Dose regimens for use of ly3154207 in the treatment of dopaminergic CNS disorders

Abstract

To provide pharmaceutical compositions and methods for treating dopaminergic central nervous system disorders.SOLUTION: The invention relates to dosing regimens and methods of using LY3154207 which is also described as 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3- methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, and / or pharmaceutical compositions thereof, for treatment of dopaminergic central nervous system disorders. Dopaminergic CNS disorders of the present dosing regimen methods include Parkinson's disease, Alzheimer's disease, Lewy body dementia (LBD), vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment disorders, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addiction disorders.SELECTED DRAWING: Figure 2

Description

Detailed Description of the Invention

[0001] The present invention provides dosing regimens and methods using LY3154207, also known as 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, and / or pharmaceutical compositions thereof, for the treatment of dopaminergic central nervous system disorders, including Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies (LBD), vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0002] Lewy body dementia (LBD) is a progressive brain disorder characterized by the accumulation of Lewy bodies (abnormal deposits of alpha-synuclein) in areas of the brain that regulate behavior, cognition, and movement. LBD is an umbrella term that encompasses two related disorders: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). Individuals with LBD may be affected by numerous symptoms spanning cognition, movement, sleep, mood, behavior, and autonomic dysfunction. Parkinson's disease (PD) is a well-known example of a dopaminergic CNS disorder resulting from dysfunction and / or loss of dopaminergic neurons and the resulting disturbance in normal dopamine signaling. PD is a progressive neurodegenerative movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra region of the brain and the formation of Lewy bodies, which reduces dopamine levels in the striatum. PD manifests as tremor along with other motor (e.g., akinesia and bradykinesia, impaired ability to maintain balance) and non-motor (e.g., cognitive dysfunction, sleep disturbances, apathy, and depression) symptoms. Executive function, visuospatial awareness, attention deficits, and memory and language dysfunction are the most frequently affected cognitive domains. These impairments are thought to be related to frontostriatal dopamine dysfunction, with early signs observed in 15%–20% of subjects at the time of PD diagnosis. PD-associated dementia has been reported in 30% of subjects with PD, with prevalence increasing with disease progression and a lifetime risk of up to 78%. Standard treatment for PD is acetylcholinesterase inhibitors (AChEIs), such as rivastigmine, which provide clinical benefit in a subset of subjects with modest efficacy but may be associated with motor side effects. Rivastigmine is currently the only approved treatment for mild to moderate dementia associated with Parkinson's disease. Therefore, improved treatments for cognitive impairment due to PD and PDD that are effective, safe, and clinically well tolerated remain an unmet medical need.

[0003] Dopamine deficiency has also been observed in subjects with Alzheimer's disease (AD). AD is an age-related neurodegenerative disease that causes a slow decline in cognitive and behavioral function in subjects, with the characteristic symptom of memory loss. Currently available therapies for the treatment of AD have modest benefit in treating cognitive dysfunction, with limited or no benefit in other symptoms in patients with mild to moderate AD, such as vigilance, depressive symptoms, daytime attention, apathy, sleep disturbances, memory dysfunction, executive function (planning / executing tasks), and hallucinations. Improved treatments for AD and associated cognitive dysfunction that are effective, safe, and clinically well-tolerated also remain an unmet medical need.

[0004] The dopamine receptor D1 subtype (D1) is the most abundant dopamine receptor in the central nervous system and plays a critical role in multiple CNS functions, including motor activity, reward, and cognitive function. D1 receptors in the prefrontal cortex are important for cognition. D1 receptors mediate acetylcholine release in various brain regions, particularly the hippocampus, and D1 receptors on dendritic spines of cortical neurons are important for intact working memory, attention, and executive function. For many years, modulation of dopamine signaling in dopaminergic CNS disorders has been attempted with direct D1 receptor agonists. However, the success of various D1 agonist agents has been severely limited due to lack of efficacy, safety, and tolerability, particularly unacceptable adverse effects, limiting their usefulness. Furthermore, D1 agonists exhibit a bell-shaped dose-response curve for cognitive endpoints, complicating and confounding their clinical use. Thus, previous attempts to develop clinically useful direct D1 receptor agonists have met with little success due to receptor desensitization, poor ADME / PK properties, and dose-limiting side effects such as hypotension. Direct-acting dopamine therapies also have limited efficacy, due in part to the development of high-dose-associated cognitive impairment, seizure risk, and tolerance. Thus, there remains a significant unmet need for safe, effective, and clinically acceptable treatments for Parkinson's disease and other dopaminergic CNS disorders.

[0005] LY3154207 is a dopamine D1 receptor positive allosteric modulator (D1 PAM) and represents a potential first-in-class treatment for dementia and other dopaminergic CNS disorders. LY3154207 (CAS Registry Number 1638667-79-4) can be chemically described as 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone and can be structurally represented as follows: [ka]

[0006] Useful forms of LY3154207 include crystalline forms (see WO 2017 / 070068) and co-crystalline forms (see WO 2014 / 193781) containing 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone and 4-hydroxybenzoic acid (CAS Registry Number 1638669-32-5). As a positive allosteric modulator, LY3154207, also known as a "potentiator" of the dopamine D1 receptor subtype, is highly selective for D1 receptors. LY3154207 exhibits very weak direct agonism of D1 receptors, is active only in the presence of dopamine, is dependent on endogenous tone, and is believed to be subject to normal feedback regulation in the subject. Thus, LY3154207 represents an innovative pharmacological agent and approach for modulating the D1 signaling pathway in PD, AD, and other dopaminergic CNS disorders in which D1 signaling may be deficient.

[0007] LY3154207 has a mechanism of action distinct from other dopamine agonists, such as direct D1 receptor agonists. LY3154207 binds to a newly discovered allosteric binding site in intracellular loop 2 of the D1 receptor, enhancing the affinity of D1 receptors for dopamine. A literature search to date suggests that no human clinical studies have been published for any D1 PAM agents. Due to the complexity of dopaminergic signaling in normal physiology and clinical disease, and the lack of clinical pharmacological guidance from D1 orthosteric agonists, there remains a significant unmet need for clinical dosing regimens for D1 PAMs. In particular, there remains a need for clinical dosing regimens for LY3154207 that provide an effective, safe, and clinically acceptable combination profile of pharmacological effects for use in the treatment of PD, AD, and other dopaminergic CNS disorders.

[0008] The present invention provides a clinical therapeutic dosing regimen and method using LY3154207 and / or its pharmaceutical composition for use in treating dopaminergic central nervous system disorders. As defined herein, dopaminergic central nervous system disorders are selected from the group consisting of Lewy body dementia (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders. In the dosing regimens of the present invention, and as used herein, LY3154207 refers to 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone in any form, including its crystalline and co-crystalline forms, particularly the benzoic acid co-crystalline form, and / or pharmaceutical compositions containing these agents. The present invention also provides a method of using LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient a dose of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof per day, up to a maximum total dose of 75 mg. The present invention further provides a method of using LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient a dose of about 0.5 mg to about 15 mg of LY3154207 or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

[0009] LY3154207 and a related D1 PAM compound, referred to herein as DPTQ, have been studied in primate and / or human phase I studies in healthy volunteers and PD patients, and LY3154207 has entered a phase II clinical study for Parkinson's disease dementia (referred to as PRESENCE, NCT03305809). Studies, including those described in Example 1 (a phase I clinical study of LY3154207) and Example 2 (spatial working memory in adult rhesus monkeys), have led to the concept that LY3154207, when used in accordance with the dosing regimens of the present invention, may induce surprisingly significant improvements in the treatment of PD or AD dementia, cognitive enhancement, and / or the signs and symptoms of dopaminergic CNS disorders, such as sleep or appetite regulation. Thus, when used in accordance with this dosing regimen, LY3154207 provides a means of improving dopamine D1 signaling in a manner that is believed to provide an effective, safe, and clinically acceptable treatment regimen in a variety of dopaminergic CNS disorders.

[0010] The dosing regimen of the present invention embodies a method that provides surprising and unpredictable benefits. In particular, patients with dopaminergic CNS disorders need to avoid significant levels or risks of undesirable cardiovascular effects, such as insomnia, agitation, and / or elevated pulse and blood pressure, while simultaneously requiring the benefits of beneficial LY3154207 activity, such as wakefulness, appetite regulation, and / or cognitive enhancement or motor control effects. Unexpectedly, it has been discovered that the clinically useful and desirable effects of LY3154207 in dopaminergic CNS disorders, such as cognitive enhancement, motor function recovery, appetite reduction, and alertness or wakefulness, can actually be separated from certain undesirable effects by using the clinical dosing regimen of the present invention.

[0011] Thus, the present invention provides specific clinical dosing regimens for daily administration of LY3154207 so that patients with dopaminergic central nervous system disorders can alleviate the signs and symptoms of dopaminergic central nervous system disorders while avoiding the effects of other D1 PAMs that could preempt these clinical benefits. Additionally, the present invention provides for chronic daily administration of LY3154207 so that patients with dopaminergic central nervous system disorders can further employ lower or higher doses of LY3154207 within the regimens of the present invention so that effective symptomatic relief is achieved for each individual patient while avoiding undesirable effects.

[0012] For example, patients can benefit from the dosing regimen of the present invention, and the wakefulness and / or appetite-reducing effects can be maximized by employing higher doses, up to 75 mg per day of LY3154207. In another embodiment, a low-dose regimen of up to 15 mg per day of LY3154207 provides a means for patients to benefit from the cognitive-enhancing effects without experiencing excessive wakefulness, arousal, and / or undesirable appetite loss. Overall, the dosing regimen of the present invention provides a means for patients to benefit from D1 PAM activity while avoiding certain undesirable adverse cardiovascular activities observed clinically, and may represent the on-target pharmacology of D1 PAM as a class. Furthermore, the dosing regimen of the present invention provides a means for treating patients with dopaminergic CNS disorders while simultaneously reducing the risk of drug-drug interactions with Cyp3A4 inhibitors.

[0013] Thus, the present invention provides a dosing regimen for the daily oral administration of LY3154207 to patients with dopaminergic central nervous system disorders, using specific doses of LY3154207 described in detail below.

[0014] In one embodiment, the present invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient a dose of about 0.5 mg to about 75 mg of LY3154207 or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day.

[0015] In one embodiment, the present invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient a dose of about 0.5 mg to about 15 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

[0016] In one embodiment, the present invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient a daily dose of LY3154207 selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, or a pharmaceutical composition thereof.

