Use of mevidalene and other D1 positive allosteric modulators in the treatment of hallucinations and dementia-related psychosis

Abstract

The present invention relates to methods of treatment and dosing regimens using mevidalene, 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 the treatment of hallucinations and / or psychosis, including dementia-related psychosis.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 157,966, filed March 8, 2021, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure provides methods of using mevidalene, 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 cocrystals and pharmaceutical compositions thereof, and / or other dopamine D1 positive allosteric modulators, for the treatment of hallucinations and / or psychosis. [Background technology]

[0003] Several neuropsychiatric disorders are associated with the development of hallucinations and psychosis. Psychosis is a common pathology in dementia and becomes more frequent as the disease progresses. Patients likely to experience hallucinations and psychosis include those with schizophrenia, bipolar disorder, and depression, as well as those with neurodegenerative disorders (e.g., Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease (PD), Huntington's disease, vascular dementia (VaD), and frontotemporal dementia (FTD)). Among patients with PD, psychosis occurs over the course of their disease in up to 60% of patients. Psychosis is common across dementia types, with a prevalence of 20% to 70%. The presence of neuropsychiatric signs and symptoms in neurodegenerative diseases predicts increased caregiver burden, reduced quality of life, earlier progression to nursing home care, severe dementia, and death. There is a close relationship between the clinical manifestations of dementia-related psychosis (DRP) and morbidity / mortality in many neurodegenerative diseases.

[0004] Currently, Neuplazid is the only pharmacological treatment approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders despite significant safety concerns. (Pimavanserin: Potential Treatment For Dementia-Related Psychosis, J. Cummings et al., The Journal of Prevention of Alzheimer's Disease - JPAD, Vol. 5, No. 4, 2018). Improved and / or alternative treatments for hallucinations and / or dementia-related psychosis that are effective, safe, clinically well tolerated, and remain a significant unmet medical need.

[0005] 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. For many years, direct-acting D1 receptor agonists have been used to attempt to modulate dopamine signaling in dopaminergic CNS disorders. 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 the usefulness of these agents. 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 therapy has also had limited efficacy, due in part to the development of cognitive dysfunction, seizure risk, and intolerance associated with high doses. Thus, there remains a significant unmet need for safe, effective, and clinically acceptable treatments for hallucinations and / or dementia-related psychosis.

[0006] Mevidalene is a dopamine D1 receptor positive allosteric modulator (D1 PAM) and represents a potential first-in-class treatment for hallucinations and / or psychosis. Mevidalene (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:

[0007] [ka]

[0008] Useful forms of mevidalene 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, mevidalene, also known as a "potentiator" of the dopamine D1 receptor subtype, is highly selective for D1. Mevidalene exhibits very weak direct agonism of the D1 receptor, is active only in the presence of dopamine or a D1 agonist, and is believed to be dependent on endogenous tone and subject to normal feedback regulation in the subject. Mevidalene therefore represents an innovative pharmacological agent and approach to modulate the D1 signaling pathway in hallucinations and / or dementia-related psychoses where D1 signaling may be deficient.

[0009] The pathophysiology underlying hallucinations and psychotic symptoms is poorly understood but involves some degree of central dopamine activation at D2 and serotonin receptors. Current therapies used to treat psychosis and hallucinations include atypical antipsychotics, which act via blockade of dopamine D2 receptors in the brain, and / or serotonin 5-HT2A antagonists (e.g., NUPLAZID® (see pimavanserin) for L-DOPA-induced psychosis / hallucinations in Parkinson's disease). However, NUPLAZID® may increase the risk of death in elderly people with dementia-related psychosis and is not currently approved for the treatment of patients with dementia-related psychosis that is not related to the hallucinations and delusions associated with Parkinson's disease psychosis.

[0010] Mevidalene has a mechanism of action different from other dopamine agonists, such as direct D1 receptor agonists. Mevidalene binds to a newly discovered allosteric binding site in the intracellular loop 2 of the D1 receptor, increasing the affinity of dopamine for the D1 receptor. Due to the complexity of dopaminergic signaling in normal physiology and clinical conditions, and the lack of clinical pharmacological guidance from D1 orthosteric agonists, there remains a significant unmet need for new therapeutic methods using mevidalene and other dopamine D1 positive allosteric modulators. There remains a need for methods of treating hallucinations and / or psychosis using dopamine D1 positive allosteric modulators, such as mevidalene, that provide a complex profile of pharmacological effects that are effective, safe, and clinically tolerable. Summary of the Invention

[0011] The D1PAM mevidalene is currently being evaluated in a Phase 2 clinical trial (called PRESENCE (NCT03305809)) in patients to assess its safety and efficacy compared to placebo in patients with mild to moderate dementia with Lewy bodies (Parkinson's disease dementia - PDD or dementia with Lewy bodies - DLB). The study had a primary endpoint of cognition and secondary endpoints including function, motor, sleep, and other non-motor symptoms. Unexpectedly, mevidalene was discovered to demonstrate a surprising improvement in hallucinations in these patients. Given this finding, it is hypothesized that mevidalene's dopamine D1 specificity is important for the improved treatment of hallucinations and / or psychosis, particularly dementia-related psychosis. The present disclosure provides methods of use of mevidalene and / or pharmaceutical compositions thereof and / or other dopamine D1 positive allosteric modulators for the treatment of hallucinations and / or dementia-related psychosis.

