5-HT2A SEROTONIN RECEPTOR SEROTONIN RECEPTOR INVERSE AGONISTS USEFUL FOR THE PROPHYLAXIS AND TREATMENT OF PARKINSONIAN SYMPTOMS ASSOCIATED WITH A NEURODEGENERATIVE DISEASE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 62/458,316 filed February 13, 2017, U.S. Provisional Application No. 62/543,637 filed August 10, 2017, and U.S. Provisional Application No. 62/614,910 filed January 8, 2018, the disclosures of which are incorporated by reference in their entireties.

SUMMARY

[0002] The present invention is directed to the use of a 5-HT ₂ A serotonin receptor serotonin receptor inverse agonist for the prophylaxis and/or treatment of the symptoms of dementia with Lewy bodies, Parkinson's disease, or a combination thereof in an individual comprising administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist. In some embodiments, the symptoms of dementia with Lewy bodies, Parkinson's disease, or a combination thereof are Parkinsonian symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist does not result in a worsening of neuropsychiatric symptoms such as, but not limited to, hallucinations and delusions. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement of neuropsychiatric symptoms such as, but not limited to, hallucinations and delusions. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement of neuropsychiatric symptoms and Parkinsonian symptoms.

BRIEF DESCRIPTION OF THE FIGURES

[0003] FIG. 1 shows a graph of changes in UPDRS scores from baseline, relative to placebo, after treatment with the 5-HT ₂ A inverse agonist nelotanserin. DETAILED DESCRIPTION

[0004] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the exemplary methods, devices, and materials are now described.

[0005] There is a significant unmet need for therapies to treat the Parkinsonian symptoms of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies and Parkinson's disease dementia. Patients suffering from these conditions do not respond well to current Parkinson's disease therapies to treat their Parkinsonian symptoms. Those patients whose Parkinsonian symptoms are managed using dopaminergic augmentation with agents such as levodopa, pramipexole or ropinirole, while seeing an improvement in Parkinsonian symptoms, often suffer a worsening of neuropsychiatric symptoms such as hallucinations as a result of these therapies which work by enhancing dopaminergic activity in the brain. Elevation of dopaminergic activity in the brain is believed to precipitate and exacerbate neuropsychiatric symptoms such as hallucinations in patients with Parkinson's disease, dementia with Lewy bodies and Parkinson's disease dementia.. For this reason, levodopa and other dopaminergic therapies are often contraindicated for patients with dementia with Lewy bodies and Parkinson's disease dementia, resulting in suboptimal management of Parkinsonian symptoms in these patients. In addition, patients with Parkinson's disease, dementia with Lewy bodies, and Parkinson's disease dementia commonly suffer from significant neuropsychiatric symptoms including hallucinations. Most existing antipsychotics aim to treat these symptoms by blocking the dopamine D ₂ receptor to limit dopamine activity. However, this activity against dopamine can exacerbate motor problems. As a result, most existing antipsychotics are avoided altogether or used with extreme caution in patients with Parkinson's disease, dementia with Lewy bodies, and Parkinson's disease dementia. 5-HT2A serotonin receptor inverse agonists are a novel drug class designed to improve neuropsychiatric symptoms without worsening of Parkinsonian motor symptoms, due to their lack of D2 blockade. Other 5-HT ₂ A serotonin receptor inverse agonists have been shown to improve neuropsychiatric symptoms in patients with Parkinson's disease psychosis but while they do not cause a worsening, have shown no improvement in Parkinsonian symptoms. In clinical studies, the 5-HT ₂ A serotonin receptor inverse agonist pimavanserin was shown to improve hallucinations and delusions associated with Parkinson's disease psychosis but did not have any impact on Parkinsonian symptoms in these patients. Surprisingly and unexpectedly, Applicant has found that the 5-HT ₂ A serotonin receptor inverse agonist nelotanserin results in an improvement in patients' Parkinsonian motor symptoms as measured by the Unified Parkinson's Disease Rate Scale (UPDRS) Part II relating to activities of daily living, and Part III relating to motor examination compared to baseline in patients with dementia with Lewy bodies or Parkinson's disease dementia who experience frequent hallucinations without any worsening of hallucinations. In other words, nelotanserin, unlike other 5-HT _2A serotonin receptor inverse agonists, may be able to not only prevent any worsening but may actually improve the neuropsychiatric symptoms, such as hallucinations, as well as the Parkinsonian signs and symptoms in patients with dementia with Lewy bodies and Parkinson's disease dementia. The UPDRS is used to measure worsening of a disease state and an improvement in an individual's UPDRS is indicative of an improvement in the disease state and efficacy of the treatment and in particular in an improvement in Parkinsonian symptoms in an individual.

[0006] Without wishing to be bound by theory, the scientific literature suggests that 5- HT2A receptors are located on glutamatergic, GABAergic, cholinergic, serotonergic and dopaminergic neurons in areas of the brain that govern emotion, behavior, sleep and motor functions. In individuals with Lewy body disease, 5HT ₂ A receptors are expressed at an increased level and are linked to a higher occurrence of visual hallucinations. In addition, the increased expression of 5HT _2A receptors may also be partially responsible for limiting the release of dopamine in motor systems in the brain, due to their location on inhibitory GABAergic interneurons.

[0007] In each of the embodiments described herein, the methods may comprise administering a therapeutically effective amount of a 5-HT _2A serotonin receptor inverse agonist. In some embodiments, the 5-HT ₂ A serotonin receptor inverse agonist is l-[3-(4-bromo-2-methyl- 2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-u rea or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof. In some embodiments, l-[3-(4-bromo- 2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro- phenyl)-urea may also be known as nelotanserin or RVT-102 and these terms may be used interchangeably. In each of the embodiments described herein, the method may consist essentially of administering a therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof. In each of the embodiments described herein, the method may consist of administering a therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof. The present invention also encompasses the use of diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of the invention. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.

[0008] The term "comprising" means "including, but not limited to." The term

"consisting essentially of means the method or composition includes the steps or components specifically recited, and may also include those that do not materially affect the basic and novel characteristics of the present invention. The term "consisting of means the method or composition includes only the steps or components specifically recited. It must be noted that, as used herein, and in the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise.

[0009] As used herein, the term "neuropsychiatric symptom" shall mean one or more psychiatric manifestation or behavioral disturbances associated with neurodegenerative diseases, such as, but not limited to depression, euphoria, delirium, delusions, flattening of affect, anxiety, dissociation, irritability, apathy, agitation, aggression, aberrant vocalizations, hallucinations, delusions, psychosis, wandering, sleep disturbances, sundowning, psychomotor retardation, cognitive impairment, disturbances of consciousness, behavioral changes, neurotic symptoms, mood disorders, Parkinsonism, nuchal rigidity, stiffness, personality change, neurological signs, somatic complaints, dementia, subcortical dementia, or disinhibition.

[0010] As used herein, the term "Parkinsonian symptom" shall mean one or more extrapyramidal motor or non-motor symptoms of Parkinson's disease including but not limited to tremor, bradykinesia, rigidity, postural instability or any combination thereof as well as non- motor symptoms including but not limited to mood disorders such as depression, anxiety and irritability, cognitive changes such as with focused attention and planning, slowing of thought, language and memory difficulties, personality changes, dementia, hallucinations and delusions, orthostatic hypotension, sleep disturbances or sleep disorders such as insomnia, excessive daytime sleepiness (EDS), rapid eye movement (REM) behavior disorder (RBD), vivid dreams, talking and moving during sleep, restless legs syndrome (RLS)/periodic leg movements disorder (PLMD), constipation and early satiety, pain, fatigue, vision problems, excessive sweating, increase in dandruff or oily skin, urinary urgency, frequency and incontinence, loss of sense of smell, sexual problems, weight loss or weight gain and impulsive control disorders such as binge eating, excessive shopping or gambling, or any combination thereof.

