Use of mevidalene and other d1 positive allosteric modulators to slow down the progression of parkinson's disease

Abstract

To provide a compound for slowing down the progress of Parkinson's disease.SOLUTION: Provided are dopamine D1 positive allosteric modulators, or pharmaceutically acceptable salts or co-crystals thereof, for use in slowing the progression of Parkinson's Disease.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 158,460, filed March 9, 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, to slow the progression of Parkinson's disease. [Background technology]

[0003] Parkinson's disease is characterized by the loss of dopamine-producing cells in the brain region known as the substantia nigra. However, the mechanism responsible for the dopaminergic cell loss in Parkinson's disease is unknown. Parkinson's disease progresses through six neuropathological stages according to the Braak classification, initially involving the deposition of intraneuronal inclusions in the anterior olfactory and dorsal motor nuclei of the vagus nerve (stage 1), which precedes the degeneration of melanocytes in the substantia nigra (stage 3). During this intermediate stage, patients begin to experience significant motor symptoms. Patients who seek medical attention at the onset of the earliest clinical symptoms are actually at an intermediate stage of their disorder, with perhaps 50% or more of the dopaminergic neurons already degenerating in the substantia nigra.

[0004] Treatment of Parkinson's disease focuses on increasing dopamine levels in the brain, and various dopamine agonists used in treatment aim to replace dopamine or prevent its breakdown (see Treatment for the progression of Parkinson's disease. Calne, Donald, et al., The Lancet. Neurology (2005), 4(4), 206). Many Parkinson's disease symptoms result from decreased dopamine levels and can be categorized into motor and non-motor symptoms. The group of motor symptoms includes i) resting tremor, which affects, for example, the arms, legs, and jaw; ii) slowness or bradykinesia; and iii) absence / rigidity or akinesia of movement. In addition, motor symptoms experienced by Parkinson's disease patients also include postural problems (postural instability) and gait problems. Non-motor symptoms in Parkinson's disease patients include neuropsychiatric symptoms, sleep disturbances and wakefulness, and autonomic symptoms. Parkinson's disease is a heterogeneous disorder with clinical manifestations that vary substantially from patient to patient. The current clinical guidelines (EMA 2012 guidelines (EMA / CHMP / 330418 / 2012 rev.2) stipulate that a clinical diagnosis of Parkinson's disease requires the presence of at least one of the following core symptoms: resting tremor, muscle rigidity, and impaired postural reflexes, along with bradykinesia.

[0005] Parkinson's disease is a characteristically progressive neurodegenerative disorder, and patients may experience a long prodromal phase followed by the well-known clinical phase of the disease. Understanding the pathogenesis of Parkinson's disease has led to the development of neuroprotective strategies aimed at early intervention, perhaps even in the prodromal phase, as an approach to altering disease progression (Jankovic J, Tan EK. J Neurol Neurosurg Psychiatry 2020;91:795-808). The progression of Parkinson's disease is evident from the patient's response to dopaminergic therapy over time. In the early stages of the disease, cardinal symptoms such as tremor, bradykinesia, and rigidity can usually be improved with dopaminergic therapy, such as dopamine agonists, monoamine oxidase inhibitors, or levodopa. While none of these conventional treatments is thought to slow the progression of Parkinson's disease, they may help patients suppress at least some of their motor symptoms. A Parkinson's patient is said to be in the ON state if they have few or no of the above symptoms. In contrast, a Parkinson's patient is said to be in the OFF state if they are not in the ON state, e.g., if they exhibit symptoms of Parkinson's disease.

[0006] In the early stages of the disease, Parkinson's disease symptoms can be improved by treatment with dopaminergic drugs, monoamine oxidase inhibitors, or levodopa. While none of these conventional treatments are thought to slow the progression of the disease, they may help at least some patients suppress disease symptoms such as tremor. After this early disease stage, the effectiveness of dopaminergic therapy declines, and most patients experience "wearing off" or "wearing off" (e.g., diurnal fluctuations in motor symptoms) and dyskinesia (drug-induced involuntary movements, including chorea and dystonia). Diurnal fluctuations in motor symptoms refer to a patient's fluctuations between on and off states. As Parkinson's disease progresses, the time spent in the off state ("off time") tends to increase and the time spent in the on state ("on time") tends to decrease. These may be dose-dependent and more predictable, or they may be non-dose-dependent. The effectiveness of levodopa may appear to decrease over time, leading some physicians to prefer to begin Parkinson's disease treatment with dopamine agonists and / or monoamine agonists, reserving levodopa treatment until later in the course of treatment. Levodopa is typically used with an AADC inhibitor, such as carbidopa or benserazide, to reduce its peripheral metabolism and reduce the required dose. Levodopa may also be used with a COMT inhibitor, such as entacapone, to further reduce its peripheral metabolism and further reduce the required dose of levodopa. These approaches are limited, and there remains a need for alternative and improved therapies to slow the progression of Parkinson's disease. The recently discovered dopamine D1 positive allosteric modulator may represent a novel approach to slowing the progression of Parkinson's disease.

[0007] The dopamine receptor D1 subtype (D1) is the most abundant dopamine receptor in the central nervous system and plays a critical role in many CNS functions. For many years, direct 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. Therefore, previous attempts to develop clinically useful direct D1 receptor agonists have been largely unsuccessful due to receptor desensitization, poor ADME / PK properties, and dose-limiting side effects such as hypotension. Direct-acting dopamine therapies have also had limited efficacy, due in part to high-dose-associated cognitive impairment, seizure risk, and tolerance development.

[0008] Mevidalene is a dopamine D1 receptor positive allosteric modulator (D1 PAM) and represents a potential first-in-class drug for slowing the progression of Parkinson's disease. 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, but can be structurally represented as follows:

[0009] [ka]

[0010] Useful forms of mevidalene include crystalline forms (see WO 2017 / 070068) and co-crystalline forms 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) (see WO 2014 / 193781). As a positive allosteric modulator, mevidalene, also known as a "potentiator" of the dopamine D1 receptor subtype, is highly selective for D1 receptors. Mevidalene exhibits very weak direct agonism of the D1 receptor, is active only in the presence of dopamine, is believed to be dependent on endogenous body conditions, and is subject to normal feedback regulation. Mevidalene therefore represents an innovative drug and approach to modulating the D1 signaling pathway to slow the progression of Parkinson's disease, where insufficient D1 signaling can lead to neuronal dysfunction and / or cell death.