[0012] In the therapeutic methods of the present disclosure and as used herein, mevidalene refers to any form of 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, including its crystalline and co-crystalline forms, particularly the benzoic acid co-crystalline form, and / or pharmaceutical compositions containing these agents. The present disclosure also provides a method of using mevidalene in the treatment of hallucinations and / or psychosis in a patient in need thereof, comprising administering to the patient a dose of about 5 mg to about 60 mg of mevidalene or a pharmaceutical composition thereof, up to a maximum total dose of 60 mg per day. Preferably, the psychosis is dementia-related psychosis. The present disclosure further provides a method of using mevidalene in the treatment of hallucinations and / or dementia-related psychosis in a patient in need thereof, comprising administering to the patient a dose of about 10 mg to about 50 mg of mevidalene or a pharmaceutical composition thereof, up to a maximum total dose of 50 mg per day. The treatment methods using mevidalene and / or other D1 PAM agents described herein provide a novel approach to preventing and / or alleviating symptoms of psychosis and / or hallucinations without the side effects associated with dopamine D2 antagonists (such as atypical antipsychotics), and can be used as a monotherapy in neurodegenerative disorders or as a combination therapy in, for example, schizophrenia and / or bipolar disorder.

[0013] Mevidalene has been studied in a Phase 2 clinical trial for Parkinson's disease dementia (PRESENCE, NCT03305809) and was found to have advantageous properties for treating hallucinations and psychosis. The PRESENCE study, the summary description of which is provided in Example 1, led to the discovery that mevidalene, when used in accordance with the methods and dosing regimens of the present disclosure, can induce surprising and significant improvements in the signs and symptoms of hallucinations and / or dementia-associated psychosis. Thus, when used in accordance with the treatment methods and dosing regimens of the present invention, mevidalene provides a means of improving dopamine D1 signaling in a manner that provides an effective, safe, and clinically acceptable treatment regimen for the prevention and / or treatment of hallucinations and / or dementia-associated psychosis.

[0014] The disclosed therapeutic methods and dosing regimens offer surprising and unexpected advantages. Patients with hallucinations or dementia-related psychosis need to benefit from D1 PAM activity to prevent or treat hallucinations and / or dementia-related psychosis symptoms while avoiding substantial risks of undesirable cardiovascular effects, such as agitation and / or elevated pulse and blood pressure. Unexpectedly, it has been discovered that the clinically useful and desirable effects of mevidalene for the prevention and / or treatment of hallucinations and / or dementia-related psychosis can actually be separated from certain undesirable effects by using the disclosed methods and clinical dosing regimens.

[0015] Schizophrenia, a debilitating, lifelong condition, affects approximately 1% of adults in the United States. See, for example, NAMI, Mental Help, PsyCom, SAMHSA studies, and NIMH data synthesis. According to the American Psychiatric Association, 30% of patients with schizophrenia (approximately 700,000 people) have an inadequate response to antipsychotic therapy. In this context, antipsychotic therapy includes, for example, quetiapine, clozapine, aripiprazole, asenapine, cariprazine, brexpiprazole, lurasidone, olanzapine, and risperidone, and / or long-acting formulations thereof, including long-acting aripiprazole or risperidone.

[0016]

[0003] One aspect of the present disclosure relates to a method for preventing or treating hallucinations and / or psychosis in a patient suffering from schizophrenia, wherein the patient has had a partial but inadequate response to other antipsychotic drug treatments. In another aspect, the present disclosure relates to a method for preventing, treating, or alleviating psychotic symptoms in a patient who has had a partial or completely inadequate response to antipsychotic drugs alone, comprising administering to a patient in need thereof an effective amount of mevidalene or a D1 PAM described herein, and continuing the administration of the initial antipsychotic drug treatment. In certain embodiments, the other antipsychotic drugs administered in combination are independently selected from the group consisting of quetiapine, clozapine, aripiprazole, asenapine, cariprazine, brexpiprazole, lurasidone, olanzapine, and risperidone, and / or long-acting formulations thereof, including long-acting aripiprazole or risperidone.

