Therapeutic regimen for Parkinson's disease

Abstract

A method of treating Parkinson's disease in a patient that accepts N doses per day of levodopa to provide X mg total daily dose of levodopa and that begins to experience motion fluctuations or begin to show a sign of "hypoefficacy", the treatment comprises administering more than N doses per day of levodopa to provide X mg of a total daily dose of levodopa, and administering Y mg of opirapone in a single daily dose, where X is from 100 to 1000, N is from 2 to 10, and Y is from 25 to 50.

Description

Technical Field

[0001] The present invention relates to optimized dosing regimens of levodopa and a COMT inhibitor for the treatment of Parkinson's disease in patients who begin to experience end-of-dose motor fluctuations (or begin to show signs of "wearing off"). Background Art

[0002] Levodopa (Levodopa, L-DOPA) has been used in clinical practice for the symptomatic treatment of various diseases including Parkinson's disease for decades. L-DOPA can cross the blood-brain barrier and then be converted into dopamine by dopamine decarboxylase (DDC), thereby increasing the dopamine level in the brain. However, the conversion of L-DOPA to dopamine may also occur in peripheral tissues, thereby possibly causing harmful effects. Therefore, the co-administration of peripheral DDC inhibitors (DDCI) (such as carbidopa (carbidopa) or benserazide (benserazide)) has become standard clinical practice, and the peripheral AADC inhibitors prevent conversion into dopamine in peripheral tissues.

[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 who receive long-term levodopa / DDCI will develop motor complications, such as end-dose 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 "efficacy reduction". Patients often report spending several hours a day experiencing end-dose motor fluctuations in the so-called "off" state, which can have a significant impact on 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 end-dose motor fluctuations, defines the transition of Parkinson's disease from the early stages to the more advanced stages of the disease. Therefore, controlling motor complications ultimately becomes a critical clinical need in almost all patients (Poewe W, Neurology, 2009, 72, S65–73).

[0004] End-of-dose fluctuations are related to the short half-life of oral levodopa (approximately 60–90 min). Adjusting the size and / or frequency of levodopa doses is a common approach to control response fluctuations. However, increasing the total daily dose of levodopa by increasing the dosing frequency may worsen the severity of dyskinesias, while dividing the total daily dose into more frequent smaller doses may be associated with intermittent recurrence of symptoms due to oscillations of plasma concentrations above and below the threshold that controls the clinical response to levodopa. Since neither of these approaches can address the short long half-life of conventional levodopa, an alternative pharmacological approach is to optimize levodopa delivery to the brain and control levodopa-related complications by administering levodopa / DDCIs and catechol-O-methyltransferase (COMT) inhibitors that increase the plasma elimination half-life of levodopa and reduce peak-to-trough variations.

[0005] Opicapone is a potent and long-acting COMT inhibitor that can reduce the degradation of levodopa into an inactive metabolite, 3-O-methyldopa. Opicapone is biologically active, bioavailable and exhibits low toxicity. Therefore, Opicapone has potentially valuable drug properties in the treatment of some central and peripheral nervous system disorders, in which the inhibition of COMT may have therapeutic benefits, such as, for example, mood disorders; movement disorders, such as Parkinson's disease, Parkinson's disorder and restless legs syndrome; gastrointestinal disorders; edema formation state; and hypertension. The development of Opicapone is described in LEKiss et al., J.Med.Chem., 2010, 53, 3396-3411, and was approved in June 2016 in the European Union, in April 2020 in the United States, and in June 2020 in Japan under the brand name "Ongentys" for use in combination with L-DOPA for the treatment of Parkinson's disease.

[0006] In the key Phase III clinical trials BIPARK-I (Ferreira et al., Lancet Neurol., 2016, 15, 154-65) and BIPARK-II (Lees et al., JAMA Neurol., 2017, 74, 197-206) supporting these approvals, the treatment regimens of the subjects were not standardized before entering the trial. Therefore, the subjects received a variety of levodopa regimens, and the effect of the levodopa treatment regimen (total daily dose and frequency of intake) on the clinical effect of opicapone in controlling motor fluctuations was not studied.

[0007] The previously licensed COMT inhibitor entacapone was tested in patients with early idiopathic Parkinson's disease (i.e., patients without motor complications) (Stocchi F et al. Initiating levodopa / carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study, Ann Neurol 2010: 68(1): 18-27). The STRIDE-PD trial is the only controlled trial to investigate long-term optimized delivery of levodopa, including the use of an enzyme inhibitor to prevent or delay motor complications at the start of treatment in levodopa-naive patients. The trial failed to demonstrate that starting levodopa therapy with a COMT inhibitor (entacapone) delayed the onset of dyskinesias or reduced their frequency compared with levodopa therapy alone. In fact, the addition of entacapone was associated with a shortened onset of motor complications and an increased frequency of dyskinesias.

[0008] Therefore, there remains a need to improve the safety and efficacy of Parkinson's disease treatments when a patient's symptoms are no longer controlled by levodopa, without inducing motor complications due to overdosing of levodopa. In particular, there remains a need for more effective regimens for treating Parkinson's disease in patients who begin to experience end-of-dose motor fluctuations (or begin to show signs of "wearing off").

[0009] The present invention is derived from the results of clinical studies conducted by the inventors. Details of the trial 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 online at the 7th European Academy of Neurology (EAN) meeting from June 19 to 22, 2021. No results were presented.