[0017] In one embodiment, the present invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily a dose of about 0.5 mg to about 75 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0018] In one embodiment, the present invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily a dose of about 0.5 mg to about 15 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0019] In one embodiment, the present invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily a daily dose of LY3154207 selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, or a pharmaceutical composition thereof, wherein the patient is treated for at least 21 consecutive days.

[0020] In one embodiment, the invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207 at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, or a pharmaceutical composition thereof, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0021] In one embodiment, the invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207 at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg, or a pharmaceutical composition thereof, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0022] In one embodiment, the invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising chronic daily administration of LY3154207, or a pharmaceutical composition thereof, to the patient at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, and the patient is treated for at least 21 consecutive days.

[0023] In one embodiment, the invention provides a method for use of LY3154207 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207 at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg, or a pharmaceutical composition thereof, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, and the patient is treated for at least 21 consecutive days.

[0024] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 0.5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0025] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 1 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0026] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 2 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0027] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 3 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0028] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0029] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 10 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0030] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 15 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0031] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 20 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0032] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 30 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0033] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 50 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0034] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 75 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0035] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of Parkinson's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0036] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of Parkinson's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0037] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of Parkinson's disease in a patient, comprising administering to the patient a daily dose of LY3154207 selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, or a pharmaceutical composition thereof.

[0038] In one embodiment, the invention provides a method for use of LY3154207 in treating Parkinson's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, wherein the patient has revised MDS criteria for PD and has mild to moderate dementia as defined by cognitive decline with an MoCA score of 10 to 23.

[0039] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of Parkinson's disease in a patient, comprising chronically administering to the patient daily a dose of about 0.5 mg to about 75 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0040] In one embodiment, the invention provides a method for the use of LY3154207 in the treatment of Alzheimer's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0041] In one embodiment, the invention provides a method for the use of LY3154207 in the treatment of Alzheimer's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0042] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of Alzheimer's disease in a patient, comprising administering to the patient a daily dose of LY3154207 selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, or a pharmaceutical composition thereof.

[0043] In one embodiment, the present invention provides a method for the use of LY3154207 in the treatment of Alzheimer's disease in a patient, comprising chronically administering to the patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0044] In one embodiment, the present invention provides a method for use of LY3154207 to induce weight loss in a patient, comprising administering to the patient a dose of about 0.5 mg to about 75 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day.

[0045] In one embodiment, the present invention provides a method for use of LY3154207 to induce weight loss in a patient, comprising administering to the patient a dose of about 0.5 mg to about 15 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

[0046] In one embodiment, the present invention provides a method for use of LY3154207 to induce weight loss in a patient, comprising administering to the patient a daily dose of LY3154207 selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, or a pharmaceutical composition thereof.

[0047] In one embodiment, the present invention provides a method for use of LY3154207 to induce weight loss in a patient, comprising chronically administering to said patient daily a dose of about 0.5 mg to about 75 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0048] In one embodiment, the present invention provides a method for use of LY3151944 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3151944, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0049] In one embodiment, the invention provides a method for use of LY3151944 in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3151944, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0050] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient one or more doses of about 0.5 mg to about 75 mg per day of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day.

[0051] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient one or more doses of LY3154207, or a pharmaceutical composition thereof, of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg per day.

[0052] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0053] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient one or more doses of LY3154207, or a pharmaceutical composition thereof, of from about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0054] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in accordance with the above embodiment, comprising chronically administering to the patient one or more doses of LY3154207, or a pharmaceutical composition thereof, of from about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg per day.

[0055] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising chronically administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg and 75 mg.

[0056] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in accordance with the above embodiments, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0057] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in accordance with the above embodiment, comprising administering to said patient a dose of about 0.5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0058] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 1 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0059] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 2 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0060] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 3 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0061] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0062] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 10 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0063] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 15 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0064] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 20 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0065] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 30 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0066] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 50 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0067] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, comprising administering to said patient a dose of 75 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0068] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, wherein the dopaminergic central nervous system disorder is Parkinson's disease.

[0069] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in accordance with the above embodiment, wherein the patient meets the revised MDS criteria for PD and has mild to moderate dementia as defined by cognitive decline with an MoCA score of 10 to 23.

[0070] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, wherein the dopaminergic central nervous system disorder is Alzheimer's disease.

[0071] In a preferred embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use according to the above embodiment, wherein the dopaminergic central nervous system disorder is obesity.

[0072] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0073] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0074] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0075] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily a dose of LY3154207, or a pharmaceutical composition thereof, of about 0.5 mg to about 15 mg, up to a maximum total dose of 15 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0076] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronic daily administration to said patient of LY3154207, or a pharmaceutical composition thereof, at a daily dose selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0077] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0078] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0079] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronic daily administration to the patient of LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, and the patient is treated for at least 21 consecutive days.

[0080] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, and the patient is treated for at least 21 consecutive days.

[0081] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 0.5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0082] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 1 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0083] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 2 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0084] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 3 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0085] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0086] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 10 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0087] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 15 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0088] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 20 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0089] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 30 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0090] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 50 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0091] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 75 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0092] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Parkinson's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0093] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Parkinson's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0094] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Parkinson's disease in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0095] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Parkinson's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, wherein the patient meets the revised MDS criteria for PD and has mild to moderate dementia as defined by cognitive decline with an MoCA score of 10 to 23.

[0096] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Parkinson's disease in a patient, comprising chronically administering to said patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0097] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Alzheimer's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0098] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Alzheimer's disease in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0099] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Alzheimer's disease in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0100] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in treating Alzheimer's disease in a patient, comprising chronically administering to said patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0101] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in inducing weight loss in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0102] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in inducing weight loss in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0103] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in inducing weight loss in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0104] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for use in inducing weight loss in a patient, comprising chronically administering to said patient daily a dose of about 0.5 mg to about 75 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0105] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0106] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of about 0.5 mg to about 15 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

[0107] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0108] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0109] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily a dose of about 0.5 mg to about 15 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0110] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronically administering to said patient daily a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg, wherein the patient is treated for at least 21 consecutive days.

[0111] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0112] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

[0113] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising chronic daily administration to the patient of LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, and the patient is treated for at least 21 consecutive days.

[0114] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to the patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, and the patient is treated for at least 21 consecutive days.

[0115] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 0.5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0116] In one embodiment, the present invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 1 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0117] In one embodiment, the invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 2 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0118] In one embodiment, the present invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 3 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0119] In one embodiment, the present invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 5 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0120] In one embodiment, the present invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 10 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0121] In one embodiment, the invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 15 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0122] In one embodiment, the present invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 20 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0123] In one embodiment, the present invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 30 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0124] In one embodiment, the invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 50 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0125] In one embodiment, the invention provides LY3154207, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient a dose of 75 mg per day of LY3154207, or a pharmaceutical composition thereof.

[0126] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Parkinson's disease in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0127] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Parkinson's disease in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0128] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Parkinson's disease in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0129] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Parkinson's disease in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, wherein the patient meets the revised MDS criteria for PD and has mild to moderate dementia as defined by cognitive decline with an MoCA score of 10 to 23.

[0130] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Parkinson's disease in a patient, comprising chronically administering to said patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0131] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Alzheimer's disease in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0132] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Alzheimer's disease in a patient, comprising administering to said patient a dose of about 0.5 mg to about 15 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

[0133] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Alzheimer's disease in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0134] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating Alzheimer's disease in a patient, comprising chronically administering to said patient daily LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0135] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in inducing weight loss in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg.

[0136] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in inducing weight loss in a patient, comprising administering to said patient LY3154207, or a pharmaceutical composition thereof, at a dose of about 0.5 mg to about 15 mg per day, up to a maximum total dose of 15 mg.

[0137] In one embodiment, the present invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in inducing weight loss in a patient, comprising administering to said patient a daily dose of LY3154207, or a pharmaceutical composition thereof, selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

[0138] In one embodiment, the invention provides LY3154207 or a pharmaceutical composition thereof for the manufacture of a medicament for use in inducing weight loss in a patient, comprising chronically administering to said patient daily a dose of about 0.5 mg to about 75 mg of LY3154207, or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day, wherein the patient is treated for at least 21 consecutive days.

[0139] As used above, and throughout the present specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0140] A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for delivery of a biologically active agent to a mammal, e.g., a human.

[0141] "Dose" refers to a predetermined amount or unit dose of LY3154207 calculated to produce a desired therapeutic effect in a patient. As used herein, "mg" refers to milligrams. As used herein, LY3154207 dose ranges and provided doses refer to the weight of the active pharmaceutical ingredient, 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, regardless of the form in which it is provided, such as the free base, co-crystal form, or any other composition or form. Preferably, the unit dose is composed of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone in co-crystal form and 4-hydroxybenzoic acid. The term "about," as used herein, means sufficiently close to the stated numerical value, for example, ±10% of the stated numerical value.

