WO2018102824A1

WO2018102824A1 - Methods for treating neurodegenerative disease

Info

Publication number: WO2018102824A1
Application number: PCT/US2017/064549
Authority: WO
Inventors: Ebenezer ASARE; Lawrence Tim Friedhoff; Ilise LOMBARDO; Shankar Ramaswamy
Original assignee: Axovant Sciences Gmbh
Priority date: 2016-12-02
Filing date: 2017-12-04
Publication date: 2018-06-07

Abstract

Methods for treating neurodegenerative diseases with a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof in, optionally in combination with one or more additional therapeutic agents. Also disclosed are methods of improving gait and balance using a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

Description

METHODS FOR TREATING NEURODEGENERATIVE DISEASE

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62/429,547, filed December 2, 2016, titled "Compositions And Methods Of Treating A Neurodegenerative Disease," U.S. Provisional Application No. 62/476,828, filed March 26, 2017, titled "Compositions And Methods Of Treating A Neurodegenerative Disease," U.S. Application No. 62/508,857, filed May 19, 2017, titled "Methods For Treating Neurodegenerative Disease," and U.S. Provisional Application No. 62/548,702, filed August 22, 2017, titled "Methods For Treating Neurodegenerative Disease," all of which are incorporated herein by reference in their entireties.

FIELD

[0002] The disclosure generally refers to the use of a 5-HT6 receptor antagonist, either alone or in combination with additional therapeutic agents, to treat a neurodegenerative disease in a subject in need thereof.

BACKGROUND

[0003] The efficacy of the very few approved treatments for Alzheimer's disease (AD), theoretically categorized as "symptomatic" compounds, including cholinesterase inhibitors that increase concentrations of acetylcholine by preventing its breakdown, is well established, though modest and limited over time (Di Santo et al. 2013; Tan et al. 2014). While tremendous effort has been expended in recent years on the development of novel drugs to specifically address the pathophysiology and symptoms of AD, there have been no new chemical entities approved for its treatment since 2003 (Cummings et al. 2016).

[0004] One novel drug class in development for the treatment of AD is the 5- hydroxytryptamine 6 (5-HT6) receptor antagonist class (for overview see (Ferrero et al. 2016; Wicke, Haupt, and Bespalov 2015)). The 5-HT6 receptor is expressed almost exclusively within the central nervous system and is localized in regions of the brain involved in cognitive function (Gerard et al. 1997; Helboe, Egebjerg, and de Jong 2015). In clinical studies, 5-HT6 receptor antagonists have demonstrated efficacy in improving cognition and function in patients with AD when combined with stable background cholinesterase therapy (Maher-Edwards et al. 2011; Wilkinson, Windfeld, and Colding-Jorgensen 2014; Maher- Edwards et al. 2015). Thus, there is a need for novel methods for treating neurodegenerative diseases, such as AD, with 5-HT6 receptor antagonists.

SUMMARY

[0005] Embodiments herein provide methods of modifying a neurodegenerative in a subject in need thereof, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof, either alone or in combination with one or more additional therapeutic agents.

[0006] Embodiments herein provide methods of improving the clinical signs and symptoms of a neurodegenerative in a subject in need thereof, comprising administering a 5- HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof, either alone or in combination with one or more additional therapeutic agents.

[0007] Embodiments herein provide methods of slowing the progression of a neurodegenerative in a subject in need thereof, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof, either alone or in combination with one or more additional therapeutic agents.

[0008] Embodiments herein provide methods of delaying the reaching of predefined milestones of a neurodegenerative in a subject in need thereof, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof, either alone or in combination with one or more additional therapeutic agents.

[0009] In some embodiments, the methods further comprise administering to the subject an ADAS-cog scale exam. In some embodiments, the subject has a greater ADAS- cog scale score compared to a control subject, group, or benchmark. In some embodiments, the subject has a greater ADAS-cog scale score compared to a baseline score. In some embodiments, the subject has an increase in their ADAS-cog scale score of at least 1 point over 24 weeks. In some embodiments, the subject is evaluated after 12, 24, 36, or 48 weeks, or some combination thereof, of treat treatment with the 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0010] In some embodiments, the methods further comprise administering to the subject an ADCS-ADL scale exam. In some embodiments, the subject has a greater total ADCS-ADL scale score, ADCS-ADL Factor 1 score, ADCS-ADL Factor 2 score, ADCS- ADL Factor 3 score, ADCS-ADL Factor 4 score, or any combination thereof, compared to a control subject, group, or benchmark. In some embodiments, the subject has a greater total ADCS-ADL scale score, ADCS-ADL Factor 1 score, ADCS-ADL Factor 2 score, ADCS- ADL Factor 3 score, ADCS-ADL Factor 4 score, or any combination thereof, compared to a baseline score. In some embodiments, the subject has an increase in their total ADCS-ADL scale score, ADCS-ADL Factor 1 score, ADCS-ADL Factor 2 score, ADCS-ADL Factor 3 score, ADCS-ADL Factor 4 score, or any combination thereof, of at least 1 point over 24 weeks. In some embodiments, the subject is evaluated after 12, 24, 36, or 48 weeks, or some combination thereof, of treat treatment with the 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0011] In some embodiments, the methods further comprise administering to the subject an PI exam. In some embodiments, the subject has a greater total NPI score, a greater score on one or more areas, clusters, or subgroups of the NPI exam, or any combination thereof, compared to a control subject, group, or benchmark. In some embodiments, the subject has a greater total NPI score, a greater score on one or more areas, clusters, or subgroups of the NPI exam, or any combination thereof, compared to a baseline score. In some embodiments, the subject has an increase in their total NPI score, their score in one or more areas, clusters, or subgroups of the NPI exam, or any combination thereof, of at least 1 point over 24 weeks. In some embodiments, the subject is evaluated after 12, 24, 36, or 48 weeks, or some combination thereof, of treat treatment with the 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0012] In some embodiments, the methods further comprise recording the number of falls experienced by a subject. In some embodiments, the subject has a reduced number of falls compared to a control subject, group, or benchmark. In some embodiments, the subject has a greater time to a first fall compared to a control subject, group or benchmark. In some embodiments, the subject is evaluated after 12, 24, 36, or 48 weeks, or some combination thereof, of treat treatment with the 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0013] Embodiments herein provide methods of improving the performance of household activities in a subject with a neurodegenerative disease, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents. In some embodiments, the methods improve the performance of one or more of the activities selected from the group consisting of picking out clothes, telephone use, doing dishes, maintaining personal belongings, drinking, cooking snacks, cleaning litter, and appliance usage. [0014] Embodiments herein provide methods of improving the performance of basic activities of daily living in a subject with a neurodegenerative disease, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents. In some embodiments, the methods improve the performance of one or more of the activities selected from the group consisting of eating, walking, toileting, bathing, grooming, and physically getting dressed.

[0015] Embodiments herein provide methods of improving the performance of communication and engagement activities in a subject with a neurodegenerative disease, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents. In some embodiments, the methods improve the performance of one or more of the activities selected from the group consisting of television, conversation, appointments, current events, reading, writing, and hobbies.

[0016] Embodiments herein provide methods of improving the performance of outside activities in a subject with a neurodegenerative disease, comprising administering a 5- HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents. In some embodiments, the methods improve the performance of one or more of the activities selected from the group consisting of travel, shopping, paying, and being left on his/her own.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 depicts a diagram describing the setup of a 48-week double-blind study, 684 subject with mild to moderate AD (MMSE score 10-26) and on stable background donepezil treatment were randomized to receive 35 mg intepirdine, 15 mg intepirdine, or placebo.

[0018] FIG. 2 depicts a graph of overall ADCS-ADL score results from the study described in FIG. 1.

[0019] FIG. 3 depicts a graph of overall ADCS-cog score results from the study described in FIG. 1.

[0020] FIG. 4 depicts a graph of overall CDR-SB score results from the study described in FIG. 1. [0021] FIG. 5 depicts Projected Baseline Dependence Level by MMSE and Treatment Group (donepezil alone).

[0022] FIG. 5 depicts Projected Baseline Dependence Level by MMSE and Treatment Group (35 mg intepirdine and donepezil).

[0023] FIG 7 depicts Projected Dependence Level by treatment group (donepezil alone).

[0024] FIG 8 depicts Projected Dependence Level by treatment group (35 mg intepirdine and donepezil).

[0025] FIG. 9 depicts projected dependence level progression by treatment group. Progressors are defined as those subjects who demonstrated an increase of one or more dependence levels

[0026] FIG. 10 depicts the change in estimated annual cost from baseline by treatment group.

DETAILED DESCRIPTION

[0027] Before the present compositions and methods are described, it is to be understood that this disclosure 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 embodiments 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 the limit the scope of the present disclosure 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 the ordinary skill in the art. All publications and references mentioned herein are incorporated by reference.

[0028] As used herein, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a composition" includes a plurality of such compositions, as well as a single composition, and a reference to "a therapeutic agent" is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. [0029] 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%.

[0030] As used herein, the term "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 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.

[0031] As used herein, the terms "disease modification" or "modification of a disease" mean a treatment or intervention that affects the underlying pathophysiology of the disease or pathophysiological disease processes and has a beneficial outcome on the course of the disease. In some embodiments, the disease modification is accompanied by improvement in the clinical signs and symptoms of the disease. In some embodiments, disease modification includes the slowing of disease progression. In some embodiments, disease modification includes a delay in reaching predefined disease milestones. In some embodiments, disease modification may be determined by an effect or effects on one or more disease biomarkers.

[0032] As used herein, the term "improves" is used to convey that the present disclosure changes either 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.

[0033] In some embodiments, the compositions and methods may be utilized with or on a subject 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 subject has been identified as having a need for the particular method or treatment and that the treatment has been given to the subject for that particular purpose.

[0034] As used herein, the term "patient" and "subject" are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present disclosure. As such, the terms "patient" and "subject" may include, but is not limited to, any non-human mammal, primate or human. In some embodiments, the "patient" or "subject" is an adult, child, infant, or fetus. In some embodiments, the "patient" or "subj ect" is a human. In some embodiments, the "patient" or "subject" is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.

[0035] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0036] As used herein, the term "pharmaceutical formulation" it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound described herein). It is understood by those of ordinary skill in this art that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and they are so used for the purposes of this application.