[0011] As used herein, the term "hallucination" means a sensory perception of the existence of something that is not real in the absence of external stimulus that has qualities of real perception. In some embodiments, hallucinations may be vivid, substantial, and are perceived to be located in external objective space. As used herein, hallucinations may occur in any sensory modality including, but not limited to visual, auditory, olfactory, gustatory, tactile, proprioceptive, equilibrioceptive, nociceptive, thermoceptive and chronoceptive. In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof.

[0012] As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.

[0013] "Optional" or "optionally" may be taken to mean that the subsequently described structure, event or circumstance may or may not occur, and that the described includes instances where the event occurs and instances where it does not.

[0014] "Administering" when used in conjunction with a therapeutic means to administer a therapeutic directly or indirectly into or onto a target tissue to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. "Administering" a composition may be accomplished by oral nasal, sublingual, buccal, transdermal, vaginal or rectal administration, injection, infusion, inhalation, absorption or by any method in combination with other known techniques. "Administering" may include the act of self-administration or administration by another person such as a health care provider.

[0015] The term "improves" is used to convey that the present invention changes the appearance, form, characteristics, structure, function and/or physical attributes of the tissue to which it is being provided, applied or administered. "Improves" may also refer to the overall physical state of an individual to whom an active agent has been administered. For example, the overall physical state of an individual may "improve" if one or more symptoms of the disease, condition or disorder are alleviated by administration of an active agent. The term "improve" as used herein may also refer to a decrease in the severity, duration, frequency, or any combination thereof, in one or more symptoms of the disease.

[0016] As used herein, the term "therapeutic" means an agent utilized to treat, combat, ameliorate or prevent an unwanted disease, condition or disorder of a patient.

[0017] As used herein, the term "dopamine D ₂ receptor" refers to the D ₂ subtype of the dopamine receptor.

[0018] As used herein, the term "5HT _2A serotonin receptor" refers to the 2A subtype of the serotonin receptor.

[0019] As used herein, the term "agonist" refers to an agent that binds to a receptor and activates the receptor to produce a biological response.

[0020] As used herein, the term "inverse agonist" refers to an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist. In some embodiments, a prerequisite for an inverse agonist response is that the receptor must have a constitutive (also known as intrinsic or basal) level activity in the absence of any ligand. An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level.

[0021] The efficacy of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% (i.e., negative) efficacy. [0022] As used herein, the term "baseline" is intended to represent an individual's status with respect to any of the diseases severity or progression scoring scales described herein prior to administration of the agents described herein.

[0023] In each of the embodiments disclosed herein, the compounds and methods may be utilized with or on an individual in need of such treatment, which may also be referred to as "in need thereof." As used herein, the phrase "in need thereof means that the individual has been identified as having a need for the particular method or treatment and that the treatment has been given to the individual for that particular purpose. "In need thereof as used herein also refers to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from prophylaxis and/or treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will be ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. In general, "in need of prophylaxis" refers to the judgment made by the caregiver that the individual will become ill. In this context, the compounds of the invention are used in a protective or preventive manner. However, "in need of treatment" refers to the judgment of the caregiver that the individual is already ill; therefore, the compounds of the present invention are used to alleviate, inhibit or ameliorate the disease, condition or disorder.

[0024] As used herein, the term "patient" and "individual" or "individual" are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention. As such, the terms "patient" and "individual" may include, but are not limited to, any non-human mammal, primate or human. In some embodiments, the "patient" or "individual" is an adult, an elderly adult, child, infant, or fetus. In some embodiments, an elderly adult is an adult of about 50 years of age or older. In some embodiments, the "patient" or "individual" is a human. In some embodiments, the "patient" or "individual" is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans. [0025] The term "therapeutically effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is from about 0.0001 to about 1,000 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is from about 10 to about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 10 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 20 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 40 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 80 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, about 0.001 mg to about 160 mg or about 10 to about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg or about 160 mg.

[0026] The term "treating" may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and/or prevention of the symptoms associated with a specific disorder, disease or condition. In some embodiments, the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition. In some embodiments, the term refers to alleviating the symptoms associated with the specific disorder, disease or condition. In some embodiments, the term refers to restoring function which was impaired or lost due to a specific disease, disorder or condition.

[0027] The term "pharmaceutical composition" shall mean a composition including at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. A pharmaceutical composition may, for example, contain nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof as the active ingredient.

[0028] "Pharmaceutically acceptable salts, hydrates, polymorphs or solvates" is meant to indicate those salts, hydrates, polymorphs or solvates which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. (1977) J. Pharm. Sciences, Vol 6. 1-19, describes pharmaceutically acceptable salts in detail. A pharmaceutical acceptable "salt" is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including, but not limited to, halogenic acid salts such as hydrobromic, hydrochloric, hydrofloric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or p-toluenesufonic, acetic, malic, fumaric, succinic, citric, benzoic gluconic, lactic, mandelic, mucic, pamoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic or glutamic acid salt. The acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric or di-organic acid salt. In all cases, the acid addition salt is used as an achiral reagent which is not selected on the basis of any expected or known preference for the interaction with or precipitation of a specific optical isomer of the products of this disclosure.

[0029] As used herein, the term "daily dose" refers to the amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof, per day that is administered or prescribed to a patient. This amount can be administered in multiple unit doses or in a single unit dose, at a single time during the day or at multiple times during the day. Multiple doses may be administered during the day, for example 2, 3 or 4, doses. In some embodiments, the dose is administered once daily in the morning, afternoon, evening, or once daily about 1 hour prior to the individual's bedtime. In some embodiments, the dose is administered about one to about four times per day, once daily in the morning, once daily about 1 hour prior to the individual's bedtime, or twice daily. In some embodiments, the dose is administered twice daily. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is from about 0.0001 to about 1,000 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is from about 10 to about 160 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 10 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 20 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 40 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 80 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 160 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is from about 0.001 mg to about 1,000 mg, about 0.001 mg to about 160 mg or about 10 to about 160 mg. In some embodiments, the daily dose of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg or about 160 mg.

[0030] "Composition" shall mean a material comprising at least two compounds or two components; for example, and without limitation, a "Pharmaceutical Composition" is a Composition comprising a compound of the present invention and a pharmaceutically acceptable carrier.

[0031] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. Moreover, the processes, compositions, and methodologies described in particular embodiments are interchangeable. Therefore, for example, a composition, dosages regimen, route of administration, and so on described in a particular embodiment may be used in any of the methods described in other particular embodiments. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods are now described. All publications and references mentioned herein are incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0032] The present invention is directed to the use of a 5-HT ₂ A serotonin receptor inverse agonist for the prophylaxis and/or treatment of the symptoms of dementia with Lewy bodies, Parkinson's disease, Parkinson's disease dementia, REM sleep behavior disorder, or a combination thereof in an individual comprising administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist. In some embodiments, the symptoms of dementia with Lewy bodies, Parkinson's disease, or a combination thereof are Parkinsonian symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist does not result in a worsening of neuropsychiatric symptoms such as, but not limited to hallucinations and delusions. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement of neuropsychiatric symptoms such as, but not limited to hallucinations and delusions. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement of neuropsychiatric symptoms and Parkinsonian symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist does not result in QT interval prolongation. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement of motor symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement of Parkinsonian motor symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement in sleep disturbances or the symptoms of a sleep disorder. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement in sleep disturbances or the symptoms of a sleep disorder, an improvement of Parkinsonian symptoms, an improvement in neuropsychiatric symptoms or any combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement in sleep disturbances or the symptoms of a sleep disorder, an improvement of Parkinsonian symptoms, or a combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement of Parkinsonian symptoms, an improvement in neuropsychiatric symptoms or a combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement in sleep disturbances or the symptoms of a sleep disorder, an improvement in neuropsychiatric symptoms or a combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement in sleep disturbances or the symptoms of a sleep disorder, an improvement of Parkinsonian symptoms, an improvement in neuropsychiatric symptoms or any combination thereof, without causing a worsening of a sleep disturbance or sleep disorder, Parkinsonian symptom, or neuropsychiatric symptom or any combination thereof.

