Treatment regimens for use in the treatment of symptoms of early idiopathic Parkinson's disease

Abstract

Opicapone for use as an adjunct therapy to levodopa and DOPA decarboxylase inhibitor (DDCI) formulations in the treatment of Parkinson's disease, characterized in that patients with Parkinson's disease are treatable with levodopa and DDCI formulations and do not have clinically diagnosed motor complications.

Description

Technical Field

[0001] The present invention relates to a treatment regimen for use in treating the symptoms of early idiopathic Parkinson's disease. In particular, the present invention relates to the use of opicapone as an adjunctive therapy to levodopa and a DOPA decarboxylase inhibitor (DDCI) in the treatment of Parkinson's disease in patients without motor complications, where the symptoms can be suppressed by levodopa and the DDCI.

Background Art

[0002] Levodopa (L-DOPA) has been used in clinical practice for decades in the symptomatic treatment of various conditions, including Parkinson's disease. Levodopa can cross the blood-brain barrier and is then converted to dopamine by the enzyme DOPA decarboxylase (DDC) therein, resulting in an increase in dopamine levels in the brain. However, the conversion of levodopa to dopamine can also occur in peripheral tissues and may cause adverse effects. Therefore, as an adjunctive therapy, co-administration of a peripheral DDC inhibitor (DDCI), such as carbidopa or benserazide, etc., has become the standard treatment. The DDCI inhibits the conversion of levodopa to dopamine in peripheral tissues. The levodopa / DCCI therapy remains the most effective treatment for managing Parkinson's disease (Ferreira J, et al., Eur. J. Neurol., 2013; 20, 5-15).

[0003] In the early stages of Parkinson's disease, levodopa / DDCI therapy can almost completely suppress the symptoms of Parkinson's disease until the next dose is administered. However, most patients receiving long-term levodopa / DDCI therapy develop motor complications after the early stages of Parkinson's disease, such as end-of-dose motor symptom fluctuations and dyskinesia, even if they continue or increase their levodopa dosage (Aquino CC, Fox SH, Mov. Disord., 2015, 30, 80-89). Patients often report spending several hours a day in so-called "off" states experiencing end-of-dose motor symptom fluctuations, which can significantly impact their quality of life (Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif et al., Mov. Disord. 2005, 20, 224-30). The progression of Parkinson's disease from early to more advanced stages is determined by the onset of motor complications, such as end-of-dose motor symptom fluctuations. Therefore, controlling motor complications ultimately becomes a crucial clinical requirement for almost all patients (Poewe W, Neurology, 2009, 72, S65-73).

[0004] End-of-dose motor symptom variability is associated with the short half-life of oral levodopa (approximately 60-90 minutes when administered with DDCI). Catechol-O-methyltransferase (COMT) inhibitors extend the plasma efflux half-life of levodopa, reducing peak-trough variability and resulting in improved clinical efficacy for Parkinson's disease patients suffering from end-of-dose motor symptom variability.

[0005] 2,5-Dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazole-3-yl]-4,6-dimethylpyridine 1-oxide (opicapone) is a potent, long-acting COMT inhibitor that reduces the breakdown of levodopa to its inactive metabolite, 3-O-methyldopa. Opicapone is physiologically active, bioavailable, and low-toxicity. Therefore, opicapone possesses potentially valuable pharmaceutical properties in the treatment of several central and peripheral nervous system disorders where COMT inhibition may have therapeutic benefits, such as mood disorders; motor disorders, such as Parkinson's disease, Parkinson's disease-like disorders, and restless legs syndrome; gastrointestinal disorders; edema-forming conditions; and hypertension.

[0006] Further research has focused on optimizing opicapone into a stable and bioavailable form. For example, WO2009 / 116882 describes various polymorphs of opicapone, with polymorph A being both kinetically and thermodynamically stable. WO2010 / 114404 and WO2010 / 114405 describe stable opicapone formulations used in clinical trials. WO2013 / 089573 describes an optimized method for producing opicapone in high yield using simple starting materials. The development of opicapone is described in LE Kiss et al, J. Med. Chem., 2010, 53, 3396-3411. Opicapone, in combination with levodopa and DCCI, was approved under the trademark "Ongentys" in Europe in June 2016, in the United States in April 2020, and in Japan in June 2020 for the treatment of Parkinson's disease.

[0007] In all cases, opicapone is approved as an adjunctive therapy to levodopa / DDCI preparations for use in patients past the early stages of Parkinson's disease. For example, the European label states, "Ongentis is indicated as an adjunctive therapy to levodopa / DOPA decarboxylase inhibitor (DDCI) preparations in adult patients with Parkinson's disease and end-of-dose motor symptom fluctuations that cannot be stabilized by the levodopa / DOPA decarboxylase inhibitor (DDCI) combination" (emphasis added). The US label states, "Ongentis is a catechol-O-methyltransferase (COMT) inhibitor needed as an adjunctive treatment to levodopa / carbidopa in patients with Parkinson's disease (PD) who have experienced an 'off' episode" (emphasis added).

[0008] The approval of opicapone is based on the primary results from two Phase III pivotal trials of opicapone in patients past the early stages of Parkinson's disease (i.e., patients who experienced end-of-dose fluctuations in motor symptoms). These clinical trials are known as BIPARK-I (Ferreira et al., Lancet Neurol., 2016, 15, 154-65) and BIPARK-II (Lees et al., JAMA Neurol., 2017, 74, 197-206).

[0009] BIPARK-I demonstrated that opicapone was superior to placebo in combination with levodopa / DCCI in its ability to reduce the amount of time patients spent in an "off" state, and was comparable to entacapone, a previously approved COMT inhibitor. BIPARK-II confirmed the efficacy and safety of opicapone. These Phase III pivotal trials confirmed the preliminary results from smaller Phase II trials. Post-hoc analyses of the BIPARK trial combinations and their open-label continuations also suggested that opicapone slowed the rate of increase in the amount of time patients spent in an "off" state. In other words, opicapone appears to slow the progression of Parkinson's disease in relation to the need for levodopa in patients with more advanced stages of Parkinson's disease, i.e., in patients who have experienced end-of-dose motor symptom fluctuations (WO2016 / 083875). It is important to note that a treatment that shows therapeutic benefits in one stage of Parkinson's disease cannot be assumed to provide the same benefits in another stage, and in fact, often does not.

[0010] Entacapone, a previously approved COMT inhibitor, was tested in patients with early idiopathic Parkinson's disease, i.e., patients without motor complications. The initial FIRST-STEP trial suggested that entacapone improved motor symptoms as assessed by the Unified Rating Scale for Parkinson's Disease (UPDRS) Parts II and III. However, the larger STRIDE-PD pivotal trial could not confirm these preliminary results. Therefore, the use of entacapone as an adjunct therapy to levodopa / DDCI in early Parkinson's disease was not followed. In fact, the addition of entacapone was associated with a shorter time to the onset of motor complications and an increased frequency of dyskinesia. Consequently, COMT inhibitors are not currently recommended as adjunct therapies to levodopa and DDCI in the treatment of early Parkinson's disease, i.e., in patients without motor complications whose symptoms can be controlled by levodopa and DDCI.

[0011] Currently, there are three main classes of drugs considered appropriate as monotherapy for patients with early-stage Parkinson's disease (Miyasaki JM, et al., Neurology, 2002, 58, 11-17; Fox SH, et al., Mov. Disord., 2011, 26, S2-41). Levodopa (in combination with DDCI), a dopamine precursor, provided the greatest anti-Parkinson's disease effect on early motor signs and symptoms, with minimal short-term side effects (Fox SH, et al., Mov. Disord., 2011, 26, S2-41; Olanow CW, et al., Mov. Disord., 2004, 19, 997-1005). However, as mentioned above, although efficacy is maintained throughout the entire duration of the disease, levodopa is associated with the development of motor complications (variability and / or dyskinesia), and typically, as a result, the use of adjunctive therapy is required to optimize the drug therapy regimen. Therefore, other classes of monotherapy are often preferred in the earliest stages of treatment. Monoamine oxidase (MAO)-B inhibitors (e.g., rasagiline, selegiline) inhibit the breakdown of dopamine in the brain in surviving dopaminergic neurons and may also be considered for early treatment of the disease (Rascol O, et al., Mov. Disord., 2016, 31, 1489-1496). However, typically, the symptomatic benefit of these drugs is small, and the majority of patients will require additional therapy to achieve symptomatic efficacy relatively quickly (Olanow CW, et al., Mov. Disord., 2004, 31, 1489-1496). Dopamine agonists (e.g., ropinirole, pramipexole, rotigotine) act directly on postsynaptic dopamine receptors, providing moderate symptomatic benefits. The use of dopamine agonists as initial monotherapy may be utilized to delay the onset of motor complications compared to levodopa, although psychological or behavioral side effects may occur in some patients (Antonini A, et al., Lancet Neurol., 2009, 8, 929-937).

[0012] As these treatments demonstrate, treating early Parkinson's disease is not simply a matter of increasing dopamine levels in the brain. In fact, levodopa overdose is directly linked to the development of motor complications in early Parkinson's disease (Stocchi F, et al., Ann. Neurol., 2010, 68, 18-27). However, as the disease progresses, virtually all patients will require the superior symptomatic benefits / efficacy of levodopa. The fact that most Parkinson's disease therapies each have specific weaknesses at all and / or different stages of the disease has led to a stage-based approach to treating Parkinson's disease (Carrarini et al., Biomolecules, 2019, 9, 388), and levodopa / DDCI remains the gold standard despite its association with motor complications.

[0013] Therefore, common strategies to increase levodopa concentration or bioavailability are not considered beneficial to patients in the early stages of Parkinson's disease (i.e., before end-of-dose motor fluctuations appear), because any potential benefits of low levodopa levels are expected to be offset by the increased dyskinesia associated with high levodopa levels (Stocchi F, et al., Ann. Neurol., 2010, 68, 18-27).

[0014] Section A1 of WO2022 / 131944 discloses an exemplary trial protocol designed to test the efficacy of opicapone as an adjunct therapy to levodopa and DDCI in the treatment of Parkinson's disease in patients whose symptoms are controlled with levodopa and DDCI without motor complications.

[0015] There remains a need for treatments that can provide and / or enhance symptomatic relief for early-stage Parkinson's disease. In particular, there remains a need for safe and effective treatment regimens that can improve the acute symptoms of early-stage Parkinson's disease without inducing motor complications. [Overview of the Initiative]

[0016] The inventors propose that opicapone can be used as an adjunctive therapy to levodopa / DDCI in the treatment of Parkinson's disease in patients without motor complications.

[0017] Accordingly, in a first general embodiment, the present invention provides opicapone for use as an adjunct therapy to levodopa and DDCI formulations in the treatment of Parkinson's disease, characterized in that patients with Parkinson's disease are treatable with levodopa and DDCI formulations and do not have clinically diagnosed motor complications.

[0018] In a second general embodiment, the present invention provides the use of opicapone in the manufacture of a pharmaceutical product for use as an adjunct therapy to a levodopa and DDCI formulation in the treatment of Parkinson's disease, characterized in that the patient is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications.

[0019] In a third general embodiment, the present invention provides a method for treating Parkinson's disease, comprising administering opicapone to patients who require it as an adjunct therapy to a levodopa and DDCI formulation, characterized in that the patient is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications.

[0020] In the fourth general embodiment, which is related to the first, second, and third general embodiments described above, administration of opicapone results in improvement in one or more of the following symptomatic readouts. Generally, the patient's improvement is compared to the symptoms shown by a patient treated for the same period with a formulation of levodopa and DDCI without opicapone. Preferably, the treatment results in improvement in one or more of the patient's symptoms compared to the same patient before initiating opicapone treatment.

[0021] In a fifth general embodiment relating to the first, second, and third general embodiments described above, opicapone administration suppresses the occurrence of one or more motor complications during opicapone treatment, despite the continuation of levodopa / DDCI therapy.

[0022] Theoretical basis for the present invention The theoretical basis for the present invention is detailed below. This supports the changing role of COMT inhibition in the treatment of Parkinson's disease (PD) due to opicapone, and explains the path to achieving efficacy in the early stages of the disease.

[0023] In summary, the inventors propose the following: Previous studies with tolcapone and entacapone were not considered to clearly demonstrate efficacy in treating PD in patients without motor complications, and therefore could not influence product labeling and the clinical use of COMT inhibitors; the inability of entacapone to treat PD in patients without clinically diagnosed motor complications may be related to insufficient understanding of pharmacokinetic parameters at the time, coupled with the fact that entacapone administration was tied to the timing of levodopa administration; a key aspect of opicapone's action in reducing motor complications in PD is related to avoiding low plasma levodopa trough levels; levodopa monotherapy does not address the problem of low levodopa trough levels, but rather may worsen pulsatileness and further affect basal ganglia output; by using opicapone to smooth the delivery of exogenous levodopa in early disease, it is possible that the deterioration of already destabilized basal ganglia processing is avoided, thereby preventing or delaying the onset of motor complications; Based on new analyses of numerous physiological, pharmacological, and clinical studies, opicapone is proposed as a new treatment option for Parkinson's disease (PD) patients without clinically diagnosed motor complications.

[0024] Levodopa is the most effective drug for treating the motor symptoms of Parkinson's disease (PD) and is the “gold standard” therapy needed by almost all patients with this common neurodegenerative disease.[1,2] However, its usefulness is often limited by the development of motor symptom fluctuations (e.g., “wearing off,” “on-off”) and other motor complications (e.g., dyskinesia-cholera, dystonia, athetosis).[3] While the occurrence of troublesome dyskinesia appears to be reduced with more carefully considered levodopa use,[4] motor symptom fluctuations (which can appear in the first few years of treatment) remain a common feature of PD. Motor symptom fluctuations include both motor and non-motor symptoms that are poorly recognized by patients and underdiagnosed by physicians.[5] Recent cohort studies have estimated the 5-year cumulative incidence of motor symptom variability to range from 29% to 54%[6–8], rising to 100% at 10 years[8], and while the impact of motor symptom variability on daily life may vary[9], numerous studies have uniformly shown that motor symptom variability has a detrimental effect on quality of life[10–13], and effective management of motor symptom variability remains an important unmet need[3,14]. This is indicated by the fact that once motor symptom variability occurs, the cumulative off-time each day can account for up to 50% of the time a patient is awake

[15] . Indeed, wearing off is reported by patients as the most important and inconvenient element of current treatment, even more so than non-troublesome dyskinesia

[16] .

[0025] Even today, the definitions of "on" and "off" remain a subject of debate. Individual physicians use various terms, and the term "wearing off" is used to encompass a range of situations associated with inappropriate levodopa administration, exacerbation of end-of-dose, or the on-off phenomenon. However, a practical and excellent definition of the wearing-off phenomenon would be the shortening of the duration of effect of individual levodopa doses as disease progression and the duration of drug treatment are prolonged. Although often considered a complication of the later stages of the disease, there is compelling evidence that it can appear within a few months of initiating levodopa therapy, yet despite vigorous research, the key pathophysiological mechanisms for wearing off remain unclear, and patient risk factors are not yet identified [17-19]. Pharmacodynamic factors involved in both presynaptic and postsynaptic changes in dopaminergic and basal ganglia function appear to be important as they counteract any changes in the peripheral pharmacokinetic profile of levodopa. Nevertheless, despite the uncertainty, it is widely accepted that a key factor in the occurrence of wearing-off is the short plasma half-life of levodopa, which is thought to cause a non-physiological "pulsatile" stimulation of striatal dopamine receptors, which in turn leads to disordered striatal output and disruption of the motor programs that control voluntary movement [20, 21].