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

[0011] The present inventors have discovered an optimized dosing regimen of levodopa and a COMT inhibitor for treating Parkinson's disease, particularly idiopathic Parkinson's disease, in patients who begin to experience end-of-dose motor fluctuations (or begin to show signs of "wearing off").

[0012] Thus, in a first general embodiment, the invention provides a method of treating Parkinson's disease in a patient who is receiving N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off," said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg; wherein: X is 100 to 1000, N is 2 to 10 and Y is 25 to 50.

[0013] In a second general embodiment, the invention provides opicapone and levodopa for use in treating Parkinson's disease in a patient who is receiving N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience motor fluctuations or begins to show signs of "wearing off," said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg, wherein X is 100 to 1000, N is 2 to 10 and Y is 25 to 50.

[0014] In a third general embodiment, the invention provides the use of opicapone and levodopa in the manufacture of a medicament for treating Parkinson's disease in a patient who receives N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience motor fluctuations or begins to show signs of "wearing off," said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg, wherein X is from 100 to 1000, N is from 2 to 10 and Y is from 25 to 50. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The present invention will now be described in detail with reference to the accompanying drawings, in which:

[0016] Figure 1 The design of the clinical study is shown. LD = Levodopa; CD = Carbidopa; PK = Pharmacokinetics; R = Randomization: V1 - V4 = Visit 1 - Visit 4.

[0017] Figure 2 shows the mean levodopa plasma profile over time following 2-week 5-ingestion (every 3 hours) daily oral administration of LD / CD 500 / 125 mg compared to 2-week 4-ingestion (every 4 hours) daily oral administration of LD / CD 400 / 100 mg plus 50 mg opicapone (A), or compared to 2-week 5-ingestion (every 3 hours) daily oral administration of LD / CD 400 / 100 mg plus 50 mg opicapone (B); LD / CD = levodopa / carbidopa.

[0018] FIG3 shows 12-hour ON- / OFF-time data reported for pharmacokinetic days superimposed with the mean levodopa plasma profile over time following 2-week 5-ingestion (every 3 hours) daily oral administration of levodopa / carbidopa 500 / 125 mg without opicapone (A) compared to 2-week 4-ingestion (every 4 hours) daily oral administration of levodopa / carbidopa 400 / 100 mg plus once daily opicapone 50 mg ( B); and 2-week 5-ingestion (every 3 hours) oral daily administration of levodopa / carbidopa 500 / 125 mg without opicapone (C), compared to 2-week 5-ingestion (every 3 hours) oral daily administration of levodopa / carbidopa 400 / 100 mg plus once daily opicapone 50 mg (D); LD / CD=levodopa / carbidopa; OPC=opicapone; arrow=ON time; bar=ON state period; vertical solid line=optimal ON time.

[0019] Figure 4 is a schematic diagram showing the following: typical levodopa pharmacokinetics; C max = maximum (rise, peak) levodopa concentration level in plasma; C min = lowest (decline, trough) levodopa concentration level in plasma; Fluctuation index (FI) = the amplitude of the rise and fall of levodopa levels in plasma, calculated as [(C max -C min ) / C avg ]*100; AUC (area under the curve) = systemic exposure of levodopa in plasma over time. DETAILED DESCRIPTION

[0020] A. Definition

[0021] Unless otherwise limited in specific instances, the following definitions apply to the terms as used throughout this specification.

[0022] The term "idiopathic Parkinson's disease" covers most (80-85%) Parkinson's disease (diagnosed according to the United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria or the Movement Disorder Society criteria) and does not include atypical Parkinson's disease, secondary [acquired or symptomatic] Parkinson's disease, and Parkinson's plus syndromes, such as drug-induced Parkinson's disease, vascular Parkinson's disease, normal pressure hydrocephalus, cortical basal degeneration, progressive supranuclear palsy, and multiple system atrophy. Idiopathic Parkinson's disease typically involves marked bradykinesia and a variety of associated extrapyramidal signs and symptoms. Idiopathic Parkinson's disease is often accompanied by degeneration of the nigrostriatal dopaminergic system, with autopsy findings of neuronal loss and reactive gliosis in the substantia nigra. In idiopathic Parkinson's disease, alpha-synuclein typically accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites).

[0023] The term "GBA1 carrier Parkinson's disease" or "GBA-associated Parkinson's disease" refers to a specific group of Parkinson's disease patients who have mutations in both copies of the GBA1 gene, which encodes the enzyme glucocerebrosidase (GCase). These heterozygous mutations are associated with a higher risk of developing Parkinson's disease. In the United States, approximately 10% of the overall patient population clinically diagnosed with Parkinson's disease carries a GBA1 mutation.

[0024] The term "symptoms of Parkinson's disease" includes motor symptoms (e.g., tremor, rigidity, bradykinesia, 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 may be assessed using one or more of the symptom readouts described below, including clinical assessments (e.g., 12-hour and 24-hour diaries and PGI-C).

[0025] The term "motor complications" relates to motor symptoms of Parkinson's disease associated with levodopa therapy. Motor complications occur when levodopa / DDCI therapy alone no longer provides complete control of the patient's symptoms. Motor complications include motor fluctuations and / or dyskinesias. Motor complications persist, but not necessarily regularly or predictably, such that motor complications have a quantifiable negative impact on the patient's quality of life (QoL). "Clinically diagnosed motor complications" typically result in a total score of MDS-UPDRS Part IV A+B+C greater than 6, preferably greater than 3, more preferably greater than 0, and / or one or more positive symptoms in the 9-item Weakness of Effect Questionnaire (WOQ-9). A total score of MDS-UPDRS Part IV A+B+C greater than 0 (zero) is the most preferred definition of a clinically diagnosed motor complication. It should be noted that motor complications can be the same as motor symptoms of Parkinson's disease. However, if the motor symptoms are initially treatable by levodopa / DDCI therapy, but the motor symptoms reappear in the later stages of the disease despite maintaining levodopa / DDCI therapy, the motor symptoms are considered motor complications.