[0033] In some embodiments, the hallucinations are selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, chronoceptive hallucinations and any combination thereof.

[0034] In some embodiments, the 5-HT ₂ A serotonin receptor inverse agonist is nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is selected from the group consisting of Form I of l-[3-(4-bromo-2-methyl-2H- pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea , Form II of l-[3-(4-bromo-2- methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-ph enyl)-urea and a combination thereof. In some embodiments, a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 10 mg to about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 20 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 40 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 80 mg. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 160 mg.

[0035] In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is administered once a day, twice a day, three times a day, or four times a day. In some embodiments, the nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is in a pharmaceutical composition configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration. In some embodiments, the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is administered about one to about four times per day, once daily in the morning, once daily about 1 hour prior to the individual's bedtime, or twice daily.

[0036] In some embodiments, the individual is a human. In some embodiments, the human is an adult with a diagnosis of a condition selected from frontotemporal dementia, progressive supranuclear palsy, Lewy body dementia, probable dementia with Lewy bodies, dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof. In some embodiments, the human has a concurrent diagnosis of hallucinations, delusions, or a combination thereof, and a condition selected from Lewy body dementia, probable dementia with Lewy bodies, dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof. In some embodiments, the human has a concurrent diagnosis of hallucinations, delusions or a combination thereof, and a condition selected from frontotemporal dementia, progressive supranuclear palsy, Lewy body dementia, probable dementia with Lewy bodies, dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof. In some embodiments, the human has a diagnosis of probable dementia with Lewy bodies. In some embodiments, the diagnosis of probable dementia with Lewy Bodies is defined by the presence of dementia and at least one of: at least two Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and one Core Criteria selected from hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and at least one Suggestive Criteria selected from REM sleep behavior disorder, severe neuroleptic sensitivity, low dopamine transporter uptake on DaT SPECT Imaging Scan; and any combination thereof. In some embodiments, the human has a diagnosis of dementia with Lewy Bodies. In some embodiments, the human has a diagnosis of Parkinson's disease. In some embodiments, the human has a diagnosis of Parkinson's disease dementia. In some embodiments, the human has a Mini Mental State Examination score of greater than, or equal to, about 18. In some embodiments, the human is an adult with a diagnosis of hallucinations, delusions or a combination thereof, associated with dementia with Lewy bodies. In some embodiments, the human is an adult with a diagnosis of hallucinations, delusions or a combination thereof, associated with Parkinson's disease. In some embodiments, the human is an adult with a diagnosis of hallucinations, delusions or a combination thereof, associated with Parkinson's disease dementia. In some embodiments, the individual has a score of zero or greater on (Scale for Assessing Positive symptoms) SAPS-H prior to administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the individual has a score of one or greater on (Scale for Assessing Positive symptoms) SAPS-H prior to administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the individual has a score of two or greater on (Scale for Assessing Positive symptoms) SAPS-H prior to administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the individual has a score of three or greater on (Scale for Assessing Positive symptoms) SAPS-H prior to administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the individual has a score of four or greater on (Scale for Assessing Positive symptoms) SAPS-H prior to administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

[0037] In some embodiments, the individual is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, ziprasidone, pimavanserin, melatonin, quetiapine, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, NMDA receptor antagonist, and a combination thereof. In some embodiments, the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist or any combination thereof. In some embodiments, the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

[0038] In some embodiments, administration of a therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in treatment, and/or prophylaxis of the Parkinsonian symptoms of dementia with Lewy bodies, Parkinson's disease, Parkinson's disease dementia, or a combination thereof.

[0039] In some embodiments, treatment, and/or prophylaxis of the Parkinsonian symptoms of dementia with Lewy bodies, Parkinson's disease, Parkinson's disease dementia, or a combination thereof results in an improvement in the individuals Unified Parkinson's Disease Rate Scale (UPDRS) compared to baseline. The UPDRS is used to measure worsening of a disease state and an improvement in an individual's UPDRS is indicative of an improvement in the disease state and efficacy of the treatment and in particular in an improvement in Parkinsonian symptoms in an individual. Parkinsonian symptoms include but are not limited to tremor, bradykinesia, rigidity, postural instability or any combination thereof as well as non- motor symptoms including but not limited to mood disorders such as depression, anxiety and irritability, cognitive changes such as with focused attention and planning, slowing of thought, language and memory difficulties, personality changes, dementia, hallucinations and delusions, orthostatic hypotension, sleep disorders such as insomnia, excessive daytime sleepiness (EDS), rapid eye movement behavior disorder (RBD), vivid dreams, talking and moving during sleep, restless legs syndrome (RLS)/periodic leg movements disorder (PLMD), constipation and early satiety, pain, fatigue, vision problems, excessive sweating, increase in dandruff or oily skin, urinary urgency, frequency and incontinence, loss of sense of smell, sexual problems, weight loss or weight gain and impulsive control disorders such as binge eating, excessive shopping or gambling.

[0040] In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals Unified Parkinson's Disease Rate Scale (UPDRS) Part II relating to activities of daily living, Part III relating to motor examination or a combination thereof compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals Unified Parkinson's Disease Rate Scale (UPDRS) Part II relating to activities of daily living, compared to baseline. In some embodiments, parameters observed in UPDRS Part II as activities of daily living, include, but are not limited to speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning in bed or adjusting clothing, falling, freezing when walking, walking, tremor, sensory complaints or any combination thereof. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals Unified Parkinson's Disease Rate Scale (UPDRS) Part III relating to motor examination or a combination thereof compared to baseline. In some embodiments, parameters observed in UPDRS Part III as related to motor examination include, but are not limited to speech, facial expression, tremor at rest, action tremor, rigidity, finger taps, hand grips, hand pronate/supinate, leg agility, arising from chair, posture, gait, postural stability, bradykinesia and hypokinesia or any combination thereof. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in a decrease in tremor and rigidity in the subject. In some embodiments, an improvement compared to baseline in any of the parameters disclosed herein may be observed within about 1 to about 4 weeks of treatment. In some embodiments, an improvement compared to baseline in any of the parameters disclosed herein may be observed within about 2 weeks of treatment, an improvement in any of the parameters disclosed above may be observed within about 4 weeks of treatment.

[0041] In some embodiments, treatment, and/or prophylaxis of the Parkinsonian symptoms of dementia with Lewy Bodies, Parkinson's disease, Parkinson's disease dementia, REM sleep behavior disorder, or a combination thereof results in no worsening of the individuals Scale for the Assessment of Positive Symptoms (SAPS) compared to baseline. In some embodiments, treatment, and/or prophylaxis of the Parkinsonian symptoms of dementia with Lewy bodies, Parkinson's disease, Parkinson's disease dementia, REM sleep behavior disorder, or a combination thereof results in an improvement in the individuals Scale for the Assessment of Positive Symptoms (SAPS) compared to baseline. The SAPS is a rating scale to measure positive symptoms in schizophrenia. SAPS is split into 4 domains, and within each domain separate symptoms are rated from 0 (absent) to 5 (severe). In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individuals score on the Scale for Assessment of Positive Symptoms (SAPS) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals score on the Scale for Assessment of Positive Symptoms (SAPS) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individuals score on the Scale for Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals score on the Scale for Assessment of Positive Symptoms - Parkinson's disease (SAPS-PD) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the in the individuals score on the Scale for Assessment of Positive Symptoms - Parkinson's disease - Hallucinations (SAPS-PD-H) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the in the individuals score on the Scale for Assessment of Positive Symptoms - Parkinson's disease - Hallucinations (SAPS-PD- H) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individual's score on the Scale for Assessment of Positive Symptoms Parkinson's disease - Delusions (SAPS-PD-D) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individual's score on the Scale for Assessment of Positive Symptoms Parkinson's disease - Delusions (SAPS-PD-D) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individuals score on the Scale for Assessment of Positive Symptoms Hallucinations/Delusions (SAPS-HD) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals score on the Scale for Assessment of Positive Symptoms Hallucinations/Delusions (SAPS-HD) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individuals score on the Scale for Assessment of Positive Symptoms - Hallucinations (SAPS-H) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals score on the Scale for Assessment of Positive Symptoms - Hallucinations (SAPS-H) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individuals score on the Scale for Assessment of Positive Symptoms - Delusions (SAPS-D) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals score on the Scale for Assessment of Positive Symptoms - Delusions (SAPS-D) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in no worsening of the individuals score on the Scale for Assessment of Positive Symptoms - Visual Hallucinations (SAPS-VH) compared to baseline. In some embodiments, administration of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof results in an improvement in the individuals score on the Scale for Assessment of Positive Symptoms - Visual Hallucinations (SAPS-VH) compared to baseline. In some embodiments, an improvement compared to baseline in any of the parameters disclosed herein may be observed within about 1 to about 4 weeks of treatment. In some embodiments, an improvement compared to baseline in any of the parameters disclosed herein may be observed within about 2 weeks of treatment, an improvement in any of the parameters disclosed above may be observed within about 4 weeks of treatment.