[0026] Modern pharmacological strategies to improve motor function assume the presence of inadequate and discontinuous stimulation of postsynaptic dopamine receptors in the striatum, and that increasing on-time is achieved by providing more sustained dopamine stimulation. In clinical practice, physicians utilize a range of strategies that attempt to improve levodopa delivery to the brain and maintain dopamine receptor stimulation. These strategies may include levodopa modification strategies such as increasing levodopa dosage, increasing the frequency of oral levodopa administration, and using controlled-release or sustained-release formulations of the drug. While these levodopa approaches are low-cost and usually effective in the short term, they do not address the problem of low levodopa trough levels, may worsen pulsatileness, and may even affect basal ganglia output. Sustained intraduodenal delivery of levodopa is often highly effective but is invasive and not available to all patients [22,23]. Another option is to use longer-acting oral dopamine agonists, such as ropinirole or pramipexole, to provide more sustained receptor stimulation [24,25], or to deliver dopamine agonists by subcutaneous injection or transdermal administration, as in the case of apomorphine and rotigotine [26,27]. However, dopamine agonists introduce other potentially significant adverse events (e.g., hallucinations, confusion, and impulse control disorders) into the risk-benefit equation and are therefore not typically used in the older PD population

[28] . Recently, non-dopamine approaches that alter basal ganglia function, such as the adenosine A2A antagonist istradefylline

[29] and the NMDA antagonist amantadine

[30] , have been suggested to be effective in improving wearing-off. Similar to dopamine agonists, these non-dopaminergic approaches typically reduce the severity of variability but do not affect the pharmacokinetic profile of levodopa and therefore do not address the underlying problem.

[0027] A strategy that has been attempted and tested has proven consistently effective in increasing the plasma profile and delivery to the brain of levodopa, as well as the duration of action of each dose, and this strategy involves the use of enzyme inhibitors that control the catabolic processes that are key to determining the efficacy of levodopa. The first of these strategies is the peripheral decarboxylase inhibitors carbidopa and benserazide, which are used as the standard to increase the availability of levodopa to the brain at all stages of the disease. Next, the irreversible monoamine oxidase B inhibitors selegiline and rasagiline were developed and are now commonly used as early monotherapy and as adjuvants to levodopa to extend the duration of action of endogenous dopamine and dopamine formed from levodopa in the brain

[31] . More recently, the reversible MAO-B inhibitor safinamide has also been introduced into treatment as an adjuvant to levodopa

[31] .

[0028] Entacapone, tolcapone, and opicapone, which are COMT inhibitors, have the effect of protecting levodopa from the major peripheral pathway of metabolism by the COMT enzyme, and were thus developed particularly for the management of wearing-off. Although tolcapone has been shown to inhibit central COMT, its clinical effectiveness appears to be mediated mainly by the inhibition of peripheral COMT and depends on the concomitant use of exogenous levodopa

[32] . Tolcapone and entacapone were introduced in the 1990s and have mainly been used in more advanced patients with chronic fluctuations in motor symptoms. However, both compounds have been found not to be ideal, as tolcapone is associated with hepatotoxicity and entacapone has a short plasma half-life and needs to be administered with each dose of levodopa

[33] . Opicapone is a third-generation COMT inhibitor that was rationally designed to reduce the risk of toxicity and improve COMT inhibitory activity and peripheral tissue selectivity compared to other COMT inhibitors

[34] . Opicapone was first approved in Europe in 2016 for the management of fluctuations in motor symptoms and has subsequently been approved for use in the United States, Japan, South Korea, Australia, and other countries. Despite having clear advantages over previous COMT inhibitors, opicapone has also been significantly restricted for use in late-stage patients with wearing-off for whom other treatment strategies have failed.

[0029] 1. Inhibition of peripheral enzymes is an important factor in determining the action of levodopa in the brain Since the combination of levodopa and DDCI has now become essential in the treatment of PD, "levodopa monotherapy" necessarily means levodopa + DDCI, and there will be no one who tries to use levodopa without DDCI from the very early stage of treatment.

[0030] However, many of the problems inherent in its use are not overcome by the combination of levodopa with DDCI. The 90-minute half-life of levodopa, often referred to as "short," actually refers to the plasma pharmacokinetics of oral levodopa in combination with carbidopa

[44] , and the degree of brain permeability of levodopa remains low, reaching only 10% when combined with DDCI. The main reason for these persistent deficiencies in the levodopa profile is related to other pathways of metabolism, namely the pathway via COMT. COMT is another ubiquitous enzyme found in the periphery and the brain and is important for the O-methylation of a wide range of catechol-containing substances. In peripheral tissues, COMT can be utilized with maximum activity mainly in the soluble cytosolic form (S-COMT), which has been shown in the liver, kidney, and gastrointestinal tract, while the membrane-bound form (MB-COMT) is predominant in the CNS

[45] . As a result, peripheral COMT inactivates the majority of each levodopa dose before it can permeate into the brain. In fact, COMT converts approximately 90% of levodopa to 3-O-methyldopa (3-OMD), which, in contrast to levodopa itself, is not a substrate for DDC, has a long plasma half-life, and accumulates with repeated levodopa administration. Although no harmful effects of 3-OMD have been reported, at the level of the blood-brain barrier, it may compete with levodopa for entry into the brain

[46] . When peripheral DDCI inhibitors are used, it has not been correctly appreciated that levodopa metabolism is short-circuited through the COMT pathway (and the formation of 3-OMD is increased) such that only 5-10% of the administered drug reaches the brain.

[0031] The theoretical conclusion that both peripheral DDC and peripheral COMT need to be blocked to maximize the effect of levodopa in PD was recognized early on, but this concept proved difficult to translate into a feasible drug treatment. Early attempts to inhibit COMT using compounds such as pyrogallol showed that these compounds were nonspecific, inhibited a wide range of enzyme systems, and, more importantly, were short-acting and toxic

[48] . It was only with the discovery of nitrocatechol ("capone" series) that the clinical feasibility of selective COMT inhibition in PD began to emerge. One of the first to be developed was nitecapone, which was effective, but it exhibited toxicity that hindered clinical development

[49] . Tolcapone was a useful and effective drug and was registered for use in the treatment of levodopa wearing-off, but the possibility of liver damage was later discovered, and its use was limited by the need for extensive monitoring, despite subsequent large-scale safety studies demonstrating the usefulness of the compound [50,51]. Entacapone also successfully registered for the treatment of PD, but its half-life was as short as levodopa's, requiring the use of these two drugs in combination to achieve sufficient inhibition of COMT. This practical limitation was overcome to some extent by the introduction of Stalevo as a combination of levodopa / carbidopa / entacapone, but the use of this "triple combination" makes it difficult for physicians to adapt the levodopa dose to the individual needs of each patient. As a result, Stalevo, despite being developed to improve compliance with drug therapy, may be difficult to use in patients with varying levodopa doses throughout the day and in patients with complex dosing regimens. Furthermore, while entacapone had some efficacy in improving the pulsatileness of the levodopa plasma profile, its efficacy was lower than that of tolcapone, and the peaks and troughs of levodopa plasma levels remained pronounced. Therefore, while second-generation COMT inhibitors began addressing the pharmacokinetic constraints of levodopa, such as inhibition of peripheral metabolism and increased levodopa delivery to the brain, the problem of optimizing levodopa delivery remained unresolved.

[0032] 2. Opicapone - Experimental Biochemistry and Pharmacology As a result of the search for a potent, selective, long-acting, non-toxic, once-daily peripheral COMT inhibitor, opicapone was developed as a third-generation molecule for the treatment of PD. Opicapone was designed as a 1,2,4-oxadiazole analog with a pyridine N-oxide residue at position 3, and is therefore chemically distinct from previous-generation nitrocatechols. Its unique pharmacophore results in high COMT inhibitory activity without cytotoxicity

[52] . Furthermore, opicapone has a sub-picomolar binding affinity to S-COMT in peripheral tissues and is thought to have no effect on COMT activity in the brain

[52] . Opicapone has a relatively short plasma half-life and is not immediately expected to provide long-lasting inhibition of COMT. However, its binding and interaction with S-COMT are long-lasting and persist longer than the clearance of the drug from the systemic circulation. In general terms, opicapone binds tightly to S-COMT but is an inferior substrate and therefore inactivates enzyme activity over a long period of time

[53] . The tight binding and slow complex dissociation properties of opicapone are the basis for its COMT inhibitory activity and once-daily dosing frequency.

[0033] The sustained enzyme inhibition achieved by opicapone leads to functional activity that can be observed both in vitro and in vivo in experimental models. In rat liver and kidney homogenates orally treated with opicapone, tolcapone, or entacapone, opicapone resulted in more pronounced and longer-lasting inhibition of COMT compared to the other drugs [54,55]. The effect on levodopa metabolism (in combination with DDCI) also reflects the long-lasting inhibition of COMT induced by opicapone. Oral administration of opicapone in combination with levodopa to rats resulted in a sustained increase in brain levodopa levels, which was evident even 24 hours after drug administration. Similar results were observed in cynomolgus monkeys, where administration of opicapone, an adjuvant to levodopa / benserazide, doubled systemic exposure to levodopa without altering Cmax levels [56,57], and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax levels by up to seven times [56,57]. These changes were accompanied by up to approximately 85% reductions in red blood cell COMT [56,57], and led to improved motor function in Parkinson's disease primates treated with MPTP

[57] .

[0034] 3. Effects of opicapone on the pharmacokinetic profile of levodopa Similar to in vitro and in vivo experimental models, the pharmacokinetics of opicapone in humans initially did not appear suitable for a once-daily pharmacopoeci. A single oral administration of opicapone in the range of 10–1200 mg to healthy male volunteers demonstrated dose-proportional exposure to the drug in plasma and a final elimination half-life of opicapone ranging from 0.8–3.2 hours. However, the duration of COMT inhibition by opicapone was dose-independent, and the half-life of COMT inhibition in erythrocytes was 61.6 hours, reflecting the estimated dissociation of the COMT-opicapone molecular complex. Thus, despite its relatively short plasma half-life, opicapone significantly and persistently inhibited peripheral S-COMT activity long after plasma clearance [59,60]. This prolonged inhibition of COMT is reflected in the changes in levodopa plasma kinetics. In PD patients, opicapone administration increases levodopa bioavailability by up to 65% in a dose-dependent manner, depending on the dose and duration of drug administration [40,43]. As assessed by AUC, opicapone is more effective than entacapone administration in increasing levodopa exposure, which reflects sustained COMT inhibition that lasts for 24 hours

[59] . Opicapone administration also increased the minimum plasma concentration (Cmin) for individual levodopa doses by up to 2.6 times. This is an important aspect of opicapone's action, as the reduction of motor symptom variability in PD is related to avoiding low plasma levodopa trough levels

[61] .

[0035] Separating the pharmacokinetic profile of opicapone from its functional activity may offer other advantages. In some PD patients, entacapone absorption interferes with levodopa absorption, resulting in a delayed tmax and decreased Cmax of levodopa when administered concurrently [62,63]. This may explain why some patients appear unresponsive to entacapone

[62] . Despite the possibility of interactions between levodopa and opicapone when administered concurrently, once-daily bedtime administration (at least one hour before or after the levodopa combination) and rapid plasma clearance minimize any drug absorption-based interactions with levodopa

[64] . Therefore, the pharmacokinetic profile of opicapone and its effect on subsequent levodopa availability leads to a treatment strategy based on once-daily administration of a single effective dose, in which case the inhibition of COMT is independent of the timing of levodopa administration or any particular levodopa product or dose (although it is relevant in the case of entacapone). This is also gentler and more convenient in terms of patient compliance and drug costs. Recently, the National Institute for Health and Medical Care (NICE) in the UK highlighted that using once-daily opicapone administration allows for flexible levodopa administration without changing the opicapone dose

[65] .

[0036] 4. Effectiveness in Parkinson's disease with fluctuations 4.1 Theoretical basis for COMT inhibition in the management of fluctuations in motor symptoms In patients receiving levodopa treatment and experiencing motor complications, there is clear and obvious rationale for using peripherally acting COMT inhibitors. Troughs in plasma levodopa levels that occur between administrations directly correspond to off-symptoms [61,66], and the goal of treatment with COMT inhibitors is to maintain levels above the threshold for on-symptoms. Adding COMT inhibitors to the levodopa regimen extends the benefit of each levodopa administration and helps avoid fluctuations associated with oral levodopa therapy without unnecessarily increasing the dose or frequency of levodopa administration

[67] . Shortcuts of levodopa metabolism to the COMT pathway are avoided, resulting in increased drug exposure. Therefore, the use of DDCIs and COMT inhibitors can maximize levodopa delivery to the brain by inhibiting both major pathways of levodopa metabolism, resulting in more sustained drug delivery.

[0037] 4.2 Clinical trials of opicapone in patients with wearing-off The efficacy of opicapone as an adjunct to reduce off-time in patients with fluctuating motor symptoms has been well established by phase 3 clinical trials and observational studies and has been extensively reviewed elsewhere [68,69]. Three randomized, double-blind, placebo-controlled trials, namely the BIPARK trial (I and II))[70,71] and, more recently, the phase 2b (COMFORT-PD) trial conducted in a Japanese population

[72] , have investigated the symptomatic effects of opicapone in PD patients with fluctuating motor symptoms.

[0038] In a pooled analysis of the BIPARK trial, double-blind treatment with opicapone (25 and 50 mg) significantly reduced absolute daily off-time. The mean [95% CI] treatment effect compared to placebo was -35.1 [-62.1, -8.2] minutes (p=0.0106) for opicapone 25 mg and -58.1 [-84.5, -31.7] minutes (p<0.0001) for opicapone 50 mg

[73] . A statistically significant increase in dyskinesia-free on-time was also observed, but troublesome dyskinesia did not increase

[73] . Similar results were observed in a trial in Japan, where the reduction in off-time compared to placebo was -0.74 hours in the opicapone 25 mg group and -0.62 hours in the opicapone 50 mg group (p<0.05 for both opicapone groups). Off-time decreased consistently and steadily in both opicapone tablet groups from week 1 to the end of the double-blind part (14-15 weeks)

[72] .

[0039] Although the BIPARK I trial was not designed to test the superiority of opicapone over entacapone (rather, it tested for non-inferiority), it did show statistically significant improvements in CGI-C and PGI-C scores with opicapone 50 mg compared to the active control, entacapone

[70] . The reduction in off-time compared to placebo in the trial for entacapone (-40.3 mins) was in full consistency with previous trials (the result of a meta-analysis of the entacapone trials was -41 mins

[74] ), and the therapeutic difference of 26.2 mins for opicapone 50 mg compared to entacapone was at the statistical significance boundary (p=0.05)

[70] . Based on these data, the levodopa equivalent dose (LED) of opicapone has recently been estimated to be 1.5, which is the same as tolcapone and higher than the LED conversion factor of entacapone, which is 1.3. Therefore, the LED of opicapon is 140–150 mg for a 100 mg levodopa dose

[75] . Clinical differences between products are further highlighted by switching from entacapone to opicapon in BIPARK I to open-label continuation. Patients previously treated with entacapone in the double-blind phase showed an average reduction of 40 minutes of off-time, followed by a further improvement of 68 minutes of off-time in patients who completed open-label opicapon 50 mg treatment

[76] . Similar cues for improved efficacy have been reported in a single European site interview of previously entacapone users

[77] . This interview included 20 patients who switched from entacapone to opicapon and 37 patients who had previously been ineffective or experienced adverse events with entacapone. In patients who continued opicapon for more than 6 months, the reduction in off-time was reported to be approximately 2 hours per day on average, as measured by interviews. Patients who switched from entacapone to opicapon were more likely to remain on opicaponone treatment than those who had previously experienced COMT inhibitor-induced adverse events.