[0037] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. The present disclosure includes pharmaceutically acceptable salts of any compound(s) described herein.

[0038] Pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

[0039] Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals {e.g., solubility, bioavailability, manufacturing, etc.) the compounds described herein can be delivered in prodrug form and can be administered in this form for the treatment of disease. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds described herein wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds described herein.

[0040] In some embodiments, the combination of compounds is a synergistic combination. The term "synergy", as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or some other beneficial effect of the combination compared with the individual components.

[0041] The terms "therapeutically effective amount" or "therapeutic dose" is used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinical professional. A clinical, biological or medical response may include, for example, one or more of the following: (1) 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 pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and/or symptoms of the disease, condition or disorder, and (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and/or symptoms experienced or exhibited by the individual.

[0042] As used herein, "treating" or "treatment" includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. "Treating" or "treatment" of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

[0043] To date the complex etiology, pathogenesis and biological heterogeneity of late-onset polygenic Alzheimer's disease (AD) has presented fundamental challenges to the successful development of novel and effective drugs. Despite numerous promising animal studies and several ongoing clinical trials, anti-cholinesterase therapy remains the mainstay for treatment of Alzheimer's disease. Although patients may experience either a temporary improvement in function or at least a reduction in the progression of symptoms, neurodegeneration is not stopped and patients' cognitive functions continue to deteriorate[l]. This has led to these treatments being regarded as symptomatic only and calls for disease- modifying treatments. However, there is a substantial amount of evidence that increasing cholinergic tone in the brain may be disease-modifying, despite the fact that it does not halt the progression of the disease. Medications with CNS cholinergic-blocking activity, for example have been implicated in the etiology of the disease. Anticholinergic use was found to increase risk for dementia by approximately 50% across various types [2] and risk for Mild Cognitive Impairment (MCI) 5-fold [3]. If cholinergic deficits are in fact located at the beginning of the chain of events that lead to β-Amyloid and Tau production and aggregation and the subsequent physical and cognitive effects, then logically cholinesterase therapy would be disease-modifying. From both animal and human research, it is now thought that enhancement of cholinergic activity in the CNS may, through either direct or indirect mechanisms, mitigate the core pathologies of Alzheimer's disease such as β-Amyloid production and deposition, Tau phosphorylation and neurofibrillary tangles (NFTs), CNS inflammation, apoptosis, gene expression and splicing, and brain volume loss.

[0044] β-Amyloid and cholinergic receptors form a feedback loop that lead to increased pathology. Cholinergic neurons in brainstem nuclei such as the nucleus basalis and pedunculopontine nucleus provide cholinergic input to cortical, sub-cortical, brainstem and cerebellar regions [4]. The cholinergic neurons in these areas tend to have the highest β- Amyloid burden in the brain and are among the first to experience pathology and neurodegeneration after the medial temporal lobe [5]. β-Amyloid can induce hyperactivation of acetylcholinesterase, leading to a reduction of acetylcholine at the synapse [5]. In addition, β-Amyloid has been shown to bind to nicotinic receptors at the ligand site, resulting in antagonism and internalization [3, 6-8]. This limits the responsivity of neurons to the already reduced acetylcholine levels [3, 6, 8]. In advanced Alzheimer's disease, β-Amyloid forms a functional blockade of cholinergic receptors, resulting in little or no cholinergic neurotransmission in these patients [6]. Indeed, it is theorized that one of the native functions of β-Amyloid is to regulate acetylcholine levels and is therefore released as necessary to block their function [5]. It would only be during excessive β-Amyloid production and accumulation that this inhibitory function would become pathological. However, there appears to be a feedback mechanism in place to prevent such pathological inhibition. Activation of muscarinic acetylcholine receptors (mAchRs) leads to release of amyloid precursor protein (APP) fragments through its downstream activation of the protein kinase C (PKC) pathway [9]. Intracellular depletion of the precursor of β-Amyloid then reduces β- Amyloid production itself [9, 10]. In addition, Ml muscarinic receptor binding can cause increased a-secretase activity, which is the enzyme responsible for non-amyloid processing of APP to sAPPa [10]. The subsequent increase in sAPPa was observed after Ml activation, which would then presumably be further cleaved by γ-secretase to the non-pathogenic p3 protein instead of β-Amyloid [10]. Acetylcholine can also preserve the soluble form of β- Amyloid, which is cytoprotective, presumably through direct binding [11]. It appears then that when β-Amyloid production reaches a certain point, the feedback mechanism whereby its production is curtailed, is subsequently overloaded. This results in reductions in AchRs, further β-Amyloid production and then finally complete blockade of the cholinergic system. By increasing acetylcholine levels at the synapse, it can compete for β-Amyloid binding at the remaining receptors, slowing both the internalization of these receptors and the buildup and aggregation of β-Amyloid itself. Through these mechanisms, it can be seen that modifying cholinergic activity in the brain may directly affect β-Amyloid, one of the core pathologies of Alzheimer's disease.

[0045] Activation of cholinergic receptors reduce Tau pathology. As with β- Amyloid, there are also feedback loops between Tau pathology, acetylcholine and β-Amyloid itself. Tau aggregates within cells when it is hyperphosphorylated, the responsible enzyme in this case being GSK3 [12]. GSK3 has two subtypes, a and β, both of which phosphorylate Tau [12]. Cytoplasmic β-Amyloid inhibits PI3 -kinase, which results in activation of GSK3P [12]. Activated GSK3P then feeds back into the β-Amyloid pathway by both increasing amyloidogenic processing of APP and reducing acetylcholine synthesis, which then further enhances β-Amyloid production [12]. At the same time, the ERK/MAPK pathway downstream of the a7-nicotinic AchR (a7nAchR) can lead to degradation of phospho-Tau [13]. MAPK2 activates the co-chaperone BAG2 by phosphorylation and activated BAG2 is then able to bind phospho-Tau and deliver it to the proteasome for ubiquitin-independent degradation [13]. Although cholinergic signaling is impaired by increasing Tau pathology over the course of Alzheimer's disease progression, activation of BAG2 through a7nAchR signaling can lead to proteolytic degradation and reduced build-up of Tau. Hence, increasing availability of acetylcholine may possibly reduce both types of protein aggregation that underlie Alzheimer's disease.

[0046] Anti-cholinesterase treatment can directly impact β-Amyloid plaques. Cholinesterase and butyrylcholinesterase have both been found to be integral components of β-Amyloid plaques [5]. β-Amyloid associates with and sequester acetylcholinesterase, butyrylcholinesterase and apolipoprotein E, another protein which is upregulated in familial Alzheimer's [5]. Donepezil has been found to compete with β-Amyloid for acetylcholinesterase, reducing its nucleation of β-Amyloid plaques and slowing their growth [5]. Both through increased cholinergic signaling at the synapse and through extrasynaptic effects, anti-cholinesterase treatment has the potential to reduce β-Amyloid build-up.

[0047] Downstream signaling from cholinergic receptors dampens inflammatory responses in the CNS. Neuroinflammation has long been regarded as one of the key mediators of synaptic deficits and neurodegeneration in Alzheimer's. Innate immunity is regulated by acetylcholine systemically to optimize resolution of inflammation [14, 15]. Acetylcholinesterase inhibition reduces inflammation in both the periphery and in the CNS through actions mediated by muscarinic AchRs, a7nAchRs, macrophages and glial cells [6, 14, 16]. During neuroinflammation, activated glial cells release nitric oxide (NO) and prostanoids such as the prostaglandin PGE2, which induce inflammation and blood vessel dilation and reduce neurotransmission and cell survival [16]. Donepezil has been shown to reduce COX2, which is responsible for PGE2 synthesis, nitric oxide synthetase, as well as proinflammatory cytokines IL-Ιβ and TNF-a from macrophages, leading to consequent reductions in inflammation and oxidative stress [16]. These effects may also be mediated by a7nAchRs on macrophages which when activated, reduce proinflammatory mediators in these cells [14]. a7nAchRs can also prevent pro-inflammatory cytokine release through toll-like receptor expression on neurons [6]. Finally, acetylcholine can protect against reactive astrogliosis and blunts activation of PLA2, which cleaves arachidonic acid to generate various inflammatory mediators [11]. Through its effects on neurons, astrocytes and macrophages, acetylcholine can be regarded as a "master switch" for resolution of neuroinflammation, thereby ameliorating the immune effects of β-Amyloid and Tau buildup in the CNS.

[0048] Enhanced cholinergic activity prevents apoptosis. β-Amyloid causes apoptosis of cells through reduced neurotransmission, inflammation (discussed above), caspase 3 production and free radicals produced by mitochondrial dysfunction [6]. Most of the anti-apoptotic effects of increased cholinergic neurotransmission are mediated through the a7nAchR [6, 8, 17, 18]. β-Amyloid binding to a7nAchR forms a complex that is endocytosed and degraded by the proteasome, leading to reduced β-Amyloid levels and reduced cell death [17]. The a7nAchR mediates calcium signaling pathways which results in enhanced scavenging of superoxide, hydroxyl and other free radical species which are toxic to cells at the high levels that result from Alzheimer' s-related inflammation [6, 8]. a7nAchRs can also act through other pathways that inhibit caspase 3-mediated apoptosis [6]. Acetylcholine binding to a7nAchR leads to binding of Fyn, JAK2 activation and then of PI3-kinase, Akt, MEK/ERK, and Bel -2 pathways which all promote cell survival [6, 8, 18]. Nicotine has also been shown to inhibit ER stress response, which is cytoprotective [6]. Astrocytes express a7nAchRs as well, and activation leads to an increase in cytoplasmic calcium levels that engage various neuroprotective mediators [6]. Thus, even further on in the progression of Alzheimer's disease when neuroinflammation become cytotoxic, increasing cholinergic signaling can protect cells from the resulting apoptotic responses.