[0017] The present disclosure provides specific clinical dosing regimens for daily administration of mevidalene to patients with hallucinations or psychotic disorders to alleviate signs and symptoms while avoiding other D1 PAM effects that preempt these clinical benefits. Furthermore, the present disclosure provides for chronic daily administration of mevidalene, allowing patients with hallucinations or psychotic disorders to further employ lower or higher doses of mevidalene within the disclosed regimens to achieve effective symptomatic relief for individual patients while avoiding undesirable effects. Overall, the disclosed dosing regimens provide a means for patients to benefit from D1 PAM activity while avoiding certain clinically observed undesirable adverse cardiovascular activities, and may represent on-target pharmacology for D1 PAMs as a class. Furthermore, the disclosed dosing regimens provide a means for treating patients with hallucinations or psychosis while simultaneously reducing the risk of drug-drug interactions with Cyp3A4 inhibitors.

[0018] Thus, the present disclosure provides a dosing regimen for the daily oral administration of mevidalene to patients with hallucinations or psychosis, particularly psychosis associated with dementia, using specific doses of mevidalene described in detail below.

[0019] In one embodiment, the disclosure provides a method for use of mevidalene in the prevention or treatment of hallucinations or psychosis in a patient in need thereof, comprising administering to the patient a dose of mevidalene, or a pharmaceutical composition thereof, from about 5 mg to about 60 mg per day, up to a maximum total dose of 60 mg.

[0020] In one embodiment, the disclosure provides a method for use of mevidalene in the prevention or treatment of hallucinations or psychosis in a patient in need thereof, comprising administering to the patient a dose of mevidalene, or a pharmaceutical composition thereof, from about 5 mg to about 60 mg per day, up to a maximum total dose of 60 mg.

[0021] In one embodiment, the present disclosure provides a dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt or co-crystal thereof, for use in the prevention or treatment of hallucinations or psychosis.

[0022] In one embodiment, the present disclosure provides a dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt, or co-crystal thereof, for use in the prevention or treatment of hallucinations or psychosis, wherein the psychosis is dementia-related psychosis.

[0023] In one embodiment, the present disclosure provides a dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt, or co-crystal thereof, for use in the prevention or treatment of hallucinations or psychosis, where the patient's hallucinations or psychosis has been refractory to two or more prior antipsychotic therapies.

[0024] In one embodiment, the present disclosure provides a dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt, or co-crystal thereof, for use in the prevention or treatment of dementia-related psychosis, wherein a patient's dementia-related psychosis has been refractory to two or more prior antipsychotic therapies.

[0025] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use in the prevention or treatment of hallucinations or psychosis.

[0026] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use in the prevention or treatment of hallucinations or psychosis, wherein the psychosis is dementia-related psychosis.

[0027] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use in the prevention or treatment of hallucinations or psychosis in a patient where the hallucinations or psychosis has been refractory to two or more previous antipsychotic therapies.

[0028] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 5 to 60 mg per dose.

[0029] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 10 to 50 mg per dose.

[0030] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose selected from the group consisting of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg per dose.

[0031] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 50 mg per dose.

[0032] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 45 mg per dose.

[0033] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 40 mg per dose.

[0034] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 35 mg per dose.

[0035] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 30 mg per dose.

[0036] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 25 mg per dose.

[0037] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 20 mg per dose.

[0038] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 15 mg per dose.

[0039] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered orally daily at a dose of 10 mg per dose.

[0040] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered simultaneously, separately or sequentially in combination with an atypical antipsychotic.

[0041] In one embodiment, the present disclosure provides mevidalene or a pharmaceutically acceptable co-crystal thereof for use according to any of the above embodiments, wherein mevidalene or a pharmaceutically acceptable co-crystal thereof is administered in combination with an atypical antipsychotic selected from the group consisting of quetiapine, clozapine, aripiprazole, asenapine, cariprazine, brexpiprazole, lurasidone, olanzapine, risperidone, and / or long-acting formulations thereof.

[0042] In one embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof.

[0043] In one embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, wherein the psychosis is dementia-related psychosis.

[0044] In an embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, wherein said patient's hallucinations or psychosis has been refractory to two or more previous antipsychotic therapies.

[0045] In one embodiment, the present disclosure provides a method of preventing or treating dementia-related psychosis in a patient in need thereof, comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, wherein said patient's dementia-related psychosis has been refractory to two or more prior antipsychotic therapies.

[0046] In one embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient mevidalene or a pharmaceutically acceptable cocrystal thereof, wherein the psychosis is dementia-associated psychosis.

[0047] In one embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient mevidalene or a pharmaceutically acceptable cocrystal thereof, wherein said patient's hallucinations or psychosis has been refractory to two or more previous antipsychotic therapies.

[0048] In one embodiment, the present disclosure provides a method of preventing or treating dementia-related psychosis in a patient in need thereof, comprising administering to the patient mevidalene or a pharmaceutically acceptable co-crystal thereof, wherein the patient's dementia-related psychosis has been refractory to two or more previous antipsychotic therapies.

[0049] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 5 to 60 mg per dose.

[0050] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is orally administered daily at a dose of 10 to 50 mg per dose.

[0051] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is orally administered daily at a dose selected from the group consisting of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg per dose.