[77] Although the superior efficacy of tolcapone compared to entacapone is well known

[78] , tolcapone's safety profile means it can only be considered after entacapone

[79] . Opicapone does not have such limitations, and its once-daily administration, combined with its indications for higher efficacy than entacapone, suggests it is a superior alternative to entacapone in patients with fluctuating motor symptoms

[69] .

[0040] In a real-world observational study, Reichmann and collaborators conducted the OPTIPARK trial, which included 506 patients treated at 68 sites in the UK and Germany.

[80] Three months after treatment with opicapone 50 mg, the majority of patients (71.3%) showed physician-investigated clinical efficacy (CGI-C), with 43% reporting significant or very significant improvement. Of the UK patients evaluated at six months (n=95), 85.3% were judged to have improved since initiation of treatment (including 8.4% very significant improvement and 49.4% significant improvement), while 8.4% were judged to have “no change” and 6.4% worsened. Importantly, this high finding of efficacy was confirmed by the patients themselves, of whom 76.9% reported improvement at three months. Despite patients receiving optimized therapy before participating in the trial (79% were receiving levodopa plus another PD drug), the trial found that opicapone adjunct therapy resulted in clinically relevant improvements in UPDRS exercise and ADL scores (improvements of 4.6 and 3.0 points, respectively)

[80] . These changes were within the estimated clinically relevant difference range of 2.0–5.2 points (for exercise score) and 0.5–2.3 points (for ADL score)

[81] , suggesting that opicapone therapy not only increased on-time but also improved the quality of on-time.

[0041] Another interesting finding was that, three months after treatment with opicapone, most patients maintained the same daily levodopa frequency (77.1% unchanged, 10.4% increased, and 12.5% ​​decreased in terms of dosing frequency), resulting in an overall mean decrease of -10 mg / day. This is consistent with pivotal trials, such as the BIPARK II trial, where nearly two-thirds (63%) of patients maintained the same dose of levodopa treatment, even though they were free to adjust the dose according to clinical need.

[71] The mean number of levodopa dosing per day also remained stable throughout this phase, ranging from 4.7 to 4.8 over the year. In all trials, the most common reason for reducing levodopa dose was to manage dopaminergic adverse events such as dyskinesia. On the other hand, in the OPTIPARK

[80] and the multi-year open-label continuation of the pivotal trial[69,73,82], the maintenance of levodopa dose in combination with opicapone suggested the possibility of delaying the need for levodopa dose increases for a long period. In fact, this concept will likely be further investigated in trials currently implementing early wearing-off.

[0042] 4.3 Opicapone in early wearing-off Motor symptom fluctuations begin much earlier than previously thought

[21] , and it is increasingly accepted that wearing-off is already common within the first few years of treatment and is underestimated by neurological clinical assessment

[83] . Reasons for the underrecognition of wearing-off include a lack of understanding of non-motor symptom fluctuations, as well as a general lack of awareness of the phenomenon by patients (and physicians)

[84] . While these issues are gradually being addressed through ongoing medical education

[85] , neurologists still have a significant tendency to underestimate the presence of wearing-off in patients within the first few years of diagnosis (disease duration <2.5 years)

[83] , perhaps because they are waiting for a more objective picture of established symptom reproduction. Predictors of wearing-off include younger age, weight, and female gender (in addition to duration of treatment and disease severity)[18,83], with women having an 80% higher risk of wearing-off

[86] .

[0043] To summarize, patients enrolled in the BIPARK trial had a disease duration of approximately 8 years, motor symptom fluctuations of approximately 3 years, and an average daily off time of more than 6 hours

[73] , and the majority of patients (83%) were receiving polypharmacy for Parkinsonian symptoms (levodopa plus at least one other PD drug treatment)

[87] . Despite this potentially representing a population with more chronic motor complications, the trial included patients with shorter off times at baseline, as well as those not receiving other adjunctive therapies. Recent post-hoc analyses of patients with wearing-off earlier in the PD and treatment progression showed that the efficacy of opicapone 50 mg was comparable to, or even enhanced than, placebo compared to the overall pooled population

[88] . For example, patients with a more recent onset of motor symptom fluctuations (within the last two years) showed a reduction of -68.5 minutes of off-time compared to placebo (p=0.0003, vs. placebo), and patients receiving less than 600 mg of levodopa per day showed a reduction of -75.5 minutes of off-time compared to placebo (p=0.0005, vs. placebo) [73, 88]. These reductions in off-time are also expected to be clinically relevant, as they exceed the estimated clinically relevant difference of one hour [81, 89]. Despite the relatively small sample size (n=67 in the opicapone 50 mg group and n=59 in the placebo group), patients receiving levodopa alone at baseline (i.e., not receiving dopamine agonists or MAO-B inhibitors as adjunctive therapy) also showed a mean reduction of -65.6 minutes with opicapone 50 mg compared to placebo (p=0.02, vs. placebo), which supports the usefulness of opicapone 50 mg immediately after the onset of wearing-off.

[0044] Finally, there is some evidence that earlier opicapone initiation compared to later initiation may be beneficial for patients with motor symptom variability. In a combined analysis of the BIPARK double-blind and open-label trial, the reduction in off-time at the end of the open-label phase was numerically greater in patients assigned to opicapone compared to those originally assigned to placebo in the double-blind phase (114.7 minutes from baseline in the group that switched from placebo to opicapone, compared to the group that received 50 mg of opicapone throughout the double-blind and open-label treatments, with a change of -141.1 minutes)

[73] . A similar trend has been previously shown for earlier entacapone initiation (compared to a 6-month delay) using data from another pooled analysis of placebo-controlled and open-label continuation

[90] , suggesting that there may be a beneficial effect of earlier COMT inhibitor initiation compared to later initiation in patients with levodopa-related variability. Although there was a decrease of over 90% in the number of participants at that point, differences were detected from baseline to 4-5 years later, suggesting that this concept is worth further prospective research.

[0045] As mentioned above, the standard treatment approach for wearing-off is to modify the usual levodopa administration regimen by increasing each levodopa dose or by “dividing” the total daily levodopa dose into smaller, more frequent doses (Brooks DJ. Neuropsychiatr. Dis. Treat.; 4(1): 39-47; 2008). Combining all the results from numerous physiological, pharmacological, and clinical trials, once-daily opicapone may be considered a promising first-line adjunctive levodopa therapy for treating wearing-off, potentially even limiting the need to increase the amount of levodopa required for long-term continuation. A randomized, parallel-group, multicenter, international, prospective, open-label exploratory clinical trial (eArly levoDopa with Opicapone in Parkinson's patients with motOr fluctuatioNs [ADOPTION] trial; EudraCT number 2020-002754-24) is currently underway to evaluate the efficacy of opicapone 50 mg in PD patients with early wearing-off. In this trial, patients (aged 30 years or older) with idiopathic PD, receiving oral levodopa 3-4 times daily at a maximum of 600 mg, exhibiting treatable signs of motor impairment, and having experienced wearing-off for less than 2 years will be randomized (in a 1:1 ratio) to receive either opicapone 50 mg once daily or levodopa in addition to 100 mg once daily for a one-month evaluation period. The endopinion of effectiveness will be based on a patient's home diary

[91] , as well as the International Association for the Study of Movement Disorders' Unified Assessment Scale for Parkinson's Disease (MDS-UPDRS)

[92] , the International Association for the Study of Movement Disorders' Non-Motor Symptom Assessment Scale (MDS-NMS)

[93] , the Parkinson's Disease Questionnaire-8 (PDQ-8)

[94] , the physician's overall impression of improvement (CGI-I), and the patient's overall impression of change (PGI-C)

[95] .

[0046] 5. Effectiveness in stable Parkinson's disease 5.1 Theoretical basis for COMT inhibition in early "stable" disease There are two reasons to consider COMT inhibition in a stable disease state, that is, before motor complications develop. The first is to prevent or delay the onset of fluctuations in motor symptoms, and the second is to alleviate current symptoms in patients in a stable state. In this context, “stable” disease refers to the period during which a patient is enjoying the benefits of levodopa therapy without being diagnosed with motor complications. In other words, what was long called the “honeymoon” period. This is not exactly the same as the “early” disease, which is often used to refer to the first few years after diagnosis (and is often confused with it). As previously mentioned, some patients develop motor complications fairly early in the course of the disease.

[0047] While the rationale for COMT inhibition in managing fluctuations in motor symptoms is relatively easy to understand, a deeper understanding of how the basal ganglia attempt to reach equilibrium is needed to understand the rationale for preventing or delaying the onset of fluctuations in motor symptoms. At the turn of the century, there was an explosion of research to understand the effects of levodopa pharmacokinetics and the “pulsatile” delivery associated with intermittent oral administration of levodopa / DDCI. In stable conditions, the key reason for achieving more sustained drug delivery (CDD) is that it results in more sustained dopamine stimulation (CDS). Preclinical and clinical evidence for both concepts has been extensively reviewed elsewhere [21, 67, 96-98]. This concept of CDS is quite complex, but the very basic premise is that under normal physiological conditions, dopaminergic neurons originating in the substantia nigra fire continuously (independent of movement), thereby bringing extracellular dopamine in the striatum to a constant baseline concentration. This maintains a background level of sustained stimulation of striatal dopamine receptors, leading to phased dopamine release in response to behavioral activity. In a normal brain, presynaptic vesicle dopamine storage acts as a neurotransmitter reservoir, providing a natural buffer to ensure the expected steady stimulation of the striatum. With degeneration of the substantia nigra and striatum, this buffering capacity is gradually lost. In the short term, this results in abnormal patterns of striatal function, including atypical changes in dopamine-mediated glutamate release from the corticostriate. In the long term, physiological consequences include abnormal plasticity of corticostriate synapses leading to severe destabilization of striatal output, changes in downstream molecules and neurophysiological changes in the rest of the basal ganglia (including changes in long-term potential (LTP) and long-term inhibition (LTD)), and ultimately, alterations in how the basal ganglia process motor information.

[99]

[0048] Under these conditions, the way levodopa is delivered and replaces endogenous dopamine is considered important. Given its short half-life, oral administration is associated with peaks and troughs in the availability of levodopa (and consequently, exogenous dopamine). This delivery pattern does not reflect the physiologically sustained stimulation that occurs in a normal brain, causing further disruption of basal ganglia processing, ultimately manifesting as motor complications such as wearing-off and dyskinesia. We believe that by using COMT inhibitors to smooth out exogenous delivery in early disease, the deterioration of already destabilized basal ganglia processing can be avoided, thereby preventing or delaying the onset of motor complications.

[0049] 5.2 Clinical Trials of COMT Inhibition in "Stable" Patients The failure of the STRIDE (STalevo Reduction In Dyskinesia Evaluation) trial, which aimed to demonstrate the delay of dyskinesia development with early use of the levodopa / carbidopa / entacapone (STalevo) combination, initially suggested that there was no benefit to early COMT inhibition

[0100] . However, we believe that the STRIDE trial was flawed in several respects. The main flaw was that the trial was initiated based on findings in MPTP marmosets that received the drug four times a day at 3.5-hour intervals

[0101] . Pharmacokinetic studies in humans were conducted only later [67, 102, 103], and this dosing interval was shown not to cause CDD [18, 102, 103]. Furthermore, these pharmacokinetic studies showed that repeated administration of entacapone increased the Cmax value of levodopa in plasma, which likely increased the risk of developing dyskinesia. Furthermore, the use of a levodopa administration schedule that increased the dose to a maximum of 400 mg / day during the first year of treatment can also be criticized, as this deviates significantly from normal clinical practice during this period. The inventors believe that a better understanding of these pharmacokinetic parameters at this point would have led to a significantly different design of STRIDE.

[0050] In contrast, treating PD patients with 50 mg of opicapone once daily increases systemic exposure to levodopa administered every 3 and 4 hours, resulting in both a decrease in peak-trough variability in levodopa concentrations and an increase in trough levodopa concentrations

[0104] . Based on this, the inventors believe that opicapone, if initiated in the early stages of the disease, can achieve the level of CDD required to avoid dyskinesia. While the concept of CDD with opicapone can be investigated in pharmacokinetic studies, clinically achieving a reduction in dyskinesia would be extremely large-scale, requiring at least 2–4 years, and therefore unlikely to be tested in a formal STRIDE-like trial, which would be difficult to enroll subjects in and costly to conduct.

[0051] Another important question is whether COMT inhibition helps to further alleviate motor symptoms in “stable” patients (i.e., patients who are capable of complete response to levodopa treatment without developing motor complications). In the Early Tolcapone Trial, 6 months of treatment with 100 or 200 mg of tolcapone three times daily resulted in significant reductions in UPDRS Part II Activities of Daily Living (ADL, -1.4 and -1.6 points, respectively) and motor scores (-2.0 and -2.3 points, respectively) in “stable” patients. These improvements were maintained up to the 12-month assessment, and fewer patients in the tolcapone group developed fluctuations in motor symptoms during the trial than in the placebo group

[0105] . Similarly, in the FIRST-STEP Trial, a significant difference in total UPDRS score with stalevo was first observed at week 4, which was maintained throughout the entire 39-week observation period, with the greatest difference occurring at week 26

[0106] . Similar findings were implied in previous trials with entacapone alone, showing that adding a COMT inhibitor to the levodopa regimen improved scores in a subgroup of stable patients, even though levodopa dose levels were maintained for six months (in contrast to increased levodopa doses in the placebo group) [107, 108]. These trials also showed that the benefit in UPDRS scores obtained with entacapone was consistently lost when the drug was discontinued [107, 108]. However, these trials were not considered to clearly demonstrate efficacy in stable conditions and therefore could not influence product labeling or the use of COMT inhibitors in PD.

[0052] In contrast, opikapone, due to its unique profile, is considered an excellent candidate for testing its benefits in "stable" patients.

[0053] A randomized, double-blind, placebo-controlled clinical trial (Early ParkinSon with L-DOPA and OpicapoNe [EPSILON] trial; EudraCT number 2020-005011-52) was designed to evaluate the efficacy of opicapone 50 mg in patients with "stable" PD. In this trial, patients with idiopathic PD, receiving oral levodopa up to 500 mg 3-4 times daily, with signs of treatable motor impairment but without motor complications (ages 30-80 years), were randomized in a 1:1 ratio to receive opicapone 50 mg once daily for a 6-month double-blind evaluation period. Patients' current levodopa / DDCI regimens were kept constant throughout the double-blind period. The primary endpoint was the change in the MDS-UPDRS Part III (Motor) score from baseline to the end of the double-blind period, while secondary outcomes included assessment of non-motor symptoms, quality of life, and overall clinical impression of change. These data are described below. At the end of the double-blind period, patients may enter an open-label period of an additional one year of treatment with opicapone 50 mg

[0109] .

[0054] 6. Non-exercise efficacy of opicapones An aspect of efficacy that has been relatively understudied is the effect of opicapone as an adjunct to non-motor symptoms. In the BIPARK II trial, non-motor symptoms were assessed by the Non-Motor Symptom Scale (NMSS) at different time points, including baseline, the end of the double-blind phase, and the end of the open-label phase. At the end of the double-blind phase, NMSS scores improved slightly in both the opicapone and placebo groups, with no significant difference between them. At the 1-year open-label endpoint, a mean improvement of -4.2 in the NMSS total score was still maintained

[71] . It is important to emphasize that no worsening of any specific domain was observed, and there was no worsening of autonomic dysfunction, hallucinations, or cognitive impairment.