[0049] Cholinergic activity modifies gene expression and splicing to reduce β- Amyloid production. Cholinergic deficiency causes global changes in gene expression and alternative splicing, generally reducing gene expression, particularly in pathways involved in oxidative stress [8, 19, 20]. Θ8Κ3β as well as various inflammation pathways activate NF- KB, which binds to cis-acting elements on the BACE1 promoter, upregulating gene expression [8]. BACE is the first enzyme to cleave APP in the amyloidogenic pathway and therefore directly leads to β-Amyloid production [21]. Cholinergic deficiency vastly increased BACE1 expression and soluble β-Amyloid as it is required to reduce NF-κΒ and Θ8Κ3β activation [19]. Additionally, Ml muscarinic signaling has been shown to reduce the stability of the BACE1 protein [19] through the heterogeneous nuclear ribonucleoprotein (hnRNP) A2B1 [22]. hnRNPs bind pre-mRNA to regulate splicing and transport [22, 23]. The Ml AchR-induced increase in hnRNP A2B1 as well as its mTOR-dependent activation of RUST (regulation by unproductive splicing and translation) prevents Alzheimer's disease- induced reductions in transcription and changes in alternative splicing [22]. Specifically, as hnRNP A2B1 shifts BACE mRNA production away from the 501 isoform, which is more stable and active, its increase will result in further reductions in BACE1 activity and β- Amyloid production [19] (Figure 3, panel B shows Ach KO). hnRNP A2B1 also induces alternative splicing of APP, reducing its activity and β-Amyloid processing [24]. Correspondingly, hnRNP A2B1 downregulation correlates with synapse and dendrite loss and learning and memory impairments [23, 24]. Through multiple mechanisms, Ml muscarinic neurotransmission interacts with BACE and hnRNP to prevent β-Amyloid production in Alzheimer's disease models.

[0050] Increasing cholinergic tone in the CNS ameliorates brain volume loss. There have been several studies in Alzheimer's disease patients which measured volume loss in various brain regions with anti-cholinesterase treatment [1, 3, 25, 26]. Cholinergic centers in the hippocampus are among the first to experience neurodegeneration in prodromal and early Alzheimer's as well as MCI [26]. Given the role of the hippocampus in the learning and memory deficits associated with Alzheimer's disease, ameliorating these volume losses would be an important way of showing that a treatment can modulate the underlying pathology. Longitudinal imaging of hippocampal volume during donepezil treatment in patients with prodromal Alzheimer's disease found a 45% reduction in the rate of hippocampal atrophy over the course of one year of treatment [25]. This shows that in human patients, increasing cholinergic tone in the brain can prevent neuronal and/or synaptic loss, likely through some of the aforementioned mechanisms.

[0051] Intepirdine can act on inhibitory neurons to further enhance cholinergic activity and thereby benefits of anti-cholinesterase treatment. One novel drug class in development for the treatment of AD is the 5-hydroxytryptamine 6 (5-HT6) receptor antagonist class, one example of which is 3-phenylsulfonyl-8-piperazin-l-yl- quinoline, also known as intepirdine. Intepirdine, through its antagonism of 5-HT6 receptors, can have effects on multiple brain regions. 5-HT6 receptor expression is limited to the CNS and is expressed most highly in the olfactory tubercle [27]. Areas with the next highest levels of expression are the frontal and entorhinal cortices and dorsal hippocampus. These are of the highest importance as relates to the putative MOA of Intepirdine as the hippocampus is particularly involved in AD pathology as well as learning and memory and both the frontal and entorhinal cortices are two of the main sources of cholinergic input to this region. In terms of localization among cell types, although 5-HT6 antagonists increase acetylcholine release, the similar 5-HT6 receptor levels in cholinergically-lesioned animals indicates that these receptors are not located on cholinergic neurons themselves [28]. In situ hybridization for 5-HT6 mRNA with cross-labeling for various classes of neurons confirmed that the majority of 5-HT6 mRNA was expressed by GABAergic neurons as well was various GABAergic subtypes across cortical and subcortical regions [29]. The presence of 5-HT6 receptors on inhibitory interneurons in the cortex and hippocampus as well as the basal ganglia indicate that antagonism of these receptors could be efficacious in enhancing neurotransmission in disorders of learning and memory (Alzheimer's) and Parkinson's disease, respectively. In particular, their presence on GABAergic spiny neurons has the potential to ameliorate Parkinsonian motor symptoms as these neurons play a large role in direct and indirect regulation of nigrostriatal dopaminergic circuitry. The next most common co-labeling was with vGluTl indicating that although rare, some excitatory neurons also express 5-HT6 receptors. Cholinergic neurons showed no labeling above background levels, as expected. There was also considerable expression in dopaminergic Dl and D2 receptor- expressing cells in the caudate/putamen and nucleus accumbens. Through its interactions with many of the pathways already discussed, 5-HT6 antagonism could have various disease- modifying and pro-cognitive effects through relieved inhibition on cholinergic a and glutamatergic neurons [30]. Glutamatergic activation can engage the MAPK pathway that targets phospho-Tau for degradation via the co-chaperone BAG2 as well as ERK which promotes cell survival [6, 13, 18, 30] (Figure 4). In addition, glutamate neurotransmission is inherently pro-cognitive as it increases LTP, synaptic plasticity, learning and memory [30].

[0052] In summary, 5-HT6 receptors are expressed widely across a variety of cortical and sub-cortical structures. Their presence mainly on GABAergic interneurons in these regions indicate that antagonism of these receptors can increase excitatory neurotransmission and in the case of the basal ganglia, potentially ameliorate Parkinsonian motor disruption. In the former case, disinhibition of cholinergic neurons in the frontal and entorhinal cortices could enhance cholinergic tone in the hippocampus. 5-HT6 receptors have been located in the brainstem, but have not been analyzed specifically in relation to the major cholinergic nuclei in this region. Nonetheless, given their distribution in other areas of the brain, it seems likely that they are expressed by GABAergic interneurons in or near these nuclei whereby their antagonism would relieve inhibition on cholinergic cells. By increasing glutamatergic neurotransmission, 5-HT6 antagonism may also activate pathways involved in phospho-Tau degradation, cell survival, LTP, synaptic plasticity, learning and memory. We can conclude that intepirdine-mediated inhibition of 5HT-6 receptors can likely increase overall cholinergic activity in areas such as the hippocampus, which are directly and most drastically affected by Alzheimer's disease pathology as well as potentially reduce phospho- Tau and apoptosis and enhance learning and memory.

[0053] Intepirdine has been investigated in multiple placebo-controlled studies in patients with mild to moderate AD. In a prior 48-week placebo-controlled study, 684 patients with mild or moderate AD were randomized to receive 35 mg intepirdine, 15 mg intepirdine or placebo on top of stable background donepezil therapy. Statistically significant benefits in cognition, as measured by the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-cog) scale, were observed with 35 mg intepirdine treatment at early and late time points in the study, including at weeks 12 (p=0.006), 24 (p=0.013), and 48 (p=0.024), with the largest magnitude of cognitive benefit observed at week 48. In addition, statistically significant benefits in function, as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale, were observed at multiple time points, including at weeks 12 (p=0.019), 24 (p=0.024), and 36 (p=0.038).

[0054] The ADAS-cog scale consists of 11 tasks that measure a patients abilities in memory, language, praxis, attention and other core cognitive abilities which often suffer in neurological disease. Lower scores on the scale indicate greater severity and progression of the disease. In some embodiments, cognitive decline is defined as a ADAS-cog score below a baseline score. In some embodiments, cognitive decline is defined as a decrease in the ADAS-cog score of at least one 1 point over 24 weeks. In some embodiments, cognitive improvement is defined as a ADAS-cog score above a baseline score. In some embodiments, cognitive improvement is defined as an increase in the ADAS-cog score of at least 1 point over 24 weeks.

[0055] The ADCS-ADL scale is a 23 item scale that asks caregivers to rate the degree to which an Alzheimer's patient can perform a variety of tasks. Lower scores on the scale indicate greater severity and progression of the disease. The 23 items on the ADCS- ADL scale have been clustered into four related Factors by Kahle-Wrobleski et al (Current Alzheimer Research, 2014) as shown in Table 1. In some embodiments, functional decline is defined as an ADCS-ADL score below a baseline score. In some embodiments functional decline is defined as a decrease in the ADCS-ADL score of at least 1 point over 24 weeks. In some embodiments, functional benefit is defined as an ADCS-ADL score above a baseline score. In some embodiments, functional benefit is defined as an increase in the ADCS-ADL score of at least 1 point over 24 weeks.

Table 1

Factor 1 Factor 2 Factor 3 Factor 4 Household Activities Basic Activities of Communication and Outside Activities

Daily Living Engagement

• Dressing - • Eating • Television • Travel

picking out • Walking • Conversation • Shopping clothes • Toileting • Appointments • Paying

• Telephone • Bathing • Current events • Being left on

• Dishes • Grooming • Reading his/her own

• Personal • Dressing - • Writing

belongings physically getting • Hobbies

• Drink dressed

• Cooking snack

• Litter

• Appliances

[0056] Other exams besides the ADAS-cog and ADCS-ADL scales are also designed to assess various aspects of a patient's functions and abilities. One such exam is the Neuropsychiatric Inventory (NPI), which is a 12 item scale that asks caregivers to assess behavioral disturbances in patients with dementia. NPI captures both the frequency and severity of the behaviors. The NPI includes 10 behavioral and 2 neurovegetative areas: delusions, hallucinations, agitation, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep, appetite/eating disorders. In some embodiments, the areas of depression/dysphoria, anxiety and apathy/indifference are considered a related cluster or subgroup.

[0057] In some embodiments, the level of dependence of each factor is defined in Table 2 wherein ADCS-ADL scores are translated to six Dependence Levels (DL) (levels 0- 5). A higher DL indicates greater dependence.

Table 2

3 Supervision on all types of IADLs or home- Extensive home care services bound with supervision OR Assisted living

4 Supervision on some BADLs Assisted living + nursing support

5 Impaired transfer of complete incontinence Nursing home

[0058] Exams such as the ADAS-cog, ADCS-ADL, and NPI can also be used in time benefit analyses, such as survival analysis and extrapolation of slopes, when multiple patient pools are compared. For example, in the intepirdine study described above, the ADAS-cog scores of the 35 mg intepirdine, 15 mg intepirdine, and placebo groups were tracked at multiple points in the study. The rate at which patients hit predefined milestones, such as, but not limited to, the first decrease in the ADAS-cog score compared to patient's baseline score, or any decrease in the ADAS-cog score, can be tracked. Such analysis is known as survival analysis. Additionally, data can be interpreted graphically, and the slopes between various time points of each group can be calculated. This extrapolation of slopes analysis can estimate the differences in the time it takes the study groups to reach predefined milestones.

