Parkinson's Disease Treatment Plan

Abstract

1. A method of treating Parkinson's disease in a patient who is receiving N doses of levodopa per day for a total daily dose of X mg of levodopa and who has begun to experience motor fluctuations or show signs of "wearing off," wherein treatment comprises administering more than N doses of levodopa per day for a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to optimal dosing regimens of levodopa and COMT inhibitors for the treatment of Parkinson's disease in patients who begin to experience motor fluctuations (or show signs of "wearing off") upon termination of treatment. [Background technology]

[0002] Background of the Invention Levodopa (L-DOPA) has been used clinically for decades as a symptomatic treatment for various conditions, including Parkinson's disease. L-DOPA can cross the blood-brain barrier, where it is subsequently converted to dopamine by the enzyme dopamine decarboxylase (DDC), increasing dopamine concentrations in the brain. However, conversion of L-DOPA to dopamine also occurs in peripheral tissues, potentially causing adverse effects. Therefore, it is standard clinical practice to coadminister peripheral DDC inhibitors (DDCIs), such as carbidopa or benserazide, to prevent L-DOPA conversion to dopamine in peripheral tissues.

[0003] In the early stages of Parkinson's disease, levodopa / DDCI therapy can almost completely suppress Parkinson's symptoms until the next dose is administered. However, most patients receiving long-term levodopa / DDCI therapy develop motor complications, such as end-of-treatment motor fluctuations and dyskinesias, beyond the early stages of Parkinson's disease, despite continued or increased levodopa administration (Aquino CC, Fox SH, Mov. Disord., 2015, 30, 80-89). This phenomenon is sometimes referred to as "wearing off." Patients often report spending several hours a day in the so-called "off" state experiencing end-of-treatment motor 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 development of motor complications, such as motor fluctuations at the end of treatment, defines the transition from early to more advanced stages of Parkinson's disease, and therefore management of motor complications ultimately becomes an important clinical need for almost all patients (Poewe W, Neurology, 2009, 72, S65-73).

[0004] End-of-dose variability is associated with oral levodopa's short half-life (approximately 60–90 minutes). Adjusting levodopa dose and / or frequency is a common approach to managing response variability. However, increasing the total daily dose of levodopa by increasing dosing frequency may worsen the severity of dyskinesia, while dividing the total daily dose into more frequent smaller doses may be associated with intermittent recurrence of symptoms due to plasma concentration fluctuations above and below the threshold that governs levodopa's clinical response. Because neither approach addresses the long-term short half-life of traditional levodopa, an alternative pharmacological approach is to optimize levodopa delivery to the brain and manage levodopa-related complications by administering levodopa / DDCIs with catechol-O-methyltransferase (COMT) inhibitors, which increase levodopa's plasma elimination half-life and reduce peak / trough variability.

[0005] Opicapone is a potent, long-acting COMT inhibitor that inhibits the breakdown of levodopa to its inactive metabolite, 3-O-methyldopa. Opicapone is bioactive, bioavailable, and has low toxicity. Therefore, opicapone possesses potentially valuable pharmacological properties for the treatment of several central and peripheral nervous system disorders in which COMT inhibition may be therapeutically beneficial, including mood disorders; movement disorders such as Parkinson's disease, parkinsonian disorders, and restless legs syndrome; gastrointestinal disorders; edematous conditions; and hypertension. The development of opicapone is described in LE Kiss et al., J. Med. Chem., 2010, 53, 3396-3411. It was approved in the EU in June 2016, the US in April 2020, and Japan in June 2020 under the trade name "Ongentys" in combination with L-DOPA for the treatment of Parkinson's disease.

[0006] In the pivotal Phase III clinical trials supporting these approvals, BIPARK-I (Ferreira et al., Lancet Neurol., 2016, 15, 154-65) and BIPARK-II (Lees et al., JAMA Neurol., 2017, 74, 197-206), subjects' treatment regimens were not standardized prior to the study initiation. Thus, subjects were enrolled with a variety of levodopa dosing regimens, and the impact of levodopa treatment regimens (both total daily dose and frequency) on the clinical efficacy of opicapone in managing motor fluctuations was not investigated.

[0007] The previously approved COMT inhibitor, entacapone, was tested in patients with early idiopathic Parkinson's disease, i.e., those who had not yet developed motor complications (Stocchi F et al. Initiating levodopa / carbidopa therapy with and without entacapone in early Parkinson's disease: the STRIDE-PD study, Ann Neurol 2010: 68(1): 18-27). STRIDE-PD is the only controlled trial to examine long-term optimized levodopa dosing, including the use of an enzyme inhibitor, to prevent or delay motor complications at the start of treatment in levodopa-naive patients. This study failed to demonstrate that initiating levodopa therapy with a COMT inhibitor (entacapone) delayed the onset or reduced the frequency of dyskinesias compared with levodopa alone. In fact, the addition of entacapone was associated with a shorter time to onset of motor complications and an increased frequency of dyskinesias.

[0008] Thus, there remains a need to improve the safety and effectiveness of treating Parkinson's disease when levodopa no longer controls a patient's symptoms, without inducing motor complications due to levodopa overdose. In particular, there remains a need for more effective dosing regimens for treating Parkinson's disease in patients who begin to experience motor fluctuations at the end of treatment (or begin to show signs of "wearing off").