[0055] The total NMSS score is difficult to explain because it is a composite concept of non-exercise items that can be simultaneously improved or worsened by dopamine agonists. More interesting, however, is the significant signal observed in the sleep / fatigue domain, where the NMSS sleep / fatigue score decreased by -1.2 points with a 50 mg dose compared to -0.5 points with placebo (p>0.05). Similar benefits in non-exercise scores, including sleep / fatigue, were also observed in the OPTIPARK trial, where improvements of -6.8 ± 19.7 points mean ± SD for the NMSS total score and -1.3 ± 6.3 points for the sleep / fatigue score were statistically significant compared to baseline (both p<0.0001)

[80] . Moving forward, the presumed efficacy of opicapone administered before bedtime and for sleep / fatigue symptoms suggests that further research to understand which phases of sleep may be improved by opicapone is worth considering. For example, the inventors believe that optimizing the pharmacokinetic and pharmacodynamic profiles of levodopa in combination with opicapone is more likely to improve nocturnal insomnia than to improve sleep construction. The OpicApone Sleep dISorder (OASIS) trial (EudraCT number 2020-001176-15) was an open-label, single-arm pilot study designed to evaluate the effect of opicapone 50 mg in PD patients with end-of-dose motor symptom variability and a Parkinson's Disease Sleep Scale (PDSS-2) score of ≥18. The primary endpoint was the change from baseline to end of the trial in the PDSS-2 total score, with secondary criteria including the change from baseline in the Parkinson's Disease Fatigue Scale (PFS-16) and the change from baseline in domain K (sleep and wakefulness) of the Non-Motor Symptom Assessment Scale (MDS-NMS) supported by the International Association for Movement Disorders

[0110] .

[0056] Finally, pain, the most common and troublesome non-motor symptom of PD, is another non-motor symptom that is often known to be associated with motor off-states and to be dopa-responsive [111-113]. In particular, optimization of the levodopa regimen may be advantageous in treating this symptom, as levodopa (but not apomorphine) is known to normalize the pain threshold in PD patients. Clearly, any trial investigating the effect of interventions on specific non-motor symptoms must ensure that the patient population includes a large number of patients who have experienced that symptom. Therefore, in another ongoing randomized, double-blind, placebo-controlled clinical trial (OpiCapone Effect on motor fluctuations and pAiN [OCEAN] trial; EudraCT number 2020-001175-32) to evaluate the effect of opicapone 50 mg in patients with end-of-dose motor symptom fluctuations and referred pain, eligible patients must have PD (Hoehn & Yahr stages I-III during ON), be stably treated with levodopajimen, experience at least 1.5 hours of OFF per day despite optimal treatment, and also have experienced PD-related pain, defined as a King's Parkinson's Disease Pain Scale (KPPS) score of ≥12, for at least 4 weeks prior to screening. The primary efficacy criterion is the change from baseline in Domain 3 (variability-related pain) of the KPPS, while secondary efficacy criteria include anxiety and depression, as well as sleep and wakefulness within the criteria

[0114] .

[0057] 7. Conclusion Improved efficacy of levodopa by inhibiting peripheral COMT activity is an established option for treating wearing-off in late-stage PD. This has been comprehensively demonstrated in clinical evaluations of entacapone, tolcapone, and more recently, opicapone. While the importance of peripheral COMT as a limiting factor in the dangerous migration of levodopa to the brain is undisputed, we hereby provide compelling pharmacological rationale for believing that early, effective COMT inhibition will yield clinical benefits in the management of long-term disease.

[0058] Part of the reason for the current late positioning of COMT inhibitors in the PD algorithm is that DDCIs are historical in that they were developed at a time when levodopa was first introduced into treatment, with no restrictions on the disease stage in which they could be used, and no alternative options available. Other reasons relate to the drug development process and regulatory approval of symptomatic treatments for PD. Standard practice for the first investigational drugs was in a large population of late-stage patients with wearing-off, where improvement in on-time became a regulatory-approved, standardized endpoint that would then bring the product to market and generate profits. As a result, the late-arriving COMT inhibitors were relegated to the back burner for this more advanced treatment group.

[0059] Another reason is a fundamental lack of basic understanding of levodopa metabolism and the importance of the COMT pathway as a limiting factor in the drug's availability to the brain, particularly the short-circuiting of levodopa metabolism into the COMT pathway when used with DDCI. This is likely because levodopa has been in circulation for over 60 years, and its effectiveness has not been questioned, so physicians have had little reason to care about how levodopa works and how its peripheral metabolism affects clinical outcomes.

[0060] Due to limitations imposed by previous generations of COMT inhibitors, it was not previously believed that COMT inhibitors could be used in all stages of Parkinson's disease (PD). The descriptions of the FIRST-STEP and STRIDE-PD trials above demonstrate why the short duration of action of entacapone was a significant limitation in its early use. In contrast, we believe there is now potential for expanding the use of COMT inhibitors, which should be thoroughly explored, based on once-daily opicapone administration, its long-lasting effect, and the clinical efficacy demonstrated by traditional late-stage application. Based on an analysis of the underlying science of opicapone and its relevance to levodopa metabolism, we proposed early use. As will be further detailed below, this hypothesis is supported by appropriate clinical evaluations in early patient populations, accompanied by outcome measurements demonstrating that opicapone improves motor function, delays the onset of motor complications, and treats some non-motor symptoms of PD. [Brief explanation of the drawing]

[0061] The present invention will be described in detail below with reference to the attached drawings. [Figure 1] Figure 1 shows the primary endpoint at the end of the double-blind phase. The change in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III total score from double-blind baseline to the end of the double-blind period was compared to placebo. Figure 1 shows a 2.2-point reduction due to symptoms (p=0.010). [Figure 2] Figure 2 shows longitudinal data confirming that the effect size of the total score on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III increased over time compared to placebo. DB = double-blind; LS = least squares; SE = standard error; p = p-value; * = statistically significant. [Figure 3a]Figure 3 shows the change in the MDS-UPDRS Part II+III total score from double-blind baseline to the end of the double-blind period compared to placebo. Figure 3a shows a 2.8-point reduction in symptoms (p=0.036). Figure 3b shows longitudinal data confirming that the magnitude of the effect increased over time compared to placebo. DB=double-blind; LS=least squares; SE=standard error; p=p-value; *=statistically significant. [Figure 3b] Figure 3 shows the change in the MDS-UPDRS Part II+III total score from double-blind baseline to the end of the double-blind period compared to placebo. Figure 3a shows a 2.8-point reduction in symptoms (p=0.036). Figure 3b shows longitudinal data confirming that the magnitude of the effect increased over time compared to placebo. DB=double-blind; LS=least squares; SE=standard error; p=p-value; *=statistically significant. [Figure 4a] Figure 4 shows the proportion of opicapone-treated patients who showed improved clinical status compared to patients who received placebo. Figure 4a shows the proportion of opicapone-treated patients who reported improved clinical status (PGI-I score) compared to patients who received placebo (p=0.026). Figure 4b shows the proportion of opicapone-treated patients who showed improved clinical status (CGI-I score) as assessed by clinicians compared to patients who received placebo (p=0.493). [Figure 4b] Figure 4 shows the proportion of opicapone-treated patients who showed improved clinical status compared to patients who received placebo. Figure 4a shows the proportion of opicapone-treated patients who reported improved clinical status (PGI-I score) compared to patients who received placebo (p=0.026). Figure 4b shows the proportion of opicapone-treated patients who showed improved clinical status (CGI-I score) as assessed by clinicians compared to patients who received placebo (p=0.493). [Figure 5] Figure 5 shows the improvement in PDSS-2 compared to placebo-treated patients (p=0.039), with no deterioration observed in the opicapone-treated group. DB = double-blind; LS = least squares; SE = standard error; p = p-value. [Figure 6a]Figure 6 shows the improvement in the MDS-UPDRS Part II total score (p=0.120) compared to placebo-treated patients, with no deterioration observed in the opicapone treatment group. Figure 6a shows a positive trend toward treatment effect in the MDS-UPDRS Part II total score. Figure 6b shows the magnitude of the difference increasing over time. DB = double-blind; LS = least squares; SE = standard error; p = p-value. [Figure 6b] Figure 6 shows the improvement in the MDS-UPDRS Part II total score (p=0.120) compared to placebo-treated patients, with no deterioration observed in the opicapone treatment group. Figure 6a shows a positive trend toward treatment effect in the MDS-UPDRS Part II total score. Figure 6b shows the magnitude of the difference increasing over time. DB = double-blind; LS = least squares; SE = standard error; p = p-value. [Figure 7] Figure 7 shows that a positive trend toward treatment efficacy was also observed in NMSS (p=0.102). DB = double-blind; LS = least squares; SE = standard error; p = p-value. [Figure 8] Figure 8 shows that the proportion of patients who reported motor complications (5.5%) was lower among those who received opicapone treatment compared to those who received placebo treatment (9.8%). [Figure 9] Figure 9 shows the design of the clinical trial, including the timeline and appropriate follow-up dates. EOS = End of trial follow-up; DDCI = DOPA decarboxylase inhibitor; L-DOPA = Levodopa; PSV = Post-trial follow-up; QD = Once daily. [Figure 10] Figure 10 shows the distribution of patients during the clinical trial, including the randomization of 355 subjects. 322 subjects completed the double-blind phase. OPC = opicapones; FAS = complete analysis set; PP = per protocol. Detailed description of the invention

[0062] A.Definition The following definitions apply to terms used throughout this specification unless otherwise specified in particular.

[0063] The term "idiopathic Parkinson's disease" encompasses most (80-85%) cases of Parkinson's disease (diagnosed according to either the clinical diagnostic criteria of the Parkinson's Society Brain Bank or the criteria of the International Society for Movement Disorders), while excluding atypical parkinsonism, secondary [acquired or symptomatic] parkinsonism, and parkinson's plus syndromes, such as drug-induced parkinsonism, vascular parkinsonism, normal pressure hydrocephalus, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. Typically, it includes marked bradykinesia and variable accompanying extrapyramidal signs and symptoms. It typically involves degeneration of the substantia nigra-striatal dopaminergic system, with neuronal defects and reactive gliosis in the substantia nigra found by autopsy. In idiopathic Parkinson's disease, α-synuclein typically accumulates in the perinuclear regions (Lewy bodies) and neurites (Lewy processes) of neurons.

[0064] The term “early idiopathic Parkinson’s disease” or “early Parkinson’s disease” refers to the early stages of the disease, where a diagnosis of idiopathic Parkinson’s disease is possible based on overt symptoms (according to either the clinical diagnostic criteria of the Parkinson’s Disease Society Brain Bank or the criteria of the International Association for Movement Disorders), but complete response to treatment is possible without the development of motor complications, such as fluctuations in motor symptoms and / or dyskinesia. In particular, this group of Parkinson’s disease patients are treatable with levodopa and DDCI formulations (i.e., their symptoms are manageable). As described below, this patient population exhibits low total scores on the MDS-UPDRS Part IV A+B+C (e.g., 0) and / or a small number of positive symptoms on the 9-item Wearing-Off Questionnaire (WOQ-9) (e.g., less than 2, preferably 0).

[0065] The term “symptoms of Parkinson’s disease” includes both motor symptoms (e.g., tremor, rigidity, bradykinesia, and postural instability) and non-motor symptoms (e.g., cognitive changes, gastrointestinal symptoms, loss of vision and / or smell, pain, fatigue, dizziness, sexual problems, sleep disturbances, and weight loss). Such symptoms can be assessed using one or more of the following symptomatic readings.

[0066] The term "motor complications" refers to Parkinson's disease symptoms associated with levodopa therapy. Motor complications occur when levodopa / DDCI therapy alone can no longer fully control the patient's symptoms. Motor complications include fluctuations in motor symptoms and / or dyskinesia. Motor complications are persistent, but not necessarily typical or predictable, to quantitatively and negatively impact the patient's quality of life (QoL). "Clinically diagnosed motor complications" generally result in a total score of greater than 6, preferably greater than 3, more preferably greater than 0, and / or one or more positive symptoms on the 9-item Wearing-Off Questionnaire (WOQ-9). A total score of greater than 0 (zero) on the MDS-UPDRS Part IV A+B+C is the most preferred definition of clinically diagnosed motor complications. It should be noted that motor complications may be the same as the motor symptoms of Parkinson's disease. However, while the condition can initially be treated with levodopa / DDCI therapy, motor symptoms that reappear in the later stages of the disease despite continued levodopa / DDCI therapy are considered motor complications at that point.

[0067] The term "motor symptom fluctuations" includes end-of-dose fluctuations (also known as the wearing-off phenomenon), paradoxical fluctuations, and unpredictable on / off periods.

[0068] The term "off period" or "off episode" is defined as a period during which a patient receiving levodopa treatment no longer receives symptomatic benefits and is said to be in an "off" state. In contrast, when a patient receiving levodopa treatment is receiving symptomatic benefits, that patient is said to be in an "on" state.

[0069] The term “end-of-dose motor symptom fluctuations” (also known as the “wearing-off” phenomenon) refers to the predictable recurrence or worsening of symptoms before the next dose of levodopa / DDCI therapy. Typically, such recurrence or worsening of symptoms begins 3–4 hours after levodopa administration as the drug is worn off. The symptoms then typically improve 15–45 minutes after the next levodopa dose is administered.

[0070] The term "dyskinesia" or "levodopa-induced dyskinesia" includes peak-dose dyskinesia, biphasic dyskinesia, and off-dyskinesia. Common symptoms include chorea and dystonia. Less common symptoms include akathisia (excessive restlessness), high-stepped, exaggerated gait, rapid leg movements (RAM), blepharospasm, and mixed patterns of abnormal movements (Fahn S., Ann. Neurol., 2000, 47, S2-S9).

[0071] Adjuvant therapy (also known as adjuvant treatment, add-on therapy, or adjuvant care) is a therapy administered in addition to primary or initial therapy to maximize efficacy. In this application, levodopa is primary therapy, and DCCI and COMT inhibitors (i.e., opicapone) are adjuvant therapy.

[0072] The term "treatment-induced adverse event" is defined as any event that did not exist before exposure to the investigational drug, or any pre-existing event that worsened in either intensity or frequency between the first dose of the investigational drug and two weeks after the last dose.

[0073] Other variations of the disclosed embodiments can be understood and implemented in the practice of the claimed invention by considering the present disclosure and the attached claims. In the claims, the term “comprising” does not exclude other elements or steps, and the indefinite articles “a” or “an” do not exclude the plural. The fact that certain criteria are described in different dependent claims does not mean that a combination of those criteria cannot be used for benefit.

[0074] Treatment of Early Parkinson's Disease with BL-DOPA / DDCI and Opicapone The present invention provides opicapone for use as an adjunct therapy to levodopa and DDCI formulations in the treatment of early Parkinson's disease, characterized in that patients with early Parkinson's disease are treatable with formulations of levodopa and DOPA decarboxylase inhibitors (DDCI) and do not have clinically diagnosed motor complications (any variation of any kind of motor symptom and / or dyskinesia).

[0075] The present invention also provides the use of opicapone in the manufacture of a pharmaceutical product for use as an adjunct therapy to levodopa and DDCI formulations in the treatment of early Parkinson's disease, characterized in that patients with early Parkinson's disease are treatable with levodopa and DDCI formulations and do not have clinically diagnosed motor complications (any variation of any kind of motor symptom and / or dyskinesia).