[0011] 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 on the intracellular loop 2 of the D1 receptor, increasing the affinity of dopamine at that site. Due to the complexity of dopaminergic signaling in normal physiological and clinical disease states, and the lack of clinical pharmacological guidance from D1 orthosteric agonists, there remains a significant unmet need for new methods to slow the progression of Parkinson's disease using mevidalene and other dopamine D1 positive allosteric modulators. In particular, there remains an unmet need for methods to slow the progression of Parkinson's disease using dopamine D1 positive allosteric modulators (e.g., mevidalene) that provide a combination profile of effective, safe, and clinically acceptable pharmacological effects. Summary of the Invention

[0012] The D1 PAM mevidalene is currently being evaluated in a Phase 2 clinical trial (called PRESENCE (NCT03305809)) 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)). Mevidalene demonstrated statistically significant and clinically meaningful benefits over the 12-week trial on prespecified outcomes across a range of motor and non-motor symptom severity. For example, treatment with mevidalene resulted in significant improvements in overall function (per the ADCS-CGIC). These observations, along with specific neuronal responses to exposure to D1 PAMs, have led to the idea that treating patients with early-stage Parkinson's disease may slow disease progression. In particular, dopamine D1 receptors are involved in synaptic plasticity, affecting the ability of neuronal synapses to strengthen or weaken them over time. Enhanced activation of dopamine D1 receptors by the D1 PAM of the present disclosure is believed to promote plasticity (neurogenesis) through enhanced neurite outgrowth and increased numbers of dendritic spines and synapses.This response is believed to have the potential to delay neuronal dysfunction and / or neuronal cell death in early-stage Parkinson's disease patients.Together, these data support the possibility that long-term D1 PAM treatment may have long-term disease-modifying effects that may positively affect the progression of Parkinson's disease.

[0013] The present disclosure provides methods for using mevidalene and / or pharmaceutical compositions thereof, and / or other dopamine D1 positive allosteric modulators to slow the progression of Parkinson's disease. As used herein, slowing the progression of Parkinson's disease refers to the effect of delaying progression for a certain period of time.

[0014] The present disclosure provides a means for slowing the progression of Parkinson's disease. As used herein, "slowing the progression of Parkinson's disease" means inhibiting, slowing, or halting to any significant extent any of the signs and symptoms of Parkinson's disease progression, as evidenced by one or more endpoints of Parkinson's disease signs and symptoms known to those of skill in the art and / or described herein. These endpoints and methods for measuring changes therein are similarly known to those of skill in the art and / or described herein, and when these endpoints are said to be improved, the improvement may be of the order of 5 percent, 10 percent, 15 percent, 20 percent, or more at a given point in the course of the disease and / or may be evidenced by a delay in progression of several weeks, months, or years. For patients treated according to the methods of embodiments of the present invention, the progression of Parkinson's disease may be delayed for a period of at least one month, preferably at least three months, or at least four months, or at least five months, or at least six months, or at least seven months, or at least nine months, or at least one year, compared to patients not receiving the treatment of the present invention.

[0015] In one embodiment, the present disclosure provides a method of slowing or delaying the progression of Parkinson's disease in a patient in need thereof and who has not previously received treatment for Parkinson's disease, comprising administering to the patient an effective amount of mevidalene.

[0016] In one embodiment, the present disclosure provides a use of mevidalene or a D1 PAM described herein to slow or delay the progression of Parkinson's disease in a patient diagnosed with Parkinson's disease but who has not previously received treatment for Parkinson's disease, comprising administering to the patient an effective amount of mevidalene or a D1 PAM described herein.

[0017] In one embodiment, the disclosure provides for the use of mevidalene or a D1 PAM as described herein, with or without concomitant treatment with levodopa, to slow the progression of idiopathic Parkinson's disease throughout the course of the disease, including late in the course when levodopa becomes less effective or more inconsistent and fluctuating therapeutic effects (end of treatment or on-off fluctuations) occur.

[0018] As used herein, a patient who has not previously been treated for Parkinson's disease includes a patient with Parkinson's disease who has not previously taken medication for the treatment of Parkinson's disease. Medications for the treatment of Parkinson's disease include dopaminergic agents, dopamine precursors such as levodopa, COMT inhibitors, MAO-B inhibitors, and anticholinergic agents. Prior to initiating treatment with embodiments of the present disclosure, such a patient may experience an average daily "off" time of up to 6 hours per day, e.g., up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, or up to 5 hours.

[0019] Prior to initiating treatment with embodiments of the present disclosure, such patients may have been diagnosed with Parkinson's disease for up to 9 years, e.g., up to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 6 months, up to 12 months, up to 2 years, up to 3 years, up to 4 years, up to 5 years, up to 6 years, up to 7 years, or up to 8 years.

[0020] Prior to initiating treatment with embodiments of the present disclosure, a patient may experience motor symptoms and / or motor complications, such as diurnal fluctuations in motor symptoms with or without dyskinesias, for up to four years, e.g., up to one month, up to two months, up to three months, up to four months, up to six months, up to twelve months, up to two years, or up to three years.

[0021] According to the Movement Disorder Society (MDS) criteria for Parkinson's disease, the clinical diagnosis of Parkinson's disease is based on a defined motor syndrome (parkinsonism) based on three major motor symptoms (MS): bradykinesia, rigidity, and resting tremor. However, non-motor symptoms (NMS), including insomnia, depression, anxiety, cognitive decline, blunted affect, neuropsychiatric disorders, and autonomic dysfunction, may be present at the onset and during disease progression. Thus, Parkinson's disease gradually impairs quality of life and activities of daily living, but high variability in clinical symptoms and disease progression can be observed among affected individuals.