[0142] Methods for making and formulating LY3154207 and / or 2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(2-hydroxy-2-methylpropyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one are known in the art and are described, for example, in WO2014 / 193781 and / or WO2017 / 070068. Methods for preparing LY3154207, and its cocrystals, and specific formulations and dosage forms thereof, are known to those skilled in the art and are described in WO2014 / 193781 and / or WO2017 / 070068. WO2014 / 193781 discloses certain 3,4-dihydroisoquinolin-2(1H)-yl compounds as positive allosteric modulators (PAMs) of the dopamine 1 receptor (D1), including 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, and co-crystal forms comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone and 4-hydroxybenzoic acid, as well as compositions thereof. WO2017 / 070068 discloses crystalline 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone. LY3154207 is preferably formulated as a pharmaceutical composition administered by any route that makes the compound bioavailable, including oral, intravenous, and transdermal routes. More preferably, such compositions are for oral administration. LY3154207 can be administered alone or in the form of a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent, or excipient.Throughout this specification, when a composition is described as having, including, or comprising a specific component, it is assumed that the composition also consists essentially of or consists of the listed components.Such pharmaceutical compositions and the processes for making them are known in the art (see, for example, Remington: The Science and Practice of Pharmacy, LV Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012).In formulations, LY3154207 is usually mixed with excipients, diluted by excipients, or enclosed in such carriers, which can be in the form of capsules, sachets, paper, or other containers.When excipients function as diluents, they can be solid, semi-solid, or liquid materials that act as vehicles, carriers, or mediums for active ingredients. Thus, the formulations can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either solid or in a liquid medium), ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents. The compounds of the invention can be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.Those skilled in the art of preparing formulations can easily select the appropriate form and mode of administration depending on the specific characteristics of the compound and / or the selected form, the disorder or condition being treated, the stage of the disorder or condition, and other relevant circumstances. The following table provides examples of selected unit dosage forms provided as tablets for oral administration according to the dosage regimen of the present invention. Those skilled in the art can use these examples, along with readily known formulation methods, to provide additional formulations and / or unit dosage forms. [Table 1]

[0143] The unit dose of the present invention is formulated as a pharmaceutical composition to be administered by any route that makes the compound bioavailable, preferably, such a composition is for oral administration. As used herein, "administration" or "administering" includes the patient self-administering LY3154207, and / or LY3154207 being administered by another person, and / or the patient being instructed and / or supervised to consume LY3154207 according to a specific regimen. Preferably, LY3154207 is administered in the morning. Preferably, the indicated unit dose of LY3154207 is taken once a day, as indicated by the use of the term "per day." Preferably, LY3154207 is taken daily. As used herein, "daily administration" includes the administration of LY3154207 as a specific therapeutic regimen intended to provide beneficial effects from long-term and regular administration of LY3154207 at a specified dose. In particular, "daily administration" includes administration for 21 or more consecutive days, or as long as needed to prevent the patient's signs and symptoms of a dopaminergic CNS disorder. If a patient occasionally misses a day, the patient may simply resume administration the next day after the designated administration, and such a case continues to refer to "daily administration." As used herein, "daily" means that LY3154207 is administered once every 24 hours or once per calendar day. As used herein, "daily" means that LY3154207 is administered continuously and continuously, and administration as used herein includes the patient administering a dose and / or the patient being instructed to administer a dose as part of a treatment regimen. When a method is described as having, including, or comprising certain process steps, the process also consists essentially of, or consists of, the described processing steps. Furthermore, it should be understood that the order of steps or the order for performing certain actions is immaterial, so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0144] As used herein, the term "patient" refers to a human being, and the patient treated by this dosing regimen is a patient with dopaminergic CNS disorder, and therefore, it is known that they share the same etiological aspect, and that the disruption of dopamine signaling contributes to these diseases.Dopaminergic CNS disorders used herein include, but are not limited to, Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies (LBD), vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, sleep disorder, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorder, lethargy, apathy and addictive disorder.The identification of patients with these dopaminergic CNS disorders can be achieved by established methods known to those skilled in the art.

[0145] In an embodiment of the present invention, the patient is a human who has been diagnosed with a medical risk, condition, or disorder, such as a dopaminergic CNS disorder, and is in need of treatment with the medication regimen described herein.If the disorder that can be treated by the method of the present invention is known by an established and accepted classification, such as AD, PD, LBD, etc., these classifications can be found in various well-known medical textbooks.For example, currently, the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) provides diagnostic tools for identifying many of the disorders described herein.In addition, the 10th edition of the International Classification of Diseases (ICD-10) provides classifications for many of the disorders described herein.Those skilled in the art will recognize that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-5 and ICD-10, and that terminology and classification systems evolve with the advancement of medical science.Cognitive dysfunction in subjects with Parkinson's disease is generally referred to as neurocognitive disorder. The diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, 5th Edition) describe evidence of significant cognitive decline from a previous level of performance (personal or informant concerns documented by neuropsychological testing) and cognitive impairment that may or may not interfere with independence in daily living. This qualifies as a major or mild neurocognitive disorder. As used herein, "weight loss" refers to weight reduction and / or chronic weight management, with treatment promoting maintenance of weight within a desired range.

[0146] Thus, the terms "treatment" and "treating" are intended to refer to any process that may slow, interrupt, arrest, control, or halt the progression of an existing disorder and / or its symptoms, but do not necessarily indicate complete elimination of all symptoms.

[0147] The attending diagnostician, as a person skilled in the art, can easily determine the dose selected from the dosage regimen provided herein by observing the results obtained from the treatment. When determining the specific dose of LY3154207 from the dosage regimen of the present invention, many factors are taken into consideration, including, but not limited to, the dopaminergic CNS disorder suffered by the patient, the patient's weight, age and general health, the degree of involvement or severity of the disorder, the response of the individual patient, the use of other concomitant medications, and other relevant circumstances.

[0148] The dosage regimen of the present invention can be used in combination with other drugs used to treat / prevent / suppress or improve dopaminergic CNS disorders. Such other drugs (several) can be administered by a route and in a commonly used amount, and therefore simultaneously or sequentially with LY3154207. For example, other active ingredients that can be combined with LY3154207 to treat Parkinson's disease include, but are not limited to, (a) dopamine precursors such as levodopa, melevodopa, and etilevodopa, and (b) dopamine agonists, including pramipexole, ropinirole, apomorphine, rotigotine, bromocriptine, cabergoline, and pergolide. [Brief explanation of the drawings]

[0149] [Figure 1] Design of Study HBEA, a single ascending dose study of the D1 receptor positive allosteric modulator LY3154207 in healthy volunteers. a Safety review completed after each dose level before escalation. b Dose escalation was terminated at 200 mg due to cardiovascular effects. CSF = cerebrospinal fluid, LY = LY3154207, PBO = placebo, PK = pharmacokinetics. [Figure 2]A Phase 1, single-dose, randomized, placebo-controlled, four-period, incomplete crossover study in HBEB, sleep-deprived healthy male subjects (n=17). Effect of a single dose of LY3154207 on wakefulness as measured by the polysomnography latency test (MSLT) in sleep-deprived healthy male subjects. Sleep onset latency is the time (in minutes) from the start of the MSLT to the first detection of sleep. If the subject did not sleep during the MSLT period, a sleep onset latency of 20 minutes was recorded. CI = confidence interval, LS = least squares, MSLT = polysomnography latency test. [Figure 3] Design of Study HBEC, a multiple ascending-dose study of LY3154207, was a randomized, double-blind, placebo-controlled, multiple ascending-dose, parallel-group study of healthy subjects (Part A) and participants with PD (Part B) who received a once-daily dose of LY3154207 (15, 30, 75, or 150 mg in Part A, up to 75 mg in Part B) or placebo for 14 days. a Each ascending-dose cohort was initiated only after review of safety data from the previous cohort through at least Day 7. b Participants with PD in Cohort 6 received titrated doses (i.e., Days 1–3: 15 mg, Days 4–6: 30 mg, and Days 7–14: 75 mg) to determine the effect of this dosing schedule on cardiovascular outcomes. Note: All cohorts were dosed for 14 days. CRU = Clinical Research Unit, LY = LY3154207, PBO = placebo, PD = Parkinson's disease, R = randomized. [Figure 4] Motor symptoms in patients with PD treated with LY3154207 for 14 days in Study HBEC. Participants with PD treated with LY3154207 had lower motor subscores, as measured by the MDS-UPDRS Part III, compared with placebo-treated participants. Cohort 5 (LY 75 mg), Cohort 6 (LY 75 mg titration) (participants with PD in Cohort 6 received 15 mg on days 1-3 and 30 mg on days 4-6), and Cohort 5 / 6 (PBO). [Figure 5] Spatial working memory in adult rhesus monkeys: acute administration of vehicle, data from a group of 10 animals, vehicle administered on day 1. [Figure 6]Spatial working memory in adult rhesus monkeys: Acute administration of 2.5 mg / kg DPTQ. [Figure 7] Spatial working memory in adult rhesus monkeys: Effects of a repeated 2.5 mg / kg DPTQ dose on day 5. [Figure 8] Spatial working memory in adult rhesus monkeys: Effects of DPTQ when administered at a low dose of 0.1 mg / kg. [Figure 9] Spatial working memory in adult rhesus monkeys: Effects of a 1.0 mg / kg dose of DPTQ on spatial working memory.

[0150] Example 1: Phase 1 Clinical Study of LY3154207 LY3154207 is currently in Phase 2 (NCT03305809) for cognitive impairment in dementia with Lewy bodies. Previous data from three completed Phase 1 clinical pharmacology studies of LY3154207, Studies HBEA, HBEB, and HBEC, provide proof of concept for the use of LY3154207 in the treatment of dopaminergic central nervous system disorders in patients, including administering to patients doses of LY3154207 or a pharmaceutical composition thereof at doses of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg per day.

[0151] HBEA is a single ascending-dose study of the D1 receptor positive allosteric modulator LY3154207 in healthy volunteers. Study HBEA aims to determine the safety, tolerability, peripheral and central pharmacokinetics (PK) of single ascending doses of LY3154207 in healthy subjects. Study HBEB aims to evaluate the effect of a single dose of LY3154207 on sleep latency, as measured by the multiple sleep latency test (MSLT), in sleep-deprived healthy male subjects. HBEA was a phase 1, two-part, randomized, double-blind, placebo-controlled study in healthy men or women. Part A was a three-period crossover design with two alternating single-ascending-dose cohorts, and subjects were randomized to LY3154207 (n=6) or placebo (n=3) in each cohort for each dosing period. Part B was a single-period, single-dose, two-cohort design with cerebrospinal fluid (CSF) sampling, in which subjects were randomized to LY3154207 (n = 8) or placebo (n = 4) in each cohort. The study design is shown in Figure 1.

[0152] HBEA Part A - Single Ascending Dose (SAD) Study This is a Phase 1, single-agent, crossover study of LY3154207 in healthy subjects conducted in two alternating cohorts with dose escalation. Subjects will receive 25 mg, 75 mg, 100 mg, 150 mg, and 200 mg or placebo. Safety parameters evaluated include adverse events (AEs), safety laboratory data, vital signs, ambulatory blood pressure monitoring (ABPM), and electrocardiogram (ECG). Subjects will provide post-dose blood samples to measure plasma concentrations of LY3154207 for PK assessment.