[0059] Time benefit analyses can also be used in fall analysis. Falls are a major problem in patients with neurodegerative diseases such as dementia, and the risk of falling increases as the disease progresses. The number of falls experienced by a patient or a group of patients can be tracked. Comparisons can be made, for example, between the percentage of patients in a group that experienced falls. Time benefit analyses can be used to estimate the difference in the time it takes the different groups to reach predefined milestones, for example, time to experience a first fall.

[0060] Disclosed herein are methods of modifying a neurodegenerative disease in a subject in need thereof, comprising administering any of the compositions described herein. In some embodiments, the methods improve the clinical signs and symptoms of the neurodegenerative disease. In some embodiments, the methods slow the progression of the neurodegenerative disease. In some embodiments, the methods delay the reaching of predefined milestones of the neurodegenerative disease. In some embodiments, the methods comprise administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, the methods comprise administering intepirdine or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents. [0061] In some embodiments, the neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis, Alzheimer's Disease, Parkinson's Disease Dementia Huntington's Disease, Lewy Body Disease, Dementia with Lewy Bodies, Mild Cognitive Impairment, Frontotemporal Dementia, an a-Synucleinopathy, a pathology associated with intracellular accumulation of TDP-43 and a Tauopathy. In yet other embodiments, neurodegenerative diseases include, but are not limited to Alzheimer's disease (including mild or early-stage Alzheimer's disease, mild to moderate Alzheimer's disease, moderate or mid-stage Alzheimer's disease, moderate to severe Alzheimer's disease, moderately severe Alzheimer's disease, severe Alzheimer's disease, Alzheimer's disease with Lewy bodies, (AD)), Parkinson's disease (including Parkinson's disease chemically induced by exposure to environmental agents such as pesticides, insecticides, or herbicides and/or metals such as manganese, aluminum, cadmium, copper, or zinc, SNCA gene-linked Parkinson's disease, sporadic or idiopathic Parkinson's disease, or Parkin- or LRRK2 -linked Parkinson's disease (PD)), Parkinson's disease syndrome (including vascular parkinsonism), autosomal -dominant Parkinson's disease, Diffuse Lewy Body Disease (DLBD) also known as Dementia with Lewy Bodies (DLB), Pure Autonomic Failure, Lewy body dysphagia, Incidental LBD, Inherited LBD (e.g., mutations of the alpha-synuclein gene, PARK3 and PARK4), multiple system atrophy (including Olivopontocerebellar Atrophy, Striatonigral Degeneration, Shy-Drager Syndrome (MSA)), combined Alzheimer's and Parkinson disease and/or MSA, Huntington's disease, synucleinopathies, disorders or conditions characterized by the presence of Lewy bodies, multiple sclerosis, Amyotrophic lateral sclerosis (ALS), dementia (including vascular dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia), Down syndrome, Psychosis (including agitation caused by a neurodegenerative disease or associated with dopaminergic therapy such as but not limited to Parkinson's disease psychosis, Alzheimer's disease psychosis, Lewy body dementia psychosis), dyskinesia (including agitation caused by a neurodegenerative disease or associated with dopaminergic therapy), agitation (including agitation caused by a neurodegenerative disease or associated with dopaminergic therapy), conditions associated with dopaminergic therapy (including dystonia, myoclonus, or tremor), synucleinopathies, diseases, disorders or conditions associated with abnormal expression, stability, activities and/or cellular processing of a-synuclein, diseases, disorders or conditions characterized by the presence of Lewy bodies, posterior cortical atrophy, primary progressive aphasia, neurodegeneration caused by infectious diseases (including neurosyphilis, HIV -related cognitive impairment, and John Cunningham virus) and combinations thereof. [0062] In some embodiments, the subject has pre-dementia and/or is asymptomatic. In some embodiments, the subject has mild cognitive impairment. In some embodiments, the subject has Alzheimer's disease. In some embodiments, the subject has prodromal Alzheimer's disease. In some embodiments, the subject has mild Alzheimer's disease. In some embodiments, the subject has mild to moderate Alzheimer's disease. In some embodiments, the subject has moderate to severe Alzheimer's disease. In some embodiments, the subject has moderately severe Alzheimer's disease. In some embodiments, the subject has severe Alzheimer's disease.

[0063] The methods disclosed herein may also optionally include selecting a subject with a neurodegenerative disease or at risk for developing a neurodegenerative disease. One of skill in the art knows how to diagnose a subject with or at risk of developing a neurodegenerative disease. For example, one or more of the follow tests can be used genetic test (e.g., identification of a mutation in TDP-43 gene) or familial analysis (e.g., family history), central nervous system imaging (e.g., magnetic resonance imaging and positron emission tomography), clinical or behavioral tests (e.g., assessments of muscle weakness, tremor, or memory), laboratory tests. The specific method for selecting a subject with a neurodegenerative disease or at risk for developing a neurodegenerative disease is not critical and can be any test known to one skilled in the art or developed in the future.

[0064] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a subject's score or performance on any one or more of the tests, exams, scales, or measurements described herein, or any one or more sections, factors, areas, clusters, or subgroups of any one or more of the tests, exams, scales, or measurements described herein. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined an analysis of a subject's score or performance on any one or more of the tests, exams, scales or measurements described herein, or any one or more sections, factors, areas, clusters, or subgroups of any one or more of the tests, exams, scales, or measurements described herein.

[0065] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale compared to a control subject or group. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having a greater score on the ADAS- cog scale compared to a control subject or group. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having an increase in the ADAS-cog score above a baseline score. In some embodiments, modifying a neurodegenerative disease, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having an increase in the ADAS-cog score of at least 1 point over 24 weeks. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by time benefit analysis of a subject's score of the ADAS-cog scale. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by survival analysis of a subject's score of the ADAS- cog scale. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by extrapolation of slopes analysis of a subject's score of the ADAS-cog scale.

[0066] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 12 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 36 weeks of treatment with a therapeutically effective amount of a 5- HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0067] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 12 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADAS-cog scale after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents.

[0068] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on one or more factors of the ADCS-ADL scale as listed in Table 1. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale compared to a control subject or group. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having a greater score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale compared to a control subject or group. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having an increase in the ADCS-ADL scale or one or more factors of the ADCS-ADL scale of at least 1 point over 24 weeks. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by time benefit analysis of a subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by survival analysis of a subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by extrapolation of slopes analysis of a subject's score on the ADCS-ADL scale or one or more factors of the ADCS- ADL scale.

[0069] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 12 weeks of treatment with a therapeutically effective amount of a 5- HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0070] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 12 weeks of treatment with a therapeutically effective amount of a 5- HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the ADCS-ADL scale or one or more factors of the ADCS-ADL scale after 48 weeks of treatment with a therapeutically effective amount of a 5- HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents.

[0071] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on one or more areas, clusters, or subgroups of the NPI exam. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam compared to a control subject or group. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having a greater score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam compared to a control subject or group. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject having an increase in the NPI exam or one or more areas, clusters, or subgroups of the NPI exam of at least 1 point over 24 weeks. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by time benefit analysis of a subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by survival analysis of a subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by extrapolation of slopes analysis of a subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam.

[0072] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 12 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0073] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 12 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the subject's score on the NPI exam or one or more areas, clusters, or subgroups of the NPI exam after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents.

[0074] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the number of falls experienced by a subject. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls experience by a subject compared to a control subject, group or benchmark. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the time to a first fall experienced by a subject. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by the time to a first fall experienced by a subject compared to a control subject, group, or benchmark.

[0075] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 12 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0076] In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 12 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 24 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 36 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, modifying a neurodegenerative disease, improving the clinical signs and symptoms of the disease, slowing the progression of the disease, delaying the reaching of predefined milestones of the disease, or a combination thereof is determined by a reduced number of falls or a delay in time to a first fall in the subject after 48 weeks of treatment with a therapeutically effective amount of a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof and a therapeutically effective amount of one or more additional therapeutic agents.

COMPOSITIONS

[0077] Embodiments herein are methods of modifying a neurodegenerative disease in a subject in need thereof, comprising administering a 5-HT6 receptor antagonist or pharmaceutically acceptable salts, hydrates or solvates thereof. In some embodiments, the methods comprise administering intepirdine or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with at least one additional therapeutic agent.

[0078] In some embodiments, the 5-HT₆ receptor antagonist is a compound of formula (I):

(I) wherein: Ri and R₂ independently represent hydrogen or Ci_-6 alkyl or Ri is linked to R₂ to form a group (CH₂)₂, (CH₂)₃ or (CH₂)₄; R₃, R₄ and R5 independently represent hydrogen, halogen, cyano, — CF₃, — CF₃0, Ci_-6 alkyl, Ci_-6 alkoxy, Ci_-6 alkanoyl or a group — CO R^Rv; R₆ and R⁷ independently represent hydrogen or Ci_-6 alkyl or together may be fused to form a 5- to 7-membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom; m represents an integer from 1 to 4, such that when m is an integer greater than 1, two R₂ groups may instead be linked to form a group CH₂, (CH₂)₂ or (CH₂)₃; n represents an integer from 1 to 3; p represents 1 or 2; A represents a group— Ar¹ or — Ar²Ar³; Ar¹, Ar² and Ar³ independently represent an aryl group or a heteroaryl group, both of which may be optionally substituted by one or more (e.g., 1, 2 or 3) substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluorom ethyl, trifluoromethoxy, Ci_-6 alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, Ci_-6 alkoxy, arylCi-6 alkoxy, Ci_-6 alkylthio, Ci-6 alkoxyCi-6 alkyl, C3-7cycloalkylCi-6 alkoxy, Ci_-6 alkanoyl, Ci_-6 alkoxycarbonyl, Ci. 6 alkylsulfonyl, Ci_-6 alkylsulfinyl, Ci_-6 alkylsulfonyloxy, Ci_-6alkylsulfonyl Ci_-6 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl Ci_-6 alkyl, Ci_-6 alkylsulfonamido, Ci_-6 alkylamido, Ci-6 alkylsulfonamido Ci_-6 alkyl, Ci_-6 alkylamidoCi-6 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido Ci_-6 alkyl, arylcarboxamido Ci_-6 alkyl, aroyl, aroylCi. 6 alkyl, arylCi_-6 alkanoyl, or a group CO R₈R₉ or S0₂ R₈R₉, wherein R₈ and R₉ independently represent hydrogen or Ci_-6 alkyl or together may be fused to form a 5- to 7- membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom; or pharmaceutically acceptable salts, hydrates or solvates thereof.