[0022] Therefore, the Hohn-Yarr scale is commonly used to compare patient groups and provide an assessment of disease progression ranging from Stage I (unilateral involvement only) to Stage V (wheelchair-bound or bedridden). In the early stages, symptoms are usually mild and unilateral, with a complete response to treatment. Symptoms tend to progress, and motor symptoms affect the contralateral side, but initial drug responses are generally effective. During the disease progression process, treatment response decreases, and antiparkinsonian medications may induce side effects. After a prolonged disease period, patients may develop several NMS for which current treatments are limited. Previous studies have reported that the mean disease duration ranges from 6.9 to 14.3 years, and the onset of dementia is the strongest predictor of increased mortality.

[0023] Both clinical features of Parkinson's disease (motor and non-motor) are described herein in relation to disease progression. Early stages may include motor symptoms, REM sleep behavior disorder (RBD), constipation, anxiety, depression, and impulse control disorders. Advanced stages may include motor symptoms, cognitive impairment, amotivation, psychotic disorders, orthostatic hypotension, and urinary dysfunction. Comorbid stages may include diurnal fluctuations in motor symptoms, dyskinesia, and super-off periods. (See, e.g., C. Carrrini et al., A Stage-Based Approach to Therapy in Parkinson's Disease, Biomolecules 2019, 9, 388.)

[0024] In the early stages, some non-motor symptoms and signs of Parkinson's disease can be observed very early in the disease. According to the Braak staging system, the pathological process of Parkinson's disease may not begin in the substantia nigra pars compacta. Synuclein deposition appears to initially involve the anterior olfactory nucleus and dorsal motor nucleus of the vagus nerve. Further subsequent findings suggest that peripheral autonomic ganglia and unmyelinated lamina-1 spinal neurons may also be involved in the early pathological stages. These findings are consistent with the typical early non-motor features of Parkinson's disease, such as olfactory impairment, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, anxiety, and depression. Quantitative assessment of clinical symptoms and progression is an essential element of any therapeutic trial in Parkinson's disease. Parkinson's disease is known to be a variable disease; therefore, classification of symptom severity can be based on a holistic assessment, including a neurological examination and a detailed assessment of how symptoms affect daily function and quality of life. Preferably, for the embodiments disclosed herein, the early stage Parkinson's disease patient is a patient diagnosed with Hohn-Yahr II who is not taking any medication.

[0025] During the progression of Parkinson's disease, the beneficial effects of initial therapy may diminish due to progressive dopaminergic neuronal loss, making management of MS more complex. Disabling manifestations of this advanced stage include worsening balance, falls, increased gait impairment, and speech disturbances. Another common symptom in advanced Parkinson's disease is dystonia. Dystonia typically follows the administration of l-dopa therapy and can exhibit several onset patterns, such as during off-phase, at peak dose, or with biphasic timing. Approximately 30% of Parkinson's disease patients treated with l-dopa tend to experience "off-dystonia," particularly the morning before the first l-dopa dose. Unlike other patterns, off-dystonia is generally painful, with the feet appearing to be the primary site of pain. In contrast, peak-dose dystonia tends to involve the neck, face, and upper limbs, while dystonia occurring as part of biphasic dyskinesia appears to primarily involve the lower limbs. Dystonia, which typically appears several years into the disease, rarely occurs in the early stages and is usually associated with early-onset Parkinson's disease and autosomal recessive genetic forms of parkinsonism (such as PARK-PARKIN (PARK2) mutations and PARK-SNCA (PARK1) mutations). Nevertheless, some non-motor features (e.g., hallucinations, psychosis, dysautonomia, mood disorders, and dementia) may appear in advanced stages. Some NMS typically develops several years before MS. However, later stages of Parkinson's disease are characterized by concomitant NMS, which is milder or less common in the early stages.

[0026] The comorbid phase typically develops after 4–6 years of treatment and can include diurnal fluctuations in motor symptoms, affecting approximately 50% of Parkinson's disease patients. While wearing-off symptoms is the most common type, other motor complications, such as treatment-related dysfunction, worsening symptoms at the onset of treatment, rebound symptoms at the end of the drug's effect, freezing of gait, and levodopa-induced dyskinesia (LID), can also develop during the course of the disease. Several treatment strategies have been employed to reduce the frequency and duration of so-called off periods (defined by recurrence of symptoms or lack of l-dopa effect), but none of these drugs can completely suppress diurnal fluctuations in motor symptoms, and their side effects can limit optimal dosing.

[0027] Methods for assessing the progression of Parkinson's disease and its signs and symptoms are well known to those skilled in the art and are described, for example, in DSM-5 and other well-known diagnostic references, such as those described herein. Furthermore, when assessing the effectiveness of a treatment on the progression of Parkinson's disease, a treated patient may be referred to as being in an ON state or an OFF state. Accordingly, therapeutic efficacy is evidenced by an increase in ON time and / or a decrease in OFF time. An increase in ON time refers to an increase in the duration of symptom relief. A decrease in OFF time refers to a decrease in the duration during which a treated Parkinson's disease patient exhibits Parkinson's disease symptoms. ON time and OFF time are traditionally determined by observation, with patients and / or physicians keeping diaries of symptoms and the timing of their occurrence. The ON time and OFF time observed in a treatment group can be compared to those in an alternative treatment group or a placebo treatment group, depending on the clinical situation.