[0042] In some embodiments, treatment, and/or prophylaxis of the Parkinsonian symptoms of dementia with Lewy Bodies, Parkinson's diseases, Parkinson's disease dementia, REM sleep behavior disorder, or a combination thereof results in an improvement in the individual's Mini- Mental State Examination score, cognition, attention, Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+) rating, neuropsychiatric inventory (NPI), North-East Visual Hallucinations Interview (NEVHI), Cognitive Drug Research (CDR) computerized assessment system, Scale for the Assessment of Positive Symptoms (SAPS), Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) scale or any combination thereof. In some embodiments, treating or prophylaxis results in fluctuations in cognition, attention or a combination thereof.

[0043] Antipsychotics are typically used to treat the neuropsychiatric symptoms of psychosis such as delusions, hallucinations, paranoia, or confused thoughts. They are also used in the treatment of schizophrenia, severe depression and severe anxiety and for stabilizing episodes of mania in people with Bipolar Disorder. Treatment with antipsychotics can however result in the manifestation of parkinsonian symptoms in patients being treated for the conditions described above. Accordingly, these patients may benefit from an agent that can treat, and, or prevent these parkinsonian symptoms. The present invention is also directed to the use of a 5- HT ₂ A serotonin receptor inverse agonist for the prophylaxis and/or treatment of the parkinsonian symptoms caused by the use of antipsychotic agents in an individual being treated for a neuropsychiatric symptoms of a condition, comprising administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist. In some embodiments, the conditions may include psychoses such as delusions, hallucinations, paranoia, or confused thoughts, schizophrenia, severe depression, severe anxiety, for stabilizing episodes of mania in people with bipolar disorder or any combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist does not result in a worsening of neuropsychiatric symptoms of the condition such as, but not limited to hallucinations, delusions, or a combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement of neuropsychiatric symptoms such as, but not limited to hallucinations, delusions, or combination thereof. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement of neuropsychiatric symptoms and Parkinsonian symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist does not result in QT interval prolongation. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT _2A serotonin receptor inverse agonist results in an improvement of Parkinsonian symptoms. In some embodiments, administering to said individual in need thereof a therapeutically effective amount of said 5-HT ₂ A serotonin receptor inverse agonist results in an improvement of Parkinsonian motor symptoms.

[0044] In some embodiments, the methods described herein can be used in the prophylaxis and/or treatment of the parkinsonian symptoms caused by the use of both typical (defined as an agent that is a selective dopamine D ₂ receptor blocker) or atypical antipsychotic agents (defined as agents with mixed receptor selectivity). Typical antipsychotic agents include but are not limited to chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, thioridazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, and zuclopenthixol. Atypical antipsychotics include but are not limited to aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, ziprasidone, quetiapine, clozapine, risperidone, and clonazepam.

[0045] One aspect of the present invention pertains to the use of pharmaceutical compositions comprising: (a) nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof; and (b) an excipient. One aspect of the present invention pertains to the use of pharmaceutical compositions comprising: (a) nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof; and (b) an excipient selected from PVP and coPVP.

[0046] One aspect of the present invention pertains to kits for the prophylaxis and/or treatment of the symptoms of dementia with Lewy bodies, Parkinson's disease, Parkinson's disease dementia, REM sleep behavior disorder, or a combination thereof in an individual comprising a container and a pharmaceutical composition of the present invention.

[0047] One aspect of the present invention pertains to methods for the prophylaxis and/or treatment of the symptoms of dementia with Lewy bodies, Parkinson's disease, Parkinson's disease dementia, REM sleep behavior disorder, or a combination thereof in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.

[0048] In some embodiments, the pharmaceutical composition is administered orally, nasally sublingually, buccally, transdermally, vaginally or rectally. In some embodiments, the pharmaceutical composition is administered orally.

[0049] One aspect of the present invention pertains to the use of a pharmaceutical composition of the present invention in the manufacture of a medicament for the prophylaxis and/or treatment of the symptoms of dementia with Lewy bodies, Parkinson's disease, or a combination thereof. [0050] In some embodiments, the individual is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, ziprasidone, pimavanserin, chlorpromazine, chlorprothixene, levomepromazine, mesoridazine, periciazine, promazine, thioridazine, loxapine, molindone, perphenazine, thiothixene, droperidol, flupentixol, fluphenazine, haloperidol, pimozide, prochlorperazine, thioproperazine, trifluoperazine, zuclopenthixol, melatonin, quetiapine, clozapine, risperidone, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, MDA receptor antagonist, an atypical antipsychotic agent, a dopaminergic agent, a benzodiazepine, an antidepressant, and a combination thereof. In some embodiments, the therapeutically effective amount of melatonin is about 1 mg to about 5 mg. In some embodiments, the therapeutically effective amount of quetiapine is about 12.5 mg to about 100 mg. In some embodiments, the therapeutically effective amount of quetiapine is less than about 25 mg. In some embodiments, the therapeutically effective amount of clonazepam is about 0.0625 mg to about 5 mg. In some embodiments, the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist or any combination thereof. In some embodiments, the therapeutically effective amount of levodopa or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 10,000 mg, or about 0.001 mg to about 8,000 mg. In some embodiments, the therapeutically effective amount of levodopa or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 285 mg, about 300 mg, about 400 mg, about 435 mg, about 500 mg, about 585 mg, about 600 mg, about 700 mg, about 735 mg, about 750 mg, about 800 mg, about 980 mg, about 1,000 mg, about 1,225 mg, about 1,250 mg, about 1,470 mg, about 1,500 mg, about 1,715 mg, about 1,750 mg, about 1,960 mg, about 2,000 mg, about 2,205 mg, about 2,250 mg, about 2,450 mg, about 2,500 mg, about 2,750 mg, about 3,000 mg, about 3,250 mg, about 3,500 mg, about 3,750 mg, about 4,000 mg, about 4,250 mg, about 5,000 mg, about 5,250 mg, about 5,500 mg, about 5,750 mg, about 6,000 mg, about 6,250 mg, about 6,500 mg, about 6,750 mg, about 7,000 mg, about 7,250 mg, about 7,500 mg, about 7,750 mg, or about 8,000 mg. In some embodiments, the therapeutically effective amount of carbidopa or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of carbidopa is from about 0.001 mg to about 1,000 mg, or from about 0.001 mg to about 700 mg. In some embodiments, the therapeutically effective amount of carbidopa is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 71.25 mg, about 80 mg, about 108.75 mg, about 146.25 mg, 183.75 mg, about 245 mg, about 245 mg, about 306.25 mg, about 367.5 mg, about 428.75 mg, about 490 mg, about 551.25 mg, or about 612.5 mg. In some embodiments, the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 30 mg. In some embodiments, the therapeutically effective amount of donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 5 mg, 10 mg, or 23 mg. In some embodiments, the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 15 mg. In some embodiments, the therapeutically effective amount of rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 1.5 mg, about 3 mg, about 4.5 mg, about 6 mg, about 9 mg, about 9.5 mg, about 12 mg, or about 13.3 mg. In some embodiments, the therapeutically effective amount of rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 30 mg. In some embodiments, the therapeutically effective amount of galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 4 mg, about 8 mg, about 12 mg, about 16 mg, or about 24 mg. In some embodiments, NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 30 mg. In some embodiments, the therapeutically effective amount of memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 5 mg, about 7 mg, about 10 mg, about 14 mg, about 20 mg, about 21 mg, or about 28 mg. In some embodiments, the therapeutically effective amount of memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for extended release, for delayed release or a combination thereof. In some embodiments, the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof. In some embodiments, the therapeutically effective amount of amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is configured for immediate release, for extended release, for delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 500 mg. In some embodiments, the therapeutically effective amount of amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 100 mg to about 400 mg. In some embodiments, the therapeutically effective amount of amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 100 mg, about 200 mg, about 300 mg or about 400 mg. [0051] In some embodiments, the at least one additional therapeutic agent is a 5HT ₆ antagonist. In some embodiments, the at least one additional therapeutic agent is 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline. In some embodiments, 3-phenylsulfonyl-8- piperazinyl-lyl-quinoline is administered in a therapeutically effective amount. In some embodiments, the therapeutically effective amount of 3-phenylsulfonyl-8-piperazinyl-lyl- quinoline or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof is configured for extended release, and the additional therapeutic agent useful for treating a neurodegenerative disease is configured for immediate release, for sustained release, for extended release, or any combination thereof. In some embodiments, the therapeutically effective amount of 3-phenylsulfonyl-8-piperazinyl-lyl-quinoline or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 0.001 mg to about 1,000 mg, about 0.001 mg to about 200 mg, about 0.001 mg to about 175 mg, or 0.001 mg to about 70 mg. In some embodiments, the therapeutically effective amount of 3-phenylsulfonyl-8-piperazinyl-lyl- quinoline or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 15 mg, about 35 mg, or about 70 mg.