[0026] The term "motor fluctuations" includes end-of-dose fluctuations (also called wearing off phenomenon), paradoxical fluctuations, and unpredictable ON / OFF periods.

[0027] The term "OFF period" or "OFF episode" is defined as the time during which a patient treated with levodopa no longer experiences the symptomatic benefit of levodopa and is referred to as being in the "OFF" state. On the other hand, the term "ON period" or "ON episode" is defined as the time during which a patient treated with levodopa experiences the symptomatic benefit of levodopa and is referred to as being in the "ON" state.

[0028] The term "optimal ON time" refers to the time until a patient experiences a maximum symptomatic effect following administration of a dose of levodopa / DDCI therapy.

[0029] The term "end-dose motor surge" is also known as the "wearing off" phenomenon and is associated with a predictable reappearance or worsening of symptoms before the next dose of levodopa / DDCI therapy is administered. Typically, this reappearance or worsening of symptoms begins 3-4 hours after levodopa administration and symptoms reappear or worsen as the drug wears off. Symptoms typically improve 15-45 minutes after the next levodopa dose.

[0030] Patients who "begin to experience motor fluctuations" or "begin to show signs of "wearing off"" include patients whose clinically confirmed motor fluctuations have lasted for up to 3 years, including up to 2 years, or even up to 1 year. Patients whose motor fluctuations have lasted for up to 1 year are referred to as "early motor fluctuation sufferers." Typically, a patient "begins to experience motor fluctuations" when they are treated with levodopa and begin to experience detectable "OFF periods" or "OFF episodes."

[0031] 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 motor restlessness), high-stepping excessive gait, rapid alternating leg movements (RAM), blepharospasm, and abnormal movements of mixed patterns (Fahn S., Ann. Neurol., 2000, 47, S2-S9).

[0032] The term "ON" with troublesome dyskinesias is a period after administration of a dose of levodopa / DDCI therapy when the patient is limited in activity due to the presence of dyskinesias, but experiences some symptom relief consistent with an "ON period".

[0033] The term "adjuvant therapy", also known as "add-on therapy", "add-on therapy" or "adjunctive care", is a therapy given in addition to the primary or initial therapy to maximize its effect. In current use, levodopa is the primary therapy, while DCCI and COMT inhibitors (i.e., opicapone) are adjuvant therapies.

[0034] The term "treatment-emergent adverse event" was defined as any event that was not present prior to exposure to study drug or any event that was present and worsened in intensity or frequency after the first intake of study drug until 2 weeks after the last intake of study drug.

[0035] The term “maximum observed plasma concentration” or “C max " is the highest (upward, peak) drug concentration level found in plasma. In the current application, it is the highest levodopa concentration level found in plasma. C max Increases in dopamine lead to an increased risk of dopamine-induced side effects such as dyskinesias.

[0036] The term “lowest observed plasma concentration” or “C min " is the lowest (decline, trough) drug concentration level found in plasma. In the current application, it is the lowest levodopa concentration level found in plasma. C min An increase in the C max The increase in C minThe risk of developing motor complications is reduced if the increase is not the same or greater than that of

[0037] The term “mean observed plasma concentration” or “C avg ” is the mean plasma drug concentration during the dosing interval at steady state.

[0038] The term “fluctuation index” or “FI” is the magnitude of the rise and fall of drug levels in plasma and is calculated as [(C max -C min ) / C avg ]*100. In current applications, the fluctuation index is the rise and fall of plasma levodopa levels. An increase in FI leads to an increased risk of developing motor complications.

[0039] The term "area under the curve" or "AUC" is the systemic exposure of a drug in plasma over time. In this application, the area under the curve is the systemic exposure of levodopa in plasma over time. An increase in AUC results in an increase in the time in the ON state (i.e., a decrease in the time in the OFF state).

[0040] Other variations to the disclosed embodiments may be understood and effected by those skilled in the art in practicing the claimed invention, by studying the disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does 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.

[0041] B. Treatment of Parkinson's disease in patients who begin to experience end-of-dose motor fluctuations (or begin to show signs of "wearing off"

[0042] The present invention provides a dosing regimen of levodopa plus opicapone for treating Parkinson's disease, particularly idiopathic Parkinson's disease, in patients who begin to experience end-of-dose motor fluctuations (or begin to show signs of "wearing off").

[0043] In a first general embodiment, the invention provides a method of treating Parkinson's disease in a patient who is receiving N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off," said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg; wherein: X is 100 to 1000, N is 2 to 10 and Y is 25 to 50.

[0044] In a second general embodiment, the invention provides opicapone and levodopa for use in treating Parkinson's disease in a patient who is receiving N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience motor fluctuations or begins to show signs of "wearing off," said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg, wherein X is 100 to 1000, N is 2 to 10 and Y is 25 to 50.

[0045] In a third general embodiment, the invention provides the use of opicapone and levodopa in the manufacture of a medicament for treating Parkinson's disease in a patient who receives N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience motor fluctuations or begins to show signs of "wearing off," said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg, wherein X is from 100 to 1000, N is from 2 to 10 and Y is from 25 to 50.