[0028] Methods used to assess on-time and off-time and other symptoms include the Unified Parkinson's Disease Rating Scale or UPDRS (see Fahn S. Unified Parkinson's disease rating scale. In Fahn S, Marsden CD, Goldstein M, and Calne DB (eds) Recent Developments in Parkinson's Disease. McMillan, 1987, New York) (used to track the long-term course of Parkinson's disease) and the Movement Disorder Society (MDS) UPDRS (see Goetz, et al. (1 January 2007). "Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan". Movement Disorders 22 (1):41-47). As known to those skilled in the art, various other approaches may be used as deemed appropriate to demonstrate clinical response and / or are described herein.Non-limiting examples of approaches that may be applicable include the PDQ-39 (Jenkinson et al., The Parkinson's disease questionnaire. User manual for the PDQ-39, PDQ-8 and PDQ Summary Index. Oxford: Health Services Research Unit, Department of Public Health, University of Oxford, 1998), NMSS (Chaudhuri et al., "The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study," Movement Disorders, vol. 22, no. 13, pp. 1901-1911, 2007), and PDSS (Chaudhuri et al. The Parkinson's disease sleep scale: A new instrument for assessing sleep and nocturnal disability in Parkinson's disease. J Neurol Neurosurg Psychiatry 2002;73:629-35), the Horn-Yahr Classification Scale, and the Schwab-England Activities of Daily Living (ADL) Scale (http: / / neurosurgery.mgh.harvard.edu / functional / pdstages.htm).Safety assessments, such as mMIDI (Grant JE. Impulse control disorders: A clinician's guide to understanding and treating behavioral addictions. New York: W.W. Norton & Company; 2008) and C-SSR (Posner et al. Columbia-Suicide Severity Rating Scale. Am J Psychiatry, 2011 168(12)1266-1277), can also be used to establish clinical endpoints.

[0029] Parkinson's disease patients also experience dyskinesia (drug-induced involuntary muscle movements) during the course of treatment. Dyskinesia is not considered a symptom of Parkinson's disease itself, but rather a side effect of the medications used to treat the condition. Dyskinesia (e.g., resulting from high levels of levodopa) can occur during the on-state, when normal Parkinson's disease symptoms would otherwise be suppressed. Levodopa-induced dyskinesia appears in patients who have taken levodopa for a long time and generally occurs during the on-state, although in later stages of the disease, dyskinesia can occur during the off-state.

[0030] Dyskinesias can be classified into three major types. The most common form is peak-dose dyskinesia, which occurs at peak levodopa levels and can be improved by reducing the levodopa dose. The second form is biphasic dyskinesia, which occurs when levodopa levels are rising or falling and can also be improved by reducing the levodopa dose. The third form of dyskinesia is off-time dystonia, which is a sustained muscle contraction that causes, for example, twisting and repetitive movements or abnormal postures. These off-time dystonias are correlated with akinesia (inability to initiate movement) when levodopa levels are low and are treatable with levodopa. A major challenge in treating Parkinson's disease is improving a patient's on-time (and / or conversely, reducing their off-time) without increasing treatment-associated dyskinesia. Late-stage Parkinson's disease patients are classified as those who, after initiating levodopa therapy, i) may experience inadequate symptom control despite levodopa treatment, and / or ii) may suffer from motor complications such as diurnal fluctuations in motor symptoms (which may be dose-dependent or non-dose-dependent) and dyskinesias. Delayed-on refers to the prolonged time required for the antiparkinsonian drug to take effect. Dose-dependent (or predictable) motor complications are related to the time of administration, such as peak-dose dyskinesias, worsening at the end of the drug's effect (or due to wearing-off), and biphasic dyskinesias. For less predictable motor complications (e.g., paroxysmal on-off phenomena, freezing), treatment is intended to reduce the duration and / or intensity of off states. Therefore, the primary efficacy variable may be a reduction in the number, duration, and / or intensity of off states. The extent to which on-time with dyskinesia and on-time without dyskinesia increase should also be clear. In highly advanced Parkinson's disease, patients can suffer from severe and highly unpredictable diurnal fluctuations of rapid motor symptoms.

[0031] Therapies to slow disease progression may prevent or postpone late motor complications or diurnal variation of late motor symptoms and / or slow disease progression. Preferably, treatment slows, stops, or substantially reduces further neurodegeneration, slowing disease progression. No drug therapy has yet demonstrated an associated slowing of disease progression. For early-stage, untreated Parkinson's disease (de novo) patients, the clinical goal to be achieved is to slow the progression of motor symptoms as assessed by changes in the UPDRS. For treated, stable Parkinson's disease patients, the clinical goal to be achieved is to slow further decline in motor impairment, prevent disability progression, and prevent motor and non-motor complications. The key outcome scale for this stage can be the appearance of so-called axial symptoms: for example, freezing of gait, loss of balance or Hohn-Yahr stage III ("bilateral disease: mild to moderate disability with impaired postural reflexes; physically independent" or "mild to moderate bilateral disease; some postural instability; physically independent").

[0032] For patients with advanced Parkinson's disease, the clinical goal to be achieved is prevention of disability. Clinical endpoints in this patient population are broad, including reduction in autonomic dysfunction or falls, reduction in cognitive symptoms, and possibly "time to" dementia and "time to" nursing home admission. The present disclosure provides embodiments in which mevidalene or other D1 PAMs described herein are administered to a patient in need thereof to slow or delay the patient's onset of any of the above stages of Parkinson's disease over any significant period of time, including weeks, months, or years, as described herein.

[0033] Mevidalene and other D1 PAMs: 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 to slow the progression of Parkinson's disease 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, per day, up to a maximum total dose of 60 mg. Preferably, the patient is in the prodromal or early stage of Parkinson's disease. The present disclosure further provides a method of using mevidalene to slow the progression of Parkinson's disease 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. Treatment methods using mevidalene and / or other D1 PAM agents described herein provide a novel approach to slowing the progression of Parkinson's disease without the side effects associated with other Parkinson's treatments.

[0034] Mevidalene has been studied in a Phase 2 clinical study (PRESENCE, NCT03305809) for Parkinson's disease dementia and has been found to have statistically significant and meaningful benefits on motor and non-motor symptoms. The PRESENCE study (outlined 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 a surprising and significant slowing or delay in the progression of Parkinson's disease. Thus, when mevidalene is used in accordance with the treatment methods and dosing regimens of the present invention, mevidalene provides a means of improving dopamine D1 signaling to provide an effective, safe, and clinically acceptable treatment regimen for slowing the progression of Parkinson's disease, preferably in patients in the early stages.