[0052] In some embodiments, the at least one additional therapeutic agent is a monoclonal antibody. In some embodiments, the at least one additional therapeutic agent is a human monoclonal antibody. In some embodiments, the at least one additional therapeutic agent is a humanized monoclonal antibody. In some embodiments the monoclonal antibody targets beta amyloid. In some embodiments the beta amyloid may comprise aggregated beta amyloid such as but not limited to soluble oligomers, insoluble fibrils deposited into amyloid plaque, or a combination thereof. In some embodiments, the monoclonal antibody is Aducanumab (BIIB037), Gantenerumab, Bapineuzumab, Crenezumab, Ponezumab, Solanezumab, SAR228810, MEDI1814, BAN2401, or any combination thereof. In some embodiments, the monoclonal antibody targets alpha-synuclein. In some embodiments, the monoclonal antibody targeting alpha-synuclein is RG-7935, Posiphen, Affitope PD03A, Affitope PD01A, or any combination thereof.

[0053] In some embodiments, the at least one additional therapeutic agent is a BACE enzyme inhibitor. In some embodiments, the BACE enzyme inhibitor is CTS-21166, MK-8931, AZD3293, LY3314814, BI1181181, LY2886721, E2609, RG7129, JNJ-5486911, TAK-070, or any combination thereof.

[0054] In some embodiments, the at least one additional therapeutic agent is a RAGE inhibitor. In some embodiments, the RAGE inhibitor is TTP488 (Azeliragon), TTP4000, FPS- ZM1, or any combination thereof.

[0055] In some embodiments, the at least one additional therapeutic agent is an antibody targeting Tau. In some embodiments, the antibody targeting Tau is AADVAC-1, AADVAC-2, ACI-35, BMS-986168, RG7345, TRx-237-015 (LMTX), AV-1451, AV-680, Posiphen, or any combination thereof.

[0056] In some embodiments, the at least one additional therapeutic agent is a a7 nicotinic acetylcholine receptor modulator. In some embodiments, the a7 nicotinic acetylcholine receptor modulator is Encenicline (EVP-6124), ABT-126, ABT 418, RG3487, Varenicline, A-867744, TC-5219, AVL3288, BMS933043, DSP-3748, or any combination thereof.

[0057] In some embodiments, the at least one additional therapeutic agent may include one or more treatments for Alzheimer's disease such as Namzaric™, Exelon®, Aricept® (donepezil hydrochloride), Namenda® (memantine hydrochloride), or galantamine hydrobromide. In some embodiments, described compositions and formulations may be administered in combination with one or more treatments for Parkinson's Disease such as ABT-126 (Abbott Laboratories), pozanicline (Abbott Laboratories), MABT-5102A (AC Immune), Affitope AD-01 (AFFiRiS GmbH), Affitope AD-02 (AFFiRiS GmbH), davunetide (Allon Therapeutics Inc.), nilvadipine derivative (Archer Pharmaceuticals), Anapsos (ASAC Pharmaceutical International AIE), ASP- 2535 (Astellas Pharma Inc.), ASP-2905 (Astellas Pharma Inc.), 1 1C-AZD-2184 (AstraZeneca pic), 1 lC-AZD-2995 (AstraZeneca pic), 18F-AZD-4694 (AstraZeneca pic), AV-965 (Avera Pharmaceuticals Inc.), AVN-101 (Avineuro Pharmaceuticals Inc.), immune globulin intravenous (Baxter International Inc.), EVP-6124 (Bayer AG), nimodipine (Bayer AG), BMS-708163 (Bristol-Myers Squibb Co), CERE-110 (Ceregene Inc.), CLL-502 (CLL Pharma), CAD-106 (Cytos Biotechnology AG), mimopezil ((Debiopharm SA), DCB-AD1 (Development Centre for Biotechnology), EGb-761 (Dr Willmar Schwabe GmbH & Co), E-2012 (Eisai Co Ltd), ACC- 001 (Elan Corp pic), bapineuzumab (Elan Corp pic), ELND-006 (Elan Pharmaceuticals Inc.), atomoxetine (Eli Lilly & Co), LY-2811376 (Eli Lilly & Co), LY-451395 (Eli Lilly & Co), m266 (Eli Lilly & Co), semagacestat (Eli Lilly & Co), solanezumab (Eli Lilly & Co), AZD-103 (Ellipsis Neurotherapeutics Inc.), FGLL (E KAM Pharmaceuticals A/S), EHT-0202 (ExonHit Therapeutics SA), celecoxib (GD Searle & Co), GSK-933776A (GlaxoSmithKline Pic, rosiglitazone XR (GlaxoSmithKline pic), SB-742457 (GlaxoSmithKline pic), R-1578 (Hoffmann-La Roche AG), HF-0220 (Hunter-Fleming Ltd), oxiracetam (ISF Societa Per Azioni ), KD- 501 (Kwang Dong Pharmaceutical Co Ltd), NGX-267 (Life Science Research Israel), huperzine A (Mayo Foundation), Dimebon (Medivation Inc.), MEM-1414 (Memory Pharmaceuticals Corp), MEM-3454 (Memory Pharmaceuticals Corp), MEM-63908 (Memory Pharmaceuticals Corp), MK-0249 (Merck & Co Inc.), MK-0752 (Merck & Co Inc.), simvastatin (Merck & Co Inc.), V-950 (Merck & Co Inc.), memantine (Merz & Co GmbH), neramexane (Merz & Co GmbH), Epadel (Mochida Pharmaceutical Co Ltd), 123I-MNI-330 (Molecular Neuroimaging Lie), gantenerumab (MorphoSys AG), NIC5-15 (Mount Sinai School of Medicine), huperzine A (Neuro-Hitech Inc.), OXIGON (New York University), NP- 12 (Noscira SA), NP-61 (Noscira SA), rivastigmine (Novartis AG), ECT-AD (NsGene A/S), arundic acid (Ono Pharmaceutical Co Ltd), PF-3084014 (Pfizer Inc.), PF-3654746 (Pfizer Inc.), RQ- 00000009 (Pfizer Inc.), PYM-50028 (Phytopharm pic), Gero-46 (PN Gerolymatos SA), PBT-2 (Prana Biotechnology Ltd), PRX-03140 (Predix Pharmaceuticals Inc.), Exebiyl-1 (ProteoTech Inc.), PF-4360365 (Rinat Neuroscience Corp), HuCAL anti- beta amyloid monoclonal antibodies (Roche AG), EVT-302 (Roche Holding AG), nilvadipine (Roskamp Institute), galantamine (Sanochemia Pharmazeutika AG), SAR-110894 (sanofi-aventis), EMM- 176 (Scigenic & Scigen Harvest), mimopezil (Shanghai Institute of Materia Medica of the Chinese Academy of Sciences), NEBO-178 (Stegram Pharmaceuticals), SUVN-502 (Suven Life Sciences), TAK-065 (Takeda Pharmaceutical), ispronicline (Targacept Inc.), rasagiline (Teva Pharmaceutical Industries), T-817MA (Toyama Chemical), PF -4494700 (TransTech Pharma Inc.), CX-717 (University of California), 18F-FDDNP (University of California Los Angeles), GTS-21 (University of Florida), 18F-AV-133 (University of Michigan), 18F-AV-45 (University of Michigan), tetrathiomolybdate (University of Michigan), 1231-IMPY (University of Pennsylvania), 18F-AV-1/ZK (University of Pennsylvania), 1 lC-6-Me-BTA-l (University of Pittsburgh), 18F-6-OH-BTA-1 (University of Pittsburgh), MCD-386 (University of Toledo), leuprolide acetate implant (Voyager Pharmaceutical Corp), aleplasinin (Wyeth), begacestat (Wyeth), GSI-136 (Wyeth), NSA-789 (Wyeth), SAM-531 (Wyeth), CTS-21166 (Zapaq), and ZSET-1446 (Zenyaku Kogyo).