[0076] The present invention also provides a method for treating early Parkinson's disease, comprising administering opicapone to patients who require it as an adjunct therapy to levodopa and DDCI formulations, characterized in that patients with early Parkinson's disease are treatable with levodopa and DDCI formulations and do not have clinically diagnosed motor complications (any variation of any type of motor symptom and / or dyskinesia).

[0077] Symptoms and their treatment An important aspect of the present invention is to improve the treatment of symptoms specific to early Parkinson's disease in patients without motor complications, where these symptoms can be treated with formulations of levodopa and DDCI. However, it is important to note that certain problems can manifest as both symptoms of early Parkinson's disease and motor complications in later stages. For example, perhaps the most typical problem in Parkinson's disease is tremor.

[0078] Tremor is a common symptom of early Parkinson's disease and may initially be completely treatable with levodopa / DDCI treatment. In this case, the tremor is not a symptom that can be improved by the adjunctive opicapone therapy of the present invention (because it is already completely treated with levodopa / DDCI treatment). Alternatively, the tremor may initially be only partially treatable with levodopa / DDCI treatment. In this case, the tremor is a symptom that can be improved by the adjunctive opicapone therapy of the present invention. Importantly, the presence of this type of tremor does not mean that the patient has a motor comorbidity (as defined herein). In summary, the symptoms treatable by the adjunctive opicapone therapy of the present invention are those present during early Parkinson's disease but which are not completely treatable with levodopa / DDCI treatment.

[0079] Tremors may also be motor complications and may appear or develop later in the disease, for example, as fluctuations in end-of-dose motor symptoms. In this case, the presence of tremors may lead to a clinical diagnosis of motor complications (as defined herein).

[0080] Methods for distinguishing between the symptoms of early Parkinson's disease (which are present to some extent throughout the entire period of effective levodopa / DDCI treatment) and motor complications (which appear or develop after long-term levodopa / DDCI treatment) are known to those skilled in the art and will be described in further detail below.

[0081] The use of opicapone as an adjunct therapy to levodopa and DDCI formulations in the treatment of early Parkinson's disease results in improvement in one or more symptoms in patients. In a preferred embodiment, opicapone treatment results in improvement in one or more symptoms in a patient compared to the symptoms shown by a patient treated for the same period with levodopa and DDCI formulations without opicapone. This means that the rate of deterioration in the patient decreases, stops, or reverses. In a more preferred embodiment, the use of opicapone results in improvement in one or more symptoms in a patient compared to the same patient before initiating opicapone treatment. This means that the rate of deterioration in the patient reverses. In an even more preferred embodiment, opicapone results in rapid improvement (e.g., 24 weeks after initiation of treatment, preferably 12 weeks, more preferably 4 weeks, and most preferably 2 weeks) in one or more symptoms in a patient compared to the same patient before initiating opicapone treatment.

[0082] In the exemplary trials described below, the primary endpoint at the end of the double-blind phase was the change from double-blind baseline to the end of the double-blind period in the International Association for the Uniform Assessment Scale for Parkinson's Disease (MDS-UPDRS) Part III total score, compared to placebo. The results, shown in Figure 1, show a 2.2-point reduction in symptoms. Thus, in a preferred embodiment, the use of opicapone according to the present invention results in an improvement in the patient's score on one or more criteria from the MDS-UPDRS Part III (Motor Symptom Survey) compared to the score obtained by patients treated for the same period without opicapone, or compared to the score of the same patients before initiating opicapone treatment. Furthermore, in a very preferred embodiment, the use of opicapone according to the present invention results in an improvement in the MDS-UPDRS Part III (Motor Symptom Survey) total score of patients treated according to the present invention. In a particularly very preferred embodiment, the use of opicapone according to the present invention results in an improvement in the MDS-UPDRS Part III (Motor Symptom Survey) total score of patients treated according to the present invention compared to the score of the same patients before initiating opicapone treatment. Figure 2 shows that longitudinal data confirmed that the effect was present from the earliest point in time and increased over time compared to placebo. This improvement was evaluated by comparing the patient's score before initiating opicapone treatment (baseline) with the patient's score when the effect of opicapone stabilized (e.g., 24 weeks after initiation of treatment, preferably 12 weeks, more preferably 4 weeks, and most preferably 2 weeks).

[0083] The MDS-UPDRS Part III (Motor Symptom Survey) total score assesses the number of symptoms, and therefore, within the scope of the preferred embodiments of the preceding paragraphs, the use of opicapone according to the present invention results in improvements in the scores of one or more criteria selected from the group consisting of speech; facial expressions; rigidity; finger tapping; hand movements; hand pronation and supination; toe tapping; lower limb agility; standing up from a chair; walking; freezing of gait; postural stability; posture; bradykinesia; postural tremor of the hand; motor tremor of the hand; amplitude of resting tremor; and persistence of resting tremor, in patients treated according to the present invention, compared to the scores obtained by patients who received placebo, and preferably compared to the scores of the same patients before initiating opicapone treatment.

[0084] Other methods for evaluating improvement in the symptomatic treatment of early Parkinson's disease are known to those skilled in the art and will be described in Section D below.

[0085] In the exemplary trial described below, secondary endpoints assessed throughout the entire double-blind phase included: (i) MDS-UPDRS scores: Parts II, II, III, and IV, as well as the total for Part II+III; (ii) Modified Hoehn & Yahr Severity Total Score during the peak "on" response; (iii) Schwab & England Scale Score; (iv) Parkinson's Disease Sleep Scale II (PDSS-2) Total Score; (v) International Society for Movement Disorders Non-Motor Symptom Scale (MDS-NMSS) Total Score and Subdomain Score; (vi) Parkinson's Disease Questionnaire (PDQ-39) Total Score and Subdomain Score; and (vii) Wearing-Off Questionnaire (WOQ-9) Total and Subsection (Motor and Non-Motor) Scores. This trial also assessed physician's overall impression (CGI-I) and / or patient's overall impression (PGI-I) of improvement. Evaluation in the open-label phase is ongoing.

[0086] Therefore, opicapone therapy of the present invention, compared to the scores of the same patient before initiating opicapone therapy, shows that in the patient: (i) MDS-UPDRS Part I total score, in particular, one or more groups selected from cognitive impairment; hallucinations and psychosis; depressed mood; anxious mood; apathy; features of dopamine dysregulation syndrome; sleep problems; daytime sleepiness; pain and other sensations; urinary problems; constipation problems; dizziness upon standing; or fatigue; (ii) MDS-UPDRS Part II total score, in particular, speech; saliva and drooling; chewing and swallowing; (iii) Improvement in one or more of the following: feeding tasks; dressing; hygiene; writing by hand; engaging in hobbies and other activities; turning over in bed; tremors; getting out of bed, in a car, or out of bed; walking and balance; or freezing of breath; (iv) modified Hoehn & Yahr severity total score during major “on” responses; (v) Schwab & England scale score; (vi) PDSS-2 total score; (vii) MDS-NMSS total score and subdomain scores; (viii) PDQ-39 total score and subdomain scores; (ix) CGI-I score; and (x) PGI-I score.

[0087] In particular, the results shown in Figure 3 indicate a 2.8-point reduction in the total score of MDS-UPDRS Part II + III (p=0.036).

[0088] Furthermore, the results shown in Figure 4a indicate that the proportion of opicapone-treated patients reporting improvement in their clinical status (PGI-I score) was significantly higher, with 57.9% showing improvement compared to 45.6% in placebo-treated patients (p=0.026). A similar trend was observed in Figure 4b, where 50.3% of opicapone-treated patients showed improvement when their clinical status (CGI-I score) was assessed by clinicians, compared to 46.2% in placebo-treated patients.

[0089] Furthermore, the results shown in Figure 5 demonstrate a significant improvement compared to patients receiving placebo on PDSS-2 (p=0.039), and no deterioration was observed in the opicapone treatment group.

[0090] The MDS-UPDRS Part II total score (Figure 6a) showed a positive trend toward treatment effectiveness, and the magnitude of this difference increased over time (Figure 6b). This suggests that statistical significance for other symptoms may be obtained with larger group sizes or longer treatment durations.

[0091] Positive trends in treatment efficacy were also observed in the NMSS (Figure 7). Similar results were observed in the total scores of subdomains of the NMSS scale, excluding domain 7 (urine). In particular, significant improvement in the urinary subdomain was observed in the opicapone treatment group compared to the placebo group at weeks 12 and 24 (p<0.05).

[0092] No significant effect was observed in the total scores of MDS-UPDRS Part I, MDS-UPDRS Part IV, or PDQ-39. However, the magnitude of change in both groups (opicapone and placebo) was less than 0.4 points for these symptoms. Therefore, a longer treatment period or longer trial is needed to observe a significant effect for these symptoms.

[0093] In summary, this data shows statistically significant improvements in the primary endpoint and several secondary endpoints, and also shows a trend towards significance in other secondary endpoints where the effect was large enough to be observed.

[0094] Therefore, this data supports the usefulness of opicapone as an adjunct therapy to levodopa and DDCI formulations for the (motor) signs and symptoms of Parkinson's disease, characterized by the fact that patients with Parkinson's disease are treatable with levodopa and DDCI formulations without clinically diagnosed motor complications.

[0095] Alternatively, this data supports the usefulness of opicapone as an adjunct therapy to levodopa and DDCI formulations in the treatment of Parkinson's disease and patients with poorly controlled (motor) signs and symptoms, characterized by the fact that patients with Parkinson's disease can be treated with levodopa and DDCI formulations without clinically diagnosed motor complications.

[0096] Furthermore, this data, coupled with the fact that opicapone is already known to treat Parkinson's disease patients who have experienced “end-of-dose motor fluctuations” (European label) or “off-phenomenon” (US label), supports the usefulness of opicapone in the treatment of Parkinson's disease that does not require evaluation or diagnosis of end-of-dose motor fluctuations. Therefore, patients only need to be diagnosed by standard clinical diagnoses of bradykinesia and at least one of the following: resting tremor, muscle rigidity, or postural reflex impairment (core symptoms). Moreover, this data supports the use of opicapone in combination with levodopa in the treatment of symptoms and signs of Parkinson's disease during the course of the disease (when the effects of levodopa become negligible or inconsistent, and when there are fluctuations in treatment response (“end-of-dose” or “on-off” type fluctuations)).

[0097] In one alternative embodiment, the use of opicapone according to the present invention results in an improvement in a patient's score on one or more criteria from MDS-UPDRS Part I (non-motor aspects of daily living) compared to a score obtained by a patient treated for the same period without opicapone, or compared to the score of the same patient before initiating opicapone treatment. More preferably, the use of opicapone according to the present invention results in an improvement in a patient's MDS-UPDRS Part I total score compared to a score obtained by a patient who received a placebo, and preferably compared to the score of the same patient before initiating opicapone treatment. In preferred examples of these embodiments, the use of opicapone results in an improvement in a patient treated according to the present invention on one or more criteria selected from the group consisting of cognitive impairment; hallucinations; psychosis; depressed mood; anxious mood; apathy; features of dopamine dysregulation syndrome; sleep problems; daytime sleepiness; pain; urinary problems; constipation problems; orthostatic dizziness; and fatigue, compared to a score obtained by a patient who received a placebo, and preferably compared to the score of the same patient before initiating opicapone treatment.

[0098] In a second alternative embodiment, the use of opicapone according to the present invention results in an improvement in the patient's score on one or more criteria from MDS-UPDRS Part II (aspects of motor symptoms experienced in daily life) compared to the score obtained by a patient treated for the same period without opicapone, or compared to the score of the same patient before initiating opicapone treatment. More preferably, the use of opicapone according to the present invention results in an improvement in the patient's MDS-UPDRS Part II total score compared to the score obtained by a patient administered a placebo, and preferably compared to the score of the same patient before initiating opicapone treatment. In preferred examples of these embodiments, opicapone results in patients treated according to the Invention improving in one or more criteria selected from the group consisting of speech; saliva; drooling; chewing; swallowing; eating tasks; dressing; hygiene; writing by hand; engaging in hobbies; turning over in bed; tremors; getting out of bed, in a car, or out of bed; walking; balance; and freezing of breath, compared to scores obtained by patients who received a placebo, and preferably compared to scores obtained by the same patients before initiating opicapone treatment.

[0099] In a third preferred embodiment, the use of opicapone according to the present invention results in an improvement in the modified Hoehn & Yahr severity total score in patients treated according to the invention, compared to the score obtained by patients who received a placebo, and preferably compared to the score of the same patients before initiating opicapone treatment.

[0100] In a fourth preferred embodiment, the use of opicapone according to the present invention results in an improvement in the Schwab & England scale score in patients treated according to the invention, compared to the score obtained by patients who received a placebo, and preferably compared to the score of the same patients before initiating opicapone treatment.

[0101] In a fifth preferred embodiment, the use of opicapone according to the present invention results in an improvement in the PDSS-2 total score in patients treated according to the invention, compared to the score obtained by patients who received a placebo, and preferably compared to the score of the same patients before initiating opicapone treatment.

[0102] In a sixth preferred embodiment, the use of opicapone according to the present invention results in improvements in MDS-NMSS total score and subdomain scores in patients treated according to the invention, compared to scores obtained by patients who received a placebo, and preferably compared to scores of the same patients before initiating opicapone treatment. In a preferred example of this embodiment, opicapone results in improvements in one or more subdomains selected from the group consisting of cardiovascular; sleep; fatigue; mood; cognition; perceptual disturbances; attention; memory; digestive; urinary tract; and sexual function in patients treated according to the invention, compared to scores obtained by patients who received a placebo, and preferably compared to scores of the same patients before initiating opicapone treatment.

[0103] In a seventh preferred embodiment, the use of opicapone according to the present invention results in improvements in PDQ-39 total scores and subdomain scores in patients treated according to the invention, compared to scores obtained by patients who received a placebo, and preferably compared to scores of the same patients before initiating opicapone treatment. In a preferred example of this embodiment, opicapone results in improvements in one or more subdomains selected from the group consisting of mobility; activities of daily living (ADL); emotions; stigma; social support; cognition; communication; and physical discomfort in patients treated according to the invention, compared to scores obtained by patients who received a placebo, and preferably compared to scores of the same patients before initiating opicapone treatment.

[0104] In an eighth preferred embodiment, the use of opicapone according to the present invention results in an improvement in the CGI-I score in patients treated according to the invention, compared to the score obtained by patients who received a placebo, and preferably compared to the score of the same patients before initiating opicapone treatment.

[0105] In a ninth preferred embodiment, the use of opicapone according to the present invention results in an improvement in the PGI-I score in patients treated according to the invention, compared to the score obtained by patients who received a placebo, and preferably compared to the score of the same patients before initiating opicapone treatment.

[0106] Improvement is generally assessed by comparing the patient's score before initiating opicapone treatment (baseline) with the score at the end of the double-blind and / or open-label period. However, in trials, symptoms are assessed at numerous points (visits) throughout the trial period, so improvement is assessed as it occurs when the effect of opicapone stabilizes. For example, improvement may be assessed 24 weeks, preferably 12 weeks, more preferably 4 weeks, and most preferably 2 weeks after the start of treatment.

[0107] Because the period between the initial and final evaluations is short, symptomatic treatment can be distinguished from any observed or possible disease-modifying effects.

[0108] Prevention of motor complications and their occurrence Although the patient population selected for treatment according to the present invention did not experience motor complications, the occurrence of motor complications was evaluated throughout the double-blind period in an exemplary trial. Evaluation during the open-label period is ongoing.