[0035] The present disclosure provides specific clinical dosing regimens for the long-term daily administration of mevidalene so that patients suffering from early-stage Parkinson's disease have relief from the signs and symptoms of Parkinson's disease progression while avoiding the side effects of other D1 PAMs that prevent these clinical benefits. Furthermore, the present disclosure provides long-term daily administration of mevidalene so that patients in the prodromal or early stages of Parkinson's disease can further employ lower or higher doses of mevidalene within the disclosed regimens so that effective slowing of disease progression can be achieved for each individual patient while avoiding undesirable effects. Overall, the disclosed dosing regimens provide a means for patients to benefit from D1 PAM activity while avoiding certain undesirable adverse cardiovascular activities observed clinically, and may represent the precise pharmacology of D1 PAMs as a class. Thus, the present disclosure provides a dosing regimen for the daily oral administration of mevidalene to patients in the early stages of Parkinson's disease, using specific doses of mevidalene described in detail below.

[0036] In one embodiment, the disclosure provides a method of using mevidalene in slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient mevidalene, or a pharmaceutical composition thereof, at a dose of about 5 mg to about 60 mg per day, up to a maximum total dose of 60 mg.

[0037] In one embodiment, the disclosure provides a method of using mevidalene in slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient mevidalene, or a pharmaceutical composition thereof, at a dose of about 5 mg to about 60 mg per day, up to a maximum total dose of 60 mg.

[0038] 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 slowing the progression of Parkinson's disease.

[0039] 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 slowing the progression of Parkinson's disease.

[0040] 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 slowing the progression of Parkinson's disease in a patient who has not previously received treatment for Parkinson's disease.

[0041] 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 slowing the progression of Parkinson's disease in a patient who has been diagnosed with Parkinson's disease but has not previously received treatment for Parkinson's disease.

[0042] 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 slowing the progression of Parkinson's disease in a patient with Parkinson's disease in the prodromal stage.

[0043] 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 slowing the progression of Parkinson's disease in patients with early stage Parkinson's disease.

[0044] 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 slowing the progression of Parkinson's disease in a patient with advanced stages of Parkinson's disease.

[0045] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 5 to 60 mg per dose.

[0046] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 10 to 50 mg per dose.

[0047] 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 the 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.

[0048] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 50 mg per dose.

[0049] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 45 mg per dose.

[0050] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 40 mg per dose.

[0051] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 35 mg per dose.

[0052] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 30 mg per dose.

[0053] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 25 mg per dose.

[0054] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 20 mg per dose.

[0055] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 15 mg per dose.

[0056] 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 the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered orally daily at a dose of 10 mg per dose.

[0057] 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 levodopa and / or deep brain stimulation.

[0058] In one embodiment, the present disclosure provides a method of slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof.

[0059] In one embodiment, the present disclosure provides a method of slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, wherein the patient is in a prodromal stage of Parkinson's disease.

[0060] In one embodiment, the present disclosure provides a method of slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, wherein the patient is in an early stage of Parkinson's disease.

[0061] In one embodiment, the present disclosure provides a method of slowing the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, wherein the patient is at an advanced stage of Parkinson's disease.

[0062] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 5 to 60 mg per dose.

[0063] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 10 to 50 mg per dose.

[0064] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above methods, 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.

[0065] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 50 mg per dose.

[0066] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 45 mg per dose.

[0067] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 40 mg per dose.

[0068] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 35 mg per dose.

[0069] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 30 mg per dose.

[0070] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 25 mg per dose.

[0071] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 20 mg per dose.

[0072] In one embodiment, the present disclosure provides a method according to any of the embodiments relating to the above method, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 15 mg per dose.

[0073] In one embodiment, the present disclosure provides a method according to any of the above methods, wherein mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 10 mg per dose.

[0074] In one embodiment, the present disclosure provides a method of slowing or delaying the progression of Parkinson's disease in a patient in need thereof, comprising administering to the patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof, in combination with deep brain stimulation.

[0075] 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:

[0076] 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.

[0077] "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 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 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.

[0078] Methods of 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 WO 2014 / 193781 and / or WO 2017 / 070068. Methods of preparing mevidalene and its cocrystals and specific formulations and dosage forms thereof are known to those skilled in the art and are described in WO 2014 / 193781 and / or WO 2017 / 070068. WO 2014 / 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. WO 2017 / 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 assumed that the composition also consists essentially of, or consists of, the listed component.Such pharmaceutical compositions and the 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, a 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 additionally contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylhydroxybenzoate and propylhydroxybenzoate; 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 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.

[0079] [Table 1]

[0080] 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 a patient self-administering mevidalene and / or mevidalene being administered by another person, and / or a patient being instructed and / or supervised to consume mevidalene according to a specific regimen. 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 administration of mevidalene as a specific therapeutic 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 may simply resume administration the next day after the scheduled administration; such cases shall continue to be referred to as "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 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. Also, two or more steps or actions can be performed simultaneously.

[0081] 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.

[0082] [ka]

[0083] Embodiments of the present disclosure include other dopamine D1 positive allosteric modulators, such as those listed below, for example, Formula Ib:

[0084] [ka] (Ib) 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.

[0085] 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.

[0086] Embodiments of the present disclosure include other dopamine D1 positive allosteric modulators, such as those listed below: 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] As used herein, the term " patient " refers to human beings, and the patient treated by this dosing regimen is an early stage Parkinson's patient, preferably a diagnosed but not yet treated Parkinson's patient, and therefore shares the epidemiological pathological aspect that the impaired dopamine signaling contributes to the progression of Parkinson's disease.The identification of the patient with early stage Parkinson's disease is known to those skilled in the art, and can be achieved by established methods described herein, for example, in Example 1.