[0009] The present invention arose from the results of a clinical trial conducted by the inventors. Details of the study design were published as an abstract in the European Journal of Neurology in 2021 (J. Ferreira et al., Eur. J. Neurol. 2021, 28 (Suppl. 1), 558-752) and presented virtually at the 7th European Academy of Neurology (EAN) Congress, June 19-22, 2021. Results were not presented.

[0010] Pharmacokinetic data were published as an abstract in the European Journal of Neurology in June 2022 (J. Ferreira et al, Eur. J. Neurol. 2022, 29 (Suppl. 1), 440-441) and presented virtually at the 8th European Academy of Neurology (EAN) Congress, June 25-27, 2022. No clinical results were presented.

[0011] The clinical data were published as an academic paper in the academic journal Movement Disorders on August 31, 2022 (J. Ferreura et al, Mov. Disord. 2022, 37, 2272-2283). Summary of the Invention

[0012] The present inventors have discovered an optimal dosing regimen of levodopa and a COMT inhibitor for treating Parkinson's disease, particularly idiopathic Parkinson's disease, in patients who begin to experience motor fluctuations (or begin to show signs of "wearing off") at the end of treatment.

[0013] Thus, in a first general embodiment, the invention provides a method of treating Parkinson's disease in a patient who has been receiving N doses per day to achieve a total daily dose of X mg levodopa and who, at the end of administration, has begun to experience motor fluctuations or show signs of "wearing off", wherein treatment comprises administering more than N doses per day of levodopa to achieve a total daily dose of X mg levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

[0014] In a second general embodiment, the invention provides opicapone and levodopa for use in the treatment of Parkinson's disease in a patient who is receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa and who has begun to experience motor fluctuations or show signs of "wearing off", comprising administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

[0015] In a third general embodiment, the invention provides use of opicapone and levodopa in the manufacture of a medicament for the treatment of Parkinson's disease in a patient who is receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and who has begun to experience motor fluctuations or show signs of "wearing off", comprising administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

[0016] The present invention will now be described in detail with reference to the accompanying drawings. [Brief explanation of the drawings]

[0017] [Figure 1]Figure 1 shows the clinical trial design. LD = levodopa; CD = carbidopa; PK = pharmacokinetics; R = randomization; V1-V4 = Visit 1-Visit 4. [Figure 2] Figure 2 shows the mean levodopa plasma profile over time after 2 weeks of oral administration of LD / CD 500 / 125 mg five times daily (every 3 hours) compared with 2 weeks of oral administration of LD / CD 400 / 100 mg plus 50 mg opicapone four times daily (every 4 hours) (A), or 2 weeks of oral administration of LD / CD 400 / 100 mg five times daily (every 3 hours) plus 50 mg opicapone (B); LD / CD = levodopa / carbidopa. [Figure 3] Figure 3 shows the 12-hour on / off time data reported on the pharmacokinetic study day overlaid with the subsequent mean levodopa plasma profile over time for two weeks of oral levodopa / carbidopa 500 / 125 mg five times daily (every 3 hours) without opicapone (A) compared with two weeks of oral levodopa / carbidopa 400 / 100 mg four times daily (every 4 hours) plus opicapone 50 mg once daily (B), and for two weeks of oral levodopa / carbidopa 500 / 125 mg five times daily (every 3 hours) without opicapone (C) compared with two weeks of oral levodopa / carbidopa 400 / 100 mg five times daily (every 3 hours) plus opicapone 50 mg once daily (D). LD / CD = levodopa / carbidopa, OPC = opicapone, arrow = time to on, bar = duration of on state, solid vertical line = time of best on. [Figure 4] Figure 4 is a schematic diagram showing typical levodopa pharmacokinetics; Cmax = highest (rising, peak) levodopa concentration level seen in plasma; Cmin = lowest (declining, trough) levodopa concentration level seen in plasma; Fluctuation Index (FI) = magnitude of rise and fall in plasma levodopa levels calculated as [(Cmax-Cmin) / Cavg]*100; AUC (area under the curve) = systemic exposure of levodopa in plasma as a function of time. DETAILED DESCRIPTION OF THE INVENTION

[0018] Detailed Description of the Invention A.Definition Unless otherwise limited, the following definitions apply to terms used throughout this specification.

[0019] The term "idiopathic Parkinson's disease" encompasses most (80-85%) Parkinson's diseases (diagnosed according to either the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria or the Movement Disorder Society criteria) and excludes atypical parkinsonism, secondary (acquired or symptomatic) parkinsonism, and parkinsonism-plus syndromes, such as drug-induced parkinsonism, vascular parkinsonism, normal pressure hydrocephalus, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. Idiopathic Parkinson's disease is usually accompanied by a variety of extrapyramidal signs and symptoms, usually associated with marked bradycardia. It is usually accompanied by degeneration of the substantia nigra dopaminergic system, with substantia nigra neuron loss and reactive gliosis evident at autopsy. In idiopathic Parkinson's disease, α-synuclein typically accumulates in neuronal cell bodies (Lewy bodies) and neuronal processes (Lewy neurites).

[0020] The terms "GBA1-carrying Parkinson's disease" or "GBA-associated Parkinsonism" refer to a specific group of Parkinson's disease patients who have mutations in both copies of the GBA1 gene, which encodes the glucocerebrosidase (GCase) enzyme. These heterozygous mutations are associated with a higher risk of developing Parkinson's disease. In the United States, approximately 10% of all patients with clinically diagnosed Parkinson's disease have GBA1 mutations.