[0058] In some embodiments, the at least one additional therapeutic agent may include one or more agents useful for the treatment of motor neuronal disorders, such as AEOL-10150 (Aeolus Pharmaceuticals Inc.), riluzole (Aventis Pharma AG), ALS-08 (Avicena Group Inc.), creatine (Avicena Group Inc.), arimoclomol (Biorex Research and Development Co), mecobalamin (Eisai Co Ltd), talampanel (Eli Lilly & Co), R-7010 (F Hoffmann-La Roche Ltd), edaravone (Mitsubishi-Tokyo Pharmaceuticals Inc.), arundic acid (Ono Pharmaceutical Co Ltd), PYM-50018 (Phytopharm pic), RPI-MN (ReceptoPharm Inc.), SB-509 (Sangamo Biosciences Inc.), olesoxime (Trophos SA), sodium phenylbutyrate (Ucyclyd Pharma Inc.), and R- pramipexole (University of Virginia).

[0059] In some embodiments, the at least one additional therapeutic agent may be an agent known to modify cholinergic transmission such as Ml muscarinic receptor agonists or allosteric modulators, M2 muscarinic antagonists, acetylcholinesterase inhibitors, nicotinic receptor agonists or allosteric modulators, 5-HT ₄ receptor partial agonists or 5HTi _A receptor antagonists and NMDA receptor antagonists or modulators, glutamate antagonists, GABA-ergic antagonists, H3 antagonists, putative metabolic/mitochondrial modulators, or disease modifying agents such as β or γ-secretase inhibitors, Tau-targeted therapeutics, β-amyloid aggregation inhibitors and β- amyloid immunotherapies, an antidepressants, for example a tricyclic, a MAOI (Monoamine oxidase inhibitor) a SSRI (Selective Serotonin Reuptake Inhibitor), a SNRI (Serotonin and Noradrenaline Reuptake Inhibitor) or a NaSSA (noradrenergeric and specific serotonergic antidepressant). Examples of specific antidepressant compounds include amitriptyline, clomipramine, citalopram, dosulepin, doxepin, fluoxetine, imipramine, lofepramine, mirtazapine, moclobemide, nortriptyline, paroxetine, phenelzine, reboxetine, sertraline, tranylcypromine, trazodone, or venlafaxine. In some embodiments, additional therapeutic agents may include antipsychotic drugs, such as olanzapine, clozapine, risperidone, quetiapine, aripiprazole or paliperiden.

[0060] In some embodiments, the at least one additional therapeutic agent may be combination of an agent known to be a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. In some embodiments, a sigma-1 receptor agonist and an uncompetitive MDA receptor antagonist may be Dextromethorphan hydrobromide and quinidine sulfate which is marketed as Nuedexta ®. In some embodiments, the daily dose of dextromethorphan hydrobromide is about 20 mg and the dose of quinidine sulfate is about 10 mg. In some embodiments, the daily dose of dextromethorphan hydrobromide is about 40 mg and the dose of quinidine sulfate is about 20 mg.

[0061] In some embodiments, the at least one additional agent may be a combination of an acetylcholinesterase inhibitor and an anti-cholinergic agent. In some embodiments, the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, tacrine, physostigmine, pyridostigmine, neostigmine, icopezil, zanapezil, ipidacrine, phenserine, ambenonium, edrophonium, ladostigil, huperzine A, pyridostigmine, ambenonium, demecarium, a phenanthrene derivative, caffeine, a piperidine tacrine (also known as tetrahydroaminoacridine), edrophonium, ladostigil, ungeremine, lactucopicrin, 6-[(3- cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)oxy]-N-me thyl-3-pyridinecarboxamide hydrochloride or l-{6-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl) oxy]-3- pyridinyl}-2-pyrrolidinone or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof.

[0062] In some embodiments, the anti-cholinergic agent is selected from the group consisting of quaternary ammonium anti-cholinergic muscarinic receptor antagonist, a quaternary ammonium non-selective peripheral Anti-Cholinergic agent, a sulfnonium nonselective peripheral Anti-Cholinergic agent, a non-selective peripheral muscarinic anticholinergic agent, (l S)-(3R)-l-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-l-phenyl-2(lH)-iso- quinolinecarboxylate (solifenacin) or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof, l-methylpiperidin-4-yl) 2,2-di(phenyl)-2-propoxyacetate (propiverine) or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof, 1,4,5,6-tetrahydro- l-methylpyrimidin-2-ylmethyl a-cyclohexyl-a-hydroxy-a-phenylacetate (oxyphencyclimine) or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof, (R)— N,N- dii sopropyl -3 -(2-hydroxy-5 -methylphenyl)-3 -phenylpropanamine (tolterodine) or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the quaternary ammonium anti-cholinergic muscarinic receptor antagonist is selected from trospium and glycopyrrolate or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the non-selective peripheral muscarinic anti-cholinergic agent is solifenacin or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the anti-cholinergic agent is a compound of formula I:

or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof, wherein R is a radical selected from the group consisting of those of formulas (a)-(e)

\

CH,

A being methyl and A' being (Cl-C4)alkyl or 2-fluoroethyl group or A and A' forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk' each being (Cl- C4)alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3- propylene, 1,4-butylene and 2-oxa- 1,3 -propylene; the corresponding counter ion being a pharmaceutically acceptable anion, such as a chloro, bromo, iodo, tartrate, hydrogen tartrate, succinate, maleate, fumarate, sulfate, hydrogen sulfate or methylsulfate anion; n and m, independently, are zero or 1 ;

(C2-C3)alkylene group; Rl and R2 are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (Cl-C4)alkyl;

R3 is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (Cl- C4)alkyl group.