[0046] The following implementations are compatible with the general implementation and with each other:

[0047] In another embodiment, Parkinson's disease is idiopathic Parkinson's disease or GBA1 carrier Parkinson's disease. In a preferred embodiment, Parkinson's disease is idiopathic Parkinson's disease, which accounts for the majority of Parkinson's disease.

[0048] In another embodiment, N is 3 to 6, preferably N is 3 to 5, more preferably 3 to 4. In an even more preferred embodiment, N is 4.

[0049] In another embodiment, "more than N doses" are N+1 or N+2 doses. In a preferred embodiment, "more than N doses" are N+1 doses.

[0050] In another embodiment, X is from 300 to 600, preferably from 300 to 500, more preferably from 300 to 400. In an even more preferred embodiment, X is 400.

[0051] In another embodiment, Y is 25 or 50. For example, Y is 25. For example, Y is 50.

[0052] In a particularly preferred embodiment, the patient receives 4 doses of levodopa to provide a total daily dose of 400 mg per day and the treatment comprises administering 5 doses of levodopa per day to provide a total daily dose of 400 mg levodopa and administering a single daily dose of 50 mg of opicapone.

[0053] In another embodiment, for each dosage, the levodopa dosage amount is not the same. For example, for an odd-numbered dosage, the levodopa dosage amount is higher. For example, for an even-numbered dosage, the levodopa dosage amount is higher. Standard levodopa dosage amounts include 250 mg, 100 mg, 75 mg, or 50 mg. Most patients take a single amount of levodopa per dosage, such as 100 mg per dosage.

[0054] In a particularly more preferred embodiment, the patient receives 4 doses of levodopa to provide a total daily dose of 400 mg per day and the treatment comprises administering 5 doses of levodopa per day to provide a total daily dose of 400 mg of levodopa and administering a single daily dose of 50 mg of opicapone, wherein the 5 doses of levodopa to provide a total daily dose of 400 mg of levodopa are administered at the following dosing schedule: 100 mg, 50 mg, 100 mg, 50 mg and 100 mg.

[0055] In another embodiment, the single daily dose of opicapone is administered at least 1 hour after the last dose of levodopa.

[0056] In another embodiment, the patient receives N doses of a dopamine decarboxylase inhibitor (DDCI) to provide a total daily dose of Z mg of DDCI, and the method further comprises administering more than N doses of DDCI per day to provide a total daily dose of Z mg of DDCI, wherein Z is 50 to 250, preferably 75 to 150.

[0057] In another embodiment, the DDCI is carbidopa or benserazide. For example, the DDCI is carbidopa. For example, the DDCI is benserazide.

[0058] In another embodiment, a dose of DDCI is administered together with a dose of levodopa.

[0059] In a particularly preferred embodiment, the patient receives 4 doses of carbidopa to provide a total daily dose of 100 mg per day, and the treatment comprises administering 5 doses of carbidopa per day to provide a total daily dose of 100 mg of carbidopa.

[0060] In a particularly preferred embodiment, the patient receives 4 doses of levodopa / carbidopa to provide a total daily dose of 400 / 100 mg of levodopa / carbidopa per day and the treatment comprises administering 5 doses of levodopa / carbidopa per day to provide a total daily dose of 400 / 100 mg of levodopa / carbidopa and administering a single daily dose of 50 mg of opicapone.

[0061] In a particularly more preferred embodiment, the patient receives 4 doses of levodopa / carbidopa to provide a total daily dose of 400 / 100 mg per day and the treatment comprises administering 5 doses of levodopa / carbidopa per day to provide a total daily dose of 400 / 100 mg of levodopa / carbidopa and administering a single daily dose of 50 mg of opicapone, wherein the 5 doses of levodopa / carbidopa to provide a total daily dose of 400 / 100 mg of levodopa / carbidopa are administered at the following dosing regimen: 100 / 25 mg, 50 / 12.5 mg, 100 / 25 mg, 50 / 12.5 mg and 100 / 25 mg.

[0062] In another embodiment, a patient who begins to experience motor fluctuations or begins to show signs of "wearing off" is a patient whose motor fluctuations have lasted for up to 3 years, preferably up to 2 years, more preferably up to 1 year.

[0063] The following results demonstrate that the addition of opicapone and splitting of one or more levodopa doses improves the treatment of Parkinson's disease (e.g., idiopathic Parkinson's disease) in patients who otherwise did not receive full treatment benefit. The findings are encompassed in the three general embodiments described above. Based on these data, it is expected that patients can reduce their total dose of levodopa (and DCCI) by adding opicapone and splitting of one or more levodopa doses.

[0064] For example, it is contemplated that the present invention may provide a method of treating Parkinson's disease in a patient who receives N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off", said treatment comprising administering less than X mg of the total daily dose of levodopa per day, and administering Y mg of a single daily dose of opicapone; wherein: X is 100 to 1000, N is 2 to 10, Y is 25 to 50 and "less than X mg of levodopa per day" involves a reduction of at least X / 2N mg, preferably "less than X mg of levodopa per day" involves a reduction of at least X / N mg. mg; the method does not include treating Parkinson's disease in a patient who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off" and the patient receives 5 doses of levodopa to provide a total daily dose of 500 mg per day, the treatment comprising administering 5 doses of levodopa per day to provide a total daily dose of 400 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the 5 doses of levodopa provide a total daily dose of 400 mg of levodopa, and are administered according to the following dosing schedule: 100 mg, 50 mg, 100 mg, 50 mg and 100 mg. Preferably, the method involves more than one single dose amount (e.g., two single dose amounts, such as a combination of 50 mg and 100 mg levodopa during one day).

