Cyclobenzaprine treatment for agitation, psychosis, and cognitive decline in dementia and neurodegenerative states

Abstract

Providing cyclobenzaprine treatment for agitation, psychosis, and cognitive decline in dementia and neurodegenerative states. [Solution] A composition comprising cyclobenzaprine, and a method for treating or preventing agitation, psychosis, and / or cognitive decline and related symptoms in dementia and other neurodegenerative conditions. The method of the present invention comprises administering a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier to a subject who has dementia or a neurodegenerative condition, or who is at risk of developing agitation, psychosis, and / or cognitive decline and related symptoms in dementia or a neurodegenerative condition.

Description

[Technical Field]

[0001] Areas of disclosure This application claims priority and interest to U.S. Provisional Patent Application No. 62 / 597,284, filed December 11, 2017 (the contents and disclosures thereof are incorporated herein by reference in their entirety).

[0002] This application relates to methods for treating or preventing agitation, psychosis and / or cognitive decline, and related symptoms in dementia or neurodegenerative states, as well as related pharmaceutical compositions. Of particular importance are pharmaceutical compositions comprising cyclobenzaprine alone or in combination with one or more of the following: cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, antidepressants, anxiolytics, antipsychotics, anticonvulsants or mood stabilizers, anti-amyloid agents, or anti-tau agents. [Background technology]

[0003] Background of Disclosure Cyclobenzapurine, or 3-(5H-dibenzo[a,d]cycloheptan-5-ylidene)-N,N-dimethyl-1-propanamine, was first approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of topical origin (Katz and Dube, 1988). Potent 5-HT 2A and α 1A The antagonist is serotonergic 2A (5-HT) during sleep. 2A ) Receptor and α-adrenergic 1A (α 1A Subsequent studies have shown that antagonism of receptors improves restorative sleep in neuropsychiatric disorders and fibromyalgia (Moldofsky et al., 2011, Moldofsky et al., 2015).

[0004] The usefulness of very low doses of cyclobenzaprine as a sleep-improving agent, a sleep-deepening agent, or for treating sleep disturbances has been previously investigated. It has been reviewed that very low-dose regimens are particularly useful in treating sleep disorders caused by, exacerbated by, or associated with fibromyalgia syndrome, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain disorders, chronic pain syndrome (type II), drug administration, autoimmune diseases, stress or anxiety, or diseases caused by or exacerbated by sleep disorders, as well as the symptoms of such diseases, generalized anxiety disorder, and post-traumatic stress disorder (PTSD). See U.S. Patent Application US20110124656A1 and U.S. Patents 6,395,788 and 6,358,944 (as incorporated herein).

[0005] Dementia (caused by diseases such as Alzheimer's disease (AD)) is a neurological syndrome affecting nearly 47 million people worldwide, and the number of cases is projected to triple by 2050 (WHO 2017). Neurodegenerative conditions associated with the symptoms of dementia are also widespread (Chaves 2010; Weintraub 2005; Diaz-Olavarrieta C. 1999; Williamson 2016). Sleep disruption associated with hyperpermeability of the blood-brain barrier and neuroinflammation is linked to the development of dementia (Kerner and Roose). It may contribute to amyloid-beta deposition in AD (Macedo 2016) and in Alzheimer's disease (Macedo 2017). Sleep recovery has been shown to improve amyloid-beta protein clearance (Xie et al, 2013).

[0006] Behavioral and psychological symptoms of dementia (BPSD) include agitation (a large group of behaviors with a reported prevalence of nearly 56% in dementia patients) and psychosis (reported prevalence of 50% of patients). BPSD is also associated with a more rapid rate of cognitive decline and greater impairment in activities of daily living (Kar 2009). Agitation is strongly associated with the activation of the stress response system and associated sleep disturbances, together with the influence of neuromodulation of monoaminergic pathways to the prefrontal cortex (PFC). Neurological evidence suggests that in dementia accompanied by agitation, the prefrontal cortex (PFC) 5-HT 2A Receptor and α 1A The abnormality of the receptors has been pointed out, and it has been shown that antagonists of these receptors can reduce such destructive excitation (Assal et al., 2004; Esiri, 1996; Wang et al., 2009).