[0052] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 50 mg per dose.

[0053] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 45 mg per dose.

[0054] In an embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 40 mg per dose.

[0055] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 35 mg per dose.

[0056] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 30 mg per dose.

[0057] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 25 mg per dose.

[0058] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 20 mg per dose.

[0059] In one embodiment, the present disclosure provides a method according to any of the above method embodiments, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 15 mg per dose.

[0060] In one embodiment, the present disclosure provides a method according to any one of the above methods, wherein mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 10 mg per dose.

[0061] In one embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, in combination with an atypical antipsychotic.

[0062] In an embodiment, the present disclosure provides a method of preventing or treating hallucinations or psychosis in a patient in need thereof, comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, in combination with an atypical antipsychotic, wherein the atypical antipsychotic is selected from the group consisting of quetiapine, clozapine, aripiprazole, asenapine, cariprazine, brexpiprazole, lurasidone, olanzapine, risperidone, and / or long-acting formulations thereof.

[0063] As used above, and throughout the description of the present invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0064] 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, eg, a human.

[0065] "Dose" refers to a predetermined amount or unit dose of mevidalene calculated to produce a desired therapeutic effect in a patient. As used herein, "mg" refers to milligrams. As used herein, mevidalene dosage 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 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 value, for example, ±10% of the stated value.

[0066] Methods for making and formulating mevidalene 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 mevidalene 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. Mevidalene 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. Mevidalene 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 particular component, it is also assumed that the composition consists essentially of, or consists of, the listed component.Such pharmaceutical compositions and processes for preparing 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 the formulation, mevidalene is usually mixed with an excipient, diluted by an excipient, or enclosed in such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When an excipient functions as a diluent, this excipient may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either as a 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 may further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preservatives such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents. The compounds of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a 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 dosing 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.

[0067] Table 1

[0068] The unit doses of the present invention are formulated as pharmaceutical compositions to be administered by any route that makes the compound bioavailable; preferably, such compositions are for oral administration. As used herein, "administration" or "administering" includes the patient self-administering mevidalene and / or mevidalene being administered by another person, and / or the patient being instructed and / or supervised to consume mevidalene according to a specific schedule. Preferably, mevidalene is administered in the morning. Preferably, mevidalene is taken daily. Preferably, the indicated unit dose of mevidalene is taken daily, i.e., once a day, as indicated by the use of the term "per day." As used herein, "daily administration" includes the administration of mevidalene as a specific treatment regimen intended to provide beneficial effects from long-term and regular administration of mevidalene at a specified dose. In particular, "daily administration" includes administration every day for 21 or more consecutive days, or for as long as needed to prevent signs and symptoms of a dopaminergic CNS disorder in a patient. If a patient occasionally misses a day, they can simply resume administration the next day after the scheduled administration, in which case it continues to refer to "daily administration." As used herein, "daily" means that mevidalene is administered once every 24 hours or once per calendar day. As used herein, "daily" means that mevidalene 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 plan. 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 can be performed simultaneously.

[0069] Embodiments of the present disclosure include other dopamine D1 positive allosteric modulators, such as those described and / or exemplified in WO 2014193781 and / or WO 2017 / 070068, and WO 2019 / 204419, and WO 2016 / 055479, including any salts and / or cocrystals thereof. For example, one such other dopamine D1 positive allosteric modulator, designated DPTQ, which is 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, is shown below.

[0070] [ka]

[0071] Embodiments of the present disclosure include other dopamine D1 positive allosteric modulators, such as those listed below, for example, compounds of Formula Ib.

[0072] [ka] or a pharmaceutically acceptable salt or co-crystal thereof, which, in its free base form, may also be named 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one.

[0073] Embodiments of the present disclosure include other dopamine D1 positive allosteric modulators, such as those disclosed herein, or pharmaceutically acceptable salts thereof or co-crystals thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0074] Embodiments of the present disclosure include other dopamine D1 positive allosteric modulators, such as those listed below.

[0075] The present invention provides a compound which is 2-(2,6-dichlorophenyl)-1-((1S,3R)-5-(1-ethyl-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0076] The present invention provides a compound which is 1-((1S,3R)-5-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0077] The present invention provides a compound which is 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0078] The present invention provides a compound which is 1-((1S,3R)-5-(1-(2-(11-oxidaneyl)ethyl)-1H-pyrazol-4-yl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2-chlorophenyl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0079] The present invention provides a compound which is 2-(2-chloro-6-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0080] The present invention provides a compound which is 2-(2-chlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0081] The present invention provides a compound which is 2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0082] The present invention provides a compound which is 2-(2-chloro-6-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0083] The present invention provides a compound which is 2-(2,6-difluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0084] The present invention provides a compound which is 2-(2-chloro-5-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0085] The present invention provides a compound which is 2-(2-chloro-4-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0086] The present invention provides a compound which is 2-(2-fluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0087] The present invention provides a compound which is 2-(2,3-difluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0088] The present invention provides a compound which is 2-(2,5-difluorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one, or a pharmaceutically acceptable salt thereof.