[0065] Specific examples of results support include:

[0066] A method of treating Parkinson's disease in a patient who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off" and who is receiving 3 doses of levodopa to provide a total daily dose of 300 mg per day, the treatment comprising administering 3 doses of levodopa per day to provide a total daily dose of levodopa of 200 mg, and administering a single daily dose of 50 mg of opicapone, wherein the 3 doses of levodopa provide a total daily dose of levodopa of 200 mg, and are administered according to the following dosing schedule: 100 mg, 50 mg, and 50 mg.

[0067] A method of treating Parkinson's disease in a patient who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off" and who is receiving 4 doses of levodopa to provide a total daily dose of 400 mg per day, the treatment comprising administering 4 doses of levodopa per day to provide a total daily dose of 300 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the 4 doses of levodopa provide a total daily dose of 300 mg of levodopa and are administered according to the following dosing schedule: 100 mg, 50 mg, 100 mg, and 50 mg.

[0068] A method of treating Parkinson's disease in a patient who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off" and who is receiving 3 doses of levodopa to provide a total daily dose of 300 mg per day, the treatment comprising administering 4 doses of levodopa per day to provide a total daily dose of levodopa of 250 mg, and administering a single daily dose of 50 mg of opicapone, wherein the 4 doses of levodopa provide a total daily dose of levodopa of 250 mg, and are administered according to the following dosing schedule: 100 mg, 50 mg, 50 mg, and 50 mg.

[0069] A method of treating Parkinson's disease in a patient who begins to experience end-of-dose motor fluctuations or begins to show signs of "wearing off" and who is receiving 4 doses of levodopa to provide a total daily dose of 400 mg per day, the treatment comprising administering 5 doses of levodopa per day to provide a total daily dose of 300 mg of levodopa, and administering a single daily dose of 50 mg of opicapone, wherein the 5 doses of levodopa provide a total daily dose of 300 mg of levodopa and are administered according to the following dosing schedule: 100 mg, 50 mg, 50 mg, 50 mg, and 50 mg.

[0070] C. Clinical Program

[0071] The present invention was discovered through a Phase II randomized, open-label trial evaluating the effects of opicapone (50 mg, once daily) on the pharmacokinetics of L-DOPA in Parkinson's disease patients with end-dose motor fluctuations using different levodopa / carbidopa (LD / CD) sparing regimens (EudraCT number: 2020-003139-12).

[0072] Subjects were aged ≥30 years, clinically diagnosed with idiopathic Parkinson's disease according to the UK Parkinson's Disease Association Brain Bank clinical diagnostic criteria, with disease severity of stage 1-3 (according to the modified Hoehn and Yahr staging) during ON, and had end-of-dose motor fluctuations and signs of "wearing off". Subjects had been treated with levodopa / DDCI for at least 1 year with significant clinical improvement.

[0073] The Hoehn and Yahr scale is used to describe the progression of Parkinson's disease symptoms. The original version (Hoehn M., Yahr M., Neurology, 1967, 17, 427-42) includes stages 1 to 5. The modified version includes additional stages 1.5 and 2.5 to record the intermediate stages of Parkinson's disease.

[0074] Although there were no specific requirements for levodopa dosing frequency, all enrolled patients received a 5-day regimen of LD / CD 500 / 125 mg. Patients were excluded if they: experienced severe and / or unpredictable "OFF" periods; had received extended-release levodopa / DDCI treatment in the last four weeks before screening; were taking contraindicated medications (neuroleptics, venlafaxine, monoamine oxidase (MAO) inhibitors [except selegiline, safinamide, or rasagiline], or antiemetics with antidopaminergic effects [except domperidone]; or had previously received any COMT inhibitor (entacapone, tolcapone, or opicapone).

[0075] Identification of research products

[0076] Opicapone can be synthesized as described in WO 2013 / 089573 and formulated as 50 mg capsules as described in WO 2010 / 114405. Opicapone is taken orally once daily in the evening at least 1 hour after the last daily dose of L-DOPA / DDCI (considered as a bedtime dose).

[0077] Table 1A Opicapone (Ongentys)

[0078] Active ingredients: Opicapon strength: 50 mg hard capsule for oral administration Manufacturer: BIAL–Portela & Ca, SA

[0079] Table 1B Levodopa / Carbidopa (fixed combination)

[0080] Active ingredients: L-3,4-dihydroxyphenylalanine (L-DOPA) / Carbidopa strength: 100mg / 25mg and 50mg / 12.5mg tablets for oral administration Manufacturer: Central Pharmacy at PRA Health Sciences,Netherlands

[0081] Clinical trial design

[0082] As described below, details of the trial 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) meeting from June 25 to 22, 2022. No results were presented.

[0083] The study design Figure 1 In the description.

[0084] Eligible subjects received the following study treatments during different study periods:

[0085] Phase 1

[0086] After screening, all subjects received the LD / CD dose and regimen, i.e., 100 / 25 mg QD5 (giving a total daily dose of 500 / 125 mg), fixed every 3 hours (8:00 to 20:00) for 14 ± 2 days. This is the reference regimen.

[0087] Phase 2

[0088] Patients were then randomized (1:1) to receive one of two different treatment regimens, opicapone 50 mg plus LD / CD (400 / 100 mg daily), for an additional 14 ± 2 days.