[0021] The term "Parkinson's disease symptoms" includes both motor symptoms (e.g., tremor, rigidity, bradycardia, and postural instability) and non-motor symptoms (e.g., cognitive changes, gastrointestinal symptoms, loss of vision, taste, and / or smell, pain, fatigue, dizziness, sexual problems, sleep disturbances, and weight loss). Such symptoms can be assessed using one or more symptom measures described below, including clinical assessments (e.g., 12-hour and 24-hour diaries, and PGI-C).

[0022] The term "motor complications" refers to Parkinson's disease motor symptoms associated with levodopa therapy. Motor complications occur when levodopa / DDCI therapy alone is no longer sufficient to completely control a patient's symptoms. These include fluctuations in motor symptoms and / or dyskinesias. Motor complications are persistent, but not necessarily regular or predictable, and have a quantitative and negative impact on a patient's quality of life (QoL). A "clinically diagnosed motor complication" generally refers to a total score of A+B+C on the MDS-UPDRS Part IV greater than 6, preferably greater than 3, and more preferably greater than 0, and / or one or more relevant symptoms on the 9-item Wearing-Off Questionnaire (WOQ-9). A total score of A+B+C on the MDS-UPDRS Part IV greater than 0 (zero) is the most preferred definition of a clinically diagnosed motor complication. Note that motor complications can be the same as Parkinson's disease motor symptoms. However, motor symptoms that were initially treatable with levodopa / DDCI therapy are considered motor complications if they reappear late in the disease despite continued levodopa / DDCI therapy.

[0023] "Motor fluctuations" include end-of-treatment fluctuations (also known as wearing-off), paradoxical fluctuations, and unpredictable on / off periods.

[0024] The term "off period" or "off episode" is defined as a period during which a patient treated with levodopa is no longer receiving its symptomatic benefit and is said to be in an "off" state, whereas the term "on period" or "on episode" is defined as a period during which a patient treated with levodopa is receiving its symptomatic benefit and is said to be in an "on" state.

[0025] The term "time to best on" is the time it takes for a patient to experience maximum symptomatic effect after administration of one dose of levodopa / DDCI therapy.

[0026] The term "end-of-dose motor fluctuations," also known as the "wearing-off" phenomenon, refers to the predictable reappearance or worsening of symptoms before the next dose of levodopa / DDCI therapy is administered. This reappearance or worsening of symptoms typically begins 3-4 hours after levodopa administration, when the medication wears off and symptoms reappear or worsen. Symptoms then typically improve 15-45 minutes after the next levodopa dose.

[0027] Patients who "began experiencing motor fluctuations" or "began showing signs of 'wearing off'" include patients who have had clinically noticeable motor fluctuations for up to 3 years, e.g., up to 2 years, or even up to 1 year. Patients with motor fluctuations for up to 1 year are known as "early motor fluctuation patients." Typically, a patient "began experiencing motor fluctuations" when they are receiving levodopa treatment and begin to experience detectable "off periods" or "off episodes."

[0028] The term "dyskinesia" or "levodopa-induced dyskinesia" includes peak-dose dyskinesia, biphasic dyskinesia, and ofdyskinesia. Common symptoms include chorea and ataxia. Less common symptoms include acatathasia (excessive motor restlessness), high-stepped overshooting gait, rapid alternating leg movements (RAM), blepharospasm, and mixed-pattern abnormal movements (Fahn S., Ann. Neurol., 2000, 47, S2-S9).

[0029] The term "'on' with dyskinesias interfering with daily living" refers to a period following administration of one dose of levodopa / DDCI therapy in which the patient's mobility is limited by the presence of dyskinesias but they receive some symptomatic relief consistent with an "on period."

[0030] The term "adjunctive therapy," also known as "adjunct therapy," "add-on therapy," or "adjuvant care," is a therapy given in addition to a primary or initial therapy to maximize its effectiveness. In this application, levodopa is the primary therapy, and DCCI and a COMT inhibitor (i.e., opicapone) are the adjunctive therapies.

[0031] The term "treatment-emergent adverse event" is defined as an event that was not present before exposure to the study drug, or an event that was already present but worsened in either intensity or frequency after the first dose of the study drug and up to 2 weeks after the last dose of the study drug.

[0032] "Maximum plasma concentration" or "C max The term "peak" refers to the highest (rising, peak) drug concentration level found in plasma. In this application, it is the highest levodopa concentration level found in plasma. max Increased dopamine levels increase the risk of developing dopamine-induced side effects such as dyskinesia.

[0033] "Minimum plasma concentration" or "C min The term "low" refers to the lowest (descending, trough) drug concentration level found in plasma. In this application, it is the lowest levodopa concentration level found in plasma. min As C increases, the time required to achieve or maintain the on-state decreases. max The increase seen in C min The risk of developing motor complications decreases if the increase is not equal to or greater than that seen in

[0034] "Mean plasma concentration" or "C avg The term "mean plasma drug concentration between doses at steady state."

[0035] The term "fluctuation index" or "FI" refers to the magnitude of rise and fall of drug levels in plasma [(C max -C min ) / Cavg ] * FI is calculated as 100. In this application, it is the rise and fall of levodopa levels in plasma. As FI increases, the risk of developing motor complications increases.