[0007] Some second-generation antipsychotics (SGAs) are 5-HT 2A Receptor and α 1A While strongly antagonizing receptors, this drug reduces agitation and associated symptoms in dementia, and its SGA class carries a high burden of side effects and may increase mortality in patients with dementia (Schneider et al., 2006, Greenblatt and Greenblatt 2016, Gareri 2014). Agitation is also known to be associated with various neurodegenerative states (Chaves 2010; Weintraub 2005; Diaz-Olavarrieta C. 1999; Williamson 2016). Therefore, there is a significant unmet medical need for an effective treatment with a safety profile suitable for the long-term management of agitation and associated symptoms in dementia and / or neurodegenerative states.

[0008] International Publication No. WO2013188847 (incorporated herein by reference) discloses a low-dose sublingual formulation of cyclobenzaprine (TNX-102 SL) that has a uniquely reduced production of norcyclobenzaprine, a long-half-life active metabolite, due to rapid transmucosal absorption into the blood and bypass of first-pass liver metabolism. In the elderly population, at an oral dose of 5 mg (IR tablets three times a day [TID]), cyclobenzaprine does not appear to cause excessive drowsiness or reduce performance on cognitive tasks.

[0009] Clinical studies with TNX-102 SL at amounts up to 5.6 mg taken sublingually at bedtime for 12 weeks or longer have shown that TNX-102 SL is well tolerated by patients with fibromyalgia (FM) and posttraumatic stress disorder (PTSD) (Clinical Trials NCT02277704, NCT01903265 and NCT02436096). There were no serious or unexpected central nervous system (CNS)-related adverse events. The systemic adverse events reported with TNX-102 SL were consistent with those listed in the labeling of commercially available cyclobenzaprine products. TNX-102 SL contains cyclobenzaprine, which retains therapeutically important biological activities, including antagonism of 5-HT 2A receptors and α 1A receptors, even in the nanomolar concentration range (see WO2013188847), and has a high safety and tolerance profile at low doses. The cyclobenzaprine sublingual (SL) formulation described herein provides additional advantages in the elderly population, where dysphagia is common (Sura et al 2012).

Prior Art Documents

Patent Documents

[0010]

Patent Document 1

Patent Document 2

[0011] Summary of the Application Disclosure In one aspect, this application discloses a method for treating or preventing agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states. The symptoms may be sleep disorders or non-sleep disorders associated with dementia and / or neurodegenerative states. The method comprises administering a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier to a subject who has dementia or a neurodegenerative state, or who is at risk of developing agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or a neurodegenerative state. In some embodiments, the composition may be administered in doses between 0.1 mg and 30 mg of cyclobenzaprine / day, or between 0.1 mg and 20 mg of cyclobenzaprine / day. In some embodiments, the composition may be administered in doses less than 10 mg of cyclobenzaprine / day or less than 5 mg of cyclobenzaprine / day. In a preferred embodiment, the composition may be administered in a dose of about 5.6 mg of cyclobenzaprine / day. In some embodiments, the composition may be administered at a dose of 2.8 mg cyclobenzaprine / day. The composition may be administered daily or once daily. In some embodiments, the composition is administered simultaneously as two dose units (2.8 mg cyclobenzaprine each). In some embodiments, the composition is administered simultaneously as two dose units, where the total amount of cyclobenzaprine in the two dose units is approximately 5.6 mg.

[0012] In some embodiments, the method may further include the step of administering one or more agents selected from the group consisting of a cholinesterase inhibitor, an N-methyl-D-aspartate (NMDA) receptor antagonist, an antidepressant, an anxiolytic, an antipsychotic, an anticonvulsant or mood stabilizer, an anti-amyloid agent, and an anti-tau agent, either sequentially or simultaneously. In some embodiments, the cholinesterase inhibitor is donepezil, rivastigmine, galantamine, or tacrine. In some embodiments, the NMDA receptor antagonist is amantadine or memantine. In some embodiments, the antidepressant is citalopram, fluoxetine, paroxetine, or sertraline. In some embodiments, the anxiolytic is lorazepam, oxazepam, or buspirone. In some embodiments, the antipsychotic agent is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone. In some embodiments, the anticonvulsant or mood stabilizer is carbamazepine, divalproex, or dextromethorphan. In some embodiments, the anti-amyloid agent is bapineuzumab, solanezumab, or verbecestat. In some embodiments, the anti-amyloid agent and / or anti-tau agent is one or more of the agents described by Cummings et al. (incorporated herein by reference) (Cummings, 2017). In some embodiments, the method may further require the step of administering the physical therapy to the subject sequentially or simultaneously.

