD patients with motor complications. These studies are heterogeneous, but there was consensus in a consistent reduction (>50%) in ‘off’ time with controversial benefit in dyskinesias [48–53]. Most of the studies were conducted in uncontrolled conditions, and patients frequently required additional oral levodopa with great variably across the studies. Albeit apomorphine infusions have demonstrated tolerability and efficacy in Europe, monotherapy can be only achieved with high doses (usually >100 mg/day), which are poorly tolerated by many patients. The most common adverse effects included subcutaneous nodules, somnolence, nausea/vomiting, orthostasis and impulse control disorders [54]. In recent years, extended-release formulations of pramipexole and ropinirole and continuous transdermal delivery of rotigotine have become available. Ropinirole 24-h prolonged release has been evaluated as an adjunct to levodopa in patients with PD and motor fluctuations (EASE-PD) [55]. The study was a double-blind, placebo-controlled, 24-week study of 393 subjects with a minimum of 3 h of ‘off’ time despite stable dopaminergic regimen. Ropinirole 24-h demonstrated a reduction in ‘off’ time by 2.1 h, allowed reduction in levodopa dose, and was well tolerated. In a retrospective analysis of early time-point data from the study, ropinirole 24-h prolonged release provided an early (2 weeks) and significant treatment benefit over placebo in contrast with the perception that the benefits of dopamine agonist therapy are delayed because of the slow titration required to ensure tolerability [55]. A multicenter, double-blind, randomized, placebo-controlled study of ropinirole prolongedrelease tablets in Chinese PD subjects with motor fluctuations was recently conducted [56]. Investigators reported that ropinirole prolonged release was effective in reducing ‘off’ time by 2.1 h compared with placebo, accompanied by an increase in ‘on’ time and ‘on’ time without troublesome dyskinesia, similar to findings of the EASE-PD investigators. Rotigotine is another non-ergot dopamine agonist formulated in a silicone-based transdermal patch approved for treatment of early PD [57]. The drug has been investigated in a double-blind prospective clinical trial in patients with advanced PD and more than 2.5 h of daily ‘off’ time despite oral levodopa therapy [58]. A total of 120 patients were randomized to receive placebo patches or rotigotine at doses of either 8 or 12 mg/24 h. There was significant reduction in mean ‘off’ time www.expert-reviews.com

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of 1.8 h/day with rotigotine, with increase in ‘on’ time without dyskinesias. Not surprisingly, common adverse reactions reported included typical dopamine agonist side effects and local skin reactions at patch sites. Similarly, extended-release pramipexole significantly improved UPDRS score and ‘off’ time compared with placebo in patients experiencing motor fluctuations by an adjusted mean of 2 and 2.5 h as an adjunct to levodopa [59]. Motor fluctuations in PD are thought to be due to fluctuating plasma concentration of oral therapies. Whereas ‘wearing off’ may be linked to low plasma concentrations of levodopa, dyskinesias appear to be related to high plasma and brain concentrations coupled with low threshold as a result of hypersensitivity of dopamine receptors. One of the reasons why it has been difficult to achieve constant plasma concentrations of levodopa with orally administered formulations is that absorption of the drug in the proximal small intestine is dependent on gastric emptying, which is highly variable. Levodopa/carbidopa intestinal gel (LCIG; Duodopa) is an aqueous gel that contains 20 mg/ml levodopa and 5 mg/ml carbidopa and is designed to be delivered directly into the duodenum via a percutaneous endogastric gastrostomy and portable infusion pump [60]. A randomized crossover trial comparing continuous nasoduodenal infusion of LCIG with individually optimized conventional combination therapies in advanced PD patients revealed that the drug is safe and clinically superior to a number of individually optimized medical options [61]. The trial included 25 patients with advanced PD with motor fluctuations evaluated for two 3-week treatment periods. Motor assessments using hourly video scoring demonstrated a significantly increased number of near-normal observations with LCIG compared with oral medications. The improvement was accompanied by a decrease in ‘off’ state without worsening of dyskinesia. Quality-of-life measures also improved and were significantly better with LCIG. There have been several small open-label studies evaluating LCIG in PD. Despite their limitations, they have shown that continuous intestinal infusion is a successful strategy to minimize motor fluctuations and dyskinesias in advanced PD patients and enhanced quality of life [60,62,63]. The most common adverse events reported are typically related to mechanical problems with the intestinal tubing and gastrostomy, including kinking, dislocation from the pump, infections, secretion from the stoma and focal pain. There are concerns about potential side effects in advanced patients, including worsening psychiatric symptoms or neuropathy, and the criteria for identification of ideal candidates remain unclear. Patients with advanced disease with neuropsychiatric contraindications for DBS appear to be the most suitable candidates. A Phase III, open-label, international, 54-week study of LCIG in patients with advanced PD and motor fluctuations despite best standard therapy has completed recruitment, and final results are awaited. An interim analysis of 192 patients indicates that LCIG produces clinically meaningful improvements of motor function. Total ‘off’ time improved substantially and consistently over 54 weeks without 97