[0089] Opicapone Regimen #1: Subjects received a LD / CD dose and regimen of 100 / 25 mg QD4 (8:00 to 20:00, fixed every 4 hours) with a total daily dose of 400 / 100 mg LD / CD plus 50 mg OPC QD at least 1 hour after the last dose of LD / CD.

[0090] Opicapone Regimen #2: Subjects received alternating LD / CD doses and schedules, i.e., 100 / 25 mg and 50 / 12.5 mg doses QD5 (fixed every 3 hours from 8:00 to 20:00) with a total daily dose of 400 / 100 mg LD / CD (i.e., 100 / 25 mg, 50 / 12.5 mg, 100 / 25 mg, 50 / 12.5 mg, and 100 / 25 mg) plus 50 mg OPC QD at least 1 hour after the last administration of LD / CD.

[0091] Phase 3

[0092] Subjects were followed up 1 to 2 weeks after completing one of two 2-week regimens of LD / CD 400 / 100 mg plus opicapone 50 mg (Post-Study Visit, POV).

[0093] Pharmacokinetic parameters

[0094] The primary endpoint was pharmacokinetic based, evaluating the effect of once-daily opicapone on the pharmacokinetics of levodopa. Pharmacokinetic study endpoints were set after 2 weeks of each treatment regimen (i.e., at the end of period 1 and at the end of period 2). Pharmacokinetic assessments were performed over 12 hours with samples taken every 30 minutes, except for the last sample after each levodopa dose in opicapone regimen #1, which was taken at 1 hour.

[0095] The pharmacokinetic parameters evaluated for each regimen included the maximum observed plasma concentration (C max ), time to peak plasma level (t max ), minimum observed plasma concentration (C min ), plasma elimination half-life (t 1 / 2 ), area under the curve (AUC) and fluctuation index (FI, as peak-to-trough fluctuation, C max and C min Relative to the average concentration C avg ).

[0096] The pharmacokinetics of the levodopa metabolite 3-O-methyldopa (3-OMD) were also evaluated.

[0097] Max C max was observed in the first 3 or 4 LD / CD doses, with the minimum C min The FI was observed in the first 3 or 4 LD / CD doses (excluding data before the first dose), and was also summarized for each treatment group based on all patients with estimable data (subjects in C max You must have at least 3 data points to estimate: 1 / 2 , C avg, AUC and FI% required for the terminal elimination rate constant).

[0098] Clinical evaluation

[0099] Clinical and safety / tolerability outcomes were also assessed as exploratory secondary outcomes. Clinical outcomes included ON and OFF-times assessed using a patient-rated tool. The researchers registered the time of the ON and OFF states during the matching 12-hour pharmacokinetic assessment (in real time) (thus only applicable to pharmacokinetic days), and patients also completed a 24-hour Hauser ON / OFF log chart (in 30-minute blocks) during the three days before each pharmacokinetic visit. The log states of interest were OFF-time and ON-time, including ON without dyskinesia, ON with no troublesome dyskinesia, and ON with troublesome dyskinesia. In addition, the patient's global impression change (PGI-C) of opicapone 50 mg compared to before the start of opicapone treatment was assessed at the end of LD / CD 400 / 100 mg plus opicapone treatment. Safety and tolerability endpoints include adverse events (TEAEs) emerging during treatment, serious TEAEs, and TEAEs leading to discontinuation.

[0100] All study evaluations were performed for each LD / CD 400 / 100 mg plus opicapone 50 mg regimen (compared to LD / CD 500 / 125 mg without opicapone).

[0101] Patient ON / OFF log

[0102] The 24-hour patient Hauser ON / OFF log chart was divided into 30-minute periods running from 00:00 to 23:30. During each 30-minute interval, patients were asked to mark the state they experienced, namely "ON without dyskinesia", "ON with troublesome dyskinesia", "ON with non-troublesome dyskinesia", "OFF", and "ASLEEP".

[0103] Patient Global Impression of Change (PGI-C)

[0104] The Patient Global Impression of Change (PGI-C) is a 7-point scale that measures a person's overall impression of change from their baseline status at the beginning of the study. The following ratings were used to determine the change in the subject's global impression: "very improved"; "much improved"; "slightly improved"; "no change"; "slightly worse"; "much worse"; or "very worse". People who improved were those who were rated as "very improved", "much improved", or "slightly improved".

[0105] For a single subject, the PGI-C scale is preferably scored by the same investigator / assessor throughout the study.

[0106] D. Clinical trial results and discussion

[0107] Overall summary

[0108] Despite a reduction in the daily LD / CD dose (400 / 100 mg instead of 500 / 125 mg), the addition of 50 mg opicapone increased the plasma half-life of levodopa (t 1 / 2 ) at least doubled. 1 / 2 The effect of levodopa on the min ) also increased significantly by 2-fold, while the systemic exposure of levodopa (AUC 总 ) also corresponds to a significant increase of about 30%.

[0109] The addition of opicapone significantly reduced the maximum levodopa concentration (C max ) time (t max Although no effect on C was observed when 50 mg of opicapone was added to either opicapone regimen #1 or #2, max However, a non-significant increase (15%) in levodopa C was observed in the 4-dose LD / CD400 / 100 mg plus 50 mg opicapone regimen (opicapone regimen #1). max .

[0110] Levodopa C min The increase and stability of C max The combination resulted in a decrease in levodopa plasma excursions (up to about 40%) as assessed by the levodopa fluctuation index (FI). Statistically significant results were achieved with 5-intake of LD / CD 400 / 100 mg plus 50 mg opicapone (opicapone regimen #2).