[0036] The term "area under the curve" or "AUC" is the systemic exposure of a drug in plasma as a function of time. In this application, it is the systemic exposure of levodopa in plasma as a function of time. As AUC increases, the time spent in the on state increases (i.e., the time spent in the off state decreases).

[0037] Those skilled in the art will understand and effect other variations to the disclosed embodiments in practicing the claimed invention, from a study of the present disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite articles "a" or "an" do not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0038] B. Treatment of Parkinson's disease in patients who have begun to experience motor fluctuations (or show signs of "wearing off") at the end of treatment. The present invention provides a dosing regimen for levodopa and opicapone in the treatment of Parkinson's disease, particularly idiopathic Parkinson's disease, in patients who begin to experience motor fluctuations (or begin to show signs of "wearing off") upon completion of treatment.

[0039] In a first general embodiment, the invention provides a method of treating Parkinson's disease in a patient who has been receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa and who, at the end of administration, begins to experience motor fluctuations or shows signs of "wearing off," wherein treatment comprises administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

[0040] In a second general embodiment, the invention provides opicapone and levodopa for use in the treatment of Parkinson's disease in a patient who is receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa and who has begun to experience motor fluctuations or show signs of "wearing off", comprising administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

[0041] In a third general embodiment, the invention provides use of opicapone and levodopa in the manufacture of a medicament for the treatment of Parkinson's disease in a patient who is receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and who has begun to experience motor fluctuations or show signs of "wearing off", comprising administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

[0042] The following embodiments are compatible with the general embodiments. In another embodiment, Parkinson's disease is idiopathic Parkinson's disease or GBA1-carrying Parkinson's disease. In a preferred embodiment, Parkinson's disease is idiopathic Parkinson's disease, which accounts for the majority of Parkinson's diseases.

[0043] In another embodiment, N is 3 to 6, preferably 3 to 5, more preferably 3 to 4. In an even more preferred embodiment, N is 4.

[0044] In another embodiment, "more than N doses" refers to N+1 or N+2 doses. In a preferred embodiment, "more than N doses" refers to N+1 doses.

[0045] In another embodiment, X is 300 to 600, preferably 300 to 500, and more preferably 300 to 400. In an even more preferred embodiment, X is 400.

[0046] In another embodiment, Y is 25 or 50. For example, Y is 25. For example, Y is 50.

[0047] In a particularly preferred embodiment, the patient is receiving four doses of levodopa for a total daily dose of 400 mg per day, and treatment comprises administering five doses of levodopa per day for a total daily dose of 400 mg of levodopa, and administering a single daily dose of 50 mg of opicapone.

[0048] In another embodiment, the levodopa dose is not the same for each dose. For example, the odd-numbered doses have a higher levodopa dose. For example, the even-numbered doses have a higher levodopa dose. Standard levodopa doses include 250 mg, 100 mg, 75 mg, or 50 mg. Most patients take a single dose of levodopa each time, for example, 100 mg each time.

[0049] In certain more preferred embodiments, the patient receives four doses of levodopa per day for a total daily dose of 400 mg, and the treatment comprises administering five doses of levodopa for a total daily dose of 400 mg levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the five doses of levodopa are administered in the following dosing schedule: 100 mg, 50 mg, 100 mg, 50 mg, and 100 mg for a total daily dose of 400 mg levodopa.

[0050] In another embodiment, the single daily dose of opicapone is administered at least 1 hour after the last levodopa dose.

[0051] In another embodiment, the patient receives N doses of a dopamine decarboxylase inhibitor (DDCI) for a total daily dose of Z mg of DDCI, and the method further comprises administering more than N doses of DDCI per day for a total daily dose of Z mg of DDCI, where Z is 50 to 250, preferably 75 to 150.

[0052] In another embodiment, the DDCI is carbidopa or benserazide. For example, the DDCI is carbidopa. For example, the DDCI is benserazide.

[0053] In another embodiment, a DDCI dose is administered with a levodopa dose.

[0054] In certain preferred embodiments, the patient receives four doses of carbidopa per day for a total daily dose of 100 mg, and treatment comprises administering five doses of carbidopa per day for a total daily dose of 100 mg of carbidopa.

[0055] In certain preferred embodiments, the patient receives four doses of levodopa / carbidopa for a total daily dose of 400 / 100 mg levodopa / carbidopa per day, and treatment comprises administering five doses of levodopa / carbidopa per day for a total daily dose of 400 / 100 mg levodopa / carbidopa, and administering a single daily dose of 50 mg opicapone.

[0056] In certain more preferred embodiments, the patient receives four doses of levodopa / carbidopa per day for a total daily dose of 400 / 100 mg, and treatment comprises administering five doses of levodopa / carbidopa per day for a total daily dose of 400 / 100 mg levodopa / carbidopa, and administering a single daily dose of 50 mg of opicapone, wherein the five doses of levodopa / carbidopa are administered in the following dosing regimens: 100 / 25 mg, 50 / 12.5 mg, 100 / 25 mg, 50 / 12.5 mg, and 100 / 25 mg for a total daily dose of 400 / 100 mg levodopa / carbidopa.

[0057] In another embodiment, patients who begin to experience motor fluctuations or show signs of "wearing off" are patients who have experienced motor fluctuations for a duration of up to 3 years, preferably up to 2 years, more preferably up to 1 year.