[0102] In an embodiment of the present invention, the patient is a person who has been diagnosed as having a medical risk of Parkinson's disease or as having prodromal or early Parkinson's disease, and who is in need of treatment using the administration regimen described herein with a D1 PAM such as mevidalene. In cases where the disease progression of the disorder can be slowed by the method of the present disclosure due to an established and accepted classification (e.g., prodromal Parkinson's disease, newly diagnosed Parkinson's disease, or early Parkinson's disease), these classifications can be found in various well-known medical textbooks. For example, the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) currently 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 as medical science advances. The stages of Parkinson's disease are well described and known to those of skill in the art, and the diagnostic methods described herein and in the medical literature are used to identify patients in need of the treatment and prevention methods of the present invention.

[0103] As used herein, the term "slowing progression" refers to any process in which there may be a significant reduction in, and / or more preferably relief from, significant signs and symptoms of Parkinson's disease progression, as described herein or known to one of skill in the art. The term "slowing progression" of an existing disorder and / or symptoms thereof does not necessarily indicate complete elimination of all symptoms.

[0104] The attending diagnostician, as a person skilled in the art, can easily determine the dosage selected from the dosage regimen provided herein by observing the results obtained from treatment.When determining the specific dosage of mevidalene from the dosage regimen of the present invention, many factors are taken into consideration.These factors include but are not limited to the patient's weight, age and general health condition; the degree or severity of the difficulty of the disorder; the response of individual patients; the use of concomitant medication; and other relevant circumstances.

[0105] The dosage regimen of the present invention can be used in combination with other drugs used to treat / prevent / suppress or improve Parkinson's disease. Such other drugs (multiple drugs) can be administered simultaneously or sequentially with mevidalene by the route and amount commonly used for that purpose. For example, other active ingredients effective in treating Parkinson's disease that can be combined with mevidalene include, but are not limited to, dopaminergic agents, dopamine precursors such as levodopa, COMT inhibitors, MAO-B inhibitors, and anticholinergic agents. [Brief explanation of the drawings]

[0106] [Figure 1] This figure shows that mevidalene treatment resulted in significant improvements in global function (ADCS-CGIC). In the PRESENCE study, participants with LBD, aged 40-85 years, with Hohn-Yahr scores of 0-4 and Montreal Cognitive Scale scores of 10-23, were randomized 1:1:1:1 to receive mevidalene 10 mg, 30 mg, or 75 mg once daily for 12 weeks, or placebo (see Example 1). CGIC is a common method for assessing the clinical significance of interventions. The mean change in mevidalene LS from baseline to week 12 was -0.7 in the 30 mg group and -0.9 in the 75 mg group (both p<0.001). These results may reflect the multidimensional benefits of mevidalene. [Example]

[0107] 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). Activation of D1 receptors improves cognitive and motor function and increases wakefulness in preclinical and clinical models. The Phase 2, 12-week PRESENCE study was designed to evaluate the effects of mevidalene on various symptoms for the treatment of cognitive and other domains associated with LBD, including motor function, sleep, mood, and affective blunting.

[0108] Participants with LBD, aged 40 to 85 years, with Hohn-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. 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 to III) and change in both MDS-UPDRS Part II (Motor Experience of Daily Living) and Part III (Motor Exam) scores. Analyses were also prespecified for Part I items: fatigue, daytime sleepiness, hallucinations, depressed mood, and apathy; and Part IV items: diurnal variation in motor symptoms and dyskinesia.

[0109] Below is provided a protocol for a study of mevidalene in Parkinson's disease 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, but will also be able to conduct similar studies with additional doses and dosing regimens of the present invention.

[0110] There remains an unmet medical need for a well-tolerated treatment to slow the progression of Parkinson's disease. As described herein, it has been observed for the first time that mevidalene, administered daily for a relatively short but prolonged period (12 weeks), improves the signs and symptoms of Parkinson's disease. The PRESENCE study is evaluating three doses of mevidalene (10 mg, 30 mg, and / or 75 mg (or 50 mg based on an interim analysis) administered orally daily (QD)) versus placebo over 12 weeks of treatment. The primary outcome was cognitive improvement, 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.

[0111] The HBEH study included subjects with mild to moderate dementia, defined by cognitive decline, but in the investigator's opinion, functional impairment, and a MoCA score of 10–23, meeting the revised MDS criteria for PD (Postuma et al. 2015). The revised MDS criteria allow PDD to be diagnosed in the presence of dementia, regardless of the relative 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 their PD diagnosis. 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). This criterion was that dementia must occur before or within one year of the onset of Parkinson's disease symptoms. The one-year rule is arbitrary and based on the past belief that Parkinson's disease is not associated with dementia. However, there is growing debate about the validity of this traditional approach to dividing diagnoses (Berg et al. 2014). In support of 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 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, the HBEH study aligns with current thinking about PDD and DLB, which suggest that the timing of cognitive impairment is distinct, they are clinically and pathologically indistinguishable, and they will likely respond 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 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. Initial 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.

[0112] 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.

[0113] [Table 2]

[0114] Abbreviations: ADAS-Cog13 = 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCS-CGIC = Alzheimer's Disease Cooperative Study-Clinician Global Impression of Change; CDR-CCB = Cognitive Drug Study-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 = Penn Parkinson's Disease Activities of Daily Living Questionnaire-15; PK = Pharmacokinetics; PoA = Attention; QD = Once daily; SBP = Systolic blood pressure.

[0115] 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 disease JN. 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,Goetzer S,Gauthitz 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 E,Pasquier EB-Pasquier JA 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.

[0116] Study Design Overview: 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 minimum 7-day to maximum 14-day screening period (Visits 1-2), a minimum 11-day 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 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 trials in subjects with PDD (Wesnes et al. 2005; Rowan et al. 2007).

[0117] Treatment Arm and Duration: Study HBEH will involve a comparison of mevidalene 10mg, 30mg, and 75mg (or 50mg 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.