[0111] The results suggest that a shorter levodopa dosing interval regimen provides the smoothest levodopa pharmacokinetic profile with less fluctuation in levodopa plasma levels compared with a longer dosing interval. Therefore, increasing the frequency of levodopa dosing when adding opicapone as adjunctive therapy may offer advantages in controlling motor fluctuations.

[0112] Alteration of the pharmacokinetic profile of levodopa by the addition of opicapone was also associated with decreased OFF time and increased ON time.

[0113] LD / CD500 / 125mg QD5 without opicapone compared to LD / CD400 / 100mg QD4 plus 50mg opicapone PK results

[0114] Compared with the 5-dose LD / CD 500 / 125 mg regimen without opicapone, the 4-dose LD / CD 400 / 100 mg regimen plus 50 mg opicapone increased the C of levodopa by 1. max Increased by 15% (maximum observed C max ), no statistical significance; L-dopa C min There was a statistically significant increase (approximately 2-fold, p=0.0016); and levodopa t max There was no significant difference. 1 / 2 also increased by 2-fold, resulting in a levodopa AUC 总 This corresponds to a statistically significant increase of 27% (p=0.0003). Although there was a decrease in levodopa FI compared to the 5-intake LD / CD 500 / 125 mg regimen without opicapone, the 10% decrease was not statistically significant. The results are shown in Tables 2 and 3.

[0115] LD / CD 500 / 125 mg QD5 without opicapone and LD / CD 400 / 100 mg QD5 plus 50 mg opicapone Comparative PK results

[0116] 5- The regimen of LD / CD 400 / 100 mg plus 50 mg opicapone had a statistically significantly higher levodopa C min (about 2.5 times, p<0.0001); and levodopa t 1 / 2 prolonged by more than 2-fold, resulting in a decrease in the AUC of levodopa 总 This corresponds to an increase of 29%, which is statistically significant (p<0.0001). max and t max There is no significant difference. Stable C max With a significant increase in C min This resulted in a statistically significant 40% reduction in the L-dopa FI ratio (last / night L-dopa / carbidopa intake was not included in the analysis, p<0.0001). See Tables 2 and 3 for results.

[0117] The results in Figure 2 show that the regimen with a shorter interval between levodopa dosing presented the most stable levodopa pharmacokinetic profile (opicapone regimen #2).

[0118] This suggests that more frequent daily dosing of levodopa provides an advantage in terms of motor fluctuations compared with less frequent dosing when opicapone is used as adjunctive therapy.

[0119] LD / CD 500 / 125mg QD5 without opicapone vs. LD / CD 400 / 100mg QD4 plus 50mg opicapone Clinical results

[0120] 12-hour patient ON / OFF monitoring

[0121] Compared to 5-LD / CD 500 / 125 mg without opicapone, a 16% decrease in OFF-time was observed with 4-LD / CD 400 / 100 mg plus 50 mg opicapone, but this was not significant, while an increase in ON-time of 16% was observed (see Figure 3). The time to ON and the time to optimal ON were decreased by 12% and 18%, respectively (the time to optimal ON was significantly decreased, p=0.0439).

[0122] 24-hour patient ON / OFF monitoring

[0123] Compared with 5-ingestion LD / CD 500 / 125 mg without opicapone, a significant decrease of 12% (p=0.0336) in total OFF-time and a significant increase of 11% (p=0.0015) in ON-time were observed for 4-ingestion LD / CD 400 / 100 mg plus 50 mg opicapone (see Figure 3). ON-time with troublesome dyskinesias was reduced by approximately 15% after the 4-ingestion LD / CD 400 / 100 mg plus 50 mg opicapone regimen.

[0124] PGI-C

[0125] Approximately 70% of patients reported an improvement in PGI-C (very improved / much improved / slightly improved) with 4-LD / CD 400 / 100 mg plus opicapone 50 mg, with approximately 33% experiencing “very improved / much improved.”

[0126] See Table 3 for the results.

[0127] LD / CD500 / 125mg QD5 without opicapone compared to LD / CD400 / 100mg QD5 plus 50mg opicapone Clinical results

[0128] 12-hour patient ON / OFF monitoring

[0129] Compared with 5-LD / CD 500 / 125 mg without opicapone, a significant decrease of 45% (p=0.0013) in OFF-time and a significant increase of 47% (p=0.0002) in ON-time were observed for 5-LD / CD 400 / 100 mg plus 50 mg opicapone (see Figure 3). The time to ON and the time to optimal ON were decreased by 34% and 15%, respectively (time to optimal ON was significantly decreased, p=0.0420).

[0130] 24-hour patient ON / OFF monitoring

[0131] Compared with 5-intake LD / CD 500 / 125 mg without opicapone, a significant decrease of 24% (p=0.0056) in total OFF-time and a significant increase of 20% (p=0.0007) in ON-time were observed for 5-intake LD / CD 400 / 100 mg plus 50 mg opicapone (see Figure 3). ON-time with troublesome dyskinesias was reduced by approximately 36% following the 5-intake LD / CD 400 / 100 mg plus 50 mg opicapone regimen.

[0132] PGI-C

[0133] Approximately 92% of patients reported an improvement in PGI-C (very improved / much improved / slightly improved) on the 5-LD / CD 400 / 100 mg plus opicapone 50 mg regimen, with approximately 41.7% experiencing “much improved.”

[0134] See Table 3 for the results.