[0058] The results described below confirm that the addition of opicapone and one or more fractionated levodopa doses improves the treatment of Parkinson's disease (e.g., idiopathic Parkinson's disease) in patients who are otherwise not receiving adequate treatment. This finding is encompassed by the three general embodiments described above. Based on these data, it is expected that patients may be able to reduce their total dose of levodopa (and DCCI) by adding opicapone and one or more fractionated levodopa doses.

[0059] For example, it is expected that the present invention may provide a method of treating Parkinson's disease in a patient who has been receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa and who, at the end of the administration, begins to experience motor fluctuations or shows signs of "wearing off," the treatment comprising administering a total daily dose of levodopa of less than X mg per day and administering a single daily dose of Y mg of opicapone, where X is 100-1000, N is 2-10, and Y is 25-50, and "less than X mg of levodopa per day" includes a reduction of at least X / 2N mg, and preferably "less than X mg of levodopa per day." "Vodopa" includes a reduction of at least X / N mg; this method excludes the treatment of Parkinson's disease in patients who, at the end of administration, began to experience motor fluctuations or show signs of "wearing off" and who are receiving five doses of levodopa for a total daily dose of 500 mg per day, wherein the treatment comprises administering five doses of levodopa per day for a total daily dose of 400 mg levodopa, and administering a single daily dose of 50 mg of opicapone, the five doses of levodopa providing a total daily dose of 400 mg levodopa, administered in the following dosing regimen: 100 mg, 50 mg, 100 mg, 50 mg, and 100 mg. Preferably, this method includes multiple individual doses (e.g., two individual doses, e.g., a combination of 50 mg and 100 mg levodopa in one day).

[0060] Specific examples supported by these results include the following: 1. A method of treating Parkinson's disease in a patient who begins to experience motor fluctuations or show signs of "wearing off" at the end of dosing and is receiving three doses of levodopa for a total daily dose of 300 mg per day, wherein the treatment comprises administering three doses of levodopa per day for a total daily dose of 200 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the three doses of levodopa provide a total daily dose of 200 mg of levodopa and are administered in the following dosing regimen: 100 mg, 50 mg, and 50 mg.

[0061] 1. A method of treating Parkinson's disease in a patient who begins to experience motor fluctuations or show signs of "wearing off" at the end of dosing and is receiving four doses of levodopa for a total daily dose of 400 mg per day, wherein the treatment comprises administering four doses of levodopa per day for a total daily dose of 300 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the four doses of levodopa provide a total daily dose of 300 mg of levodopa and are administered in the following dosing regimen: 100 mg, 50 mg, 100 mg, and 50 mg.

[0062] 1. A method of treating Parkinson's disease in a patient who has begun to experience motor fluctuations or show signs of "wearing off" at the end of treatment and is receiving three doses of levodopa for a total daily dose of 300 mg per day, wherein the treatment comprises administering four doses of levodopa per day for a total daily dose of 250 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the four doses of levodopa provide a total daily dose of 250 mg of levodopa and are administered in the following dosing regimens: 100 mg, 50 mg, 50 mg, and 50 mg.

[0063] 1. A method of treating Parkinson's disease in a patient who begins to experience motor fluctuations or show signs of "wearing off" at the end of dosing and is receiving four doses of levodopa for a total daily dose of 400 mg per day, wherein the treatment comprises administering five doses of levodopa per day for a total daily dose of 300 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the five doses of levodopa provide a total daily dose of 300 mg of levodopa and are administered in the following dosing regimens: 100 mg, 50 mg, 50 mg, 50 mg, and 50 mg.

[0064] C. Clinical Protocol The invention was discovered through a Phase II randomized, open-label study evaluating the effect of opicapone (50 mg once daily) on the pharmacokinetics of L-DOPA in patients with Parkinson's disease who were receiving different levodopa / carbidopa (LD / CD)-sparing dosing regimens (EudraCT number: 2020-003139-12) and had motor fluctuations at the end of treatment.

[0065] Subjects were aged 30 years or older and had a clinical diagnosis of idiopathic Parkinson's disease according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria, with stage 1-3 severity (modified Hoehn & Yahr staging) during the on-state and motor fluctuations and signs of "wearing off" at the end of treatment. Subjects had been treated with levodopa / DDCI for at least one year and had demonstrated clear clinical improvement.

[0066] The Hoehn and Yahr scale is used to describe the progression of symptoms of Parkinson's disease. The original version (Hoehn M., Yahr M., Neurology, 1967, 17, 427-42) includes stages 1 to 5. The revised version adds stages 1.5 and 2.5 to record the intermediate stages of Parkinson's disease.

[0067] There were no specific requirements regarding the frequency of levodopa administration, but all recruited patients were already receiving a daily treatment regimen of LD / CD 500 / 125 mg, taken five times. Patients were excluded if they had severe and / or unpredictable "off" periods, had been treated with extended-release levodopa / DDCI within 4 weeks before screening, were taking prohibited medications (neuroleptics, venlafaxine, monoamine oxidase (MAO) inhibitors [except selegiline, safinamide, or rasagiline], or antiemetics with antidopaminergic properties [except domperidone]), or had previously received a COMT inhibitor (entacapone, tolcapone, or opicapone).