[0089] Embodiments of the present disclosure include the above-described dopamine D1 positive allosteric modulators and / or salts or cocrystals thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0090] As used herein, the term "patient" refers to a human, and patients treated by the present dosing regimen are hallucination and / or psychosis patients, preferably dementia-related psychosis patients, and therefore share an etiopathological aspect in that impaired dopamine signaling contributes to these hallucinations and / or psychosis. Identification of patients with hallucinations and / or psychosis can be achieved by established methods known to those skilled in the art and described herein, for example, in Example 1.

[0091] In an embodiment of the present invention, the patient is a human diagnosed with a medical risk, condition, or disorder, such as hallucinations or dementia-related psychosis, requiring treatment with a D1 PAM such as mevidalene, using the dosing regimen described herein. When the disorder that can be prevented or treated by the methods of the present invention is known by an established and accepted classification, such as hallucinations and / or psychosis, those classifications can be found in various well-known medical textbooks. For example, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) currently provides diagnostic tools for identifying many of the disorders described herein. The International Classification of Diseases, Tenth Edition (ICD-10) also 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 advances in medical science. Hallucinations, delusions, and psychosis are well described and known to those skilled in the art, and the diagnostic methods described herein and in the medical literature can be used to identify patients in need of the treatment and prevention methods of the present invention. Patients with dementia-related hallucinations, delusions, and psychosis are preferred patients for the present methods, but patients with hallucinations, delusions, and / or psychosis of various other disease origins are also patients in need of prevention and / or treatment according to the methods described herein. The diagnostic criteria in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) describe evidence of significant clinical impact and impact on quality of life resulting from hallucinations, delusions, and psychosis, and the condition may or may not interfere with independence in daily activities.

[0092] The APA and the World Health Organization narrowly define psychosis by requiring the presence of hallucinations (without insight into their pathological nature), delusions, or both hallucinations and delusions without insight. In both current diagnostic classification systems, impaired reality testing remains conceptually central to psychosis. In contrast to earlier diagnostic classification systems, current systems operationalize impaired reality testing by identifying symptoms that provide evidence of such impairment. Delusions (i.e., fixed false beliefs) are, by definition, evidence of impaired reality testing: delusional beliefs that are stably maintained even in the face of evidence that incontrovertibly contradicts them. Similarly, hallucinations (i.e., perceptions occurring in the absence of corresponding external or somatic stimuli) are evidence of impaired reality testing when the individual experiencing them fails to recognize the hallucinatory nature of such experiences. Both the current APA and World Health Organization classification systems recognize that "formal thought disorder" (i.e., disorganized thinking, including illogical, tangential, repetitive, neologisms, disruptive thinking, digressions, or some combination of these thought disorders) is one of several commonly co-occurring features of psychotic disorders. The DSM-5 allows formal thought disorder to replace hallucinations and delusions in the diagnosis of psychotic disorders when it is accompanied, alone or in combination, by severely disorganized behavior, catatonia (for schizophrenia, schizophreniform disorder, brief psychotic disorder, and schizoaffective disorder), and / or negative symptoms (for schizophrenia, schizophreniform disorder, and schizoaffective disorder, but not for brief psychotic disorder). Because mildly disorganized speech is common and diagnostically nonspecific, the degree of thought disorder required to meet this DSM-5 criterion must be severe enough to substantially impair effective communication. As used herein, the term psychosis may refer to the presence of delusions, hallucinations without insight, or both. These symptoms are well-defined common features of psychosis in both psychiatric disorders and neurological conditions.They are captured by informal and structured clinical assessments (see Psychosis, David B. Arcineigas, Continuum (Minneap, MN) 2015;21(3):715-736).

[0093] Hallucinations are defined as sensory perceptions in the absence of corresponding external or physical stimuli and are described according to the sensory domain in which they occur. Hallucinations can occur with or without insight into their hallucinatory nature. Lack of insight into a hallucination defines it as a psychotic symptom, i.e., a hallucination in which reality testing is impaired. Hallucinations without insight are contrasted with hallucinations that individuals perceive as unreal. Examples of hallucinations with preserved insight include visual hallucinations of migraine aura, hypnagogic (falling asleep) and hypnopompic (wakefulness) hallucinations associated with sleep transitions, and auditory hallucinations of a person's name, which many psychiatrically and neurologically healthy individuals occasionally experience.