[0013] In some embodiments, the pharmaceutical compositions of this application are formulated for sublingual, oral, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, membrane, transdermal, parenteral, rectal, or vaginal administration. In some embodiments, the pharmaceutical compositions are administered in combination with psychotherapeutic interventions, behavioral interventions, or environmental interventions. In some embodiments, the pharmaceutical compositions are administered sublingually, orally, orally, as suppositories, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, via membrane, transdermally, parenterally, rectally, or vaginally.

[0014] In another aspect, the application discloses a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine in combination with one or more agents selected from the group consisting of cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, antidepressants, anxiolytics, antipsychotics, or anticonvulsants or mood stabilizers, anti-amyloid agents, and anti-tau agents. The amount of cyclobenzaprine in the pharmaceutical composition may be any of the following: between 0.1 mg and 30 mg; between 0.1 mg and 20 mg; less than 10 mg; less than 5 mg; about 5.6 mg; or about 2.8 mg. The pharmaceutical composition may be administered daily or once daily.

[0015] In yet another aspect, the present application discloses a method for selecting an effective dose of cyclobenzaprine to be administered to a subject suffering from or at risk of developing dementia or a neurodegenerative condition, as well as excitation, psychosis, and / or cognitive decline and related symptoms in dementia or a neurodegenerative condition. The method includes obtaining a genetic sample from the subject, using the sample to determine the CYP3A, CYP1A2, CYP3A4, or CYP2D6 genotype of the subject, and selecting a therapeutically effective dose of cyclobenzaprine based on the genotype. The CYP3A, CYP1A2, CYP3A4, or CYP2D6 genotype can be determined, for example, by identifying one or more alleles of the gene using a gene chip or PCR technology. Different CYP alleles metabolize cyclobenzaprine at different rates. For individuals having cytochrome alleles known to metabolize cyclobenzaprine more rapidly, a higher dose of cyclobenzaprine is preferably administered. For individuals having isoforms known to metabolize cyclobenzaprine more slowly, a lower dose of cyclobenzaprine is preferably administered. The present invention provides, for example, the following items. (Item 1) A method for treating or preventing excitation and related symptoms in dementia and neurodegenerative conditions, the method comprising administering to a subject having a need or being at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier. (Item 2) A method for treating or preventing cognitive decline and related symptoms in dementia and neurodegenerative conditions, the method comprising administering to a subject having a need or being at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier. (Item 3) A method for treating or preventing psychosis and related symptoms in dementia and neurodegenerative conditions, the method comprising administering to a subject in need thereof or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier. (Item 4) The method according to any one of items 1 to 3, wherein the pharmaceutical composition is administered daily. (Item 5) The method according to item 4, wherein the composition comprises cyclobenzaprine between 0.1 mg and 30 mg. (Item 6) The method according to item 4, wherein the composition comprises cyclobenzaprine between 1 mg and 20 mg. (Item 7) The method according to item 4, wherein the composition comprises less than 10 mg of cyclobenzaprine. (Item 8) The method according to item 4, wherein the composition comprises less than 5 mg of cyclobenzaprine. (Item 9) The method according to item 4, wherein the composition comprises about 5.6 mg of cyclobenzaprine. (Item 10) The method according to item 4, wherein the composition comprises about 2.8 mg of cyclobenzaprine. (Item 11) The method according to item 9, wherein the composition is administered simultaneously as two dosage units, each dosage unit comprising 2.8 mg of cyclobenzaprine. (Item 12) The method according to item 9, wherein the composition is administered simultaneously as two dosage units, and the total amount in the two dosage units is 5.6 mg of cyclobenzaprine. (Item 13) The method according to any one of items 1 to 12, wherein the composition is administered once a day. (Item 14) The method according to any one of items 1 to 3, further comprising the step of administering one or more drugs selected from the group consisting of cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, antidepressants, anxiolytics, antipsychotics, anticonvulsants or mood stabilizers, anti-amyloid agents, and anti-tau agents sequentially or concurrently. (Item 15) The method according to any one of items 1 to 3, further comprising the step of administering physical therapy to the subject sequentially or simultaneously. (Item 16) The method according to item 14, wherein the cholinesterase inhibitor is donepezil, rivastigmine, galantamine, or tacrine. (Item 17) The method according to item 14, wherein the NMDA receptor antagonist is amantadine or memantine. (Item 18) The method according to item 14, wherein the antidepressant is citalopram, fluoxetine, paroxetine, or sertraline. (Item 19) The method according to item 14, wherein the anxiolytic is lorazepam, oxazepam, or buspirone. (Item 20) The method according to item 14, wherein the antipsychotic agent is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone. (Item 21) The method according to item 14, wherein the anticonvulsant or mood stabilizer is carbamazepine, divalproex, or dextromethorphan. (Item 22) The method according to item 14, wherein the anti-amyloid agent is bapineuzumab, solanezumab, or verbecestat. (Item 23) The pharmaceutical composition according to any one of items 1 to 3, formulated for sublingual, oral, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, nasal, via membrane, transdermal, parenteral, rectal, or vaginal administration. (Item 24) The pharmaceutical composition according to any one of items 1 to 3, administered sublingually, orally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, via a thin membrane, percutaneously, parenterally, rectally, or vaginally. (Item 25) The aforementioned pharmaceutical composition is administered in combination with a psychotherapeutic intervention, a behavioral intervention, or an environmental intervention. The method described in any one of items 1 to 3. (Item 26) A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, and one or more agents selected from the group consisting of cholinesterase inhibitors, NMDA receptor antagonists, antidepressants, anxiolytics, antipsychotics, anticonvulsants or mood stabilizers, anti-amyloid agents, and anti-tau agents. (Item 27) The pharmaceutical composition described in item 26, wherein one or more of the aforementioned agents are donepezil, rivastigmine, galantamine, tacrine, amantadine, memantine, citalopram, fluoxetine, paroxetine, sertraline, lorazepam, oxazepam, promazine, aripiprazole, ziprasidone, quetiapine, olanzapine, risperidone, carbamazepine, divalproex, or dextromethorphan. (Item 28) The composition is the pharmaceutical composition described in item 26, comprising 0.1 mg to 30 mg of cyclobenzaprine. (Item 29) The composition is the pharmaceutical composition described in item 26, comprising 0.1 mg to 20 mg of cyclobenzaprine. (Item 30) The aforementioned composition is the pharmaceutical composition described in item 26, comprising less than 10 mg of cyclobenzaprine. (Item 31) The aforementioned composition is the pharmaceutical composition described in item 26, comprising less than 5 mg of cyclobenzaprine. (Item 32) The composition is the pharmaceutical composition described in item 26, comprising approximately 5.6 mg of cyclobenzaprine. (Item 33) The composition is the pharmaceutical composition described in item 26, comprising approximately 2.8 mg of cyclobenzaprine. (Item 34) A method for selecting a therapeutically effective dose of cyclobenzaprine for a subject suffering from dementia and neurodegenerative conditions, or at risk of one or more of the following conditions in dementia and neurodegenerative conditions: (1) A step of obtaining a gene sample from the subject, (2) A step of determining the CYP3A, CYP1A2, CYP3A4, or CYP2D6 genotype of the subject using the sample. (3) A step of selecting a therapeutically effective dose of cyclobenzaprine based on the genotype, A method of including. (Item 35) The CYP3A, CYP1A2, CYP3A4, or CYP2D6 genotype is determined using a gene chip or PCR technology, as described in item 34. [Modes for carrying out the invention]