[0153] Eighteen subjects were enrolled, and 17 completed the study. The mean (SD) age of the subjects was 33.6 (13.0), 16 were male (89%), and 16 were Caucasian (89%). One subject withdrew due to anxiety after the 150 mg dose. A total of 111 treatment-emergent AEs occurred, most of which were mild (101 / 111). Insomnia, anorexia, anxiety, dizziness, headache, nausea, epigastric pain, and dysgeusia were the most common AEs, with the majority (69 / 111) occurring at doses ≥100 mg. Dose-related signals of increased pulse and blood pressure occurred and resolved within 24 hours. Cmax and AUC were proportional to the administered dose. Median Tmax and t1 / 2 were approximately 2-3 hours and 12 hours, respectively. Urinary excretion of 0.02% of the administered LY3154207 dose was observed. LY3154207 has demonstrated an acceptable safety profile and linear PK profile across the dose range of 25 to 200 mg. This data from Phase 1 in healthy volunteers suggests that the dosing regimen of the present invention may provide appetite-reducing effects in patients with dopaminergic central nervous system disorders or healthy subjects. Data demonstrating dose-related signals for increased pulse and blood pressure also indicate that the dosing regimen of the present invention may provide an improved combination of efficacy, safety, and clinical tolerability for the use of LY3154207, which may avoid and / or minimize these undesirable effects. LY3154207 was well tolerated, with an increase in AEs related to central activation at doses ≥ 75 mg. In HBEA Part A, treatment-related adverse events (AEs) occurred primarily at doses ≥ 100 mg and were mostly mild. In HBEA Part B, treatment-related AEs occurred only at 75 mg (25% of subjects) and were all mild: increased energy, anxiety, decreased appetite, and dizziness. No serious or severe AEs occurred. LY3154207 produced dose-related increases in ambulatory blood pressure monitoring (ABPM) blood pressure and pulse rate while maintaining circadian rhythm. Dose-related increases in systolic and diastolic blood pressure and pulse rate were observed from ABPM, peaking 4 to 12 hours after dosing and largely resolving within 24 hours.Based on ABPM, the 4-8 hour estimates of least squares mean differences for LY3154207 200 mg vs. placebo were 32 beats per minute (bpm) for pulse rate and 14 mmHg and 10 mmHg for systolic and diastolic blood pressure, respectively. The results are shown in Table A. [Table 2]

[0154] HBEA Part B - Cerebrospinal Fluid HBEA Part B is a study of the cerebrospinal fluid (CSF) and plasma pharmacokinetic (PK) profiles of LY3154207 after a single dose in healthy volunteers. The objective of this study is to determine the CSF and plasma PK profiles of LY3154207 in a single-dose study in healthy volunteers. The study consists of two cohorts: a single-dose, single-period, placebo-controlled, randomized, double-blind, parallel-group study. Subjects were randomized to 25 mg and 75 mg doses and underwent serial blood and CSF sampling 2 hours pre-dose and 24 hours post-dose to measure LY3154207 concentrations. Twenty-four subjects were enrolled, and all completed the study. The mean (SD) age of subjects was 29.4 (9.8), 22 were male (92%), and 22 were white (92%). LY3154207 concentrations in CSF were detectable for up to 8 hours after dosing with 25 mg and up to 24 hours after dosing with 75 mg. At each dose, approximately 1% of the total LY3154207 exposure in plasma was available in CSF. At 25 mg and 75 mg, central penetration of LY3154207 was confirmed by measuring LY3154207 in CSF, supporting its use according to the dosing regimen of the present invention in dopaminergic CNS disorders. LY3154207 demonstrated linear plasma PK and evidence of central penetration. LY3154207 demonstrated linear plasma PK with a median maximum concentration (tmax) of approximately 2-3 hours, a terminal half-life (t1 / 2) of approximately 12 hours, an apparent clearance (CL / F) of 19-25 L / h across doses, and negligible renal excretion. The maximum concentration (Cmax) and the area under the concentration versus time curve from time 0 to infinity (AUC0-∞ ) increased proportionally with doses of LY3154207 from 25 to 200 mg. In the CSF, the median tmax of LY3154207 was 3 to 4 hours, and the t½ was 8 hours. Approximately 1% of the total LY3154207 exposure in plasma was available in the CSF, with a CSF / unbound plasma ratio of 0.3. Thus, central penetration of LY3154207 was confirmed by CSF PK in HBEA Part B at doses of 25 and 75 mg.

[0155] Phase 1 sleep onset latency study in HBEB healthy volunteers Dose-dependent adverse events were also observed in the single ascending dose study. To determine the effect of a single dose of LY3154207 on wakefulness as measured by the multiple sleep latency test (MSLT) in sleep-deprived healthy male subjects, HBEB was a phase 1, single-dose, randomized, placebo-controlled, four-period, incomplete crossover study in sleep-deprived healthy male subjects (n=17). Subjects were randomized to receive a single dose of either placebo, LY3154207 at 15, 30, or 75 mg (double-blind), or modafinil (open-label control). In each period, subjects were sleep-deprived for approximately 26 hours before dosing and approximately 12 hours after dosing. MSLTs were performed every 2 hours until 10 hours after dosing. A mixed-model repeated-measures analysis included treatment, period, time, and treatment-by-time interactions as fixed effects, and subject as a random effect. Overall sleep latency was the mean of sleep latency after four doses. All subjects were randomized to receive four of five available single-dose treatments (15, 30, or 75 mg LY3154207, placebo, or modafinil 200 mg), with all subjects receiving placebo. The washout period was at least 7 days. The MSLT was the primary assessment of wakefulness. Secondary outcomes included the Karolinska Sleepiness Scale (KSS), EEG, and a simple response performance task. Blood samples were collected to measure plasma concentrations of LY3154207 and modafinil. Seventeen subjects were enrolled and received at least one dose of study drug, and 16 subjects completed all four periods of the study. Dose-dependent increases in MSLT were observed compared to placebo, with least squares mean (95% CI) differences of 5.2 minutes (3.3, 7.1) for 75 mg, 3.2 minutes (1.4, 5.1) for 30 mg, and 1.3 minutes (-0.6, 3.2) for 15 mg, as shown in Figure 2. LY3154207 also demonstrated a dose-dependent increase in alertness as measured by the Karolinska Sleepiness Scale. PK was linear with a Cmax and t1 / 2 of approximately 3 and 9 hours across the dose range. These results are depicted in Figure 2.LY3144207 increased wakefulness in sleep-deprived healthy volunteers, providing human clinical evidence of the involvement of D1 receptor signaling and the resulting promotion of wakefulness in a phase 1 sleep-onset latency study (HBEB). Thus, central pharmacodynamic activity was confirmed through a dose-dependent increase in wakefulness. An HBEB phase 1 sleep-onset latency study in healthy volunteers showed that LY3154207 improved wakefulness in a dose-dependent manner in sleep-deprived healthy men, supporting the use of LY3154207 in the treatment of excessive daytime sleepiness and other disorders associated with dopaminergic central nervous system disorders according to the dosing regimen of the present invention.

[0156] HBEC, LY3154207 multiple ascending dose study: In this randomized, double-blind, placebo-controlled, multiple-ascending-dose, parallel-group study, participants with HBEC, healthy subjects (Part A), and PD (Part B) received a once-daily dose of LY3154207 (15, 30, 75, or 150 mg in Part A and up to 75 mg in Part B) or placebo for 14 days, as shown in Figure 3 .

[0157] Study outcomes included 24-hour ambulatory blood pressure monitoring (ABPM), treatment-emergent adverse events (TEAEs), and PK assessment in both healthy subjects and participants with PD, as well as Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) assessment to evaluate the effects of LY3154207 on motor function in participants with PD. The objectives were to investigate the safety, tolerability, and pharmacokinetics (PK) of multiple oral daily doses of LY3154207 in healthy subjects (Part A) and participants with PD (Part B).

[0158] HBEC Part A Study: Cognitive outcomes from Phase 1 of healthy volunteers and motor symptoms in PD patients over 14 days of treatment with LY3154207 In healthy subjects and participants with PD, TEAEs were mostly mild, with no severe or serious TEAEs or TEAEs leading to discontinuation. In participants with PD who received LY3154207, treatment-related adverse events (AEs) were epigastric pain (n = 1), hallucinations (n ​​= 1), headache (n = 1), and hypoesthesia (n = 1). In healthy subjects, the incidence of TEAEs increased dose-dependently after multiple doses of LY3154207. In healthy subjects who received LY3154207, common treatment-related AEs (mainly at the 150 mg dose) were insomnia (n = 4), dizziness (n = 3), nervousness (n = 3), palpitations (n ​​= 3), and nausea (n = 2). The effects of LY3154207 on vital signs in participants with PD were less pronounced than in healthy subjects. The results are shown in Table B. Multiple once-daily doses of LY3154207, up to 150 mg in healthy subjects and 75 mg in participants with PD, were well tolerated. The initial increases in SBP, DBP, and pulse rate observed with the first dose of LY3154207 showed adaptation with repeated dosing in both healthy subjects and participants with PD, although the adaptation effect was less pronounced in participants with PD. The PK properties of LY3154207 were generally similar between healthy subjects and participants with PD, although a small increase in LY3154207 exposure was observed in participants with PD. [Table 3]

[0159] As shown in Figure 4, participants with PD treated with LY3154207 showed more consistent improvements in motor test subscores, as measured by the MDS-UPDRS Part III, than participants treated with placebo, suggesting potential efficacy for motor symptoms of PD.

[0160] PK parameters of LY3154207 in healthy subjects and participants with PD demonstrate a dose-dependent increase in exposure and minimal accumulation with repeated dosing. LY3154207 exposure in healthy subjects and participants with PD on day 14 after 75 mg of LY3154207 demonstrates an increase in Cmax and AUC(0-24) of 25% and 42%, respectively, in participants with PD. [Table 4]

[0161] a Participants with PD received titrated doses: days 1–3: 15 mg, days 4–6: 30 mg, and days 7–14: 75 mg. b The cumulative ratio was day 14:day 1. Note: All values ​​reported in the tables are geometric means unless otherwise specified. AUC(0-24) = area under the concentration versus time curve from 0 to 24 hours, CLr = renal clearance, CLss / F = apparent systemic clearance of the drug at steady state calculated after extravascular administration, Cmax = maximum drug concentration, LY = LY3154207, NC = not calculated, PD = Parkinson's disease, RA = accumulation rate (day 14:day 1), tmax = time to maximum drug concentration.