[0094] The management of patients with hallucinations or psychosis is often inadequate because available acute and preventive therapies are ineffective or poorly tolerated. Acute treatment of hallucinations or psychosis has been limited to the use of atypical antipsychotics and 5HT-2A antagonists. Mevidalene represents an innovative approach for the acute treatment or prevention of hallucinations or psychosis by selectively targeting and positively modulating dopamine D1 receptors. While some patients can successfully manage hallucinations and psychosis with current antipsychotic drugs alone, a group of patients cannot successfully manage their hallucinations and psychosis with these drugs. These patients may continue to experience significant impairment due to the number of hallucinations per day or per month. Furthermore, some patients, referred to herein as resistant patients, will fail to successfully manage hallucinations and psychosis and will suffer from hallucinations and psychosis that are resistant to two or more conventional antipsychotic drug prevention and / or treatment regimens. As defined herein, a patient with resistant hallucinations and / or psychosis, or a patient with resistant dementia-related psychosis, is a patient who continues to experience hallucinations or psychosis for one or more days per month despite two or more previous prevention or treatment plans. As used herein, a previous prevention or treatment plan refers to a previous unsatisfactory treatment attempt using antipsychotic treatment plans (e.g., quetiapine, clozapine, aripiprazole, asenapine, cariprazine, brexpiprazole, lurasidone, olanzapine, risperidone, and / or their long-acting formulations), alone or in combination. Resistant patients represent a significant unmet need because they have not yet achieved substantial freedom from recurrent hallucinations or psychosis. These resistant patients' failure to achieve adequate relief from multiple conventional treatment plans demonstrates that their disease is particularly difficult to treat, and efficacy in this population represents a surprisingly excellent result.

[0095] The term prevention or preventing, as used herein, refers to any process in which there may be a significant reduction and / or more preferably elimination of significant signs and symptoms of hallucinations and / or psychosis.

[0096] 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 does not necessarily indicate complete elimination of all symptoms.

[0097] 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 mevidalene from the dosage regimen of the present invention, many factors are taken into consideration, including, but not limited to, the dopaminergic CNS disorder from which the patient suffers, 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.

[0098] The dosage regimen of the present invention can be used in combination with other drugs used to treat / prevent / suppress or improve hallucinations and / or dementia-related psychosis. Such other drugs (or drugs) can be administered by a route and in a commonly used amount, simultaneously or sequentially with mevidalene. For example, other active ingredients effective in treating Parkinson's disease that can be combined with mevidalene include, but are not limited to, atypical antipsychotics and 5HT-2A antagonists described herein. [Brief explanation of the drawings]

[0099] [Figure 1] Mevidalene treatment resulted in significant improvement in hallucinations and psychosis. In the PRESENCE study, participants aged 40 to 85 years with LBD, Hoen and Yahr scores of 0 to 4, and Montreal Cognitive Assessment scores of 10 to 23 were randomized 1:1:1:1 to receive mevidalene 10 mg, 30 mg, or 75 mg or placebo once daily for 12 weeks (see Example 1). [Example]

[0100] Example 1: Phase 2 Clinical Trial for Parkinson's Disease Dementia (PRESENCE, hereafter referred to as NCT03305809) The purpose of this study was to evaluate the motor and non-motor effects of mevidalene in patients with dementia with Lewy bodies (LBD) as measured by the MDS-UPDRS. Mevidalene is a D1 receptor positive allosteric modulator (D1PAM). D1 receptor activation improves cognitive and motor function and enhances wakefulness in preclinical and clinical models. The Phase 2, 12-week PRESENCE study was designed to evaluate the symptomatic effects of mevidalene for the treatment of cognition and other areas related to LBD, including motor function, sleep, mood, and apathy.

[0101] Participants with LBD, age 40-85 years, Hoen and Yahr scores of 0-4, and Montreal Cognitive Assessment scores of 10-23 were randomized 1:1:1:1 to receive mevidalene 10 mg, 30 mg, or 75 mg or placebo once daily. The primary cognitive outcome was the CDR-CoA. Secondary outcomes included change from baseline to week 12 in the MDS-UPDRS total score (sum of Parts I-III) and change in both MDS-UPDRS Part II (Motor Experience of Daily Living) and Part III (Motor Examination) scores. Analyses were also prespecified for Part I items: fatigue, daytime sleepiness, hallucinations, depressed mood, and lethargy, and Part IV items: motor fluctuations and dyskinesia.

[0102] Below is provided a protocol for a study of mevidalene in PD using specific doses of the treatment methods and dosing regimens described herein. Those skilled in the art will be able to apply the teachings of this Example 1 and other disclosures provided herein to conduct similar studies with additional doses and dosing regimens of the present invention.

[0103] A well-tolerated treatment for hallucinations and / or dementia-related psychosis remains an unmet medical need. As described herein, mevidalene has been observed for the first time to improve hallucinations and / or dementia-related psychosis in a relatively short period of chronic daily administration (12 weeks). As a symptomatic treatment, mevidalene is important for patients who continue to suffer from hallucinations and / or dementia-related psychosis.

[0104] The PRESENCE study evaluated three doses of mevidalene 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 was a measure of cognition, but additional endpoints described herein were also evaluated. PRESENCE is a randomized, placebo-controlled trial in patients with Parkinson's disease dementia that evaluated the safety and efficacy of mevidalene (three doses of the investigational drug) for 12 weeks in participants with mild to moderate Parkinson's disease dementia.