[0063] In some embodiments, R=(a), A=A'=CH3, L=H; n=l; m=0; Rl=R2=n-C3H7; and R3=H. In some embodiments, R=(a), A=CH3, A'=isopropyl, L=H; n=l; m=0; Rl=phenyl; R2=cyclopentyl; and R3=H. In some embodiments, R=(a), A=CH ₃ , A -2-fluoroethyl, L=H; n=l; m=0; R ₁ =R ₂ =phenyl; and R ₃ =QH. In some embodiments, R=(a), A=A'=CH ₃ , L=H; n=l; m ^: =0; R=phenyl; and R ₂ — R ₃ — H. In some embodiments, R~(a), A~CH ₃ , A -isopropyl, L=H; n=l; m=0; R ₁ =R ₂ =n-C ₃ H ₇ ; and R ₃ =H. In some embodiments, R=(a), A=A'=CH ₃ , L=H; n=l; m~0;

L=methoxy; n=l; m=0; R ₁ =R ₂ =phenyl, and R ₃ =OH. In some embodiments, R=(a), A+A -1,4- butylene, L=H; n=l; m=0; R ₁ =R ₂ =phenyl; and R ₃ =OH. In some embodiments, R=(b)-3-, Alk=m ethyl; n=l; m=0; R ₁ =R ₂ =phenyl; and R ₃ =OH. In some embodiments, R=(b)-3-, Aik=methyl; n=l; m=0; In some embodiments, R=(c)-3-, both Alk and Alk -ethyl; n=l ; m=0; R ₁ =R ₂ =phenyl; and R ₃ =OH. In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n=l; m=0; R ₁ =R ₂ =phenyl; and R ₃ =OH. In some embodiments,

R ₂ =cyclopentyl; and R ₃ =H. In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n=l; In some embodiments, R==(c)-3-, both Alk and Alk -methyl In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n=l; m=0; In some embodiments, R=(c)-2-, both Alk and Alk -methyl; n=l ; m=l ; X=l ,2-ethylene; R^phenyl; R ₂ =cyclohexyl; and R ₃ =OH. In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n=l; m=0; R | phenyl: R ₂ =cyclopentyl; and R ₃ ==OH. In some embodiments, R ^: =(c)-3-, bot Alk and Alk -methyl; n=l; m=0; R]=phenyl; R ₂ =cyclopentyl; R ₃ = OH. In some embodiments, R=(d), Aik ^: =methyl, Y==] ,2-ethylene; n=l; m=l; X=l ,2-ethyiene; R ₁ ==R ₂ =phenyl; and R ;==()! I In some embodiments, R=(d), R ₂ =l- cyclohexenyi; and R ₃ =H. In some embodiments, R=(d), Alk=methyl, Y=l,2-ethylene; n=0; R ₂ =2-thienyl; and R ₃ =OH. In some embodiments, R ^: =(e); n=l; m==l; X=l,2-ethylene; Rr=phenyl; R^cyclohexyl; and R ₃ =H. In some embodiments, R=(e); n=l; m=l; X=l,2-ethylene;

R ₂ =cyclohexyl; and R ₃ — OH.

[0064] In some embodiments, the anti -cholinergic agent is selected from the group consisting of anisotropine methylbromide, ciclotropium bromide, flutropium bromide, homatropine methylbromide, sintropium bromide, tematropium metiisulfate, tropenziline bromide, trospium chloride, clidinium bromide, droclidinium bromide, benzilonium bromide, benzopyrronium bromide, cyclopyrronium bromide, glycopyrronium bromide (glycopyrroiate), heteronium bromide, hexopyrronium bromide, oxypyrroniura bromide, ritropirronium bromide, etipirium iodide, fenclexonium methyl sulfate, tricyclamol chloride (procyclidine methochioride), tiemonium iodide, hexasonium iodide, and oxysonium iodide or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof

[0065] In some embodiments, the anti -cholinergic agent is selected from the group consisting of Azoniaspiro[3P-benziloyloxy-(la,5a-nortropane-8, l '-pyrrolidine]chloride (formula II, A+A'=l,4-butylene) described in U.S. Pat. No. 3,480,626, known under its International Nonproprietary Name trospium chloride, the tartrate, maleate, fumarate and succinate salts of trospium, solifenacin, described in U.S. Pat. No. 6,017,927 and the compound thereof with succinic acid, propiverine, described in DD 106643, and the hydrochloride thereof, oxyphencyclimine, described in GB 795758, and the hydrochloride thereof, tolterodine, described in U.S. Pat. No. 5,382,600, and the hydrogen tartrate thereof.

[0066] In some embodiments, the anti-cholinergic agent is selected from the group consisting of a pharmaceutically acceptable salt of trospium, especially trospium chloride, succinate, maleate, fumarate or tartrate, a pharmaceutically acceptable salt of solifenacin, especially its compound with succinic acid 1 : 1, a pharmaceutically acceptable salt of propiverine, especially its hydrochloride, a pharmaceutically acceptable salt of oxyphencyclimine, especially its hydrochloride or a pharmaceutically acceptable salt of tolterodine, especially its L-hydrogen tartrate. In some embodiments, suitable anti-cholinergic agents include, but are not limited to clinidium, cimetidine, ranitidine, digoxin, scopolamine, dantrolene, chlordiazepoxide, atropine, nifedipine, amantadine, propantheline, propantheline, furosemide, amoxapine, paroxetine, disopyramide, hydroxyzine, diphenhydramine, orphenadrine, olanzapine, clozapine, chlorpheniramine, desipramine, doxepin, biperiden, oxybutynin, benzatropine, promethazine, imipramine, nortriptyline, protriptyline, prochlorperazine, cyclobenzaprine, trihexyphenidyl, cyproheptadine, clomipramine, amitriptyline, chlorpromazine, tolterodine, meclizine, dicyclomine, and thioridazine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof.

[0067] In some embodiments, the combination of an acetylcholinesterase inhibitor and an anti-cholinergic agent is donepezil and glycopyrrolate. In some embodiments, the combination of an acetylcholinesterase inhibitor and an anti-cholinergic agent is donepezil and trospium. In some embodiments, the combination of an acetylcholinesterase inhibitor and an anti-cholinergic agent is rivastigmine and glycopyrrolate. In some embodiments, the combination of an acetylcholinesterase inhibitor and an anti-cholinergic agent is rivastigmine and trospium. In some embodiments, the combination of an acetylcholinesterase inhibitor and an anti-cholinergic agent is donepezil and solifenacin.

[0068] The compounds described herein may be formulated as pharmaceutical compositions that may comprise a pharmaceutically acceptable excipient. Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tableting lubricants, and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.

[0069] The compounds described herein can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R., et al.).

[0070] While it is possible that, for use in the prophylaxis and/or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.

[0071] The invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.

[0072] Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation, insulation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan.

[0073] The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

[0074] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.

[0075] Compounds of the present invention or a solvate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as 5 -HT ₂ A receptor modulators. The term "active ingredient" is defined in the context of a "pharmaceutical composition" and shall mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing no pharmaceutical benefit.

[0076] The dose when using the compounds of the present invention can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention. Representative doses of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, about 0.001 mg to about 500 mg, about 0.001 mg to about 250 mg, about 0.001 mg to about 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Representative doses of the present invention include, but are not limited to, about 0.0001 to about 1,000 mg, about 10 to about 160 mg, about 10 mg, about 20 mg, about 40 mg, about 80 mg or about 160 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. In some embodiments, the dose is administered once daily in the morning, twice daily, or once daily about 1 hour prior to the individual's bedtime. In some embodiments, the dose is administered about one to about four times per day, once daily in the morning, once daily about 1 hour prior to the individual's bedtime, or twice daily. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.

[0077] The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human. However, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, whether an acute or chronic disease state is being treated or prophylaxis is conducted, or whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen. One skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.

[0078] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.