[0162] In the Digit Symbol Substitution Test (DSST), all arms (including placebo) improved over time, with the greatest improvement from baseline seen at the Day 13 assessment, suggesting that learning effects were still present at Day 13. The 15 mg dose of LY3154207, the lowest dose of LY tested, surprisingly provided the highest mean change from baseline at both post-dosing time points. The Hopkins Verbal Learning Test (HVLT) provided some evidence of an inverse dose-response relationship, with 15 mg of LY3154207 providing the greatest mean improvement from baseline. This data from Phase 1 in healthy volunteers suggests that a low-dose range dosing regimen, with a maximum total dose of up to 15 mg per day, may provide cognitive-enhancing effects in dopaminergic central nervous system disorders or healthy subjects.

[0163] Abbreviations: AUC(0-24) = area under the concentration versus time curve from 0 to 24 hours. AUC0-∞ = area under the concentration versus time curve from time 0 to infinity, CI = confidence interval, CL / F = apparent clearance, CLr = renal clearance, CLss / F = apparent total body clearance of the drug at steady state calculated after extravascular administration, Cmax = maximum concentration, tmax = time to maximum drug concentration, CSF = cerebrospinal fluid, LS = least squares, LY = LY3154207, MSLT = polysomnographic latency test, PBO = placebo, PK = pharmacokinetics, t½ = terminal half-life, tmax = time to maximum concentration. bpm = beats per minute, DBP = diastolic blood pressure, SBP = systolic blood pressure, LS = least squares, LY = LY3154207, MDS-UPDRS = Movement Disorder Society-Unified Parkinson's Disease Rating Scale, NC = not calculated, PD = Parkinson's disease, RA = accumulation rate (day 14:day 1), AE = adverse event, TEAE = treatment-emergent adverse event.

[0164] Example 2: Spatial working memory in adult rhesus monkeys It has been established that the core cognitive function of working memory is highly dependent on D1 receptor signaling in the prefrontal cortex. While D1 agonists have demonstrated drug problems due to excessive stimulation and tolerance, D1 positive allosteric modulators (PAMs) show promise in selectively enhancing appropriate D1 activity in response to the spatiotemporal dynamics of dopamine transmission, thus circumventing these issues. A D1 PAM compound called DPTQ or LY3151944, 2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(2-hydroxy-2-methylpropyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, as shown below, surprisingly demonstrated sustained improvements in spatial working memory in adult rhesus monkeys. [ka]

[0165] DPTQ tended to reduce spatial working memory performance in rhesus monkeys at acute doses of 2.5–10 mg / kg IM, but had little effect in protecting against ketamine-induced cognitive impairment. However, despite this apparent lack of acute cognitive-enhancing effects, it showed a surprisingly consistent and significant effect on performance when tested several days after administration. Specifically, performance was significantly reduced 24–48 h after injection but significantly enhanced when tested 96–120 h later.

[0166] Studies were conducted to evaluate the effects of low doses of DPTQ alone, 0.1, 1.0, and 10.0 mg / kg, as well as the effects of a single 2.5 mg / kg dose repeated during delayed cognitive enhancement. A moderate dose-dependence was observed in the magnitude of delayed cognitive decline and enhancement, which may provide important insights into treatment efficacy. Repeated doses of 2.5 mg / kg during enhancement were found to induce a transient deficit that later led to long-term cognitive enhancement. This unique and unexpected finding demonstrates the chronic and intermittent effects of repeated administration.

[0167] Experimental Overview: Groups of both aged and non-aged animals were tested with a single dose of 2.5 mg / kg, and their performance was tracked daily for the first 6 days, then every other day. This was to ensure that the previously observed effects could be replicated at the lowest possible dose. The effects of repeating this dose on day 5, 120 hours, were tested to determine (i) whether the immediate decline in performance could be seen the next day, and (ii) whether the treatment could achieve a relatively consistent and durable enhancement of performance over the following days. Because this dose may also induce a short-term decline in performance, the effects of single administration at lower doses of 0.1 and 1.0 mg / kg were tested.

[0168] All animals were rhesus macaques, with the exception of one stumptail macaque (Macaca arctoides). Animal demographic details are presented with each set of results. Younger animals were preferred in each study, but older animals were studied for dominance, with females outnumbering males by a factor of 2 or 3 to 1. The spatial delayed response task has been established as one of the most reliable, sensitive, and valuable models for testing spatial working memory in primates. The spatial delayed response task is rigorously implemented in a fully systematic format that is uniform within and between animals and across studies. The spatial delayed response task is designed to normalize performance across animals, with all animals typically performing at approximately 70% accuracy. The spatial delayed response task directly challenges the same spatial working memory circuitry in humans and nonhuman primates, including the dorsolateral prefrontal cortex, posterior parietal cortex, and dorsomedial thalamus. The spatial delayed response task is sensitive to multiple neuropharmacological manipulations, whether administered locally or systemically, including dopaminergic, nicotinic, glutamatergic, and GABAergic agents. In this task, one of several well locations is fitted with a food reward within the animal's line of sight and covered with an identical plaque. The plaque's shutter is then lowered and then raised for one of five variable delays, allowing the animal to respond to one of the well locations and retrieve the food reward. Before any administration began, each animal was stabilized (65-75% accuracy ± ≤ 2.5%) by varying the number of wells and the length of the delay. Each test session consisted of 20 trials, four trials at each of five delays (semi-randomly distributed) ranging from 0, 1, 2, 3, and 4 N seconds, where N increased from 1 to 10 depending on performance. The number of wells ranged from 2 to 7, and stability was achieved by gradually varying the number of wells and N factor. An initial baseline is achieved during the first training session and standardized over 20 sessions, after which animals typically undergo periodic testing to ensure a reasonably stable baseline. A minimum of three robust baseline sessions is required prior to any experimental condition.Animals are not deprived of food but are instead rewarded for correct responses with the most preferred reward (such as yogurt raisins, gummy bears, and almonds) and are given a normal amount of nutritional biscuits immediately after the cognitive test.

[0169] DPTQ was formulated as a suspension in 20% Captisol / PBS at pH 8. Careful consideration was taken to preserve the compound during sonication, and the compound was injected (at a volume of 0.2 ml / kg) into the gluteus maximus muscle via a 21G hypodermic needle (to avoid blockage) within 2 hours of formulation (while kept on ice). Vehicle was refrigerated in sterile injectable vials for up to 1 month. Animals were fully acclimated to all procedures before enrollment in any study. They were assigned at study baseline preparation, and where relevant, assignment was semi-randomized between vehicle and treatment arms. IM injections were administered in the animals' home cages 1 hour before cognitive testing. Testing was conducted in a sound-attenuating chamber based on the standard WGTA design in a dedicated treatment room adjacent to the animal enclosure.

[0170] The effects of a single dose of DPTQ were observed over a 14-day period. The single dose was originally tested at 2.5 mg / kg compared to vehicle, and the same vehicle data can reasonably be applied to subsequent studies of single doses of 0.1 and 1.0 mg / kg DPTQ. Separate but overlapping baselines were used for the two conditions.

[0171] Vehicle data for groups of 10 animals are shown in Figure 5. Group performance changed little from baseline over the next two weeks, with group means varying by only 5%. Vehicle given on day 1 did not produce long-term changes in cognitive performance.

[0172] Figure 6 shows acute administration of DPTQ at 2.5 mg / kg. Treatment data for a group of nine animals are shown in Figure 6. While no immediate effects were observed on Day 1, a decline in performance became apparent by Day 2 and became robust by Day 3 (ANOVA F[1,14] = 4.543, p = 0.051 vs. baseline). This apparent cognitive impairment was immediately followed by a sustained cognitive enhancement from Day 4 onward (ANOVA F[1,14] = 45.061, p < 0.001 vs. baseline). Of these nine animals, five were aged and four were non-aged. By combining scores from Days 4, 5, and 6, it was possible to compare these two groups. No significant differences were found between the two (ANOVA: F[1,22] = 0.066, p = 0.799). Although no acute effect of DPTQ was observed, a functional impairment of approximately 10% became evident on the third day, followed by a long-term enhancement of nearly 10% again from the fourth day onwards.

[0173] The effects of repeated administration of DPTQ on day 5 of the 14-day observation period were also evaluated. Figure 7 shows the effects of repeated administration of a 2.5 mg / kg dose on day 5. In this study, a 2.5 mg / kg dose was administered acutely on day 1 (1 hour before testing), followed by either vehicle or a booster dose of 2.5 mg / kg on day 5 (immediately after testing). Animals were semi-randomly assigned to receive either vehicle or treatment initially for the repeated administration. When 2.5 mg / kg was again administered as a second dose on day 5, a second subsequent decline in performance was observed on day 6 (Figure 7). Performance was not significantly below baseline levels, but it did show a significant drop from the enhancement seen on the previous two days. Nevertheless, performance recovered within 2 days (ANOVA Day 4: F[1,10] = 15.564, p = 0.003) and appeared to remain elevated for 1 week (ANOVA Day 10, f[1,10] = 25.912, p < 0.001). The initial decline in performance was seen again on Day 3, but was not significant. Following an acute dose on Day 1, there was another decline on Day 3, followed by a rebound enhancement on Day 4. However, following a repeated dose on Day 5, there was a distinct decline in performance on Day 6, followed quickly by an enhancement over the following week.

[0174] To better understand the dynamic range of these effects, administration of DPTQ at a lower dose of 0.1 mg / kg was evaluated. Figure 8 shows the effects of DPTQ when administered at a low dose of 0.1 mg / kg. No signs of a decline in performance were observed, but the enhancement seen was slight. Interestingly, in the group of 10 animals, no deficits were observed on day 3; instead, signs of modest enhancement were observed, showing some persistence over the course of the 2-week period (Figure 8). Nevertheless, day 4 showed a significant improvement over baseline (ANOVA: F[1,18] = 24.132, p < 0.001). Within this group, there were six aged animals and four non-aged animals. When scores were compared across days, no significant differences were observed between them (ANOVA F[1,8] = 0.816, p = 0.393).

[0175] The effects of administration of DPTQ at a dose of 1.0 mg / kg on spatial working memory were evaluated. As shown in Figure 9, no initial deficits were evident, and enhancement appeared stronger than with the 0.1 mg / kg dose, reaching significance on day 5 (ANOVA F[1,14] = 22.449, p < 0.001). The group now includes six aged animals and two non-aged animals, as well as two additional non-aged animals that have not yet completed the study. There was no indication of any difference in scores between the two age groups.