[0105] Study HBEH included subjects with mild to moderate dementia who met the revised MDS criteria for PD (Postuma et al. 2015) and were defined by cognitive decline, functional impairment, and MoCA scores of 10–23, in the investigator's opinion (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 may include subjects who would have met the traditional criteria for DLB (dementia before motor onset or within 1 year of onset) based on the timing of their dementia (Mckeith et al. 2005). The 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 was not associated with dementia. However, there is growing debate about the validity of this traditional approach to dividing diagnoses (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, including predominantly visual perceptual abnormalities and improved cued memory. Both are associated with prominent psychosis, neuroleptic sensitivity, and altered arousal. 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 gene 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 the safety data generated and enabling more robust comparisons between mevidalene and placebo data. Three dose levels of mevidalene were selected to assess the dose-exposure response for safety and efficacy. The first visits (Visits 3–7) were chosen to occur weekly to provide a detailed assessment of mevidalene's efficacy and safety during initial treatment. A 12-week treatment period was selected, presumably the minimum period during which beneficial effects on cognition could be observed.

[0106] The primary objective was to test the hypothesis that mevidalene, 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 was the change in the CDR-CCB CoA composite score from baseline to week 12. Secondary objectives are described below.

[0107] [Table 2] 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 = Sustained 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 Assessment; NPI = Neuropsychiatric Inventory; PD = Parkinson's disease; PDD = Parkinson's disease dementia; PDAQ-15 = Parkinson's Disease Activities of Daily Living Questionnaire-15; PK = Pharmacokinetics; PoA = Attention; QD = Once daily; SBP = Systolic blood pressure.

[0108] References: 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 C,Perry EK,Aarsland D,Arai H,Ballard CG,Boeve B,Burn DJ,Costa D,Del Ser T,Dubois B,Galasko 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ワーキンググループ。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 Edition. 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.

[0109] 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 mevidalene (10, 30, or 75 mg administered orally 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 includes a screening period (Visits 1-2) of at least 7 days and a maximum of 14 days, a pretreatment period (Visits 2-3) of at least 11 days and a maximum of 17 days, 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 mevidalene (10, 30, or 75 mg QD) or placebo. The primary objective of this study was to test the hypothesis that 12 weeks of mevidalene treatment, compared with placebo, will result in significant improvements in cognition in subjects with mild to moderate PDD as measured by the change in the continuity of attention (CoA) composite score of the Cognitive Drug Research-Computerized Cognitive Battery (CDR-CCB) from baseline to week 12. CoA has shown significant treatment effects in previous studies in subjects with PDD (Wesnes et al. 2005; Rowan et al. 2007).

[0110] Treatment Arm and Duration: Study HBEH will involve a comparison of mevidalene 10 mg, 30 mg, and 75 mg (or 50 mg at interim analysis) administered orally QD versus placebo over 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.

[0111] 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 performed 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 will be provided in SAP. The MMRM model accounts for longitudinal data assessed throughout the study at 1, 2, 4, 6, 8, 10, and 12 weeks of medication. 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 will be the contrast between treatment and placebo (least squares mean difference) for the change from baseline at week 12. Secondary efficacy outcomes: Changes from baseline (or composites) at 12 weeks for the Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC), 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), Parkinson's Disease Activities of Daily Living Questionnaire-15 (PDAQ-15), and Delis-Kaplan Executive Function System (D-KEFS) were analyzed using the same analytical methods described above. Missing records for some scales (e.g., ADAS-Cog) were imputed as detailed in the statistical analysis plan. For scales without imputation, missing items were considered missing for the aggregate or total that included that item. No adjustments for multiple comparisons were made.

[0112] Safety Analysis: Safety analyses are based on the safety population and 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 the change in in-clinic blood pressure (BP) and pulse rate measured on the first day of study drug dosing (V3) from pretreatment 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 analyses 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.

[0113] Pharmacokinetics (PK): Pharmacokinetic analysis is performed in subjects who receive at least one dose of the test drug and have one measurable concentration. Model-based approaches can be implemented using nonlinear mixed-effects modeling (NONMEM) or other appropriate software to estimate PK parameters.

[0114] Additional endpoint and biomarker data collected during the study may be evaluated in an exploratory manner.

[0115] Interim Analysis: Safety interim analyses will be conducted on the number of subjects from each treatment who meet potentially clinically significant vital sign criteria at three consecutive time points for 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 mevidalen 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. 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.

[0116] 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):

[0117] 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 as determined by three consecutive BP / pulse rate measurements in a seated position: 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. 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.

[0118] 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 possible 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 the presence of more than two red flags. If one red flag is present, it must be offset by one supportive criterion, and if two red flags are present, it must be offset by two supportive criterion.

[0119] 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.