[0068] Identity of the investigational drug Opicapone can be synthesized as described in WO2013 / 089573 and formulated into 50 mg capsules as described in WO2010 / 114405. Opicapone was taken orally once daily in the evening at least 1 hour after the final daily dose of L-DOPA / DDCI (considered a bedtime dose).

[0069] [Table 1]

[0070] Clinical trial planning Details of the study design, as shown below, were published as an abstract in the European Journal of Neurology in 2021 (J. Ferreira et al, Eur. J. Neurol. 2021, 28 (Suppl. 1), 558-752) and presented virtually at the 7th European Academy of Neurology (EAN) Congress, June 19-22, 2021. Results were not shown.

[0071] The study design is shown in Figure 1.

[0072] Eligible subjects received the following study treatments during different study periods: 1st period After screening, all subjects received the LD / CD dose and a fixed 100 / 25 mg QD5 (total daily dose of 500 / 125 mg) every 3 hours (8:00 AM - 8:00 PM) dosing schedule for 14 ± 2 days. This was the base dosing schedule. 2nd period Patients were then randomized (1:1) to receive one of two different dosing regimens: opicapone 50 mg and LD / CD (400 / 100 mg daily) for an additional 14±2 days. Opicapone Regimen #1: Subjects received LD / CD and 100 / 25 mg QD4 (fixed, every 4 hours, 8:00-20:00) for a total daily LD / CD dose of 400 / 100 mg, plus 50 mg OPC QD at least 1 hour after the last dose of LD / CD. Opicapone Regimen #2: Subjects received alternating LD / CD administration and 100 / 25 mg and 50 / 12.5 mg doses QD5 (fixed, every 3 hours, 8:00-20:00) for a total daily LD / CD dose of 400 / 100 mg (i.e., 100 / 25 mg, 50 / 12.5 mg, 100 / 25 mg, 50 / 12.5 mg, and 100 / 25 mg) and a 50 mg OPC QD regimen at least 1 hour after the last dose of LD / CD. 3rd period After completing one of two 2-week LD / CD 400 / 100 mg and 50 mg opicapone regimens, subjects were followed up for 1-2 weeks (post-study visit, POV).

[0073] Pharmacokinetic parameters The primary endpoint was pharmacokinetic-based, assessing the effect of once-daily administration of opicapone on levodopa pharmacokinetics. Pharmacokinetic study endpoints were established after each 2-week treatment regimen (i.e., at the end of Period 1 and Period 2). Pharmacokinetic assessments were performed over 12 hours, with sampling every 30 minutes, except for the final sampling at 1 hour after each levodopa dose in opicapone regimen #1.

[0074] Pharmacokinetic parameters evaluated for each dosing regimen included maximum plasma concentration (C max ), time to reach peak plasma levels (t max ), minimum plasma concentration (C min ), plasma elimination half-life (t 1 / 2 ), area under the curve (AUC), and variability index (mean concentration C avg The peak / trough ratio, i.e., the average concentration C avg C against max and C min FI) as a representation of

[0075] The pharmacokinetics of the levodopa metabolite, 3-O-methyldopa (3-OMD), was also evaluated.

[0076] Max C maxwas observed over the first three or four LD / CD doses, excluding data before the first dose, and the minimum C min FI was observed across the first three or four LD / CD doses, and FI was summarized for each treatment group based on all patients with estimable data (subjects were t 1 / 2 , C avg To estimate the terminal elimination rate constant required to estimate AUC and FI%, C max (You must have at least three data points after the

[0077] Clinical evaluation Clinical and safety / tolerability outcomes were also evaluated as exploratory secondary outcomes. Clinical outcomes included on- and off-time, assessed using a patient assessment tool. The timing of on- and off-states was registered by the investigator (in real time) during the 12-hour pharmacokinetic assessment and therefore only applied on the pharmacokinetic assessment day. Patients also completed a 24-hour Hauser on / off diary (30-minute increments) for the 3 days prior to each pharmacokinetic assessment visit. Diary states of interest were off-time and on-time, including on-time without dyskinesias, on-time with non-interfering dyskinesias, and on-time with interfering dyskinesias. Additionally, the Patient Global Impression-of-Change (PGI-C) score for opicapone 50 mg was assessed at the end of LD / CD 400 / 100 mg plus opicapone treatment compared with the baseline score. Safety and tolerability endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation.

[0078] All study evaluations were performed comparing each treatment regimen of LD / CD 400 / 100 mg plus opicapone 50 mg with the regimen of LD / CD 500 / 125 mg without opicapone.

[0079] Patient on / off diary A patient's 24-hour Hauser On / Off diary is divided into 30-minute intervals from 00:00 to 23:30. During each 30-minute interval, patients are asked to mark which state they are experiencing: "On without dyskinesias," "On with interfering dyskinesias," "On with non-interfering dyskinesias," "Off," and "Sleep."

[0080] Patient Global Impression-Change (PGI-C) The Patient Global Impression-Change (PGI-C) is a 7-point scale that measures the change in the patient's global impression relative to the baseline state at the start of the study. The following ratings are used to determine the change in subject global impression: "very improved," "much improved," "slightly improved," "no change," "slightly worse," "much worse," and "very worse." Improvers are those who are rated as "very improved," "much improved," or "slightly improved."

[0081] For each individual subject, the PGI-C scale is preferably scored by the same investigator / rater throughout the study.