[0176] Thus, DPTQ at doses of 1-10 mg / kg or less may improve spatial working memory (since even the lowest dose studied showed significant improvement). Surprisingly, cognitive-enhancing effects were observed at low doses of 0.1 and 1 mg / kg IM in monkeys. Higher doses of DPTQ, 2.5 mg / kg or higher, showed a slight decrease in performance in the first 48 hours, but then demonstrated sustained positive effects lasting for at least 14 days. These data provide evidence that DPTQ and / or LY3154207 can enhance cognitive performance in primates in a time-dependent manner. This primate cognitive signal at 0.1 mg / kg (approximately equivalent to a 1 mg oral dose of LY3154207 in humans) suggests that DPTQ may have cognitive-enhancing effects at lower doses without evidence of an initial loss of efficacy, likely due to overactivation. PK-PD predictions estimate that a 1.0 mg / kg IM dose of DPTQ corresponds to 10 mg of LY3154207 in humans, and a 2.5 mg / kg dose of DPTQ corresponds to 25 mg of LY3154207 in humans. Phase 1 clinical data for the 15 mg dose of LY3154207 also showed a trend toward better cognitive effects in the DSST task compared to higher doses.

[0177] These data, taken together with the data from the Phase 1 study described above, lead to the notion that the present dosing regimen, in the low dose range of 0.5 mg to 15 mg, not only avoids the high levels of stimulation observed at higher doses, such as 20 mg to 75 mg, and certain undesirable dose-related cardiovascular effects, such as excessive wakefulness leading to insomnia, and / or elevated pulse rate and blood pressure, but also provides effective enhancement of certain D1 signaling-mediated responses, such as cognitive-enhancing effects, while reducing the risk of drug-drug interactions with Cyp3A4 inhibitors. More specifically, it has been discovered that high dosing schedules of LY3154207 above 75 mg per day may be associated with mild to moderate insomnia and agitation, and / or undesirable cardiovascular effects, as doses above 75 mg may cause acute and / or sustained increases in blood pressure and pulse rate. In Study HBEB, a linear, dose-dependent effect on sleep onset latency was observed across doses from 15 mg to 75 mg in healthy sleep-deprived subjects receiving a single dose of LY3154207. Activation adverse events, such as insomnia, are observed with a substantial increase in frequency above the 75 mg dose of LY3154207. Thus, in the current dosing regimen, the 75 mg dose represents a surprising and unpredictable separation of desirable and undesirable effects of LY3154207.

[0178] Thus, the combined results of the Phase 1 human and primate studies led to the concept of the present invention, which provides improved clinical therapeutic dosing regimens and methods using LY3154207 and / or pharmaceutical compositions thereof for the treatment of dopaminergic central nervous system disorders. In particular, daily administration of LY3154207 provides an improved means for alleviating the signs and symptoms of dopaminergic central nervous system disorders in a clinically advantageous manner, achieving safe, tolerable, and effective alleviation of clinical signs and symptoms.

[0179] In particular, the present invention further provides methods using low-dose administration regimens that are believed to promote normalization of endogenous dopaminergic signaling in a variety of dopamine-mediated disease states, while being less prone to certain effects seen at higher doses, such as overstimulation, and less likely to develop the intolerance and adverse effects associated with orthosteric D1 agonists. As a result of this normalizing effect, the LY3154207 clinical dosing regimens of the present invention, particularly low-dose regimens, offer an improved means for the treatment of a range of dopamine-mediated CNS disorders, with a surprising and unexpected combination of favorable human clinical pharmacological efficacy, safety, and tolerability.

[0180] LY3154207 is currently in a Phase 2 study for cognition in dementia with Lewy bodies (NCT03305809). The results of this clinical trial may further support the surprising and unexpected benefits of this medication regimen and dose for use in treating dopaminergic CNS disorders such as LBD, PD, and AD.

[0181] Example 3: Protocol for a Dosage Regimen Study in PD - Study HBEH also known as "PRESENCE" Below is provided a protocol for a dosage regimen study in PD at specific doses of the dosage regimen of the present invention. Those skilled in the art will be able to apply the teachings of this Example 3 and other disclosures provided herein to conduct similar studies with additional doses and dosage regimens of the present invention.

[0182] A well-tolerated treatment for cognitive impairment due to PDD remains an unmet medical need. By promoting the response to residual brain dopamine (or administered levodopa) in subjects with PDD, D1PAM should improve cognitive performance. Furthermore, D1PAM should have a positive effect on motor impairment, depression, and daytime sleepiness observed in subjects with PD.

[0183] LY3154207 may improve various areas important to people with dementia with Lewy bodies, including signs of parkinsonism such as motor symptoms, alertness, mood, and function. LY3154207 was developed to treat the cognitive impairment symptoms of dementia and may result in improvement with a relatively short period of chronic daily dosing (12 weeks or less). As a symptomatic medication, LY3154207 is important because patients continue to suffer from dementia symptoms even when medications that slow progression are available. By enhancing the response to remaining brain dopamine (or administered levodopa) in subjects with Parkinson's disease, LY3154207 is believed to improve cognitive performance and provide a treatment for Parkinson's disease subjects with neurocognitive dysfunction. The outcome goal for the use of LY3154207 is improvement of cognition in PD dementia (PDD), including dementia with Lewy bodies (DLB), with additional benefits in motor and / or alertness.

[0184] The PRESENCE study is evaluating three doses of LY3154207 versus placebo (10 mg, 30 mg, and / or 75 mg (or 50 mg based on an interim analysis) daily (QD) oral dosing) over 12 weeks of treatment. The primary outcome is a measure of cognition, with additional measures of cognition being evaluated as key secondary endpoints. PRESENCE is a randomized, placebo-controlled trial evaluating the safety and efficacy of LY3154207 (three doses of the investigational drug) over 12 weeks in participants with mild to moderate Parkinson's disease dementia. The primary outcome is a measure of cognition, with additional measures of cognition being key secondary endpoints. D1 PAM mechanisms can affect various domains important to people with Lewy body dementia, and measures of parkinsonism (including motor symptoms), wakefulness, mood, and function are being evaluated.

[0185] Study HBEH included subjects with mild to moderate dementia who met the revised MDS criteria for PD (Postuma et al. 2015) and who, in the investigator's opinion, had cognitive decline, resulting in functional impairment and an MoCA score of 10–23 (Trzepacz et al. 2015). The revised MDS criteria allow for a diagnosis of PDD in the presence of dementia, regardless of the timing of dementia onset relative to the PD diagnosis. Subjects diagnosed with dementia with Lewy bodies (DLB) should also be considered to have PD if they meet the MDS PD criteria. Thus, subjects may have had dementia before, at the time of, or after the diagnosis of PD. Unlike registry trials of symptomatic therapy in PDD (Emre et al. 2004), the current study includes subjects who would have met the traditional criteria for DLB based on the timing of their dementia (dementia before motor onset or within 1 year of onset) (Mckeith et al. 2005). This criterion was that dementia must occur before or within one year of Parkinson's disease symptoms. The one-year rule is arbitrary and based on the historical belief that PD is not associated with dementia. However, the validity of this traditional approach to dividing diagnoses is increasingly controversial (Berg et al. 2014). Supporting the proposed approach, both disorders share various clinical, genetic, and pathological features (Lippa et al. 2007, Postuma et al. 2009, Johansen et al. 2010). Both DLB and PDD are associated with similar impairments in cognition, with predominantly visual perceptual abnormalities and improved cued memory. Both are associated with prominent psychosis, neuroleptic sensitivity, and altered wakefulness. Prodromal features (e.g., rapid eye movement [REM] sleep behavior disorder, anosmia) are the same in both conditions. Nonmotor symptoms, including depression, anxiety, autonomic dysfunction, and sleep disturbances, occur with similar relative frequency in both. The same genetic mutations (alpha-synuclein duplication, glucocerebrosidase mutation) are associated with the development of both conditions.Finally, they share a common pathology of alpha-synuclein and Lewy body formation in the brainstem and cortex. Therefore, Study HBEH aligns with current thinking about PDD and DLB, which suggest that cognitive impairment is distinct in timing, clinically and pathologically indistinguishable, and likely responds to similar treatment approaches (Aarsland et al. 2004, Ballard et al. 2006). A placebo was included as a control blinded to investigators, site staff, and subjects, allowing for unbiased evaluation of generated safety data and more robust comparisons between LY3154207 and placebo data. Three dose levels of LY3154207 were selected to assess dose-exposure response for safety and efficacy. The initial visits (Visits 3–7) were chosen to occur weekly to provide a detailed assessment of the efficacy and safety of LY3154207 during initial treatment. A 12-week treatment period was selected, presumably the minimum period during which beneficial effects on cognition could be observed.

[0186] The primary objective is to test the hypothesis that LY3154207, administered at oral doses of 10 mg, 30 mg, and / or 75 mg (or 50 mg based on interim analysis) daily (QD) for 12 weeks, significantly improves cognitive function compared with placebo in subjects with mild to moderate PDD. The primary endpoint is the change in the CDR-CCB CoA composite score from baseline to week 12. Secondary objectives are described below. [Table 5]

[0187] Abbreviations: ADAS-Cog13 = 13-item Alzheimer's Disease Assessment Scale-cognitive subscale, ADCS-CGIC = Alzheimer's Disease Collaborative Study-Clinician Global Impression of Change, CDR-CCB = Cognitive Drug Research-Computerized Cognitive Battery, CoA = Continuity of Attention, D-KEFS = Delis-Kaplan Executive Function System, ESS = Epworth Sleepiness Scale, MDS-UPDRS = Movement Disorder Society Unified Parkinson's Disease Rating Scale, MoCA = Montreal Cognitive

[0188] Assessment, NPI = Neuropsychiatric Symptom Assessment, PD = Parkinson's disease, PDD = Parkinson's Disease Dementia, PDAQ-15 = Penn-Parkinson Activities of Daily Living Questionnaire-15, PK = Pharmacokinetics, PoA = Attention, QD = Once daily, SBP = Systolic blood pressure.