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any concurrent increase in ‘on’ time with troublesome dyskinesias [64]. Side effects led to discontinuation of therapy in only 7.3% patients, and neuropsychiatric adverse effects were relatively infrequent with a paucity of symptoms associated with dopaminergic toxicity, such as hallucinations or behavioral changes. Another approach for overcoming the pharmacokinetic limitations of oral levodopa after development of motor fluctuations in PD involves the use of prodrugs, as theoretically these products could accomplish a more consistent delivery throughout the GI tract. Several drugs have been tested in preclinical studies with limited efficacy [65,66]. XP21279 is a sustained-release prodrug formulation of a levodopa that is actively transported by high-capacity nutrient pathways located throughout the lower GI tract, allowing for increased absorption time compared with regular levodopa. A Phase I trial demonstrated that XP21279 indeed provided sustained blood concentrations of levodopa compared with regular carbidopa/levodopa. A multiple-dose, multicenter, open-label, two-period, sequential treatment Phase Ib study of XP21279 was conducted in 14 PD patients with motor fluctuations [67]. Compared with carbidopa/levodopa at baseline, XP21279 treatment in 6 of 10 subjects resulted in ‡30% reduction in mean daily ‘off’ time. Further studies are necessary to corroborate these preliminary results. The investigational drug IPX066 is an oral extended-release capsule that contains beads of carbidopa and levodopa that dissolve at various rates in the GI tract, allowing for absorption over a longer period of time. In an open-label crossover study, 27 advanced PD patients were randomized to 8-day treatment with immediate-release carbidopa/levodopa followed by 8 days with IPX066, or IPX066 followed by immediate-release carbidopa/levodopa [68]. IPX066 provided more sustained plasma levodopa concentrations than immediate-release carbidopa/ levodopa with longer dosing intervals of approximately 6 h. In addition, patient diaries suggested that ‘off’ time was reduced 2.1 h/day during the IPX066 periods, relative to 0.1 h with immediate-release carbidopa/levodopa (p < 0.0001). Importantly, there was no significant difference in ‘on’ time with troublesome dyskinesia. The results of a follow-up Phase III, randomized, double-blind, double-dummy, active-control, parallel-group trial of 393 PD patients with motor fluctuations treated with IPX066 have been published [69]. IPX066 given a mean of 3.6-times per day reduced mean daily ‘off’ time by an extra 1.17 h compared with immediate-release carbidopa/ levodopa administered a mean of 5.0-times per day. The drug showed increased ‘on’ time without troublesome dyskinesia and demonstrated benefits in secondary measures of quality of life. Adverse events were minor and comparable between the two groups. Current status of deep brain stimulation for treatment of motor fluctuations

Over the past decades, DBS has emerged as an effective treatment for motor fluctuations in PD patients. Several randomized trials have shown benefits for surgery over best medical treatment in advanced PD [70–72]. DBS has largely replaced lesional 98

surgery for treatment of medically intractable fluctuations and dyskinesias, demonstrating long-term efficacy and improvement in patient’s quality of life [73,74]. Improved surgical techniques, patient selection and management of complications have translated into better surgical outcomes. Recent advances in the field of neuromodulation include better understanding of DBS mechanisms, identification of more effective and individualized or symptom-dependent stimulation parameters and research into ‘closed-loop’ or adaptive DBS devices that can suppress abnormal oscillatory activity at the basal ganglia level with adjustable response based on motor physiology, with reduction of adverse effects [75]. This concept has achieved ‘proof of concept’ with pallidal DBS in a primate model of PD [76]. Advances in new implantable pulse generators including constant current stimulation, current steering, better DBS programming tools and novel stimulation waveforms are currently investigated [77]. Although DBS has been shown to be effective for motor fluctuations, it carries risks, is expensive and is contraindicated in patients with cognitive dysfunction and significant psychiatric comorbidities. There has been growing interest in examining whether earlier implantation of DBS may be associated with larger and longer-lasting improvements in quality of life, before social and occupational activities are threatened. There are no specific recommendations regarding the timing of surgery, and decisions to undergo the procedure are individualized. Optimizing quality of life during the period when patients have the greatest response to dopaminergic therapy and neurostimulation should be considered a major goal of current treatments. Based on encouraging preliminary results, a 2-year, randomized, multicenter, parallel-group clinical trial comparing neurostimulation plus medical therapy with medical therapy alone was conducted in Europe [78]. The primary end point was the difference in mean change in quality of life from baseline to 2 years, assessed with the use of the summary index of the PDQ-39. The mean score for the neurostimulation group improved by 7.8 points, and that for the medical therapy group worsened by 0.2 points. These results raise important questions regarding candidacy and timing in considering neurostimulation for treatment of early motor fluctuations, as the procedure carries serious risks of neuropsychiatric complications. Further studies adhering to strict ethical standards are needed. Expert commentary