[0082] D. Clinical Trial Results and Discussion overview Despite a reduction in the daily dose of LD / CD (from 500 / 125 mg to 400 / 100 mg), the addition of 50 mg opicapone significantly reduced the plasma half-life (t 1 / 2 ) at least doubled. 1 / 2 The effect on levodopata trough concentration (C min ) was also significantly increased by 2-fold, and the systemic exposure of levodopa (AUC total ) by approximately 30%, which had two direct consequences.

[0083] Addition of opicapone increased the maximum levodopa concentration (C max ) until the time (t max) was not affected by the addition of 50 mg opicapone to either opicapone regimen #1 or #2. max Although no significant effect was observed on levodopa C, the four-dose LD / CD 400 / 100 mg + 50 mg opicapone regimen (opicapone regimen #1) significantly reduced levodopa C max was observed to be non-significantly high (15%).

[0084] Levodopa C min Increased and stable C max resulted in a reduction (up to approximately 40%) in levodopa plasma fluctuations, as assessed by the levodopa fluctuation index (FI). Five doses of LD / CD400 / 100 mg plus 50 mg opicapone (opicapone regimen #2) reached statistical significance.

[0085] These results suggest that a short-interval levodopa dosing regimen results in less fluctuation in levodopa plasma levels and the smoothest levodopa pharmacokinetic profile compared with a long-interval dosing regimen. Therefore, when adding opicapone as adjunctive therapy, more frequent levodopa dosing may be beneficial in terms of managing motor fluctuations.

[0086] Modification of the pharmacokinetic profile of levodopa by the addition of opicapone was also associated with a reduction in OFF time and an increase in ON time.

[0087] PK results of LD / CD 500 / 125mg QD5 without opicapone compared with LD / CD 400 / 100mg QD4 + 50mg opicapone The four-dose LD / CD 400 / 100 mg + 50 mg opicapone regimen significantly increased the C of levodopa compared with the five-dose LD / CD 500 / 125 mg regimen without opicapone. max (Maximum observed C max ) resulted in a 15% increase, which was not statistically significant, and the C min was statistically significantly increased (approximately 2-fold, p=0.0016), and levodopa t 1 / 2 There was no significant difference in the levodopa concentration. 1 / 2 The AUC of levodopa was totalA corresponding statistically significant 27% increase in levodopa FI was achieved (p=0.0003). Levodopa FI was reduced compared to the 5-dose LD / CD 500 / 125 mg regimen without opicapone, but this 10% reduction was not statistically significant. See Tables 2 and 3 for results.

[0088] PK results of LD / CD 500 / 125mg QD5 without opicapone compared with LD / CD 400 / 100mg QD5 + 50mg opicapone The five-dose LD / CD 400 / 100 mg + 50 mg opicapone regimen resulted in a statistically significant increase in levodopa C min (approximately 2.5 times longer, p<0.0001); and 2 times longer levodopa t 1 / 2 resulting in a lower levodopa AUC total There was a corresponding 29% increase, which was statistically significant (p<0.0001). max or t max There was no significant difference between the stable C max There was a significant increase in C min This resulted in a statistically significant 40% lower levodopa FI ratio (final / evening levodopa / carbidopa intake was not included in the analysis, p<0.0001). See Tables 2 and 3 for results.

[0089] The results in Figure 2 show that the closely spaced levodopa dosing regimen provided the smoothest levodopa pharmacokinetic profile (opicapone regimen #2).

[0090] This suggests that when opicapone is included as adjunctive therapy, more frequent daily dosing of levodopa is more advantageous in terms of motor fluctuations than less frequent dosing.

[0091] Clinical outcomes of LD / CD 500 / 125mg QD5 without opicapone compared with LD / CD 400 / 100mg QD4 + 50mg opicapone 12-hour patient on / off monitoring Four doses of LD / CD 400 / 100 mg + 50 mg opicapone resulted in a non-significant 16% decrease in OFF time and a 16% increase in ON time compared to five doses of LD / CD 500 / 125 mg without opicapone (see Figure 3). Time to ON and time to best ON were decreased by 12% and 18%, respectively (for time to best ON, the decrease was significant, p=0.0439).

[0092] 24-hour patient on / off monitoring Four doses of LD / CD 400 / 100 mg + 50 mg opicapone resulted in a significant 12% decrease in total OFF time (p=0.0336) and an 11% increase in ON time (p=0.0015) compared with five doses of LD / CD 500 / 125 mg without opicapone (see Figure 3). ON time with interfering dyskinesias decreased by approximately 15% following the four doses of LD / CD 400 / 100 mg + 50 mg opicapone regimen.

[0093] PGI-C With the four-dose LD / CD 400 / 100 mg + 50 mg opicapone regimen, approximately 70% of patients reported improvement (very improved / quite improved / slightly improved) on the PGI-C, and approximately 33% experienced "very improved / quite improved."

[0094] See Table 3 for results.

[0095] Clinical outcomes of LD / CD 500 / 125mg QD5 without opicapone compared with LD / CD 400 / 100mg QD5 plus 50mg opicapone 12-hour patient on / off monitoring Five doses of LD / CD 400 / 100 mg plus 50 mg opicapone resulted in a significant 45% decrease (p=0.0013) in OFF time and a significant 47% increase (p=0.0002) in ON time compared with five doses of LD / CD 500 / 125 mg without opicapone (Figure 3). Time to ON and time to best ON were reduced by 34% and 15%, respectively (for time to best ON, the reduction was significant, p=0.0420).