[0189] reference: Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G.MDS clinical diagnostic criteria for Parkinson's disease.Mov Disord. 2015;30(12):1591-1601. Trzepacz PT, Hochstetler H, Wang S, Walker B, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative.Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults. BMC Geriatr.2015;15:107. Emre M,Aarsland D,Albanese A,Byrne EJ,Deuschl G,De Deyn PP,Durif F,Kulisevsky J, van Laar T,Lees A,Poewe W,Robillard A,Rosa MM,Wolters E,Quarg P,Tekin S,Lane R.Rivastigmine for dementia associated with Parkinson's disease.N Engl J Med. 2004;351(24):2509-2518. McKeith IG,Dickson DW,Lowe J,Emre M,O'Brien JT,Feldman H,Cummings J,Duda JE, Lippa J,Perry EK,Aarsland D,Arai H,Ballard CG,Boeve B,Burn DJ,Costa D,Del Ser T, Dubois B,Galasco D,Gauthier S,Goetz CG,Gomez-Tortosa E,Halliday G,Hansen LA, Hardy J,Iwatsubo T,Kalaria RN,Kaufer D,Kenny RA,Korczyn A,Kosaka K,Lee VM, Lees A,Litvan I,Londos E,Lopez OL,Minoshima S,Mizuno Y,Molina JA, Mukaetova-Ladinska EB,Pasquier F,Perry RH,Schulz JB,Trojanowski JQ,Yamada M; Consortium on DLB.Diagnosis and management of dementia with Lewy bodies:third report of the DLB Consortium.Neurology.2005;65(12):1863-1872. Berg D,Postuma RB,Bloem B,Chan P,Dubois B,Gasser T,Goetz CG,Halliday GM,Hardy J,Lang AE,Litvan I,Marek K,Obeso J,Oertel W,Olanow CW,Poewe W,Stern M, Deuschl G.Time to redefine PD?Introductory statement of the MDS Task Force on the definition of Parkinson’s disease.Mov Disord.2014;29(4):454-462. Lippa CF,Duda JE,Grossman M,Hurtig HI,Aarsland D,Boeve BF,Brooks DJ,Dickson DW,Dubois B,Emre M,Fahn S,Farmer JM,Galasko D,Galvin JE,Goetz CG,Growdon JH, Gwinn-Hardy KA,Hardy J,Heutink P,Iwatsubo T,Kosaka K,Lee VM,Leverenz JB, Masliah E,McKeith IG,Nussbaum RL,Olanow CW,Ravina BM,Singleton AB,Tanner CM,Trojanowski JQ,Wszolek ZK;DLB / PDD Working Group.DLB and PDD boundary issues:diagnosis,treatment,molecular pathology,and biomarkers.Neurology. 2007;68(11):812-819. Postuma RB,Gagnon JF,Vendette M,Montplaisir JY.Idiopathic REM sleep behavior disorder in the transition to degenerative disease.Mov Disord.2009;24(15):2225-2232. Johansen KK,White LR,Sando SB,Aasly JO.Biomarkers:Parkinson disease with dementia and dementia with Lewy bodies.Parkinsonism Relat Disord.2010;16(5):307-315. Aarsland D,Ballard CG,Halliday G.Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity?J Geriatr Psychiatry Neurol.2004;17(3):137-145. American Psychiatric Association.Diagnostic and statistical manual of mental disorders.5th ed.Washington,DC;2013. Ballard C,Ziabreva I,Perry R,Larsen JP,O’Brien J,McKeith I,Perry E,Aarsland D. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology.2006;67(11):1931-1934. Yesavage JA,Brink TL,Rose TL,Lum O,Huang V,Adey M.,Leirer VO.Development and Validation of a geriatric depression screening scale:A preliminary report.J Psychiatr Res. 1983;17:37-49. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version.Clin Gerontologist.1986;5:165-173.

[0190] Study Design Summary: Study I7S-MC-HBEH (HBEH) is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, fixed-dose, Phase 2a study comparing three doses of LY3154207 (10, 30, or 75 mg orally administered once daily [QD] [or 50 mg based on an interim analysis]) with placebo over 12 weeks in subjects with mild to moderate PDD. The study included a minimum 7- to maximum 14-day screening period (Visits 1-2), a minimum 11- to maximum 17-day pretreatment period (Visits 2-3), a 12-week treatment period (Visits 3-11), and a 14-day safety follow-up period (Visits 11-801 or early termination [ET] / discontinuation [DC] visit to Visit 801). Subjects who meet the entry criteria will be randomized in a 1:1:1:1 ratio to receive LY3154207 (10, 30, or 75 mg QD) or placebo. The primary objective of this study is to test the hypothesis that 12 weeks of LY3154207 administration will result in significant improvements in cognition, as measured by the change from baseline to week 12 in the Consistency of Attention (CoA) composite score of the Cognitive Drug Research-Computerized Cognitive Battery (CDR-CCB), compared with placebo, in subjects with mild to moderate PDD. CoA has demonstrated significant therapeutic effects in previous studies in subjects with PDD (Wesnes et al. 2005; Rowan et al. 2007).

[0191] Treatment Arms and Duration: Study HBEH will involve comparison of 10 mg, 30 mg, and 75 mg (or 50 mg at interim analysis) of LY3154207 administered orally QD versus placebo for 12 weeks. Number of Subjects: Approximately 400 subjects will be screened to achieve 340 randomized and an estimated total of 85 evaluable subjects per treatment arm.

[0192] statistical analysis Efficacy Analysis: All subjects in the evaluable patient population (EPP) are included in the efficacy analysis. The primary analysis for CoA will be conducted when all subjects have completed 12 weeks of treatment. The analysis of CoA will utilize a Bayesian MMRM model. Bayesian analysis may use uninformative priors for all terms in the model. These are diffuse normal distributions centered at zero. The prior distribution for variance follows an inverse gamma distribution. Details of the Bayesian analysis are provided in SAP. The MMRM model accounts for longitudinal data assessed throughout the study at 1, 2, 4, 6, 8, 10, and 12 weeks after dosing. The change in CoA from baseline to week 12 is the dependent variable. The model includes fixed (baseline value, treatment, visit) and random effects (subject) and interaction terms (treatment by visit, baseline value by visit). An unstructured variance structure will be applied to the model; however, if convergence fails, other appropriate structures will be explored. The primary comparison is the contrast between treatment and placebo (least squares mean difference) for the change from baseline at week 12. Secondary efficacy outcomes: Change from baseline at 12 weeks in the Alzheimer's Disease Cooperative Study-Clinician Global Impression of Change (ADCS-CGIC) total score (or composite), CDR-CCB Attention (PoA), 13-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog13), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), Epworth Sleepiness Scale (ESS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Penn-Parkinson's Activities of Daily Living Questionnaire-15 (PDAQ-15), and DeLisCaplan Executive Function System (D-KEFS) will follow the same analytical methods as above. Missing records in some scales (e.g., ADAS-Cog) will be imputed as detailed in the statistical analysis plan. For scales without imputation, missing items will be considered missing for the aggregate or total including that item. No adjustment for multiple comparisons will be made.

[0193] Safety Analysis: Safety analyses are based on the safety population, and analyses include a list and / or summary of the following: adverse events (AEs), serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), laboratory measurements, vital signs, electrocardiogram readings, and the number of subjects who met potentially clinically significant vital sign criteria at three consecutive time points at Visit 3 (Day 1 stopping rule). A mixed-model repeated-measures analysis will be used to compare in-clinic blood pressure (BP) and pulse rate changes from pretreatment measured on the first day of study drug dosing (V3) up to 8 hours post-dose. Two baselines will be considered in the change from baseline analysis: the V3 pretreatment value and the time-matched baseline from Visit 2 (time values ​​0-6 hours). For the second baseline, the V3, 7-hour, and 8-hour time points will be used, with the V2 6-hour time point used as the baseline value. A separate change from baseline analysis will be completed per baseline approach. Mixed-model repeated-measures analysis will also be used to compare in-clinic BP and pulse rate changes from V2 (daily average 0–6 h) to Week 6 / Visit 8 and Week 12 / Visit 11 (daily average 0–6 h) and to assess changes in BP and pulse rate over the 12 weeks of medication.

[0194] Pharmacokinetics (PK): Pharmacokinetic analysis is performed on subjects who have received at least one dose of the investigational drug and have one measurable concentration. A model-based approach can be implemented using nonlinear mixed-effects modeling (NONMEM) or other appropriate software to evaluate PK parameters.

[0195] Additional endpoint and biomarker data collected during the study may be evaluated in an exploratory manner.

[0196] Interim Analysis: The safety interim analysis was A safety interim analysis will be conducted for the number of subjects on each treatment who meet the potentially clinically important vital sign criteria at three consecutive time points at Visit 3 (Day 1 stopping rule). This will occur after 50, 100, and 150 subjects have completed Visit 3. If there is a greater than 60% probability that the difference in the proportion of subjects meeting the Day 1 stopping rule for 75 mg of LY3154207 compared to placebo is >0.3, the 75 mg dose level will be replaced by 50 mg for subsequently enrolled subjects. Those already at the 75 mg dose who pass the Day 1 stopping rule will remain at 75 mg. In the event of an unacceptable proportion of subjects meeting the Day 1 stopping rule at other doses, dose adjustments may be made for subsequently randomized subjects at the discretion of the Internal Review Committee (IAC). Additional efficacy analyses may be conducted at the time of these interim safety analyses. The safety and efficacy interim analyses will be conducted when 170 randomized subjects have completed the Visit 11 (Week 12) evaluation. All potential efficacy analyses may be used for internal decision making but are not planned to stop the study.

[0197] Study HBEH includes men and women aged 40–85 years with mild to moderate PDD. Subjects are eligible for inclusion in the study only if they meet all of the following criteria at enrollment (Visit 1) (note that inclusion criteria [6]–

[10] must be met or additional visit(s) are possible):

[0198] Subject type and disease characteristics: [1] Male and female subjects aged 40-85 years (inclusive). [2] Idiopathic PD according to MDS criteria with PD symptoms for at least 2 years (Postuma et al. 2015). [3] Dementia defined by cognitive decline resulting in functional impairment in the investigator's opinion. [4] MoCA score of 10-23 at screening. [5] Modified Hoen and Yahr stage 1-4. [6] BP or pulse rate at Visit 1 and Visit 3 determined by three consecutive BP / pulse rate measurements in a seated position:

[0199] For subjects <60 years of age: mean systolic blood pressure (SBP) of 140 mmHg or less, mean diastolic BP of 90 mmHg or less, mean pulse rate of 90 beats / min or less in a seated position, and each of three SBP measurements must be less than 180 mmHg.

[0200] For subjects ≥ 60 years of age: mean SBP ≤ 150 mmHg, mean diastolic BP ≤ 90 mmHg, and mean pulse rate ≤ 90 beats / min in a seated position, with each of the three SBP measurements required to be < 180 mmHg.