The debilitating consequences of the motor and non-motor complications associated with PD progression and long-term levodopa administration require effective and usually complex pharmacological therapy. Although levodopa-based strategies for managing motor complications in PD are available (including fragmentation of levodopa daily dose, dose adjustments, adjunct therapies and rescue medications), other therapies besides manipulation of levodopa often must be used to smooth out the motor fluctuations and control dyskinesias. An important aspect of management of motor fluctuations that deserves increasing attention is the occurrence of nonExpert Rev. Neurother. 14(1), (2014)

Treatment of motor fluctuations in Parkinson’s disease

motor fluctuations (NMS). NMS have been increasingly recognized in PD and symptoms range from genitourinary symptoms to neuropsychiatric concerns including depression, anxiety, apathy or impaired cognition. NMS have a direct negative impact on health-related and perceived quality of life and are commonly under recognized [79]. Two screening instruments have been developed to assess NMS in PD including the NMS Questionnaire (NMS Quest), a screening tool designed for detecting NMS and the Non-Motor Symptoms Scale (NMSS), a validated tool to assess the frequency and severity of various domains of NMS including cardiovascular, sleep/ fatigue, attention/memory, gastrointestinal, urinary, mood/ cognition, perception/hallucinations, sexual function and miscellaneous [80,81]. Virtually all clinical studies assessing motor fluctuations investigate secondary outcomes using additional scales including the UPDRS Parts I–IV, clinician or patient global impressions I, Clinical Global Impression I, sleep assessment and the PDQ-39, depression and anxiety inventories and cognitive scales. These instruments cannot properly assess the occurrence of non-motor fluctuations although they can compare changes in specific domains from baseline. There is an imperative need to develop validated, sensitive and applicable instruments to assess non-motor fluctuations in clinical trials. A few clinical trials are starting to incorporate NMS scales as primary outcomes. An international, multicenter, prospective 6-month assessment of intrajejunal L-dopa/carbidopa gel infusion utilized the non-motor symptom scale as the primary outcome measure along with the Parkinson’s disease sleep scale [82]. Another small, single center study aiming to assess the effect of duodenal levodopa infusion on blood pressure and sweating showed statistically significant benefit in several subscores in NMSS at 2-month control compared with baseline [83]. The RECOVER study, a randomized controlled trial of rotigotine transdermal system, was the first prospective controlled trial to use the NMSS scale as an exploratory outcome for assessment of treatment effects on non-motor symptoms. Post hoc analysis demonstrated improvement in non-motor symptoms such as fatigue, symptoms of depression, anhedonia and apathy [84]. Besides traditional dopaminergic approaches, newer therapeutic targets continue to evolve along with our understanding of the neurophysiological and neurochemical changes in the basal ganglia in advanced PD. Adenosine A2A antagonists appear to have a role in the treatment of wearing off, as their symptomatic benefits are comparable with currently available add-on agents including MAO-B inhibitors and COMT inhibitors. The theoretical advantage of adenosine A2A antagonists is that they should have a lower tendency to induce dyskinesia, which is a common side effect of MAO-B inhibitors and COMT inhibitors. However, clinical studies using the A2A antagonists have reported that dyskinesia does occur, although it may not be non-functionally disabling. In everyday clinical practice, one option to reduce dyskinesias is to reduce individual doses of levodopa. To date, no randomized trials have used lower or subtherapeutic doses of levodopa in combination with www.expert-reviews.com