[0079] Alkyl groups, whether alone or as part of another group, may be straight chain or branched and the groups alkoxy and alkanoyl shall be interpreted similarly. In some embodiments, alkyl moieties are Ci_-4 alkyl, e.g., methyl or ethyl. The term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.

[0080] The term "aryl" includes phenyl and naphthyl. The term "heteroaryl" is intended to mean a 5-7 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such monocyclic aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like. Heteroaryl groups, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where otherwise indicated above. It will be appreciated that wherein the above mentioned aryl or heteroaryl groups have more than one substituent, said substituents may be linked to form a ring, for example a carboxyl and amine group may be linked to form an amide group.

[0081] In some embodiments, Ri represents hydrogen, methyl, ethyl, isopropyl, isobutyl or 2,2-dimethylpropyl. In some embodiments, Ri represents hydrogen or methyl, especially hydrogen. In some embodiments, R₂ represents hydrogen, methyl (e.g., 3-methyl, 2-methyl, 3,3-dimethyl or 2,5-dimethyl) or is linked to Ri to form a (CH₂)₃ group. In some embodiments, R₂ represents hydrogen or methyl (e.g., 3-methyl), especially hydrogen.

[0082] In some embodiments, R₃ represents hydrogen, methyl (e.g., 6-methyl) or halogen (e.g., 7-chloro). In some embodiments, R₃ represents hydrogen.

[0083] In some embodiments, R₄ and R₅ independently represent hydrogen or methyl, especially hydrogen.

[0084] In some embodiments, n represents 1. In some embodiments, m and p independently represent 1 or 2. In some embodiments, m and p both represent 1. In some embodiments, m represents 2 and both R₂ groups are linked to form a CH₂ group linking C-2 and C-5 of the piperazine ring.

[0085] In some embodiments, when A represents a group— Ar¹, Ar¹ represents optionally substituted phenyl or pyridyl, or in some embodiments, a phenyl optionally substituted with halogen (e.g., chlorine, fluorine or bromine), cyano, trifluoromethyl or trifluoromethoxy. In some embodiments, Ar¹ is unsubstituted phenyl or phenyl substituted by halogen (e.g., 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3-fluoro, 4-fluoro or 4-bromo), Ci_-6 alkyl (e.g., 2-methyl or 4-methyl), Ci_-6 alkoxy (e.g., 2-methoxy), trifluoromethyl (e.g., 2- trifluoromethyl or 3 -trifluoromethyl) or trifluoromethoxy (e.g., 2-trifluoromethoxy).

[0086] In some embodiments, when A represents a group— Ar²-Ar³, Ar² and Ar³ both independently represent phenyl or monocyclic heteroaryl group as defined above. In some embodiments, A represents a group — Ar¹. In some embodiments, — Ar s unsubstituted phenyl.

[0087] The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids, e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids, e.g., succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. The present disclosure includes within its scope all possible stoichiometric and non-stoichiometric forms. [0088] The compounds of formula (I) may be prepared in crystalline or noncrystalline form, and, if crystalline, may optionally be solvated, e.g., as the hydrate. This disclosure includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water). Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g., diastereomers and enantiomers) and the disclosure extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The disclosure also extends to any tautomeric forms and mixtures thereof.

[0089] In some embodiments, the 5-HT6 receptor antagonist is 3 -phenyl sulfonyl - 8-piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof. 3-phenylsulfonyl-8-piperazin-l-yl-quinoline, also known as intepirdine, is a potent and selective 5HT₆ receptor antagonist. Reference is made throughout this application to intepirdine, which is also known as SB742457 or RVT-101. As used herein intepirdine may be 3-phenylsulfonyl-8-piperazinyl-lyl-quinoline or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, thereof. In some embodiments, intepirdine may be a compound of the formula (II):

(Π) or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, thereof. Intepirdine has been shown to be potentially useful in the treatment and/or prevention of

neurodegenerative diseases. [0090] In some embodiments, the therapeutically effective amount of 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline 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 200 mg, about 0.001 mg to about 175 mg, about 0.001 mg to about 70 mg, or about 0.001 mg to about 35 mg. In some embodiments, the therapeutically effective amount of 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is from about 1 mg to about 1000 mg, about 15 mg to about 1000 mg, about 35 mg to about 1000 mg, about 70 mg to about 1000 mg, about 120 to about 1000 mg, or about 200 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of 3-phenylsulfonyl-8-piperazinyl-lyl-quinoline or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 15 mg, about 35 mg, about 70 mg, or about 120 mg.

[0091] In some embodiments, the therapeutically effective amount of 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is an amount selected from the group consisting of an amount of 3-phenylsulfonyi-8-piperazinyl-lyl-quinoline that may cause convulsions in a subject to which it is administered; an amount that would be expected to exceed the maximum tolerated dose for the subject to which it is administered; an amount associated with systemic exposures characterized by an AUC_tes of about 8.2 μ§.η/ηι1, a C_inax of about 0.26 ^ig/ml; or a combination thereof an mount associated with systemic exposures characterized by an AUC, C_am, or combinations thereof, that are about 2 to about 3 times higher than the mean clinical exposure achieved at the proposed clinical dose for monotherapy with 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline (i .e. mean AUC_tau-ss o about 3.2 μg.h/ml and C_max of about 0.180 μg/rnl), an amount associated with a recorded systemic clinical exposure that is greater than the highest recorded systemic clinical exposure (AUC₀-_∞ of about 9.25 μg.h/mi and C_Bmx of about 0.293 μg/mi), or any combination thereof.

[0092] In some embodiments, the therapeutically effective amount of 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is an amount selected from the group consisting of a dose of 3-phenylsulfonyI-8-piperazinyl-l yl-quinoiine that is greater than about 10 mg/kg/day, a dose of 3-phenylsuifonyl-8-piperazinyl- lyl-quinoline that is greater than 15 mg/^'day, a dose of 3- phenylsulfonyl-8-piperazinyl-lyl-quinoline that is greater than about 35 mg/^'day, a dose of 3- phenylsuifonyl-8-piperaziiiyl-lyl-quinoline that is greater than about 70 mg/day, a dose of 3- phenylsulfonyl-8-piperazinyl- lyl-quinoline that is greater than about 125 mg day, a dose of 3-phenylsulfonyl-8-piperazinyl-lyl-quinoline that is greater than about 200 mg/day, or any combination thereof.

[0093] 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 immediate release, extended release, delayed release, or any combination thereof.

[0094] In some embodiments the compositions described herein may further comprise at least one additional therapeutic agent.

[0095] In some embodiments, the least one additional therapeutic agent is an acetylcholinesterase inhibitior. 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-methyl-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.

[0096] In some embodiments, the acetylcholinesterase inhibitor is galantamine. In some embodiments, galantamine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is galantamine hydrobromide. In some embodiments, the therapeutically effective amount of galantamine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of galantamine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates 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 pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 4 mg, about 8 mg, about 12 mg, about 16 mg, or about 24 mg. In some embodiments, the therapeutically effective amount of galantamine is about 1.001 to about 1,000 times greater than a recommended maximal dose level approved by the U.S. FDA. In some embodiments, the therapeutically effective amount of galantamine is about 1.5 to about 4 times greater than a recommended maximal dose level approved by the U.S. FDA. For Example, the dose of galantamine may be from about 36 mg to about 96 mg.

[0097] In some embodiments, the acetylcholinesterase inhibitor is tacrine. In some embodiments, tacrine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is tacrine hydrochloride. In some embodiments, the therapeutically effective amount of tacrine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of tacrine 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 640 mg. about 0.001 mg to about 160, or about 0.001 mg to about 120 mg In some embodiments, the therapeutically effective amount of tacrine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 120 mg, or about 160 mg. In some embodiments, the therapeutically effective amount of tacrine is about 1.001 to about 1,000 times greater than a recommended maximal dose level approved by the U.S. FDA. In some embodiments, the therapeutically effective amount of tacrine is about 1.5 to about 4 times greater than a recommended maximal dose level approved by the U.S. FDA. For Example, the dose of tacrine may be from about 240 mg to about 640 mg.

[0098] In some embodiments, the acetylcholinesterase inhibitor is donepezil or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the acetylcholinesterase inhibitor is donepezil hydrochloride. In some embodiments, the therapeutically effective amount of donepezil or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of donepezil 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 30 mg, or about 34.5 mg to about 92 mg. In some embodiments, the therapeutically effective amount of donepezil or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 5 mg, 10 mg, or 23 mg. In some embodiments, the therapeutically effective amount of donepezil is about 1.001 to about 1,000 times greater than a recommended maximal dose level approved by the U.S. FDA. In some embodiments, the therapeutically effective amount of donepezil is about 1.5 to about 4 times greater than a recommended maximal dose level approved by the U.S. FDA. For Example, the dose of donepezil may be from about 34.5 mg to about 92 mg. [0099] In some embodiments, the acetylcholinesterase inhibitor is rivastigmine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the therapeutically effective amount of rivastigmine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, for extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of rivastigmine 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 48 mg, about 12 mg to about 48 mg, about 19 mg to about 54 mg or about 0.001 mg to about 60 mg. In some embodiments, the therapeutically effective amount of rivastigmine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates 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, about 13.3 mg, about 24 mg, or about 48 mg. In some embodiments, the therapeutically effective amount of rivastigmine is about 1.001 to about 1,000 times greater than a recommended maximal dose level approved by the U.S. FDA. In some embodiments, the therapeutically effective amount of rivastigmine is about 1.5 to about 4 times greater than a recommended maximal dose level approved by the U.S. FDA. For Example, the dose of rivastigmine may be from about 18 mg to about 48 mg.

[00100] In some embodiments, the least one additional therapeutic agent is an anticholinergic agent. 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) and its pharmaceutically acceptable salts, 1- methylpiperidin-4-yl) 2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceutically acceptable salts, 1,4,5, 6-tetrahydro-l-methylpyrimidin-2-ylmethyl a-cyclohexyl-a-hydroxy- a-phenyl acetate (oxyphencyclimine) and its pharmaceutically acceptable salts, (R)— N,N- diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine (tolterodine) and its pharmaceutically acceptable salts.