[0109] As shown in Figure 8, patients treated with opicapone had a lower rate of reporting motor complications (5.5%) compared to patients treated with placebo (9.8%). Therefore, in a very preferred embodiment, the treatment according to the present invention suppresses the occurrence of one or more motor complications during opicapone treatment, even while continuing levodopa / DDCI therapy.

[0110] The occurrence of one or more motor complications during treatment according to the present invention was evaluated using the method for evaluating motor complications described in Section D below.

[0111] In particular, in this highly preferred embodiment, the suppression of the occurrence of motor complications during treatment according to the present invention results in one or more of the following: the number of positive symptoms in WOQ-9 that improve after the next administration of levodopa is maintained at 2 or less, preferably 1 or 0, more preferably 0; and / or the average daily off time is maintained at less than 1.5 hours, preferably less than 1.0 hour, more preferably less than 0.5 hours, most preferably 0 hours.

[0112] In the following trials, the primary endpoint at the end of the open-label phase will be the change in the MDS-UPDRS Part IV (Motor Complications) total score from the open-label baseline to the end of the open-label period. Thus, in a very preferred embodiment, opicapone therapy of the present invention results in a reduction in the increase in the patient's MDS-UPDRS Part IV total score compared to the increase observed when opicapone therapy is not administered over the same period. In this very preferred embodiment, opicapone therapy reduces the patient's MDS-UPDRS Part IV total score by 80% or less, preferably 60% or less, more preferably 40% or less, even more preferably 20% or less, and most preferably 10% or less, compared to the total score observed when opicapone therapy is not administered over the same period.

[0113] Stability of levodopa / DDCI therapy During sustained levodopa / DDCI therapy, patients may require dose increases of levodopa, for example, from 100 mg levodopa three times daily (300 mg daily dose) to 100 mg levodopa four times daily (400 mg daily dose). Therefore, in a very preferred embodiment, the treatment according to the present invention enables patients to maintain a stable daily dose of levodopa / DDCI therapy for a period of at least 3 months, preferably at least 24 weeks, and more preferably at least 1 year. More preferably, the treatment according to the present invention enables patients to maintain a stable frequency of administration of levodopa / DDCI therapy (e.g., more frequent, lower doses of levodopa / DDCI therapy throughout the day) for a period of at least 3 months, preferably at least 24 weeks, and more preferably at least 1 year.

[0114] In a more preferred embodiment, the treatment according to the present invention allows a patient to reduce the daily dose of L-DOPA / DDCI by widening the dosing interval and / or reducing the amount of L-DOPA / DDCI per dose. For example, a patient can reduce the number of daily doses of levodopa / DDCI to once per day, preferably twice per day, or more preferably three times per day. For example, the dose can be reduced from four doses of 100 mg levodopa per day (daily dose of 400 mg) to three doses of 100 mg levodopa per day (daily dose of 300 mg), and preferably from five doses of 100 mg levodopa per day (daily dose of 500 mg) to three doses of 100 mg levodopa per day (daily dose of 300 mg).

[0115] Patient group Treatment of early Parkinson's disease with levodopa / DDCI and opicapone is preferably for humans, more preferably for adults, and even more preferably for adults aged at least 30 years, preferably at least 50 years, and more preferably at least 65 years.

[0116] Patients with Parkinson's disease preferably have idiopathic Parkinson's disease. As this data shows, opicapone can treat patients with end-of-dose motor fluctuations and those who have not yet experienced motor fluctuations, so patients only need to be diagnosed by a standard clinical diagnosis of bradykinesia and at least one of the following: resting tremor, muscle rigidity, or postural reflex impairment (core symptoms). In another embodiment, patients with Parkinson's disease have poor control of (motor) signs and symptoms despite receiving levodopa / DDCI treatment.

[0117] The use of opicapone in addition to levodopa / DDCI further improves the treatment of one or more of the above-mentioned symptoms of idiopathic Parkinson's disease that are already partially treated in patients when levodopa / DDCI therapy is initiated.

[0118] Patients with early idiopathic Parkinson's disease do not have motor complications. Methods for assessing the presence or absence of motor complications are known to those skilled in the art. Section D below describes methods for assessing symptoms in Parkinson's disease, including methods for assessing motor complications.

[0119] The most widely used clinical scale for assessing the clinical status of patients with Parkinson's disease is the Unified Parkinson's Disease Rating Scale (UPDRS) (Fahn S, Elton RL, UPDRS Program Members. Unified Parkinson's disease rating scale. In Recent Developments in Parkinson's Disease, Vol. 2, eds Fahn S, Marsden CD, Goldstein M. Florham Park, NJ, USA: Macmillan Healthcare Information, 1987:153-63, 293-304). The primary criterion for determining whether a patient has early idiopathic Parkinson's disease is based on a total score of less than 6, preferably less than 3, and especially 0 (zero) on the MDS-UPDRS Part IV A+B+C. The MDS-UPDRS Part IV specifically assesses motor complications of treatment.

[0120] Therefore, in the most preferred embodiment of the present invention, the total MDS-UPDRS Part IV A+B+C score shown by a Parkinson's disease patient who is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications is 0 when treated with the levodopa and DDCI formulation.

[0121] In an alternative preferred embodiment, the number of positive WOQ-9 symptoms that improve after the next administration of levodopa in patients who are treatable with a levodopa and DDCI formulation and who do not have clinically diagnosed motor complications is 2 or less, preferably 1 or less, and more preferably 0.

[0122] In a more preferred embodiment of the above, motor complications absent in patients with Parkinson's disease who are treatable with a levodopa and DDCI formulation and who do not have clinically diagnosed motor complications are selected from the group consisting of tremor, mood swings, slowness of movement, decreased dexterity, rigidity, anxiety / panic attacks, drowsy thinking / slow thinking, muscle spasms, and pain / tingling. These are the motor complications listed in WOQ-9. More preferably, motor complications absent in patients with Parkinson's disease who are treatable with a levodopa and DDCI formulation and who do not have clinically diagnosed motor complications are selected from the group consisting of tremor, anxiety / panic attacks, and slowness of movement. These particular symptoms are best suited to supplement patients with motor complications, such as end-of-dose fluctuations in motor symptoms (Stacy M. and Hauser R., J. Neural. Transm. 2007, 114, 211-217).

[0123] In another alternative preferred embodiment, the motor complications are selected from a group consisting of fluctuations in motor symptoms and / or dyskinesia, which are examined by a skilled clinician.

[0124] Generally, patients with early idiopathic Parkinson's disease are likely to have received treatment for Parkinson's disease for a shorter period than patients who have passed the early stage of the disease. In a preferred embodiment, the patient has initiated treatment with levodopa within the past five years, preferably within the past one to three years, more preferably within the past one year, and even more preferably within the past six months, and most preferably, the patient has not previously received treatment with levodopa.

[0125] Generally, patients with early idiopathic Parkinson's disease will have a lower modified Hoehn & Yahr stage compared to patients who have passed the early stage of Parkinson's disease. In a preferred embodiment, prior to treatment with opicapone, in the on state, the patient's modified Hoehn & Yahr stage is 1 to 3, preferably 1.0 to 2.5, more preferably 1.0 to 2.0.

[0126] Generally, patients with early idiopathic Parkinson's disease receive a lower daily dose of levodopa than patients who have passed the early stage of Parkinson's disease. In a preferred embodiment, patients receive 600 mg or less per day, preferably 500 mg or less per day, more preferably 400 mg or less per day, even more preferably 300 mg or less per day, and most preferably less than 300 mg per day of levodopa.

[0127] Generally, patients with early idiopathic Parkinson's disease receive fewer doses of levodopa per day than patients who have passed the early stage of Parkinson's disease. In a preferred embodiment, the patient receives levodopa six times or less per day, preferably five times or less, more preferably four times or less, and even more preferably three times or less.

[0128] In a particularly preferred embodiment, a patient with early idiopathic Parkinson's disease has been treated with levodopa / DDCI (e.g., controlled-release, immediate-release, or controlled-immediate-release combined) for at least one year, and has been treated with a stable regimen of 300-500 mg per day, 3-4 times per day, for at least four weeks prior to initiating opicapone.

[0129] Generally, patients with early idiopathic Parkinson's disease are unlikely to have previously received treatment with COMT inhibitors. In a preferred embodiment, the patient is not currently receiving treatment with COMT inhibitors, and preferably, the patient has never received treatment with COMT inhibitors.

[0130] Generally, patients with early idiopathic Parkinson's disease who are receiving treatment with levodopa will receive immediate-release levodopa, as controlled-release levodopa does not offer any additional benefit compared to immediate-release levodopa. In a preferred embodiment, the patient is not currently receiving treatment with controlled-release levodopa, and more preferably, the patient has never received treatment with controlled-release levodopa.

[0131] Patients with very early-stage idiopathic Parkinson's disease may have never received any treatment for Parkinson's disease using pharmaceutical interventions. In a preferred embodiment, the patient has never received any treatment for Parkinson's disease.

[0132] Opicapone dosage and regimen Opicapone is a long-acting COMT inhibitor compared to other known COMT inhibitors. In preferred embodiments, opicapone is administered once daily or once weekly, preferably once daily.

[0133] Opicapone is effective with low toxicity and exhibits good pharmacodynamic properties at relatively low doses. In preferred embodiments, the unit dose of opicapone is 5 to 100 mg, preferably 25 to 75 mg, more preferably 25 or 50 mg, and most preferably 50 mg.

[0134] Opicapone may interact with food. In a preferred embodiment, opicapone is administered at least one hour before or after a meal.

[0135] Opicapone may interact with levodopa. In a preferred embodiment, opicapone is administered at least one hour before or after the administration of levodopa.

[0136] In a more preferred embodiment, opicapone is administered before bedtime, or close to bedtime, for example, less than one hour before bedtime, or even less than 30 minutes before bedtime.

[0137] Opicapone demonstrated good tolerability and a low incidence of adverse events (AEs), including treatment-induced adverse events. In fact, opicapone was well-tolerated in patients without clinically diagnosed motor complications and showed a better safety profile compared to previous studies in patients with clinically diagnosed motor complications. Patients treated with opicapone did not experience an increase in treatment-related adverse events, including neurological disorders such as dyskinesia.

[0138] In a preferred embodiment, the treatment lasts for at least 24 weeks, preferably at least 1 year.

[0139] In a preferred embodiment related to the above-described embodiment, administration of opicapone results in improvement in one or more of the above-described symptomatic readout information without inducing one or more of the above-described motor complications.

[0140] In another preferred embodiment related to the embodiments described above, administration of opicapone results in improvement in one or more of the symptomatic readout information without inducing one or more of the adverse events that occur as a result of the above treatment.

[0141] The embodiments described above and preferred embodiments also apply equally to the use of opicapone in the manufacture of the pharmaceutical product described first in Section B, and to methods for treating the symptoms of Parkinson's disease.

[0142] C. Clinical Protocols Clinical trial design The applicant conducted a Phase III trial to evaluate the efficacy and safety of opicapone (50 mg) in patients with early idiopathic Parkinson's disease who were receiving treatment with levodopa / DDCI and who did not have any signs of motor complications (e.g., variability in motor response and / or involuntary movements and / or dyskinesia).

[0143] Participants had to be between 30 and 80 years of age (including 30 and 80 years), have been diagnosed with early idiopathic Parkinson's disease within the past 5 years according to the clinical diagnostic criteria of the Parkinson's Disease Society Brain Bank, have a disease severity of stage 1 to 2.5 (modified Hoehn & Yahr), and have an MDS-UPDRS Part III score of ≥20. Alternatively, participants had to be diagnosed with early idiopathic Parkinson's disease within the past 5 years according to the criteria of the MDS Non-Motor Symptom Scale (MDS-NMSS), have a disease severity of stage 1 to 2.5 (modified Hoehn & Yahr), and have an MDS-UPDRS Part III score of ≥20. Prior to randomization, participants had received treatment with a stable regimen of levodopa / DDCI for at least 4 weeks, had no signs of motor complications (consisting of variability in motor responses and / or involuntary movements or dyskinesia), and were naive to COMT inhibitors.

[0144] Selection Criteria A subject was only eligible to be included in the study if they met all of the following criteria: 1. You may submit a signed informed consent form. 2. Participants must be between 30 and 80 years of age (including those aged 30 and 80) at the time they sign informed consent for the double-blind trial. 3. You have been diagnosed with idiopathic Parkinson's disease within the past five years according to the clinical diagnostic criteria of the Parkinson's Disease Society Brain Bank and / or according to the MDS-NMSS Non-Motor Symptom Scale within the past five years. 4. Disease severity is stage 1-2.5 (modified Hoehn & Yahr scale) 5. Despite receiving stable antiparkinsonian therapy, the patient has signs of treatable motor impairment for at least four weeks prior to screening, with a minimum threshold of ≥20 on the MDS-UPDRS Part III score, at both screening and visit 2. 6. The patient has been receiving treatment with L-DOPA / DDCI (controlled-release, immediate-release, or controlled-immediate-release combined) for at least one year, and prior to visit 2, has been receiving treatment for at least four weeks with a stable regimen of 300-500 mg per day, 3-4 times daily. 7. It is naive to COMT inhibitors (including opicapone). 8. Male or female Male participants must agree to use contraception during the treatment period and until PSV is reached, and must also agree to refrain from donating sperm during this period. Women are eligible to participate if they are not pregnant, not breastfeeding, and meet at least one of the following conditions: (i) are not women of childbearing potential (WOCBP); (ii) are WOCBP who have agreed to follow contraception guidelines throughout the treatment period and until PSV. 9. The results of the screening clinical tests are deemed clinically acceptable by the investigator (i.e., not clinically relevant to the welfare of the subject or the purpose of the trial).

[0145] Exclusion criteria Participants were excluded from the test if they met any of the following criteria: 1. Non-idiopathic Parkinson's disease (e.g., atypical parkinsonism, secondary [acquired or symptomatic] parkinsonism, parkinson's syndrome). 2. A total score of 0 (0) on MDS-UPDRS Part IV A+B+C is a sign of exercise complications. 3. Treatment with prohibited drugs, namely COMT inhibitors (e.g., entacapone, tolcapone), antiemetics with antidopaminergic effects (except domperidone), or Duopa® (carbidopa / levodopa enteral solution) within four weeks prior to screening. 4. Concomitant use of monoamine oxidase (MAO-A and MAO-B) inhibitors not intended for PD treatment (e.g., phenelzine, tranylcypromine, and moclobemide). 5. Past or planned deep brain stimulation (during the entire duration of the study). 6. Stereotactic brain surgery for Parkinson's disease in the past (e.g., globus pallidus ablation, thalamus ablation), or stereotactic brain surgery planned during the trial period. 7. Any investigational drug used within 3 months prior to screening (or within 5 times its half-life, whichever is longer). 8. Any medical condition that could increase the patient's risk or interfere with the evaluation of the trial. 9. Past (within the last year) or present history of suicidal ideation or suicide attempts, as determined by an affirmative response ("yes") to question 4 or 5 (screening question) in the suicidal ideation section of the Columbia Suicide Rating Scale (C-SSRS). 10. A current or past (within the last year) diagnosis of psychosis, severe major depression, or other mental disorder that, based on the judgment of the investigating physician, could increase the patient's risk or interfere with the evaluation. 11. Clinically relevant electrocardiogram (ECG) abnormalities (the relevance should be evaluated by a cardiologist as necessary). 12. Current evidence of unstable cardiovascular disease, including, but not limited to, poorly controlled hypertension, myocardial infarction with significant systolic or diastolic dysfunction, unstable angina, congestive heart failure (Class III or higher on the New York Heart Association functional classification), and significant cardiac arrhythmias (second or third degree atrioventricular block on Mobitz II, or any other arrhythmia causing hemodynamic effects such as symptomatic bradycardia or syncope). 13. Past kidney transplant or current kidney dialysis. 14. Chromaffin cell tumors, paragangliomas, or other catecholamine-secreting tumors. 15. Known hypersensitivity to any component of the investigational drug. 16. History of neuroleptic malignant syndrome (NMS), NMS-like syndrome, or non-traumatic rhabdomyolysis. 17. Malignant tumors within the past five years (e.g., melanoma, prostate cancer), excluding basal cell carcinoma or squamous cell carcinoma of the skin that have been dissipated by excision. 18. Unstable progressive narrow-angle glaucoma or unstable wide-angle glaucoma 19. History or current evidence of any relevant disease (e.g., relevant liver disease) in the context of this study, i.e., relating to the safety of the subject or to the conditions of the study, which may affect the absorption or metabolism of the investigational drug. 20. Any abnormality in the results of a screening clinical test for liver enzymes (alanine aminotransferase [ALT] and / or aspartate aminotransferase [AST]) that is more than twice the upper limit of the normal range. 21. Plasma sodium level less than 130 mmol / L, white blood cell count less than 3000 cells / mm3, or any other relevant clinical laboratory abnormality that, in the opinion of the investigator, could impair the safety of the patient. 22. Evidence for Impulse Control Disorder (ICD) (one or more positive modules in the Revised Minnesota Impulse Disorder Interview (mMIDI)). A module is considered positive if the patient gives a positive response to the gateway (first) question, and then gives a positive response to any of the other questions (rare=1, sometimes=2, frequently=3).