[0120] 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 revised 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 and stand without assistance; Stage 5: wheelchair-bound or bedridden unless assisted.

[0121] Montreal Cognitive Assessment Scale: Enrolled individuals must have a MoCA score of 10-23 at screening.

[0122] 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."

[0123] 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. The C-SSRS, included here as a screening assessment, is described in detail in Section 9.4.4. The "Baseline" version of the C-SSRS is used at screening, and the survey results 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 the subject is determined to have suicidal ideation or behaviors at this baseline assessment, the subject will not be randomized and will be discontinued from the study.

[0124] Table 1: Dose-dependent effects of mevidalene on hallucinations and psychosis observed in PRESENCE. The following table provides MDS-UPDRS Part I, item-level data presented as LS mean change difference from baseline to week 12, along with P values ​​(treatment difference vs. placebo) and effect size = treatment difference from LS mean difference at week 12 / SD from the VAR-COV matrix.

[0125] [Table 3]

[0126] The PRESENCE trial also provided evidence that cardiovascular effects, reflected by rapid increases in blood pressure and heart rate, were observed and that these effects were mitigated at doses as low as 10 and 30 mg. However, the adverse event profile and cardiovascular effects at the 75 mg dose may limit the clinical usefulness of higher doses. Thus, the preferred dosing regimen of the present invention is 10 mg to 50 mg daily for the prevention and / or treatment of hallucinations and / or dementia-related psychosis.

[0127] The data presented in Table 1 above provide evidence of therapeutic efficacy in preventing and / or alleviating hallucinations and / or psychosis following daily administration of mevidalene at the doses indicated. See also Figure 1. This effect represents a surprising and specific response, in that other endpoints studied did not demonstrate similar dose-dependent responses (e.g., item-level data for the MDS-UPDRS Part I, blunted affect, anxious mood, and depressed mood scales did not demonstrate dose-dependent treatment effects). Administration of mevidalene as described herein provides a novel approach for treating hallucinations and / or dementia-related psychosis occurring in a variety of pathological conditions, including neurodegenerative disorders such as Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). Clinical data and research evidence suggest that psychotic symptoms can manifest independently of the underlying dementia subtype. The therapeutic method of the present invention using mevidalene is believed to treat hallucinations and / or psychosis occurring in a range of neuropsychiatric disorders, particularly dementia. The methods described herein are particularly useful for patients with the aforementioned neurodegenerative conditions, who are further diagnosed with hallucinations and / or psychosis. As described herein for hallucinations and psychosis, improvement of neuropsychiatric signs and symptoms in neurodegenerative diseases is expected to provide a variety of potential real-world clinical benefits for the care of affected patients, including reduced caregiver burden, improved quality of life, and potentially delayed progression to nursing home care or severe dementia.

Claims

1. 1. A medicament for preventing or treating hallucinations in a patient in need thereof, the medicament comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone (mevidalene), or a pharmaceutically acceptable salt or co-crystal thereof.

2. 10. The method of claim 1, wherein the patient's hallucinations have been refractory to two or more previous antipsychotic treatments.

3. The agent according to claim 1 or 2, wherein the 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, or a pharmaceutically acceptable salt or cocrystal thereof is mevidalene or a pharmaceutically acceptable cocrystal thereof.

4. 4. The method of claim 3, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is orally administered daily at a dose of 5 mg to 60 mg per dose.

5. 5. The method of claim 4, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is orally administered daily at a dose of 10 mg to 50 mg per dose.

6. 6. The method of claim 5, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is orally administered daily at a dose selected from the group consisting of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg per dose.

7. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 50 mg per dose.

8. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 45 mg per dose.

9. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 40 mg per dose.

10. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 35 mg per dose.

11. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 30 mg per dose.

12. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 25 mg per dose.

13. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 20 mg per dose.

14. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 15 mg per dose.

15. 7. The method of claim 6, wherein the mevidalene or a pharmaceutically acceptable cocrystal thereof is administered orally daily at a dose of 10 mg per dose.

16. A drug for preventing or treating hallucinations in a patient in need thereof, the drug comprising 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone (mevidalene), or a pharmaceutically acceptable salt or co-crystal thereof, wherein the 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, or a pharmaceutically acceptable salt or co-crystal thereof, is administered simultaneously, separately, or sequentially to the patient in combination with an atypical antipsychotic.

17. The agent according to claim 16, wherein the 2-(2,6-dichlorophenyl)-1-[(1S,3R)-3-(hydroxymethyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]ethanone, or a pharmaceutically acceptable salt or co-crystal thereof is mevidalene or a pharmaceutically acceptable co-crystal thereof.

18. 18. The method of claim 16 or 17, wherein the atypical antipsychotic is selected from the group consisting of quetiapine, clozapine, aripiprazole, asenapine, cariprazine, brexpiprazole, lurasidone, olanzapine, risperidone, and / or long-acting formulations thereof.

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