[0016] Detailed explanation Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings generally understood by those skilled in the art. In case of any conflict, this specification shall prevail, including definitions.

[0017] Throughout this specification and its embodiments, variations such as “comprise,” “comprises,” or “comprising” are understood to mean the inclusion of the described complete or group of completes, but not the exclusion of any other complete or group of completes.

[0018] The terms "including" or "includes" are used to mean "including but not limited to." "Includes" and "includes but not limited to" are interchangeable.

[0019] Any examples following the term "e.g." or "for example" are not intended to be exhaustive or limiting.

[0020] Unless otherwise required by the circumstances, singular terms shall include their plural forms, and plural terms shall include their singular forms.

[0021] The articles “a,” “an,” and “the” are used herein to refer to one or more (i.e., at least one) grammatical objects of the articles.

[0022] Although the disclosed numerical ranges and parameters are approximate, the numbers shown in the specific examples are reported as accurately as possible. However, any numbers inherently contain a certain degree of error that inevitably arises from the standard deviation found in each of those test measurements. Furthermore, it should be understood that all ranges disclosed herein encompass any and all subranges incorporated therein. For example, the range stated as "1 to 10" should be interpreted as encompassing any and all subranges between the minimum value of 1 and the maximum value of 10 (and including both ends); that is, all subranges starting at the minimum value of 1 or greater (e.g., 1 to 6.1) and ending at the maximum value of 10 or less (e.g., 5.5 to 10).