[0118] 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 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; if convergence fails, other appropriate structures will be explored. The primary comparison was the contrast between treatment and placebo for change from baseline at week 12 (least squares mean difference). Secondary efficacy outcomes: Alzheimer's Disease Cooperative Study-Clinician 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 Changes from baseline in the sum (or composite) scores of the Exercise Sleepiness Scale (ESS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Penn Parkinson's Disease Activities of Daily Living Questionnaire-15 (PDAQ-15), and Delis-Kaplan Executive Function System (D-KEFS) at 12 weeks were analyzed using the same methods described above. Missing records in some scales (e.g., ADAS-Cog) were imputed as detailed in the statistical analysis plan. For scales without imputation, missing any item was considered missing for the aggregate or total that included that item. No adjustments for multiple comparisons were made.

[0119] 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 from pretreatment measured on the first day of study drug dosing (Visit 3) up to 8 hours post-dose. Two baselines will be considered in the change from baseline analysis: the pretreatment value at Visit 3 and the time-matched baseline from Visit 2 (time values ​​0-6 hours). For the second baseline, the 7-hour and 8-hour time points at Visit 3 will be used with the 6-hour time point at Visit 2 as the baseline value. A separate change from baseline analysis will be completed for each baseline approach. Mixed-model repeated-measures analyses will also be used to compare in-clinic BP and pulse rate changes from Visit 2 (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.

[0120] Pharmacokinetics (PK): Pharmacokinetic analysis is performed on subjects who receive at least one dose of the study drug and have one measurable concentration. Model-based approaches may be implemented using nonlinear mixed-effects modeling (NONMEM) or other appropriate software for estimating PK parameters. Additional endpoint and biomarker data collected during the study may be evaluated in an exploratory manner.

[0121] Interim Analysis: Safety interim analyses will be conducted for the number of subjects in each treatment group who meet potentially clinically significant 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 mevidalen compared to placebo is greater than 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.

[0122] 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) may be required):

[0123] Subject type and disease characteristics: [1] Male and female subjects aged 40-85 years (inclusive). [2] PD symptoms for at least 2 years, with idiopathic PD according to MDS criteria (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 Hoehn-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: For subjects under 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 per minute or less in a seated position, and each of the three SBP measurements must be less than 180 mmHg.

[0124] For subjects aged 60 years and older: mean SBP of 150 mmHg or less, mean diastolic BP of 90 mmHg or less, and mean pulse rate in a seated position of 90 beats per minute or less, with each of the three SBP measurements required to be less than 180 mmHg.

[0125] 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 the presence of more than two red flags; if one red flag is present, it must be counterbalanced by one supporting criterion; if two red flags are present, it must be counterbalanced by two supporting criterion.

[0126] In addition to meeting criteria for PD, subjects must also meet the 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.

[0127] Modified Hoehn-Yarr Scale: Enrolled individuals must be in Hoehn-Yarr Stages 1–4 at screening. The Hoehn-Yarr 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-Yarr Scale is as follows: Stage 0: no signs of disease; Stage 1: unilateral disease; Stage 1.5: unilateral plus axial difficulty; Stage 2: bilateral disease without balance dysfunction; Stage 2.5: mild bilateral disease, recovery with pull testing; Stage 3: mild to moderate bilateral disease, some postural instability, physically independent; Stage 4: severe disability, still able to walk or stand without assistance; Stage 5: wheelchair-bound or bedridden unless aided.

[0128] Montreal Cognitive Assessment Scale: Enrolled individuals must have a MoCA score of 10–23 at screening.

[0129] Geriatric Depression Scale: Enrolled individuals must score 6 or less on the Geriatric Depression Scale-Short Form (GDS-S) 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 five indicate depression if answered "no."

[0130] 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 considered to be those at the time of administration of 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 removed from further study participation.

[0131] Dose-dependent effects of mevidalene on motor and non-motor endpoints observed in PRRESENCE. The Phase 2, 12-week PRESENCE study was designed to evaluate the effects of mevidalene on various symptoms for the treatment of cognitive and other domains associated with LBD, including motor function, sleep, mood, and blunted affect. Participants with LBD, aged 40 to 85 years, with Hohn-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. 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 to III) and change in both the MDS-UPDRS Part II (Motor Experience of Daily Living) and Part III (Motor Examination) scores. Analyses were also pre-specified for Part I items of fatigue, daytime sleepiness, hallucinations, depressed mood and lethargy, and for Part IV items of diurnal variation in motor symptoms and dyskinesia.

[0132] Although mevidalen did not improve primary cognitive outcomes, there was a significant dose-dependent improvement in the MDS-UPDRS total score. Compared to placebo, the LS mean changes for mevidalen were -6.58 (p=0.026), -7.56 (p=0.014), and -10.77 (p<0.001) for the 10, 30, and 75 mg doses, respectively. There was a significant dose-dependent improvement in Part II of the MDS-UPDRS for the 30 and 75 mg doses (p=0.014 and p<0.001, respectively), and in Part III for the 75 mg dose (p=0.032). Analysis of the individual items showed significant improvements in Part I items, fatigue, and daytime sleepiness at all doses, significant improvements in several items in Part II, significant improvements in Part III bradykinesia items (at all doses) and rigidity items (significant at 30 mg mevidalene), and a dose-dependent worsening of Part IV dyskinesia items (significant at 75 mg mevidalene). Notably, treatment with mevidalene resulted in significant improvements in global function (ADCS-CGIC) (see Figure 1).

[0133] Mevidalene, which utilizes a novel mechanism of action (D1 PAM), provided symptomatic improvement of motor and selected non-motor symptoms of LBD-associated parkinsonism while avoiding the worsening of non-motor symptoms associated with conventional dopaminergic therapy. Mevidalene utilizes a novel mechanism of action (D1 PAM) that may have the potential to slow or delay disease progression, preferably when used in patients in the prodromal or early stages of the disease.

[0134] 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 lower doses of 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. A preferred dosing regimen for slowing or delaying the progression of Parkinson's disease is 10 mg to 50 mg per day.