[00101] In some embodiments, the quaternary ammonium anti-cholinergic muscarinic receptor antagonist is selected from trospium and glycopyrrolate. In some embodiments, the quaternary ammonium anti-cholinergic muscarinic receptor antagonist is glycopyrrolate. In some embodiments, the therapeutically effective amount of glycopyrrolate is from about 0.1 mg to about 10.0 mg. In some embodiments, the therapeutically effective amount of glycopyrrolate is from about 0.1 mg to about 0.8 mg. In some embodiments, the therapeutically effective amount of glycopyrrolate is from about 2.0 mg to about 4.0 mg. In some embodiments, the therapeutically effective amount of glycopyrrolate is from about 3.0 mg to about 10.0 mg. In some embodiments, the therapeutically effective amount of glycopyrrolate is an amount from about 20% to about 600% of the amount of glycopyrrolate that is currently administered for anti-cholinergic therapy. In some embodiments, the therapeutically effective amount of glycopyrrolate is an amount from about 0.2 mg to about 60 mg of the amount of glycopyrrolate that is currently administered for anti-cholinergic therapy.

[00102] In some embodiments, the non-selective peripheral muscarinic anticholinergic agent is solifenacin. In some embodiments, the therapeutically effective amount of solifenacin is an amount from about 20% to about 600% of the amount of solifenacin that is currently administered for anti-cholinergic therapy. In some embodiments, the therapeutically effective amount of solifenacin is an amount from about 1 mg to about 30 mg.

[00103] In some embodiments, the anti-cholinergic agent is a compound of formula III:

(Π)

wherein R is a radical selected from the group consisting of those of formulas (a)-(e):

(a) (b) (c) (d) (e)

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; X is a (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 (Ci-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.

[00104] 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=CH₃, A -2- fluoroethyl, L=H; n=l; m=0; R₁=R₂=phenyl; and R₃=OH. In some embodiments, R=(a), A=A -CH₃, L=H; n=l; m=0; R=phenyl; and R₂— R₃— H In some embodiments, R^:=(a), A=CH₃, A -isopropyl, L=H; n=l; m=0;

In some embodiments, R==(a), Λ .V (H i. ! . ! !: n ! . m 0; R, phenyl : R₂=COOC₂H₅; and R₃=H. In some embodiments, R=(a), A=A -CH₃, L=methoxy; n=l ; m=0; R₁=R₂=phenyl, and R₃=OH. In some embodiments, R=(a), A+A'=l,4-butylene, L=H; n=l; m=0; R₁=R₂=phenyl; and R₃=OH. In some embodiments, R=(b)-3-, Alk=methyl; n=l; m=0; R₁=R₂=phenyl; and R₃=OH. In some embodiments, R=(b)-3-, Alk=methyl; n=l; m=0; R₃=phenyl; R₂=cyclopentyl; and R₃— OH In some embodiments, R=(c)-3-, both Alk and Alk'-ethyl; n=l ; m=0; R₁=R₂=phenyl; and R₃=OH. In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n=l; m^:=0; R₁==R₂=phenyl; and R ;==()! I In some embodiments, R^:=(c)-3-, Aik=methyl and Alk -ethyl; n=l; m=0;

In some embodiments, R=(c)-3~, both Alk and Alk -methyl;

R₂=cyclopentyl; and R₃=H. In some embodiments, R=(c)-3-, both Alk and Alk -methyl n=l; m=0; R]=phenyi; R₂=2-thienyl; and R₃=OH. In some embodiments, R=(c)-3-, both Alk and Alk -methyl;

In some embodiments, R=(c)-2-, both Alk and Alk -methyl; n=l; m=l; X=l,2-ethyiene; Rj=phenyi; R₂=cyclohexyl; and R₃=OH. In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n^:= l; m^:=0; Ri=phenyi; R₂=cyclopentyl; and R₃=OH. In some embodiments, R=(c)-3-, both Alk and Alk -methyl; n^:= l; m=0; Rr ^:=phenyl; R₂=cyclopentyl; R₃=OH. In some embodiments, R=(d), Alk=methyl, Y=l ,2-ethylene; n=l; m=l; X=l ,2-ethylene; R₁=R₂=phenyl; and R₃=OH. In some embodiments, R=(d), Alk=CH₃, Y= 1,3 -propylene; n=0; m=l; X=l,2-ethyiene; Ri=phenyl; R₂= 1 -cyclohexenyl; and R₃=H, In some embodiments, R=(d), Alk=methyl, Y=l,2-ethylene; n=0; m=l; X=l,2-ethylene; R]=phenyl; R₂=cyciohexyi; and R₃=OH. In some embodiments, R^:=(d), Alk=m ethyl, Y=2-oxa- 1,3 -propylene; n^:=0; m= l ; X=l,2-ethylene;

R₂=2-thienyl; and In some embodiments, R=(e); n=l; m=l; X=l,2- ethylene;

X=l,2-et

[00105] 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 metilsulfate, tropenziline bromide, trospium chloride, clidinium bromide, droclidinium bromide, benzilonium bromide, benzopyrronium bromide, cyclopyrronium bromide, glycopyrronium bromide (glycopyrrolate), heteronium bromide, hexopyrronium bromide, oxypyrronium bromide, ritropirronium bromide, etipirium iodide, fenclexonium methylsulfate, tricyclamol chloride (procyclidine methochloride), tiemonium iodide, hexasonium iodide, and oxysonium iodide.

[00106] 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 Non-proprietary 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.

[00107] 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 anticholinergic 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. [00108] In some embodiments, the least one additional therapeutic agent is an NMDA receptor antagonist. In some embodiments, the NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, and ketamine. In some embodiments, the NMDA receptor antagonist is memantine. In some embodiments, the memantine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof comprises memantine hydrochloride. In some embodiments, the therapeutically effective amount of memantine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for extended release, delayed release or any combination thereof. In some embodiments, the therapeutically effective amount of memantine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates 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 pharmaceutically acceptable salts, hydrates, polymorphs, or solvates 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, memantine or pharmaceutically acceptable salts, hydrates or solvates thereof is administered to a subject in need thereof in an amount that is considered to be sub therapeutic. In some embodiments, the NMDA receptor antagonist is amantadine. In some embodiments, the amantadine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof comprises amantadine hydrochloride. In some embodiments, the therapeutically effective amount of amantadine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of amantadine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 500 mg. In some embodiments, amantadine or pharmaceutically acceptable salts, hydrates or solvates thereof is administered to a subject in need thereof in an amount that is considered to sub therapeutic. In some embodiments, the therapeutically effective amount of amantadine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is from about 100 mg to about 400 mg. In some embodiments, the therapeutically effective amount of amantadine or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 100 mg, 200 mg, 300 mg or about 400 mg.

[00109] In some embodiments, the least one additional therapeutic agent is a 5- HT2A inverse agonist. In some embodiments, the 5-HT2A inverse agonist is nelotanserin, pimavanserin, pruvanserin, eplivanserin, volinanserin, glemanserin, ketanserin, ritanserin, clozapine, or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof comprises 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-phenyl)-urea or a combination thereof. In some embodiments, the 5-HT2A inverse agonist is administered to a subject in need thereof in an amount that is considered to sub therapeutic. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is from about 0.001 mg to about 1,000 mg, or about 0.001 mg to about 100 mg. In some embodiments, nelotanserin or pharmaceutically acceptable salts, hydrates or solvates thereof is administered to a subject in need thereof in an amount that is considered to sub therapeutic. In some embodiments, the therapeutically effective amount of nelotanserin or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 20 mg, about 40 mg, or about 80 mg.

[00110] In some embodiments, the at least one additional therapeutic agent is a lithium compound or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof. In some embodiments, the therapeutically effective amount of a lithium compound or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of a lithium compound or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof, is from about 0.001 mg to about 1000 mg, from about 0.001 mg to about 500 mg, from about 0.001 mg to about 100 mg, from about 0.001 mg to about 50 mg, from about 0.001 mg to about 10 mg, from about 0.001 mg to about 1 mg, from about 0.001 mg to about 0.1 mg, or from about 0.001 mg to about 0.01 mg. In some embodiments, the therapeutically effective amount of a lithium compound or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof, is about 0.01 mg, about 0.1 mg, about 1 mg, about 5 mg, or about 10 mg. In some embodiments, the lithium compound is present in a sub therapeutically effective amount. In some embodiments, the sub therapeutically effective amount of a lithium compound or pharmaceutically acceptable salts, hydrates, polymorphs or solvates thereof, is an amount resulting in a serum concentration of between about 0.4 mM and about 1.6 mM, below about 0.4 mM, below about 0.5 mM, below about 0.4 mM, below about 0.3 mM, below about 0.2 mM, below about 0.1 mM, or below about 0.05 mM when administered to a subject. In some embodiments, the therapeutically effective amount of a lithium compound or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for extended release, delayed release, or any combination thereof.

[00111] In some embodiments, the at least one additional therapeutic agent is levodopa or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the therapeutically effective amount of levodopa or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, delayed release, or any combination thereof. In some embodiments, the therapeutically effective amount of levodopa or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates 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 pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is about 285 mg, about 300 mg, about 400 mg, about 435 mg, 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 at least one additional therapeutic agent useful for treating a neurodegenerative disease is levodopa or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof and carbidopa or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof. In some embodiments, the therapeutically effective amount of levodopa further comprises carbidopa. In some embodiments, the therapeutically effective amount of carbidopa or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof is configured for immediate release, extended release, 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.

[00112] In some embodiments, the at least one additional therapeutic agent is an anticonvulsant. In some embodiments, anticonvulsants for use herein may include, but are not limited, to levetiracitam (Keppra), AMPA receptor antagonists, barbiturate anticonvulsants, benzodiazepine anticonvulsants, carbamate anticonvulsants, carbonic anhydrase inhibitor anticonvulsants, dibenzazepine anticonvulsants, fatty acid derivative anticonvulsants, gamma-aminobutyric acid analogs, gamma-aminobutyric acid reuptake inhibitors, hydantoin anticonvulsants, miscellaneous anticonvulsants, neuronal potassium channel openers, oxazolidinedione anticonvulsants, pyrrolidine anticonvulsants, succinimide anticonvulsants, triazine anticonvulsants or combinations thereof. In some embodiments, the anticonvulsant is administered to a subject in need thereof in a therapeutically effective amount. In some embodiments, the anticonvulsant or pharmaceutically acceptable salts, hydrates or solvates thereof is administered to a subject in need thereof in an amount that is considered to sub therapeutic.