[0096] 24-hour patient on / off monitoring Five doses of LD / CD 400 / 100 mg + 50 mg opicapone resulted in a significant 24% reduction in total OFF time (p=0.0056) and a significant 20% increase in ON time (p=0.0007) compared with five doses of LD / CD 500 / 125 mg without opicapone (see Figure 3). ON time with interfering dyskinesias decreased by approximately 36% following the five doses of LD / CD 400 / 100 mg + 50 mg opicapone regimen.

[0097] PGI-C With the five-dose LD / CD 400 / 100 mg + 50 mg opicapone regimen, approximately 92% of patients reported improvement (very improved / quite improved / slightly improved) on the PGI-C, with approximately 41.7% experiencing "much improvement."

[0098] See Table 3 for results.

[0099] [Table 2]

[0100] [Table 3]

Claims

1. 1. A method of treating Parkinson's disease in a patient who is receiving N doses of levodopa per day for a total daily dose of X mg of levodopa and who has begun to experience motor fluctuations or show signs of "wearing off," wherein treatment comprises administering more than N doses of levodopa per day for a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100-1000, N is 2-10, and Y is 25-50.

2. 1. Opicapone and levodopa for use in the treatment of Parkinson's disease in a patient who is receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa and who has begun to experience motor fluctuations or show signs of "wearing off", comprising administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, where X is 100-1000, N is 2-10, and Y is 25-50.

3. 1. Use of opicapone and levodopa in the manufacture of a medicament for the treatment of Parkinson's disease in a patient who is receiving N doses of levodopa per day to achieve a total daily dose of X mg of levodopa and who has begun to experience motor fluctuations or show signs of "wearing off", comprising administering more than N doses of levodopa per day to achieve a total daily dose of X mg of levodopa, and administering a single daily dose of Y mg of opicapone, wherein X is 100 to 1000, N is 2 to 10, and Y is 25 to 50.

4. 4. The method according to claim 1, the product for use according to claim 2, or the use according to claim 3, wherein Parkinson's disease is idiopathic Parkinson's disease.

5. 5. The method according to claim 1 or 4, the product for the use according to claim 2 or 4, or the use according to claim 3 or 4, wherein N is 3 to 6.

6. 6. The method, product for use or use according to claim 5, wherein N is 4.

7. 7. The method of any one of claims 1 or 4 to 6, the product for use of any one of claims 2 or 4 to 6, or the use of any one of claims 3 to 6, wherein X is from 300 to 600.

8. 8. The method, product for use or use according to claim 7, wherein X is 400.

9. 9. The method of any one of claims 1 or 4 to 8, the product for use of any one of claims 2 or 4 to 8, or the use of any one of claims 3 to 8, wherein Y is 25 or 50.

10. 10. The method, product for use or use of claim 9, wherein the patient is receiving four doses of levodopa for a total daily dose of 400 mg per day and the treatment comprises administering five doses of levodopa per day for a total daily dose of 400 mg levodopa, and administering a single daily dose of 50 mg of opicapone.

11. The method according to any one of claims 1 or 4 to 10, the product for use according to any one of claims 2 or 4 to 10, or the use according to any one of claims 3 to 10, wherein the levodopa dose is not the same from administration to administration.

12. 12. The method, product for use or use according to claim 11, wherein the levodopa dosage is higher in odd-numbered doses.

13. 12. The method, product for use or use according to claim 11, wherein the even doses of levodopa are high.

14. 13. The method, product for use or use of any one of claims 10 to 12, wherein five doses of levodopa to provide a total daily dose of 400 mg of levodopa are administered in the following dosage regime: 100 mg, 50 mg, 100 mg, 50 mg and 100 mg.

15. 15. The method of any one of claims 1 or 4 to 14, the product for use of claims 2 or 4 to 14, or the use of any one of claims 3 to 14, wherein the single daily dose of opicapone is administered at least 1 hour after the last levodopa dose.

16. 16. The method of any one of claims 1 or 4 to 15, the product for use of claims 2 or 4 to 15, or the use of any one of claims 3 to 15, wherein the patient is receiving N doses of dopamine decarboxylase inhibitor (DDCI) for a total daily dose of Z mg of DDCI, and the method further comprises administering more than N doses of DDCI per day for a total daily dose of Z mg of DDCI, where Z is between 50 and 250.

17. 17. The method, product for use or use according to claim 16, wherein the DDCI is carbidopa or benserazide.

18. 18. The method, product for use or use according to claim 16 or 17, wherein the DDCI dose is administered together with the levodopa dose.

19. 19. The method, product for use or use of claim 17 or 18, wherein the patient is receiving four doses of carbidopa per day for a total daily dose of 100 mg, and the treatment comprises administering five doses of carbidopa per day for a total daily dose of 100 mg of carbidopa.

20. 20. The method, product for use or use of any one of claims 1 to 19, wherein the treatment results in a reduction in "time to best on".

21. 21. The method, product for use or use of any one of claims 1 to 20, wherein treatment results in a reduction in on-time associated with disabling dyskinesias.

22. 22. The method, product for use or use according to any one of claims 1 to 21, wherein the treatment results in an improvement in the patient's global impression change.

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