[0135] A study published in Neurology (Hacker ML, Turchan M, Heusinkveld LE, et al. Deep brain stimulation in early-stage Parkinson's disease: five-year outcomes. Neurol. July 28, 2020;95 (4)) found that implanted deep brain stimulation (DBS) for early-stage Parkinson's disease (PD) reduces the risk of disease progression and the need for multiple concurrent prescription medications. The authors concluded that the results suggest that early-stage DBS provides long-term motor benefits beyond standard drug therapy while reducing the need for and complexity of Parkinson's disease medications. The U.S. Food and Drug Administration has approved a prospective, multicenter, pivotal clinical trial (IDEG050016) of DBS for early-stage Parkinson's disease. Deep brain stimulation (DBS) is a well-established treatment for Parkinson's disease. Clinical trials have shown that DBS improves motor symptoms, diurnal motor fluctuations, and quality of life compared with medication alone. The target, usually located in the subthalamic nucleus (STN-DBS) or globus pallidus interna (STN-GPi), has similar motor benefits, but thalamic DBS is also an option for treating tremor. Surgical treatment tends to be considered when diurnal motor fluctuations and dyskinesias result in limb disability, even though motor features continue to respond to l-dopa. Previously, surgical strategies were evaluated 10–13 years after Parkinson's disease diagnosis. Multicenter randomized clinical trials have shown that quality of life can be improved after STN-DBS compared with optimal medication when DBS is performed early in the disease course. Despite the effectiveness of DBS, dopaminergic-resistant symptoms (i.e., axial symptoms) that respond poorly to this technique may exist. Therefore, new targets (e.g., the pedunculopontine nucleus, substantia nigra, and thalamus) are emerging for the treatment of motor function.

[0136] The present disclosure provides the concept that treatment with mevidalene and / or D1 PAM agents described herein, preferably in the early stages of Parkinson's disease, can provide a means of pharmacologically enhancing dopaminergic signaling, and, similar to DBS, can provide a means of achieving at least some of the benefits of DBS without surgical intervention, and when applied in the early stages, can slow, inhibit, or alleviate at least some aspects of Parkinson's disease progression in some patients. Mevidalene and D1 PAM can also be used in combination with DBS to slow the progression of Parkinson's disease, according to the methods and embodiments described herein.

[0137] The administration of mevidalene as described herein provides a novel approach to slowing or preventing the progression of Parkinson's disease in one or more aspects of its progression. Therapeutic methods of the present invention using mevidalene are believed to slow or prevent the onset and / or progression of Parkinson's disease in one or more aspects of its progression in patients in the prodromal stage, as described herein and known to those skilled in the art, and to slow the progression to early-stage symptoms. Therapeutic methods of the present invention using mevidalene are believed to slow or prevent the progression of Parkinson's disease in one or more aspects of its progression in patients in the early stage, as described herein, and to slow the progression to advanced-stage symptoms. Therapeutic methods of the present invention using mevidalene are believed to slow or prevent the progression of Parkinson's disease in one or more aspects of its progression in patients in the advanced stage, as described herein, and to slow the progression to complicated-stage symptoms. The methods described herein are particularly useful for patients who have been identified and / or diagnosed as being at risk for Parkinson's disease and / or having the aforementioned stages of the disease, and who have been further diagnosed as experiencing one or more signs and symptoms of Parkinson's disease risk or symptoms. Using mevidalene and D1 PAM agents disclosed herein to slow the progression of Parkinson's disease 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. A dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt or co-crystal thereof, for use in slowing the progression of Parkinson's disease.

2. 2. The dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt or co-crystal thereof, for use according to claim 1, wherein the patient has Parkinson's disease in the prodromal stage.

3. 2. The dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt or co-crystal thereof, for use according to claim 1, wherein the patient has early stage Parkinson's disease.

4. 2. The dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt or co-crystal thereof, for use according to claim 1, wherein the patient has been diagnosed with Parkinson's disease but has not previously received treatment for Parkinson's disease.

5. 5. The dopamine D1 positive allosteric modulator, or a pharmaceutically acceptable salt or co-crystal thereof, for use according to any one of claims 1 to 4, wherein the D1 positive allosteric modulator is mevidalene, or a pharmaceutically acceptable co-crystal thereof.

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

7. 7. The use of mevidalene, or a pharmaceutically acceptable cocrystal thereof, according to claim 6, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 10 to 50 mg per dose.

8. 8. The use of claim 7, 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.

9. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 50 mg per administration.

10. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 45 mg per administration.

11. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 40 mg per administration.

12. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 35 mg per administration.

13. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 30 mg per administration.

14. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 25 mg per administration.

15. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 20 mg per administration.

16. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 15 mg per administration.

17. 9. The use of claim 8, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 10 mg per administration.

18. 6. The use of claim 5, wherein the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered in combination with levodopa simultaneously, separately, or sequentially.

19. 19. The use of claim 18, wherein the mevidalene, or a pharmaceutically acceptable co-crystal thereof, is administered in combination with deep brain stimulation.

20. 1. A method of slowing the progression of Parkinson's disease in a patient in need thereof, said method comprising administering to said patient a dopamine D1 positive allosteric modulator, or a salt or co-crystal thereof.

21. 21. The method of claim 20, wherein the patient has a prodromal stage of Parkinson's disease.

22. 21. The method of claim 20, wherein the patient has early stage Parkinson's disease.

23. 21. The method of claim 20, wherein the patient has an advanced stage of Parkinson's disease.

24. 21. The method of claim 20, wherein the patient has not previously been treated for Parkinson's disease.

25. 25. The method of any one of claims 20 to 24, wherein the D1 positive allosteric modulator is mevidalene, or a pharmaceutically acceptable co-crystal thereof.

26. 26. The method of claim 25, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 5 to 60 mg per dose.

27. 26. The method of claim 25, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 10 to 50 mg per dose.

28. 26. The method of claim 25, 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.

29. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 50 mg per administration.

30. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 45 mg per administration.

31. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 40 mg per administration.

32. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 35 mg per administration.

33. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 30 mg per administration.

34. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 25 mg per administration.

35. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 20 mg per administration.

36. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is administered orally daily at a dose of 15 mg per administration.

37. 29. The method of claim 28, wherein the mevidalene, or a pharmaceutically acceptable cocrystal thereof, is orally administered daily at a dose of 10 mg per administration.

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