[0146] Randomization After a screening period of up to four weeks, eligible subjects were randomized in a 1:1 ratio to one of two treatment groups (opicapone (50 mg) or placebo) and entered a 24-week placebo-controlled, parallel-group, double-blind period (Figures 9 and 10).

[0147] The investigational drug was administered in combination with existing L-DOPA / DDCI treatment (Table 1).

[0148] Randomization was performed at visit 2 after eligibility was confirmed. Controls were randomized in a 1:1 ratio to either opicapone or placebo. Preferably, no stratification was performed during randomization.

[0149] Participants were randomized to the investigational drug using an automated voice / web response system (IVRS / IWRS). Prior to the start of the trial, each trial site provided a telephone number and instructions for the IVRS, and / or login information and instructions for the IWRS.

[0150] The trial was a double-blind study with restricted access to the randomization code. The investigational drug capsules and placebo capsules were identical in appearance. The treatment each subject received was not disclosed to the investigator, site staff, subjects, sponsor, or trial vendor. The investigational drug code was held by the IVRS / IWRS vendor.

[0151] Post-trial monitoring (PSV) visits were conducted approximately two weeks after the end-of-trial (EOS) visit or early termination (EDV) visit.

[0152] At the end of the double-blind period, many subjects entered an additional one-year open-label period at the discretion of the investigator, where all subjects received treatment with opicapone (50 mg). The double-blind period was deblinded after the database was locked for data analysis purposes. However, subjects and clinical trial sites remained blinded to the double-blind treatment until the end of the open-label phase.

[0153] Change of dosage The levodopa / DDCI dose was adjusted when medically necessary, for example, due to motor complications such as troublesome or dangerous dyskinesia. Changes to the investigational drug dose (opicapone or placebo) were not permitted.

[0154] statistical methods The primary efficacy analysis was performed after all subjects had completed the trial. In double-blind trials, deblinding was performed after the database was locked for data analysis purposes.

[0155] D. Symptomatic readout information: The International Association for Movement Disorders' Unified Assessment Scale for Parkinson's Disease The International Movement Disorders Association's Unified Assessment Scale for Parkinson's Disease (MDS-UPDRS) (Goetz C. et al., Mov. Disord., 2008, 23, 2129-70) is an extended version of the widely used Unified Assessment Scale for Parkinson's Disease (UPDRS), supported by the MDS. The MDS-UPDRS was administered as follows: MDS-UPDRS Part I (Non-motor aspects experienced in daily life). MDS-UPDRS Part II (Aspects of motor skills experienced in daily life). MDS-UPDRS Part III (Motor Symptom Assessment) score (Primary efficacy endpoint). MDS-UPDRS Part IV (Exercise Complications). Methods for calculating the total score, as well as analysis of subsections, are known to those skilled in the art.

[0156] Hoehn & Yahr severity levels The modified Hoehn & Yahr scale is used to describe the progression of symptoms in Parkinson's disease. The original version (Hoehn M., Yahr M., Neurology, 1967, 17, 427-42) includes stages 1-5.

[0157] Schwab & England scale The Schwab & England Activities of Daily Living Scale is a scale for assessing daily living function, ranging from 0 (indicating minimum function) to 100 (indicating no impairment) (Schwab R., England A., 1969;152-7).

[0158] Parkinson's disease sleep scale The Parkinson's Disease Sleep Scale Version 2 (PDSS-2) is a special scale for assessing sleep disturbances in patients with Parkinson's disease (Chaudhuri K. et al., Mov. Disord., 2006, 21, 916-23). ​​The PDSS-2 is used to examine nocturnal symptoms and should be completed with a general assessment by the physician.

[0159] Non-motor symptom scale Non-motor symptoms have a significant impact on patients with Parkinson's disease. The MDS-NMSS (Medical Disorders-Non-Motor Symptoms Scale) is a scale specifically designed for the comprehensive assessment of non-motor symptoms in patients with Parkinson's disease (Chaudhuri K. et al., Mov. Disord., 2007, 22, 1901-11). The MDS-NMSS consists of 30 items across nine domains: cardiovascular, sleep / fatigue, mood / cognition, perceptual disturbances, attention / memory, digestive system, urinary tract, sexual function, and other.

[0160] The MDS-NMSS was completed based on the physician's overall impression.

[0161] Parkinson's Disease Questionnaire The study assessed various aspects of functionality and well-being adversely affected by Parkinson's disease by having participants complete the Parkinson's Disease Questionnaire (PDQ-39). The PDQ-39 is the most widely used Parkinson's disease-specific health status scale. It consists of 39 questions covering eight aspects of quality of life: mobility, activities of daily living (ADL), emotions, stigma, social support, cognition, communication, and physical discomfort. This scale was developed based on interviews with people diagnosed with Parkinson's disease and has been widely validated (Peto V et al., Qual. Life Res., 1995, 4, 241-8; Jenkinson C et al., Age Ageing, 1997, 26, 353-7).

[0162] The PDQ-39 scale was completed based on the physician's overall impression.

[0163] Questionnaire for patients with 9 items of "wearing" off The Wearing-Off Patient Questionnaire (WOQ-9) (Stacy M., et al., Clin. Neuropharmacol., 2006, 29, 312-21) lists nine symptoms associated with Parkinson's disease: tremor, mood swings, slowness of movement in any area, decreased dexterity, rigidity in any part of the body, anxiety / panic attacks, drowsy / thought-distraction, muscle spasms, and pain / tingling. Patients are asked to mark which of these symptoms they experience and whether those symptoms usually improve after the next dose of medication. If they report that their symptoms improve after the next dose, it is considered a "positive response."

[0164] Doctor's overall impression The Physician's Overall Impression of Improvement (CGI) (CGI-I) is a 7-point scale (marked improvement, improved, slightly improved, no change, slightly worsened, worsened, marked worsened) that assesses how much a patient's condition has improved or worsened compared to baseline. Patients with "improvement" are those who were rated as markedly improved, improved, or slightly improved.

[0165] For each individual patient, the CGI scale was preferably scored by the same investigator / evaluator throughout the trial.

[0166] Patient's overall impression The Patient Overall Impression (PGI) Improvement Scale (PGI-I) consists of items derived from a patient-adapted Computational Impression (CGI). The investigator assesses the patient before the patient performs their own assessment. Preferably, the patient uses the PGI Improvement Scale (PGI-I) to assess their own condition compared to their condition at the time they were admitted to participate in the trial.

[0167] E. Clinical trials of opicapone therapy Opicapone was synthesized as described in WO2013 / 089573 and formulated into 50 mg capsules as described in WO2010 / 114405. The investigational drug (opicapone or matching placebo) was administered orally once daily at night, at least one hour after the last daily dose of L-DOPA / DDCI (considered to be administered before bedtime).

[0168] Patients' L-DOPA / DDCI regimens were not modified throughout the double-blind phase of the study unless adjustments were necessary for patient safety. During the open-label period (ongoing), adjustments to the L-DOPA / DDCI dose and the introduction of new antiparkinson's drugs were permitted if necessary for patient safety and / or to treat deterioration of the patient's condition, but no other adjustments were permitted.

[0169] [Table 1]

[0170] Clinical trial design The applicant conducted a phase III, multicenter, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of opicapone in patients with early idiopathic Parkinson's disease who were receiving treatment with levodopa / DDCI and had no signs of motor complications (e.g., variability in motor response and / or involuntary movements and / or dyskinesia). Patients in this trial had early Parkinson's disease and no motor complications. However, the WOQ-9 and MDS-UPDRS Part IV were used to track the development of any motor complications. Based on the WOQ-9 questionnaire, the proportion of subjects who experienced improved signs or symptoms of Parkinson's disease after the study was higher in the opicapone-treated group, with improvements observed in tremor (65.5%), slowness of movement (66.2%), muscle stiffness (56.9%), manual dexterity (56.6%), and muscle spasms (28.3%). In the placebo group, the proportion of subjects showing improvement in drug treatment after the study was similar to that of the opicapone group for most items, except for manual dexterity, where 44.1% of subjects in the placebo group showed improvement. 335 subjects were randomized at an estimated 85 sites in 13 countries. 322 subjects completed the double-blind phase (Figure 10). This trial includes an additional 52 weeks of open-label continuation (ongoing).

[0171] Period 1 - Screening (V1) Screening visits were conducted within four weeks prior to visit 2. Informed consent for the double-blind period was obtained using the Informed Consent Form (ICF) without performing any procedures related to the study.

[0172] Period 2 - Double-blind period (V2~V9) At visit 2, subjects had maintained stable levodopa / DCCI therapy for at least 4 weeks. Eligible subjects were randomized in a 1:1 ratio to one of two investigational groups (opicapone (50 mg) or placebo) and entered a 24-week double-blind trial. The investigational drug was administered in combination with the subjects' existing levodopa / DCCI therapy.

[0173] Table 2 shows the basic characteristics of the subjects.

[0174] Basic characteristics - Patient traits [Table 2]

[0175] Table 3 shows the basic characteristics of the treatment regimens used by the subjects.

[0176] [Table 3]

[0177] The subjects continued receiving the investigational drug in combination with levodopa / DDCI and participated in seven trial visits (V2-V8) at four-week intervals.

[0178] The End of Study (EOS) visit was visit number 9 and was for subjects who did not immediately enter the open-label period. In all other cases, subjects immediately entered the open-label period (ongoing). In cases of early termination of the study, subjects participated in the Early Termination Visit (EDV).

[0179] Post-suppression visits (PSV) were conducted at the study site approximately two weeks after the end-of-situation (EOS) visit, or after the end-of-situation visit (EDV) for subjects who were not in the open-label period (ongoing).

[0180] Primary efficacy analysis The primary efficacy parameter, the change in MDS-UPDRS Part III total score from baseline (visit 2) at the end of the double-blind period (visit 9), was analyzed using a mixed-model repeated measures (MMRM) approach, with baseline, center / country, (randomized) treatment, visit, treatment with visit interaction, and baseline with visit interaction as fixed effects, and control as the random effect. Differences between treatment groups (opicapone vs. placebo) were estimated from this model.

[0181] As shown in Figure 1 and Table 4, at the end of the 24-week double-blind period, subjects treated with opicapone showed statistically significantly lower motor impairment compared to those in placebo.

[0182] Primary outcome measure: Change in MDS-UPDRS Part III total score from baseline to 24 weeks. [Table 4] DB = Double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error CI = Confidence Interval, Diff = Difference, and the significance level is two-sided 5%.

[0183] As shown in Figure 2 and Table 5, the longitudinal data support the finding that the magnitude of the effect increased over time compared to placebo.

[0184] Primary endpoint: Longitudinal data showing the change in MDS-UPDRS Part III total score from baseline to 24 weeks. [Table 5] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0185] At every point in time, the effect of opikapone was greater than that of placebo. The fact that the magnitude of the effect increased over time suggests that the therapeutic effect may be maintained (or increased), and that less significant effects may become significant in long-term treatment as the placebo effect subsides. Similarly, the placebo effect at the initial point in time may mask the magnitude of the therapeutic effect.

[0186] Sensitivity analysis Sensitivity analyses were performed for the primary endpoint using an analysis of covariance (ANCOVA) approach with baseline, site / country, and (randomized) treatment as fixed effects, or using MMRM analysis. Missing data were imputed using multiple imputation for sensitivity analyses of the primary endpoint only.

[0187] Secondary efficacy analysis A similar MMRM analysis to the one used for the primary endpoint was used for relevant secondary endpoints during the double-blind period. The secondary endpoints included the following: The following shows the change in scores from baseline (visit 2) to subsequent visits during the double-blind trial. MDS-UPDRS score: Parts I, II, III, and IV, and the total for Part II+III Modified Hoehn & Yahr Severity Total Score between Maximum "On" Responses Schwab & England Scale Score Parkinson's Disease Sleep Scale 2 (PDSS-2) Total Score MDS Non-Motor Symptom Scale (MDS-NMSS) Total Score and Subdomain Score Parkinson's Disease Questionnaire (PDQ-39) Total Score and Subdomain Score 9-Item Wearing-Off Questionnaire (WOQ9) Total and Subsection (Motor and Non-Motor) Scores Physician's overall impression of improvement (CGI-I) Patient's overall impression of improvement (PGI-I)

[0188] As shown in Figure 3a and Table 6, at the end of the 24-week double-blind period, subjects treated with opicapone showed statistically significantly lower MDS-UPDRS Part II+III total scores compared to those in placebo.

[0189] Change in MDS-UPDRS Part II + III total score from baseline to week 24 [Table 6] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0190] As shown in Figure 3b and Table 7, longitudinal data support the finding that the magnitude of the effect increased over time compared to placebo.

[0191] Longitudinal data showing the change in MDS-UPDRS Part II+III total score from baseline to 24 weeks. [Table 7]

[0192] The magnitude of the opicapone effect remained constant over time, and as the placebo effect subsided, the effect compared to the placebo became significant.

[0193] Furthermore, the results shown in Figure 4a indicate that the proportion of opicapone-treated patients reporting improvement in their clinical status (PGI-I score) was significantly higher, with 57.9% showing improvement compared to 45.6% in placebo-treated patients (p=0.026). Figure 4b shows a similar trend when clinical status was assessed by clinicians (CGI-I score), with 50.3% showing improvement compared to 46.2% in placebo-treated patients (p=0.493).

[0194] As shown in Figure 5 and Table 8, at the end of the 24-week double-blind period, subjects treated with opicapone showed a statistically significant improvement in PDSS-2 compared to patients treated with placebo (p=0.039), and no deterioration was observed in the opicapone treatment group.

[0195] Change in PDSS-2 total score from baseline to week 24 [Table 8] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0196] As shown in Figure 6a and Table 9, at the end of the 24-week double-blind period, subjects treated with opicapone showed a positive trend in the treatment effect on the MDS-UPDRS Part II total score.