[0135] Table 2 - Comparison of daily oral administration of LD / CD400 / 100 mg plus 50 mg opicapone with 2-week 4-ingestion (every 4 hours) Compared with 2-week 5-ingestion (every 3 hours) daily oral administration of LD / CD 400 / 100 mg plus 50 mg opicapone, 2-week 5- Pharmacokinetics of L-DOPA after daily oral administration (every 3 hours) of LD / CD500 / 125 mg without opicapone parameter.

[0136]

[0137] Group A: 5-dose LD / CD 500 / 125 mg and 4-dose LD / CD 400 / 100 mg plus OPC 50 mg

[0138]

[0139]

[0140] Group B: 5-intake LD / CD 500 / 125mg and 5-intake LD / CD 400 / 100mg plus OPC 50mg

[0141]

[0142] In addition to max All values ​​are expressed as mean (%CV) except where values ​​are expressed as median (range); + 11 subjects; $ 10 subjects ++ 9 subjects; *8 subjects; **7 subjects; # 6 subjects; ## 5 subjects. AUCτ, area under the concentration-time curve (AUC) during the dosing interval; AUC 总 , AUC from zero hour to the last measurable time point; Cmax , the highest observed plasma concentration; C max,max , the highest observed C max ; C min , lowest observed plasma concentration; C min,min , the lowest observed C min (excluding before the first dose); FI, fluctuation index (calculated as: [(C max -C min ) / C avg ]*100); CV, coefficient of variation; LD / CD, levodopa / carbidopa; OPC, opicapone; t max , reaching C max The time required; SD, standard deviation 1 / 2 , terminal plasma half-life

[0143] Table 3 - Daily oral administration of LD / CD 400 / 100 mg plus 50 mg opicapone with 2-week 4-ingestion (every 4 hours) Compared with 2-week 5-ingestion (every 3 hours) daily oral administration of LD / CD 400 / 100 mg plus 50 mg opicapone, 2- Week 5 - Intake (every 3 hours) of major levodopa pharmacokinetics following daily oral administration of LD / CD500 / 125 mg without opicapone Paired t-test analysis of kinetic and efficacy parameters.

[0144]

[0145]

[0146] Group B: 5-intake LD / CD 500 / 125 mg and 5-intake LD / CD 400 / 100 mg plus OPC

[0147]

[0148] C max , the highest observed plasma concentration; C max,max , the highest observed C max ; C min , lowest observed plasma concentration; C min,min , the lowest observed C min (excluding before the first dose); AUC 总 , area under the curve (AUC) from zero hour to the last measurable time point; FI, fluctuation index (calculated as: [(C max -C min ) / C avg ]*100); CI, confidence interval; LD / CD, levodopa / carbidopa; OPC, opicapone.

Claims

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

2. Opicapone and levodopa for use in treating Parkinson's disease in a patient who is receiving N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and who begins to experience motor fluctuations or begins to show signs of "wearing off", said treatment comprising administering more than N doses of levodopa per day to provide a total daily dose of levodopa of X mg, and administering a single daily dose of opicapone of Y mg, wherein X is from 100 to 1000, N is from 2 to 10 and Y is from 25 to 50.

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

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

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

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

7. The method according to claim 1 or 4 to 6, the product for use according to claim 2 or 4 to 6 or the use according to claim 3 to 6, wherein X is 300 to 600.

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

9. The method according to claim 1 or 4 to 8, the product for use according to claim 2 or 4 to 8 or the use according to claim 3 to 8, wherein Y is 25 or 50.

10. The method, product for use or use according to claim 9, wherein the patient receives 4 doses of levodopa to provide a total daily dose of 400 mg per day and the treatment comprises administering 5 doses of levodopa per day to provide a total daily dose of 400 mg of levodopa and administering a single daily dose of 50 mg of opicapone.

11. The method according to claim 1 or 4 to 10, or the product for use according to claim 2 or 4 to 10, or the use according to claim 3 to 10, wherein the levodopa dosage amount is not the same for each dose.

12. The method, product for use or use according to claim 11, wherein the levodopa dosage amount of a single dose is higher.

13. The method, product for use or use according to claim 11, wherein the levodopa dosage amount of the double-numbered dose is higher.

14. The method, product for use or use according to claims 10 to 12, wherein the 5 doses of levodopa providing a total daily dose of 400 mg of levodopa are administered according to the following dosing regimen: 100 mg, 50 mg, 100 mg, 50 mg and 100 mg.

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

16. The method according to claim 1 or 4 to 15, the product for use according to claim 2 or 4 to 15 or the use according to claim 3 to 15, wherein the patient receives N doses of a dopamine decarboxylase inhibitor (DDCI) to provide a total daily dose of Z mg of the DDCI, the method further comprising administering more than N doses of the DDCI per day to provide a total daily dose of Z mg of DDCI, wherein Z is 50 to 250.

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

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. The method, product for use or use according to claim 17 or 18, wherein the patient receives 4 doses of carbidopa to provide a total daily dose of 100 mg per day and the treatment comprises administering 5 doses of carbidopa per day to provide a total daily dose of 100 mg of carbidopa.

20. A method, a product for use or a use according to any preceding claim, wherein the treatment results in a reduction in "optimal ON time".

21. A method, a product for use or the use according to any preceding claim, wherein the treatment results in a reduction in ON time associated with troublesome dyskinesias.

22. A method, product for use or use according to any preceding claim, wherein the treatment results in an improvement in the patient's Global Impression of Change.

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