[00113] In some embodiments, the at least one additional therapeutic agent is a monoclonal antibody. In some embodiments, the second therapeutic agent is a human monoclonal antibody. In some embodiments, the second 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.

[00114] 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, BI 1181181, LY2886721, E2609, RG7129, JNJ-5486911, TAK-070, or any combination thereof.

[00115] 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. [00116] 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.

[00117] 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.

[00118] In some embodiments, the at least one additional therapeutic agent may include one or more treatments for Alzheimer's disease such as Namzaric™, Ex el on®, 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 lC-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), EL D-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 (ENKAM 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), Exebryl-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), INM-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- FMPY (University of Pennsylvania), 18F-AV-1/ZK (University of Pennsylvania), l lC-6- Me-BTA-1 (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).

[00119] 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).

[00120] In some embodiments, the compositions described herein may include one or more agents 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-HT4 receptor partial agonists or 5HT1A receptor antagonists and MDA 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 S RI (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.

[00121] The therapeutic agents in the methods and compositions described herein may be administered simultaneously or sequentially and, when administration is sequential, either may be administered first, second or third. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

[00122] The therapeutic agents in the methods and compositions described herein may be used either as separate formulations or as a single combined formulation. In some embodiments, the therapeutic agents in the methods and compositions described herein may be configured into separate formulations. In some embodiments, the therapeutic agents in the methods and compositions described herein may be combined into a single formulation. In yet other embodiments, the therapeutic agents in the methods and compositions described herein may be configured into multiple separate compositions. When combined in the same formulation, it will be appreciated that the compounds must be stable and compatible with each other and the other components of the formulation.

[00123] In some embodiments, the compositions described herein may further comprise at least one pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, mannitol, sodium starch glycolate, hydroxypropyl methylcellulose, purified water, magnesium stearate, croscarmellose sodium, a glue, and any combination thereof.

[00124] When the compounds of this disclosure are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease, or condition, being treated."

[00125] If pharmaceutically acceptable salts of the compounds of this disclosure are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl -propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.

[00126] Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

[00127] The compounds utilized in the compositions and methods of this disclosure may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those, which increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and/or alter rate of excretion.

[00128] According to a preferred embodiment, the compositions of this disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human being. Such pharmaceutical compositions are used to ameliorate, treat or prevent any of the diseases described herein including but not limited to neurodegenerative diseases in a subject.

[00129] Agents of the disclosure are often administered as pharmaceutical compositions comprising an active therapeutic agent, i.e., and a variety of other pharmaceutically acceptable components. See Remington's Pharmaceutical Sciences (19th Edition (Mack Publishing Company, 1995)). The preferred form depends on the intended mode of administration and therapeutic application. The compositions can also include, depending on the formulation desired, pharmaceutically acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.

[00130] In some embodiments, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of a described compound, formulated together with one or more pharmaceutically acceptable excipients including but not limited to, carriers (additives) and/or diluents for use in treating the diseases described herein, including, but not limited to a neurodegenerative disease. While it is possible for a described compound to be administered alone, it is preferable to administer a described compound as a pharmaceutical formulation (composition) as described herein. Described compounds may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.

[00131] As described in detail, pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or nonaqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or delayed-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.

[00132] In some embodiments, the compositions described herein can be configured as overcoated tablet formulations. In some embodiments, the compositions described herein can be configured as an encased product coated edge-to-edge tablet formulations. In some embodiments, a flat-oval edge-to-edge formulation might also be obtained from a hard-gelatin or HPMC capsule manufactured using a flattened mold rather than a circular mold. In some embodiments a "flattened" capsule would be a more desirable alternative to the standard circular capsule.

[00133] Pharmaceutically acceptable salts of compounds described herein include conventional nontoxic salts or quaternary ammonium salts of a compound, e.g., from nontoxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. In other cases, described compounds may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

[00134] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[00135] Examples of pharmaceutically acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[00136] Formulations for use in accordance with the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound, which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[00137] In certain embodiments, a formulation as described herein comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present disclosure. In certain embodiments, an aforementioned formulation renders orally bioavailable a described compound of the present disclosure.

[00138] The compositions described herein optionally contain inactive carriers and diluents known to one of skill in the art such as, for example microcrystalline cellulose (10- 150 mg), mannitol (10-100 mg), sodium starch glycolate (0.001 -20 mg, or 1 -20 mg), hydroxypropyl methylcellulose (1-20 mg), magnesium stearate (1-10 mg), and purified water.

[00139] Methods of preparing formulations or compositions comprising described compounds include a step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients (excipients). In general, formulations may be prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[00140] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) 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 mannitol, 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. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica, or a similar alcohol. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[00141] In some cases, in order to prolong the effect of a drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00142] Injectable depot forms are made by forming microencapsule matrices of the described compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.

[00143] The pharmaceutical compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers, which are commonly used include but are not limited to lactose and cellulose (carboxymethylcellulose). Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include but are not limited to lactose and cellulose (carboxymethylcellulose). When aqueous suspensions and solutions and propylene glycol are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[00144] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compounds described herein may also be administered as a bolus, electuary or paste.

[00145] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), an active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00146] Tablets may be made by compression or molding, optionally with one or more accessory ingredients (excipients). Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent. If a solid carrier is used, the preparation can be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier will vary, e.g., from about 0.01 to 800 mg, preferably about 0.01 mg to 400 mg, about or 3 mg to about 400 mg. When a liquid carrier is used, the preparation can be, e.g., in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.

[00147] Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may alternatively or additionally be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

[00148] Liquid dosage forms for oral administration of compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. [00149] Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[00150] Suspensions, in addition to active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00151] The pharmaceutical compositions of this disclosure may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this disclosure with a suitable non-irritating excipient, which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[00152] Topical administration of the pharmaceutical compositions of this disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-administered transdermal patches are also included in this disclosure. Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Dissolving or dispersing the compound in the proper medium can make such dosage forms. Absorption enhancers can also be used to increase the flux of the compound across the skin. Either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel can control the rate of such flux.

[00153] The pharmaceutical compositions of this disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

[00154] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[00155] Examples of suitable aqueous and nonaqueous carriers, which may be employed in the pharmaceutical compositions of the disclosure, include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00156] Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inclusion of one or more antibacterial and/or antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like, may be desirable in certain embodiments. It may alternatively or additionally be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin.

[00157] In certain embodiments, a described compound or pharmaceutical preparation is administered orally. In other embodiments, a described compound or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administrations.

[00158] When compounds described herein are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[00159] Preparations described herein may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for the relevant administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[00160] Such compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[00161] Regardless of the route of administration selected, compounds described herein which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[00162] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[00163] The pharmaceutical compositions described herein may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, and is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

[00164] Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tableting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

[00165] Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavorings or colorants.

[00166] For parenteral administration, fluid unit dosage forms are prepared utilizing a compound and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

[00167] The compositions described herein, used in the treatment of a neurodegenerative disease will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide, such unit doses will preferably be administered once a day, although administration more than once a day may be required; and such therapy may extend for a number of weeks or months.

[00168] The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

[00169] Compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pack may, for example, comprise metal or plastic foil, such as a blister pack. Where the compounds are intended for administration as two separate compositions these may be presented, for example, in the form of a twin pack.

[00170] Pharmaceutical compositions may also be prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions.

[00171] It will be understood that the administration of the combination by means of a single patient pack, or patient packs of each composition, including a package insert directing the patient to the correct use of the combination is a desirable additional embodiment. Some embodiments are directed to a patient pack comprising at least one active ingredient, of the combination and an information insert containing directions on the use of the combination. Some embodiments are directed to a double pack comprising in association for separate administration of a therapeutically effective amount of 3-phenylsulfonyl-8- piperazinyl-lyl-quinoline or pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof and a therapeutically effective amount of at least one additional therapeutic agent useful for treating a neurodegenerative disease.

[00172] The dose when using the compounds of the present disclosure 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 disclosure. Representative doses of the present disclosure include, but are not limited to, about 0.001 mg to about 5,000 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. Depending on the individual and as deemed appropriate from the patient's physician or care-giver it may be necessary to deviate upward or downward from the doses described herein.

[00173] 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, on whether an acute or chronic disease state is being treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present disclosure and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this disclosure is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and 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 disclosure.

[00174] 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.

[00175] Other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may alternatively or additionally be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

EXAMPLES

[00176] The following examples are illustrative, but not limiting, of the methods and compositions described herein. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in therapy and that are obvious to those skilled in the art are within the spirit and scope of the compounds and methods described herein.

Example 1 : Intepirdine as an adjust to donepezil in mild-to-moderate Alzheimer's disease: efficacy on activities of daily living domain. [00177] Intepirdine is an orally administered 5-HT6 receptor antagonist under development for the treatment of mild-to-moderate Alzheimer's disease (AD). The following results are from an analysis of efficacy on ADCS-ADL domains and factors in a randomized, double-blind, placebo-controlled phase 2b study of 684 adults with mild to moderate AD, in which intepiridine also demonstrated statistically significant benefits in cognition (on the ADAS-cog scale) compared to placebo.

[00178] In this 48-week double-blind study, 684 subject with mild to moderate AD (MMSE score 10-26) and on stable background donepezil treatment were randomized to receive 35 mg intepirdine, 15 mg intepirdine, or placebo (FIG. 1). Primary outcomes were assessed at week 24. Multiple cognitive and functional endpoints were evaluated during the study, including the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS- Cog), the Alzheimer's Disease Cooperative Study Activities of Daily Living scale (ADCS- ADL), and the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scales at weeks 12, 24, 36, and 48. The following data are the analysis of results on the overall ADCS-ADL scale as well as scores on domains of the ADCS-ADL (Basic Score, Instrumental Score, and Total Independence Score) and scores on ADCS-ADL Factors (Household Activities, Basic ADLs, Communications and Engagement, and Outside activities).

[00179] Overall ADCS-ADL results are in Table 3 below, and are depicted graphically in FIG. 2.

[00180] ADCS-ADL domain scores are shown in Tables 4-6 below. For the basic score in Table 4, the score was calculated as the sum of questions l-6b and ranges from 0-22 points (items: eating, walking, using the toilet, bathing, grooming and dressing).