[0023] Where a situation or embodiment is described in relation to the Markush Group or other grouping of options, this application as a whole encompasses not only the entire enumerated group, but also each member of the group individually, as well as all possible subgroups of the principal group and the principal group in which one or more of its members do not exist. This application also assumes the explicit exclusion of one or more of the members of the group in its embodied disclosure.

[0024] While exemplary methods and materials are described herein, similar or equivalent methods and materials may also be used in the implementation or testing of various aspects and embodiments thereof. These materials, methods, and examples are illustrative and not intended to be limiting.

[0025] definition To make this disclosure more easily understandable, certain terms are first defined. These definitions should be read and understood in light of the remainder of this disclosure as they would be understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would be generally understood by those skilled in the art. Further definitions are provided throughout the detailed description.

[0026] In one aspect, this application discloses methods for treating or preventing agitation, psychosis and / or cognitive decline and associated symptoms in dementia or neurodegenerative states.

[0027] The above method comprises the step of administering a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier to a subject who has a need for or is at risk of having such a condition. The symptoms may be sleep disorders or non-sleep disorders.

[0028] As used herein, the term “treat” and its related terms refer to the complete or partial direct improvement or modulation of agitation, psychosis, and / or cognitive decline or at least one recognizable symptom in dementia or neurodegenerative conditions. In some embodiments, “treat” means improvement or direct improvement of agitational behavior as measured on the Cohen-Mansfield Agitation Scale (CMAI), which consists of a diverse range of agitational behaviors (each assessed on a multi-point scale of frequency). A subject’s CMAI agitation score may be measured before and after treatment. An improved score indicates a successful “treatment” (see, e.g., Mansfield, 1991). In certain embodiments, “to treat” means improvement or direct improvement in agitational behavior as measured by the Modified Alzheimer's Disease Cooperative Study Clinical Global Impression of Change Agitation Domain (mADCS-CGIC-Agitation) score. The standard ADCS-CGIC assessment has been modified to better evaluate aspects related to studying agitation in Alzheimer's disease (Drye et al., 2012). The mADCS-CGIC-Agitation assessment includes questions about agitation and an assessment of the clinician’s impression of change that specifically focuses on agitation. In certain embodiments, “to treat” and its corollaries mean slowing or reversing the progression of agitation, psychosis and / or cognitive decline and associated symptoms in dementia or neurodegenerative states compared to an untreated control. In some embodiments, “to treat” and its corollaries mean to inhibit or reduce the progression of agitation, psychosis and / or cognitive decline and associated symptoms in dementia or neurodegenerative conditions.In some embodiments, “to treat” and its corollaries mean reducing the severity of agitation, psychosis, and / or cognitive impairment in the subject. In some embodiments, “to treat” means improvement in cognition as measured by the Alzheimer's Disease Assessment Scale-Cog (ADAS-Cog) and / or the Mini-Mental State Examination (MMSE). The subject’s cognitive score may be measured before and after treatment. An improved score indicates a successful “treatment” (see, e.g., Fleisher 2007 and Folstein 1975).

[0029] As used herein, “prevent” and its related terms mean delaying the onset of agitation, psychosis, and / or cognitive decline or related symptoms in dementia or neurodegenerative conditions, or delaying the time of recurrence, or reducing the risk of such occurrence, compared to an untreated control. As used herein, “delaying the time of the reoccurrence” and its related terms mean delaying the recurrence of agitation, psychosis, and / or cognitive decline or related symptoms in dementia or neurodegenerative conditions, in individuals who are prone to developing such agitation, psychosis, and / or cognitive decline or related symptoms, or in individuals who have previously developed such agitation, psychosis, and / or cognitive decline or related symptoms, compared to an untreated control.