[0079] The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.

[0080] For preparing pharmaceutical compositions from the compounds of the present invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0081] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

[0082] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desired shape and size.

[0083] The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0084] For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0085] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0086] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0087] The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0088] Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0089] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.

[0090] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0091] For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.

[0092] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0093] Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0094] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved, for example, by means of a metering atomizing spray pump.

[0095] Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant. If the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well-known to a person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide, CFC's, such as, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

[0096] In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.

[0097] Alternatively, the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler: [0098] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0099] Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.

[0100] The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977); incorporated herein by reference in its entirety.

[0101] The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

[0102] Compounds of the present invention can be converted to "pro-drugs." The term "prodrugs" refers to compounds that have been modified with specific chemical groups known in the art, and when administered into an individual, these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug" approach is utilized to facilitate oral absorption. A thorough discussion is provided in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

[0103] Some embodiments of the present invention include a method of producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.

EXAMPLES

Example 1 : Nelotanserin Improves Motor Function in Patients with Lewy Body Dementia

[0104] Background: Spontaneous parkinsonism and well-formed visual hallucinations are core clinical features of Lewy Body Dementia (LBD), which includes the diagnoses of dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD). In patients with LBD, levodopa is less commonly prescribed for motor symptoms due to its potential to worsen psychosis In addition, visual hallucinations can cause severe distress to the patients and their caregivers, and often require treatment with antipsychotics. However, most antipsychotics worsen motor functions due to dopaminergic antagonism, making the management of these patients complex. Nelotanserin is a selective and potent serotonin 2A (5HT ₂ A) inverse agonist. We hypothesized that modulation of 5HT ₂ A receptor function with nelotanserin may result in improvement in both psychiatric and motor symptoms in LBD patients. Here we present results from an interim analysis of an ongoing Phase 2 study of nelotanserin in subjects with LBD.

[0105] Methods: Subjects with a primary diagnosis of LBD (eitherDLB or PDD) were enrolled in a multisite, double-blind, randomized, placebo-controlled, cross-over Phase 2 study (NCT 02640729). Subjects were randomized to receive either placebo followed by nelotanserin or nelotanserin followed by placebo. Bot treatment periods were 4 weeks, with a 4-week washout between treatments. In the active treatment period, subjects received 40 mg nelotanserin during the first 2 weeks and 80 mg nelotanserin during the subsequent 2 weeks. The primary outcome measures of the study were safety parameters, and extrapyramidal signs as assessed by Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (activities of daily living) and III (motor examination) at baseline and at week 4. The treatment differences for the change from baseline to week 4 in the UPDRS scores within each treatment period were estimated using LME models with treatment, period, disease type, treatment by period interaction, and treatment by disease type interaction as fixed effects and subject-within-sequence as a random effect. Baseline value of UPDRS was included as a covariate. In addition, a 5-item subscale of the UPDRS was assessed, which has been proposed as a reliable and generally applicable instrument for the assessment of parkinsonism in DLB patients (Ballard, 1997), independent of the severity of cognitive impairment. The five items included are tremor at rest, action tremor, body bradykinesia, facial expression, and rigidity. Secondary outcome measures in this study included changes in the severity and frequency of visual hallucinations, including multiple subscales from the Scale for the Assessment of Positive Symptoms (SAPS). A planned interim analysis was performed and included the first 11 patients (8 DLB patients and 3 PDD patients) to complete the study

[0106] Results: The study population had a mean age of 72 years. All subjects were Caucasian, and had a recent diagnosis of LBD (mean time since diagnosis of 1.7 years). Nine subjects reported spontaneous parkinsonism as a core feature of their LBD. None of the 8 DLB subjects received antiparkinson medications and all 3 PDD subjects were maintained on a stable levodopa regimen during the study. Baseline UPDRS Part II and III scores were 17.2 and 34.3, respectively. Nelotanserin was associated with an 8.7 point improvement in the mean change from baseline in UPDRS II+III relative to placebo at week 4 (p = 0.012, see FIG. 1). For UPDRS Part III alone, nelotanserin was associated with a 7.9 point improvement in the mean change from baseline relative to placebo at week 4 (p = 0.005, see FIG. 1). On the 5-item subscale of the UPDRS, nelotanserin was associated with a 5.8 point improvement on the mean change from baseline relative to placebo at week 4 (p = 0.003).

[0107] Conclusion: LBD is a serious medical condition associated with significant debilitating motor symptoms and visual hallucinations. In an interim analysis of an ongoing Phase 2 study, nelotanserin was associated with a statistically significant improvement in motor function in subjects with LBD. This Phase 2 placebo-controlled study represents an initial effort to develop a treatment for LBD.

Example 2: Nelotanserin Improves Resting Tremor in Prelininary Study

[0108] Background: A randomized, open-label, single-dose, 16-patient study was conducted to evaluate the effect of single-dose nelotanserin on finger tap rhythm, finger tap speed, finger tap amplitude, resting tremor, and postural tremor in subjects with DLB, PDD, or PD using dose and exposure response-relationships.

[0109] Methods: Patients were given either a 20 mg or a 80 mg single dose of nelotanserin and then evaluated multiple times in the subsequent 24 hours (4 times in the first 2 hours, then once per hour until hour 10, then once at hour 12 and once at hour 24). Symptom assessment was based on specific clinically validated tasks performed by the patients, and follows the UPDRS scoring system.

[0110] Results: Interim data from 9 of the 16 subjects shows a greater reduction in resting tremor in the 80 mg dose of nelotanserin compared to the 20 mg dose. The full data set is required for additional interpretation.

[0111] Example 3 - Pilot Phase 2 Visual Hallucination study

[0112] Nelotanserin met its prespecified primary endpoint of safety in the pilot Phase 2 Visual Hallucination study. In addition, in this exploratory study, nelotanserin treatment resulted in a positive trend in efficacy in a prespecified intent to treat (ITT) analysis of the motor function scale, the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Nelotanserin treatment also resulted in an efficacy signal in a post-hoc subset analysis of patients with higher baseline scores on the Scale for the Assessment of Positive Symptoms - Parkinson's Disease (SAPS-PD). In the pilot study of nelotanserin in patients with DLB and Parkinson's disease dementia (PDD) who were experiencing visual hallucinations, the primary endpoint was safety, including an assessment of symptoms as measured by the UPDRS. On this primary endpoint, nelotanserin was generally well tolerated. A number of exploratory efficacy assessments were conducted, including the UPDRS Part III; the Scale for the Assessment of Positive Symptoms (SAPS); SAPS-PD; the Patient Global Impression of Change of Visual Hallucinations (PGIC-VH); and an internally developed patient diary. In a prespecified ITT analysis, nelotanserin treatment versus placebo (n=27) resulted in a 3.12 point improvement in the UPDRS Part III with a positive trend (p=0.075, unadjusted). Notably, in a prespecified analysis of the DLB patient subset (n=19), nelotanserin improved the UPDRS Part III by 4.00 points (p=0.041, unadjusted).

[0113] Although nelotanserin did not significantly improve the SAPS-PD (n=27) in the entire efficacy evaluable population (0.88 point improvement, p=0.519, unadjusted), in a post- hoc subset analysis of patients with a baseline SAPS-PD score greater than 8.0 (n=19), indicating greater severity, nelotanserin treatment at 40 mg for two weeks followed by 80 mg for two weeks resulted in a 1.21 point improvement (p=0.011, unadjusted). No other trends of improvement were seen on the full SAPS, PGIC-VH, or in the patient diary.

[0114] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0115] Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non- claimed element essential to the practice of the invention.

[0116] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0117] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the individual matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0118] Specific embodiments disclosed herein may be further limited in the claims using "consisting of or "consisting essentially of language, rather than "comprising". When used in the claims, whether as filed or added per amendment, the transition term "consisting of excludes any element, step, or ingredient not specified in the claims. The transition term "consisting essentially of limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

[0119] In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.