Treatment Effect 35 mg intepirdine

Difference vs.

Visit P Value

Donepezil Alone

Week 12 0.10 0.720

Week 24 0.20 0.510

Week 36 0.40 0.244

Week 48 0.40 0.251

For the instrumental score in Table 5, the score was calculated as the sum of questions 7-23 and ranges from 0-56 points (items: using the telephone, watching television, conversations, clearing dishes, personal belongings, making drinks, making snacks, taking rubbish out, getting out and about, shopping, keeping appointments, being left alone, current events, reading, writing, pastimes/hobbies, household chores).

The total independence score in Table 6 was a dichotomous recalculation of the 23 ADCS- ADL items, by scoring an item as 1 point if the highest performance was obtained, and 0 points for any other response. The score ranges from 0-23 points, with a score of 23 suggesting complete independence.

Table 6: Total Independence

Treatment Effect 35 mg intepirdine

Visit Difference vs. P Value Donepezil Alone

Week 12 0.5 0.059

Week 24 1.0 0.001

Week 36 0.7 0.029

Week 48 0.7 0.087

[00181] ADCS-ADL factor scores are shown in Tables 7-10 below. A description of the 4 ADCS-ADL factors are shown in Table 1. Factor 1 groups household activities.

Factor 3 groups communication and engagement activities.

Table 9: Factor 3 Communication and Engagement

Treatment Effect 35 mg intepirdine

Visit Difference vs. P Value Donepezil Alone

Week 12 0.73 0.0142

Week 24 1.03 0.0018

Week 36 1.06 0.0065

Week 48 0.87 0.0438

Factor 4 groups outside activities.

[00182] Conclusion: in this Phase 2b study of adults with mild to moderate AD, 35 mg intepirdine demonstrated statistically significant benefits on the overall ADCS-ADL scale, including on the instrumental and total independence domain scores. Moreover, 35 mg intepirdine showed a statistically significant effect on the clustered communication and engagement factors of the ADCS-ADL.

Example 2: Cost Estimation.

[00183] Outcome measures in Alzheimer's disease trials generally measure cognition, function, and behavior as distinct domains. Dependence, defined as the assistance that patients require, has been proposed as a more holistic measure of AD severity that can be more easily interpreted by health providers, patients, and payers. The Dependence Scale is a 13-item, 15-point questionnaire that assesses dependence in dementia patients. The Dependence Scale has demonstrated good reliability and validity and has been shown to be easily interpretable across multiple cross-sectional and longitudinal studies. Dependence, as captured by the Dependence Scale, is correlated with cognition, function, and behavior, but measures a concept distinct from each domain. The Dependence Scale is also highly correlated with cost and resource utilization. This poster presents an analytical framework to project the cost benefit of intepirdine based on changes in dependence in a Phase 2b study of intepirdine in mild-moderate Alzheimer's disease.

[00184] Total costs were estimated from the Predictors 2 study, a longitudinal study of 225 patients with early stage AD (modified Mini-Mental State Examination (mMMS) score >30, approximately >16 on the original MMSE), which enrolled patients from 1998 to 2004. The Predictors 2 study collected self-reported medical and non-medical costs, and determined the DL of study participants. Cost data from the Predictors 2 study was assigned to this study by DL (Table 11). Costs associated with both direct medical and nonmedical care were included. Informal caregiving costs were not included. Changes in annual costs from baseline were compared between treatment groups.

Table 11

[00185] Annual self-reported costs associated with donepezil alone were projected to increase by US$ 473 at week 12 and US$ 1,241 at week 48, while costs associated with the 35 mg intepirdine plus donepezil were projected to decrease by US$ 604 at week 12 and US$ 33 at 48 weeks. Over all visits an annual cost benefit of US$ 1,151 was observed with 35 mg intepirdine

[00186] Table 12 shows the change in estimated self-reported annual cost over all visits by baseline dependence level.

Table 12

[00187] Intepirdine is a novel 5HT6 receptor antagonist in development for the treatment of AD and DLB. Based on this conversion from ADCS-ADL to Dependence Levels defined by the DS using a published algorithm, the addition of 35 mg intepirdine on top of stable donepezil therapy was associated with reduced progression in dependence over 48 weeks. In the analytical framework presented here, using self-reported annual costs, 35 mg intepirdine on top of stable background donepezil therapy was projected to result in a cost benefit of US$ 1, 151 over all visits. [00188] Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

[00189] 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 disclosure. 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 disclosure 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.

[00190] 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 disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[00191] Groupings of alternative elements or embodiments of the disclosure 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.

[00192] Certain embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. 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 disclosure to be practiced otherwise than specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject 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 disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[00193] It is to be understood that the embodiments of the disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that may be employed are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that precisely as shown and described.

[00194] Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference in their entireties. A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made. Accordingly, other embodiments are within the scope of the following claims.

Claims

CLAIMS What is claimed:

1. A method of modifying a neurodegenerative disease in a subject in need thereof, comprising:

administering 36 mg or greater of 3-phenylsulfonyl-8-piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents,

wherein the method improves the clinical signs and symptoms of the

neurodegenerative disease, slows the progression of the neurodegenerative disease, delays the reaching of predefined milestones of the neurodegenerative disease, or any combination thereof.

2. The method of claim 1, wherein the method further comprises administering to the subject an ADAS-cog scale exam.

3. The method of claim 2, wherein the subject has a greater ADAS-cog scale score compared to a control subject, control group, benchmark, baseline score, or any combination thereof.

4. The method of claim 2, wherein the subject has an increase in their ADAS-cog scale score of at least 1 point over 24 weeks.

5. The method of claim 1, wherein the method further comprises administering to the subject an ADCS-ADL scale exam.

6. The method of claim 5, wherein the subject has a greater total ADCS-ADL scale score, ADCS-ADL Factor 1 score, ADCS-ADL Factor 2 score, ADCS-ADL Factor 3 score, ADCS-ADL Factor 4 score, or any combination thereof, compared to a control subject, control group, benchmark, baseline score, or any combination thereof.

7. The method of claim 5, wherein the subject has an increase in their total ADCS-ADL scale score, ADCS-ADL Factor 1 score, ADCS-ADL Factor 2 score, ADCS-ADL Factor 3 score, ADCS-ADL Factor 4 score, or any combination thereof, of at least 1 point over 24 weeks.

8. The method of claim 1, wherein the method further comprises administering to the subject an PI exam.

9. The method of claim 8, wherein the subject has a greater total NPI score, a greater score on one or more areas, clusters, or subgroups of the NPI exam, or any combination thereof, compared to a control subject, control group, benchmark, baseline score, or any combination thereof.

10. The method of claim 8, wherein the subject has an increase in their total NPI score, their score in one or more areas, clusters, or subgroups of the NPI exam, or any combination thereof, of at least 1 point over 24 weeks.

11. The method of claim 1, wherein the method further comprises recording the time and number of falls experienced by a subject.

12. The method of claim 11, wherein the subject has a reduced number of falls or a greater time to first fall compared to a control subject, control group, benchmark, baseline score, or any combination thereof.

13. The method of claim 1, wherein the neurodegenerative disease is selected from Alzheimer's disease, mild or early-stage Alzheimer's disease, mild to moderate Alzheimer's disease, moderate or mid-stage Alzheimer's disease, moderate to severe Alzheimer's disease, moderately severe Alzheimer's disease, severe Alzheimer's disease, Alzheimer's disease with Lewy bodies, Parkinson's disease, Parkinson's disease chemically induced by exposure to environmental agents such as pesticides, insecticides, or herbicides and/or metals such as manganese, aluminum, cadmium, copper, or zinc, SNCA gene-linked Parkinson's disease, sporadic or idiopathic Parkinson's disease, Parkin- or LRRK2-linked Parkinson's disease, autosomal-dominant Parkinson's disease, Diffuse Lewy Body Disease also known as Dementia with Lewy Bodies, Pure Autonomic Failure, Lewy body dysphagia, Incidental LBD, Inherited LBD, multiple system atrophy, Olivopontocerebellar Atrophy, Striatonigral Degeneration, Shy-Drager Syndrome, combined Alzheimer's and Parkinson disease and/or MSA, Huntington's disease, synucleinopathies, disorders or conditions characterized by the presence of Lewy bodies, multiple sclerosis, Amyotrophic lateral sclerosis dementia, vascular dementia, Lewy body dementia, Parkinson's dementia, frontotemporal dementia, Down syndrome, Psychosis, agitation caused by a neurodegenerative disease or associated with dopaminergic therapy, Parkinson's disease psychosis, Alzheimer's disease psychosis, Lewy body dementia psychosis, dyskinesia, agitation caused by a neurodegenerative disease or associated with dopaminergic therapy, agitation, conditions associated with dopaminergic therapy, dystonia, myoclonus, or tremor, synucleinopathies, diseases, disorders or conditions associated with abnormal expression, stability, activities and/or cellular processing of a-synuclein, diseases, disorders or conditions characterized by the presence of Lewy bodies, and combinations thereof.

14. The method of claim 1, wherein the subject is administered from about 70 mg to about 200 mg of 3-phenylsulfonyl-8-piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof.

15. A method of improving the performance of household activities in a subj ect with a neurodegenerative disease, comprising administering 36 mg or greater of 3-phenylsulfonyl-8- piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents.

16. The method of claim 15, wherein the method improves the performance of one or more of the activities selected from the group consisting of picking out clothes, telephone use, doing dishes, maintaining personal belongings, drinking, cooking snacks, cleaning litter, and appliance usage.

17. The method of claim 15, wherein the subject is administered from about 70 mg to about 200 mg of 3-phenylsulfonyl-8-piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof.

18. A method of improving the performance of basic activities of daily living in a subject with a neurodegenerative disease, comprising administering 36 mg or greater of 3- phenylsulfonyl-8-piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof in combination with one or more additional therapeutic agents.

19. The method of claim 18, wherein the method improves the performance of one or more of the activities selected from the group consisting of eating, walking, toileting, bathing, grooming, and physically getting dressed.

20. The method of claim 18, wherein the subject is administered from about 70 mg to about 200 mg of 3-phenylsulfonyl-8-piperazin-l-yl-quinoline or pharmaceutically acceptable salts, hydrates or solvates thereof.