Review

adenosine A2A antagonists to evaluate this potentially superior approach. Due to lack of efficacy in clinical trials, there are no plans to pursue regulatory filings for market registration for Preladenant and Merck has discontinued extension phases. Safinamide also appears to be a potentially useful agent, with perhaps the added benefit of an action on reducing wearing off without inducing dyskinesia. Tolerability appears to be adequate. Despite the increasing attention and interest in glutaminergic antagonists, most compounds have been evaluated over short periods only (1-month duration). Targeting specific subtypes with higher affinity to basal ganglia (metabotropic subtype of glutamate receptor) has generated increasing interest, as the drugs provide a wider therapeutic index without compromising efficacy. Further studies are needed to fully evaluate the clinical potential of these drugs in PD. There is a need for additional medical treatments of dyskinesias in advanced PD, both to reduce the unwanted effects of dyskinesia and to allow more liberal use of dopaminergic medications. Whether antidyskinetic medications currently in development can achieve sufficiently robust efficacy to fulfill this role is currently unclear. Ultimately, it will be important in clinical trials to demonstrate not only a reduction in a dyskinesia but also that the reduction provides a clinically relevant benefit. While a promising target, clinical applicability of 5-HT1A agonists as treatments for dyskinesia has not proven as successful as initially hoped, and it is important to recognize that 5-HT1A agonists can reduce dopamine release and therefore exacerbate parkinsonism, which will limit the use of these therapies. Regarding newer dopaminergic therapies in advanced PD, selection of adequate candidates for upcoming therapies will represent a major challenge. The highly controlled and complex environments observed in clinical trials might complicate the implementation of these therapies in clinical practice. At present, it appears that subcutaneous apomorphine pumps have the potential to reduce motor complications in the short term. The efficacy and duration of effect of this intervention are not known, and additional clinical trials are necessary. The population in which LCIG infusion can be considered is basically similar to the DBS population, that is, patients whose fluctuations and dyskinesias cannot be adequately managed with available oral medications. However, LCIG may be considered in patients with mild dementia and those with hallucinations or other psychiatric comorbidities, a group that would not normally be acceptable for DBS. The main drawbacks are the invasiveness of the procedure, the inconvenience of carrying the external pump and the problems associated with managing device malfunctions. In clinical practice, IPX066 may be particularly useful for patients when they first develop wearing off on immediate-release carbidopa/levodopa administered three-times a day or four-times a day. However, the best way to switch patients from immediate-release carbidopa/levodopa to IPX066 is not clear, because the impact of the addition of other adjunctive medications with IPX066 is uncertain. Currently, IPX066 remains an investigational 99

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compound; the review process for US FDA approval is in progress. The drug is not approved or licensed anywhere in the world and registration in other countries is not intended. Other concerns associated with IPX066 formulation are a slightly higher incidence of impulse control disorder and higher levodopa doses required to control motor symptoms. Although this can theoretically translate to a higher risk of dyskinesia and motor fluctuations, there was adequate control of fluctuations in current trials, but longer follow-up is necessary.

facilitate new drug development and reduce the failure rate of drugs proven to be effective in current animal models. Implementation of continuous levodopa delivery remains an area of great interest. DBS remains a successful treatment for motor fluctuations, but the cost, limited applicability and risks limit its widespread use. Advances in neuroimaging, target localization, implantable pulse generators and newer adaptive devices might provide more effective and efficient treatment with improved outcomes in selected patients. The utility and feasibility of these devices remain to be determined.

Five-year view

Understanding the molecular and neurobiochemical mechanisms behind PD and identifying potential neuroprotective strategies are the main focus of current bench research. Nevertheless, there is a need for better treatments for advanced disease motor and non-motor fluctuations. Newer strategies targeting non-dopaminergic systems in PD are important because of the multisystem nature of the disease. Many novel agents are being evaluated in clinical trials and have shown good promise at the preclinical stage. The identification of adequate and predictive animal models of PD in the future will

Financial & competing interests disclosure

A Ramirez-Zamora received speaker’s bureau from Teva Neurosciences. E Molho received speaker’s bureau and consultation fees from US World Meds, and received grant support from Merz, Cure Huntington’s Disease Initiative, Teva Neurosciences, US World Meds, Auspex Pharmaceuticals and Acadia Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Chronic levodopa treatment in Parkinson’s disease (PD) is associated with the development of motor complications (fluctuations in motor response and dyskinesia) in the majority of patients, leading to marked disability. • Several non-dopaminergic treatments are being evaluated as potential therapies to treat motor symptoms of PD. • Adenosine A2A receptors including istradefylline and preladenant have been shown to improve motor disability without inducing dyskinesia in animal models of PD and in small clinical trials. • Glutamate antagonists have received increased attention in recent years as potential therapies for motor fluctuations and levodopainduced dyskinesia. Several drugs have shown promising results in early preclinical trials, and further studies are needed. • Adrenergic and serotoninergic agents are newer targets for treatment of motor fluctuations in PD, but the efficacy and applicability of these compounds remains unclear. • Dopamine agonist extended-release formulations have shown reduction of ‘off’ time as adjunct therapies in subjects with advanced PD with motor fluctuations. • Levodopa/carbidopa intestinal gel is a successful intervention to minimize motor fluctuations in advanced PD patients and enhance quality of life. • A new extended-release levodopa formulation has been effective in reducing ‘off’ time with adequate tolerability in a large Phase III clinical trial. • Deep brain stimulation remains an effective alternative for treatment of motor fluctuations in PD and newer technologies may provide improve outcomes providing better targeting, adjustable stimulation and correction for patient’s specific variance.

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