[0197] Change in MDS-UPDRS Part II total score from baseline to week 24 [Table 9] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0198] As shown in Figure 6b and Table 10, longitudinal data support the finding that the magnitude of the effect increased over time compared to placebo.

[0199] Longitudinal data showing the change in MDS-UPDRS Part II total score from baseline to 24 weeks. [Table 10] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0200] This suggests that larger groups or longer treatment periods may achieve statistical significance.

[0201] As shown in Figure 7 and Table 11, at the end of the 24-week double-blind period, subjects treated with opicapone showed a positive trend toward the therapeutic effect of NMSS.

[0202] Changes in NMSS from baseline to week 24 [Table 11] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0203] As shown in Table 12, no significant effect was observed on the MDS-UPDRS Part I total score at the end of the 24-week double-blind period.

[0204] Change in MDS-UPDRS Part I total score from baseline to week 24 [Table 12] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0205] As shown in Table 13, no significant effect was observed on the MDS-UPDRS Part IV total score at the end of the 24-week double-blind period.

[0206] Change in MDS-UPDRS Part IV total score from baseline to week 24 [Table 13] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0207] The patient population selected for treatment according to the present invention did not experience motor complications, but the study evaluated the occurrence of motor complications throughout the double-blind period. As shown in Figure 8, at the end of the 24-week double-blind period, the proportion of patients treated with opicapone who reported motor complications (5.5%) was lower than that of patients treated with placebo (9.8%).

[0208] As shown in Table 14, no significant effect on the PDQ-39 total score was observed at the end of the 24-week double-blind period.

[0209] Change in PDQ-39 total score from baseline to week 24 [Table 14] DB = double-blind, MDS-UPDRS = Unified Parkinson's Disease Rating Scale of the Movement Disorders Association, N = number of patients in the analysis set, n = number of patients with data, SD = standard deviation, OPC = opicapone 50 mg, MMRM = mixed model of repeated measures, LS = least squares method, SE = standard error, CI = confidence interval, Diff = difference, significance level is two-sided 5%.

[0210] The change in MDS-UPDRS Part I, MDS-UPDRS Part IV, or PDQ-39 total score in both groups (opicapone and placebo) was less than 0.4 points. Therefore, longer treatment periods or larger trials may be needed to observe significant effects on these symptoms.

[0211] At the endpoint at the end of the double-blind period (visit 9), the proportion of patients showing improvement in the CGI-I score from baseline (preferably compared to before the initiation of treatment) and the proportion of patients showing improvement in the PGI-I score from baseline (preferably compared to the time when participation in the trial was permitted) are analyzed using logistic regression analysis, including (randomized) treatment in this model.

[0212] Figure 4a shows that the proportion of patients reporting improvement in clinical status (PGI-I score) was significantly higher in the opicapone group compared to the placebo group, with 57.9% showing improvement compared to 45.6% in the placebo group (p=0.026). A similar trend was observed in the clinical status assessment by clinicians (CGI-I score) in Figure 4b, with 50.3% showing improvement compared to 46.2% in the placebo group, with no significant difference observed (p=0.493).

[0213] As shown in Tables 15 and 16, opicapone was well-tolerated and had a low incidence of adverse events (AEs), including treatment-related adverse events, during the double-blind trial period.

[0214] Therapeutic emergency adverse events (TEAEs) during a double-blind trial. [Table 15]

[0215] Specific TEAEs during the double-blind period [Table 16]

[0216] Opicapone demonstrated better tolerability and a more favorable safety profile in patients without clinically diagnosed motor complications compared to previous studies involving patients with clinically diagnosed motor complications. Patients treated with opicapone did not experience an increase in treatment-related adverse events, including neurological disorders such as dyskinesia. This is in stark contrast to the STRIDE-PD trial, where entacapone was associated with a shorter time to onset and a higher incidence of dyskinesia compared to placebo. Therefore, using opicapone in the treatment of Parkinson's disease patients without clinically diagnosed motor complications dramatically improves treatment efficacy without increasing dyskinesia.

[0217] Period 3 - Open-label period (V9~V15) At the end of the double-blind period, subjects may enter an additional one-year open-label period (ongoing) in which all subjects will receive opicapone (50 mg) in combination with the levodopa / DDCI already being administered. During the open-label period, adjustments to the levodopa / DDCI dose and the introduction of new antiparkinson's drugs are permitted if necessary for patient safety and / or to treat deterioration of the patient's condition, but no other adjustments are permitted.

[0218] The dosage of levodopa / DDCI therapy is recorded in the electronic case report form (eCRF).

[0219] The primary endpoint in the open-label phase is the change in the MDS-UPDRS Part IV total score from baseline (visit 9) to the end of the open-label period (visit 15). Secondary endpoints include the following: The following shows the change in scores from double-blind baseline (visit 2) to open-line baseline (visit 9). MDS-UPDRS score: Parts I, II, III, and IV, and the total for Part II+III Modified Hoehn & Yahr Severity Total Score between Maximum "On" Responses Schwab & England Scale Score PDSS-2 Total Score MDS-NMSS total score and subdomain score PDQ-39 Total Score and Subdomain Score WOQ-9 total and subsection (athletic and non-athletic) scores Compare with CGI-I, preferably the state before the start of treatment. Compare the PGI-I, preferably the condition at the time of admission to the trial.

[0220] As described above, the active drug treatment containing opicapone (50 mg) shows signs of good efficacy in the primary endpoint and several secondary endpoints.

[0221] Period 4 - Double - blind period and open - label period (V2~15) During the process of the double - blind period and open - label period (ongoing), evaluate the safety and tolerability of once - daily opicapone (50 mg) as an adjunctive therapy to stable levodopa / DDCI therapy in patients with early Parkinson's disease. The factors to be evaluated are as follows. Treatment - emergent adverse events (TEAE), including serious adverse events (SAE) Clinical laboratory tests for safety (biochemistry, hematology, blood coagulation, and urine tests) Physical and neurological examinations Vital signs 12 - lead ECG readings Columbia Suicide Severity Rating Scale (C - SSRS) Revised Minnesota Impulse Disorder Interview (mMIDI)

[0222] References

Table 17

Claims

1. Opicapone for use as an adjunct therapy to levodopa and DDCI formulations in the treatment of Parkinson's disease, characterized in that patients with Parkinson's disease are treatable with levodopa and DOPA decarboxylase inhibitor (DDCI) formulations and do not have clinically diagnosed motor complications.

2. The opicapone for use according to claim 1, wherein the treatment results in improvement in one or more symptoms of a patient compared to the symptoms of a patient treated for the same period with a formulation of levodopa and DDCI without opicapone.

3. The opicapone for use according to claim 1, wherein the treatment results in improvement in one or more symptoms of the patient compared to the same patient before initiating opicapone treatment.

4. The improvement is evaluated by comparing the disease score of the patient(s) before the start of treatment with the patient(s)(s)(s) when the effect of opicapone has stabilized, for example, 24 weeks, preferably 12 weeks, more preferably 4 weeks, and most preferably 2 weeks after the start of treatment, opicapone for use according to claim 2 or 3.

5. Opicapone for use according to any one of claims 1 to 4, wherein the treatment results in an improvement in the patient's score on one or more criteria from the International Association for Movement Disorders' Unified Assessment Scale for Parkinson's Disease (MDS-UPDRS) Part III (Assessment of Motor Function).

6. Opicapone for use according to any one of claims 1 to 5, wherein the treatment results in an improvement in the patient's total score on the International Association for Movement Disorders' Unified Assessment Scale for Parkinson's Disease (MDS-UPDRS) Part III (Assessment of Motor Function).

7. Opicapone for use according to claim 5 or 6, wherein the treatment results in improvement in one or more criteria selected from the group consisting of speech; facial expression; rigidity; finger tapping; hand movement; hand pronation and supination; toe tapping; lower limb agility; standing up from a chair; walking; freezing of gait; postural stability; posture; bradykinesia; postural tremor of the hand; tremor of the hand during movement; amplitude of resting tremor; and duration of resting tremor.

8. Opicapone for use according to any one of claims 1 to 7, wherein the treatment results in an improvement in the patient's score on one or more criteria from MDS-UPDRS Part I (non-motor aspects experienced in daily life).

9. Opicapone for use according to any one of claims 1 to 8, wherein the treatment results in an improvement in the patient's MDS-UPDRS Part I (non-motor aspects experienced in daily life) total score.

10. Opicapone for use according to claim 8 or 9, wherein the treatment results in improvement in one or more criteria selected from the group consisting of cognitive impairment; hallucinations; psychosis; depressed mood; anxious mood; apathy; features of dopamine dysregulation syndrome; sleep problems; daytime sleepiness; pain; urinary problems; constipation problems; orthostatic dizziness; and fatigue.

11. Opicapone for use according to any one of claims 1 to 10, wherein the treatment results in an improvement in the patient's score on one or more criteria from MDS-UPDRS Part II (aspects of motor symptoms experienced in daily life).

12. Opicapone for use according to any one of claims 1 to 11, wherein the treatment results in an improvement in the patient's MDS-UPDRS Part II (aspects of motor symptoms experienced in daily life) total score.

13. Opicapone for use according to claim 11 or 12, wherein the treatment results in improvement in one or more criteria selected from the group consisting of speech; saliva; drooling; chewing; swallowing; feeding tasks; dressing; hygiene; writing by hand; engaging in hobbies; turning over in bed; tremors; getting out of bed, in a car, or out of bed; walking; balance; or freezing.

14. Opicapone for use according to any one of claims 1 to 13, wherein the treatment results in an improvement in the patient's Parkinson's Disease Sleep Scale 2 (PDSS-2) total score.

15. Opicapone for use according to any one of claims 1 to 14, wherein the treatment results in an improvement in the patient's total and / or subdomain scores of the International Society for Movement Disorders Non-Motor Symptom Scale (MDS-NMSS), preferably in the total MDS-NMSS or urinary subdomain.

16. Opicapone for use according to any one of claims 1 to 15, wherein the treatment results in an improvement in the patient's modified Hoehn & Yahr total severity score.

17. Opicapone for use according to any one of claims 1 to 16, wherein the treatment results in an improvement in the patient's Schwab & England scale score.

18. Opicapone for use according to any one of claims 1 to 17, wherein the treatment results in an improvement in the patient's Parkinson's Disease Questionnaire-39 (PDQ-39) total and / or subdomain scores.

19. Opicapone for use according to any one of claims 1 to 18, wherein the treatment results in an improvement in the physician's overall impression (CGI-I) score for the patient's improvement.

20. Opicapone for use according to any one of claims 1 to 19, wherein the treatment results in an improvement in the patient's overall impression (PGI-I) score regarding the patient's improvement.

21. Opicapone for use according to any one of claims 1 to 20, wherein the patient has Parkinson's disease that is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications, and the total score of MDS-UPDRS Part IV (Motor Complications) A+B+C shown by the patient is 0.

22. Opicapone for use according to any one of claims 1 to 21, wherein the positive WOQ-9 symptom, which improves after the next administration of levodopa, is 2 or less in patients with Parkinson's disease who are treatable with a levodopa and DDCI formulation and who do not have clinically diagnosed motor complications.

23. Opicapone for use according to claim 22, wherein the patient has Parkinson's disease that is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications, and does not exhibit motor complications selected from the group consisting of tremor, mood swings, slowness of movement, decreased dexterity, rigidity, anxiety / panic attacks, drowsy thinking / slow thinking, muscle spasms, and pain / tingling.

24. Opicapone for use according to claim 23, wherein the patient has Parkinson's disease that is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications, and does not exhibit motor complications selected from the group consisting of tremor, anxiety, mood swings, slowness of movement, decreased dexterity and rigidity.

25. Opicapone for use according to claim 24, wherein the patient has Parkinson's disease that is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications, and does not exhibit motor complications selected from the group consisting of tremor, anxiety / panic attacks and slowness of movement.

26. Opicapone for use according to any one of claims 1 to 25, wherein the patient has Parkinson's disease that is treatable with a levodopa and DDCI formulation and does not have clinically diagnosed motor complications, and does not exhibit motor complications selected from the group consisting of fluctuations in motor symptoms and dyskinesia.

27. The opicapon for use according to any one of claims 1 to 26, wherein the patient has been diagnosed with idiopathic Parkinson's disease within the past five years.

28. The opicapon for use according to any one of claims 1 to 27, wherein the patient has been diagnosed with idiopathic Parkinson's disease in accordance with the clinical diagnostic criteria of the British Parkinson's Disease Society Brain Bank.

29. Opicapone for use according to any one of claims 1 to 28, wherein the patient has been treated with levodopa / DDCI for at least one year and, prior to initiating opicapone, has been treated for at least four weeks with a stable regimen of 300 to 500 mg per day, three to four times per day.

30. Opicapone for use according to any one of claims 1 to 29, wherein, prior to treatment with opicapone, the patient's modified Hoehn & Yahr stage is 1 to 3.

31. The opicapon for use according to any one of claims 1 to 30, wherein the patient receives administration of levodopa at a dose of 600 mg or less per day.

32. The opicapone for use according to any one of claims 1 to 31, wherein the patient receives administration of levodopa six times or less per day.

33. The opicapone for use according to any one of claims 1 to 32, wherein the patient is not currently receiving treatment with a COMT inhibitor.

34. The opicapone for use according to any one of claims 1 to 33, wherein the patient has never received treatment with a COMT inhibitor.

35. The opicapone for use according to any one of claims 1 to 34, wherein the patient is not currently receiving treatment with controlled-release levodopa.

36. The opicapone for use according to any one of claims 1 to 35, wherein the patient has never received treatment with controlled-release levodopa.

37. The opicapone for use according to any one of claims 1 to 36, wherein the opicapone is administered once daily.

38. The opicapone for use according to any one of claims 1 to 37, wherein the unit dose of opicapone is 5 to 100 mg, preferably 25 to 75 mg, more preferably 25 to 50 mg, and most preferably 50 mg.

39. The opicapone for use according to any one of claims 1 to 38, wherein the opicapone is administered at least one hour before or after a meal.

40. The opicapone for use according to any one of claims 1 to 39, wherein the opicapone is administered at least one hour before or after the administration of levodopa.

41. The opicapone for use according to any one of claims 1 to 40, wherein the opicapone is administered before or near bedtime.

42. The opicapon for use according to any one of claims 1 to 41, wherein the treatment lasts for at least 24 weeks, preferably at least 1 year.

43. Opicapone for use according to any one of claims 1 to 42, wherein a patient with Parkinson's disease has not been evaluated or diagnosed for end-of-dose motor variability.

44. Opicapone for use as an adjunct therapy to levodopa and DDCI formulations in the treatment of motor signs and symptoms of Parkinson's disease, in patients with Parkinson's disease who are treatable with levodopa and DDCI formulations without clinically diagnosed motor complications.

45. Opicapone for use as an adjunctive therapy to levodopa and DDCI formulations in the treatment of patients with Parkinson's disease and inadequately controlled motor signs and symptoms, who are treatable with levodopa and DDCI formulations without clinically diagnosed motor complications.

46. The use of opicapone in the manufacture of a pharmaceutical product for use as an adjunct therapy to levodopa and DDCI formulations in the treatment of Parkinson's disease, characterized in that the patient is treatable with levodopa and DDCI formulations and does not have clinically diagnosed motor complications.

47. A method for treating Parkinson's disease, characterized in that patients with Parkinson's disease are treatable with levodopa and DDCI preparations and do not have clinically diagnosed motor complications, comprising administering opicapone to those in need as adjunct therapy to levodopa and DDCI preparations.

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