[0201] The following PD severity and cognitive assessments, as well as the Columbia-Suicide Severity Rating Scale (C-SSRS), will be administered at Visit 1 as part of subject eligibility assessment: Movement Disorder Society (MDS) Clinical Diagnostic Criteria for Parkinson's Disease. Enrolled individuals meet MDS criteria for clinically probable PD (Postuma et al. 2015). Subjects must have resting tremor and / or bradykinesia with rigidity. Subjects must not have any of the absolute exclusion criteria listed in Appendix 5. Subjects must not have more than two red flags present; if one red flag is present, it must be offset by one supportive criterion; if two red flags are present, it must be offset by two supportive criterion.

[0202] In addition to meeting criteria for PD, subjects must also meet criteria for dementia (Montreal Cognitive Assessment [MoCA] scale), as described below. The MDS criteria do not consider dementia an exclusion criterion for PD, and therefore do not restrict the timing of dementia relative to the development of motor features of PD.

[0203] Modified Hoehn and Yahr Scale: Enrolled individuals must be in Hoehn and Yahr Stages 1–4 at screening. The Hoehn and Yahr Scale (Hoehn and Yahr 1967) is used to describe the progression of PD symptoms. The scale was originally described in 1967 and included Stages 1–5. It was subsequently modified to include Stages 1.5 and 2.5 to describe intermediate stages of PD. The modified Hoehn and Yahr Scale is as follows: Stage 0: No signs of disease; Stage 1: Unilateral disease; Stage 1.5: Unilateral plus axial involvement; Stage 2: Bilateral disease without balance dysfunction; Stage 2.5: Mild bilateral disease, recovery on pull test; Stage 3: Mild to moderate bilateral disease, some postural instability, physical independence; Stage 4: Severe disability, still able to walk or stand without assistance; Stage 5: Wheelchair-bound or bedridden unless aided.

[0204] Montreal Cognitive Assessment Scale: Enrolled individuals must have a MoCA score of 10-23 at screening.

[0205] Geriatric Depression Scale: Enrolled individuals must have a Geriatric Depression Scale-Short Form (GDS-S) score of ≤6 at screening. The GDS is a site-administered questionnaire regarding depression in older adults (Yesavage et al. 1983). Users respond in a "yes / no" format. Originally developed as a 30-item scale (long form), it was subsequently shortened to a 15-item scale (short form), which can be completed in approximately 5–7 minutes (Sheikh and Yesavage 1986). Of the 15 items, 10 indicate depression if answered "yes," and 5 indicate depression if answered "no."

[0206] Columbia-Suicide Severity Rating Scale-Children's Version: The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the corresponding assessment period. Included here as a screening assessment, the C-SSRS is described in detail in Section 9.4.4. The "Baseline" version of the C-SSRS is used at screening, and the findings constitute the baseline assessment. The C-SSRS is administered to subjects after cognitive and functional assessments. Responses from subjects are taken into account when administering the scale. If a subject is determined to have suicidal ideation or behaviors at this baseline assessment, they will not be randomized and will be discontinued from the study.

[0207] Example 4 Protocol for Studying Dosage Regimen in AD LY3154207 is believed to be effective in improving cognitive impairment in Alzheimer's disease through activation of cortical neurons, enhancement of synaptic plasticity, and neurotransmitter release. Other potential effects of LY3154207, such as reduced daytime sleepiness, improved mood and / or apathy, and goal-directed behavior leading to reduced apathy (via activation of D1 receptors in the cortex and striatum), may also be beneficial in the Alzheimer's disease population. Using methods known to those of skill in the art, usefulness in AD can be demonstrated in patients with mild to moderate AD (MMSE 13-26) in clinical studies of 24 weeks or longer duration, in which patients are administered LY3154207 or a pharmaceutical composition thereof at doses of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, and efficacy, safety, and tolerability are assessed by methods known to those of skill in the art, including, for example, ADAS-Cog13, MMSE, ADCS-CGIC, ADCS-ADL, AD-QOL, NPI, and ESS.

[0208] Example 5: Other Dopaminergic CNS Disorders Usefulness in various other dopaminergic CNS disorders, including vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive impairment, sleep disorders, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders, may be demonstrated by clinical studies in which patients with the disorder are administered LY3154207 or a pharmaceutical composition thereof at doses of about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg, and efficacy, safety, and tolerability are assessed by methods known to those of skill in the art.

Claims

1. LY3154207 or a pharmaceutical composition thereof for use in treating a dopaminergic central nervous system disorder in a patient, comprising administering to said patient one or more doses of from about 0.5 mg to about 75 mg per day of LY3154207 or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day.

2. 10. The method of claim 1, comprising administering to said patient one or more doses of about 0.5 mg to about 15 mg of LY3154207 or a pharmaceutical composition thereof per day, up to a maximum total dose of 15 mg per day.

3. 10. The method of claim 1, comprising administering to the patient a daily dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

4. 10. The method of claim 1, comprising chronically administering to said patient one or more doses of LY3154207 or a pharmaceutical composition thereof from about 0.5 mg to about 75 mg per day, up to a maximum total dose of 75 mg per day, wherein said patient is treated for at least 21 consecutive days.

5. 5. The use of claim 4, comprising chronically administering to said patient one or more doses of about 0.5 mg to about 15 mg per day of LY3154207 or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

6. 5. The method of claim 4, comprising chronically administering to said patient a daily dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

7. 7. The use of LY3154207 or a pharmaceutical composition thereof according to any one of claims 1 to 6, wherein the dopaminergic central nervous system disorder is selected from the group consisting of dementia with Lewy bodies (LBD), Parkinson's disease, Alzheimer's disease, vascular dementia, schizophrenia, ADHD, depression, autism, chronic musculoskeletal pain, fibromyalgia, cognitive dysfunction, excessive daytime sleepiness, narcolepsy, shift work disorder, traumatic brain injury, chronic traumatic encephalopathy, obesity and appetite regulation, mood disorders, lethargy, apathy, and addictive disorders.

8. 4. The method of claim 3, comprising administering to said patient a dose of 0.5 mg per day of LY3154207 or a pharmaceutical composition thereof.

9. 4. The method of claim 3, comprising administering to said patient a dose of 1 mg per day of LY3154207 or a pharmaceutical composition thereof.

10. 4. The method of claim 3, comprising administering to said patient a dose of 2 mg per day of LY3154207 or a pharmaceutical composition thereof.

11. 4. The method of claim 3, comprising administering to said patient a dose of 3 mg per day of LY3154207 or a pharmaceutical composition thereof.

12. 4. The method of claim 3, comprising administering to said patient a dose of 5 mg per day of LY3154207 or a pharmaceutical composition thereof.

13. 4. The method of claim 3, comprising administering to said patient a dose of 10 mg per day of LY3154207 or a pharmaceutical composition thereof.

14. 4. The method of claim 3, comprising administering to said patient a dose of 15 mg per day of LY3154207 or a pharmaceutical composition thereof.

15. 4. The method of claim 3, comprising administering to said patient a dose of 20 mg per day of LY3154207 or a pharmaceutical composition thereof.

16. 4. The method of claim 3, comprising administering to said patient a dose of 30 mg per day of LY3154207 or a pharmaceutical composition thereof.

17. 4. The method of claim 3, comprising administering to said patient a dose of 50 mg per day of LY3154207 or a pharmaceutical composition thereof.

18. 4. The method of claim 3, comprising administering to said patient a dose of 75 mg per day of LY3154207 or a pharmaceutical composition thereof.

19. 8. LY3154207 or a pharmaceutical composition thereof for use according to claim 7, wherein the dopaminergic central nervous system disorder is Parkinson's disease.

20. 20. LY3154207 or a pharmaceutical composition thereof for use according to claim 19, wherein the patient meets the revised MDS criteria for PD and has mild to moderate dementia defined by cognitive decline with a MoCA score of 10-23.

21. 8. LY3154207 or a pharmaceutical composition thereof for use according to claim 7, wherein the dopaminergic central nervous system disorder is Alzheimer's disease.

22. 8. LY3154207 or a pharmaceutical composition thereof for use according to claim 7, wherein the dopaminergic central nervous system disorder is obesity.

23. 1. A method of treating a dopaminergic central nervous system disorder in a patient in need thereof, comprising administering to said patient LY3154207 or a pharmaceutical composition thereof at a dose of about 0.5 mg to about 75 mg, up to a maximum total dose of 75 mg per day.

24. 24. A method of treating a dopaminergic central nervous system disorder in a patient in need thereof according to claim 23, comprising administering to the patient a dose of about 0.5 mg to about 15 mg of LY3154207 or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

25. 24. A method of treating a dopaminergic central nervous system disorder of claim 23 in a patient in need thereof, comprising administering to the patient a daily dose of LY3154207 or a pharmaceutical composition thereof selected from the group consisting of 0.5 mg, 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 50 mg, and 75 mg.

26. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 0.5 mg per day of LY3154207 or a pharmaceutical composition thereof.

27. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 1 mg per day of LY3154207 or a pharmaceutical composition thereof.

28. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 2 mg per day of LY3154207 or a pharmaceutical composition thereof.

29. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 3 mg per day of LY3154207 or a pharmaceutical composition thereof.

30. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 5 mg per day of LY3154207 or a pharmaceutical composition thereof.

31. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 10 mg per day of LY3154207 or a pharmaceutical composition thereof.

32. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 15 mg per day of LY3154207 or a pharmaceutical composition thereof.

33. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 20 mg per day of LY3154207 or a pharmaceutical composition thereof.

34. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 50 mg per day of LY3154207 or a pharmaceutical composition thereof.

35. 24. A method of treating a dopaminergic central nervous system disorder according to claim 23 in a patient in need thereof, comprising administering to the patient a dose of 75 mg per day of LY3154207 or a pharmaceutical composition thereof.

36. 24. A method for use of LY3151944 in treating a dopaminergic central nervous system disorder in a patient according to claim 23, comprising administering to said patient a dose of about 0.5 mg to about 75 mg of LY3151944 or a pharmaceutical composition thereof, up to a maximum total dose of 75 mg per day.

37. 24. A method for use of LY3151944 in treating a dopaminergic central nervous system disorder in a patient according to claim 23, comprising administering to said patient a dose of about 0.5 mg to about 15 mg of LY3151944 or a pharmaceutical composition thereof, up to a maximum total dose of 15 mg per day.

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