[0030] As used herein, the term “agitation” means agitation and symptoms of agitation in dementia and / or neurodegenerative states, as well as related symptoms. These symptoms include: changes in personality, general emotional distress (rapid mood swings, irritability, and outbursts), anxiety, depression, delusions (firm beliefs about things that are not real), hallucinations (seeing, hearing, or feeling things that are not there), excessive motor activity (e.g., pacing, constant movement, rocking, gestures, pointing, restlessness, performing repititious behaviors). Mannerisms, checking and rechecking doors or fixtures, tearing tissues, unusual abusive language or threats. Behaviors associated with agitation may be persistent or recur frequently for at least two weeks and may indicate a deviation from the patient's normal behavior. Further symptoms associated with agitation in dementia and / or neurodegenerative states include, but are not limited to, delirium, psychosis, cognitive decline, sleep disorders, insomnia, evening syndrome, aggression, belligerence, mood instability, anger, pain, akathisia, compulsive behaviors, obsessions, and urinary incontinence. Many symptoms associated with agitation in degenerative states include, but are not limited to, verbal aggression (e.g., yelling, speaking excessively loudly, using blasphemous language, shouting, yelling); physical aggression (e.g., grabbing, poking, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing things, and destroying possessions); and significant impairment in one or more of the following: interpersonal relationships, other aspects of social functioning, and the ability to perform or participate in activities of daily living (Alexopoulos et al. 1998; Gareri 2014; Rose et al. 2015; Shneider et al. 2005, Alzheimer's Association 2004).All other symptoms, as defined by the International Psychogeriatric Association Agitation Definition Work Group (Cummings 2014), are included herein. These symptoms are generally measured by techniques known to a clinician with ordinary experience in the field.

[0031] As used herein, the term “sleep disturbance” means a set of symptoms including difficulty falling asleep, early morning awakening, nightmares, and poor quality sleep. Sleep quality (“sleep disturbance”) may be determined, among other things, by asking the patient whether he / she wakes up tired or unable to recover from fatigue “never,” “seldom,” “often or usually,” or “always.” Responses “often or usually” or “always” may be scored as positive, while other responses may be scored as negative. Patient reports of feeling healthy, or free from feelings of "zombie" or "spacey," "run down," and difficulty concentrating during waking hours, are signs of better sleep quality or deeper, restorative sleep. A commonly used assessment scale for evaluating sleep quality is the Functional Outcomes of Sleep Questionnaire (FOSQ), described in Weaver et al., (1997).

[0032] As used herein, the term “sundowning” refers to neuropsychiatric symptoms and behavioral disturbances occurring at dusk and / or after dusk in subjects with dementia and / or neurodegenerative conditions. Sundowning is associated with circadian rhythm disturbances. It includes one or more of the following: anxiety, agitation, aggression, pacing, wandering, defiance, shouting, yelling, visual and auditory hallucinations, sleep disorders, and confusion (see, e.g., Canavelli et al., 2016; Shih, et al., 2017).

[0033] As used herein, “dementia” means a broad range of conditions associated with a long-term and gradual decline in memory or other cognitive abilities, severe enough to reduce an individual’s ability to perform daily activities. It may be associated with inflammation in the brain and other parts of the body. Dementia may be associated with one or more of the following: Alzheimer’s disease (AD), Parkinson’s disease (PD), vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease (CJD), normal pressure hydrocephalus, Huntington’s disease (HD), Wernicke-Korsakoff syndrome, head trauma, alcoholism, viral or bacterial infection, drug side effects, pneumonia, dehydration, malnutrition, bladder infection, diabetes, and asthma. Subjects at risk of developing dementia include subjects with mild cognitive impairment. Dementia refers to the condition as defined by the DSM-5 guidelines, where dementia is associated with a moderate or substantial decline in cognitive function and is referred to as mild neurocognitive disorder or major neurocognitive disorder (Sachdev 2015).

[0034] As used herein, the term “neurodegenerative condition” and its related terms refer to diseases affecting neurons in the human central or peripheral nervous system. These neurodegenerative conditions may be associated with abnormal protein aggregation and accumulation, as well as / or inclusion body formation (Ross and Poirier, 2004; Chaves 2010). For example, the accumulated proteins may be α-synuclein, amyloid-beta, and tau proteins. In some embodiments, neurodegenerative conditions may include conditions in which inflammatory cytokines are associated with the pathogenesis of the condition, e.g., multiple sclerosis and traumatic brain injury. Neurodegenerative conditions may also include: PD, AD, HD, amyotrophic lateral sclerosis (ALS), motor neuron diseases, schizophrenia, multiple system atrophy, synucleopathies, Lewy body dementia, and frontotemporal dementia. (e.g., Chaves 2010; Weintraub) See 2005; Diaz-Olavarrieta C. 1999; Williamson 2016.

[0035] The terms "patient," "subject," or "individual" are interchangeable and preferably refer to a human being.

[0036] As used herein, the term "cyclobenzaprine" means cyclobenzaprine or its metabolites, or cyclobenzaprine prodrugs or their metabolites. Cyclobenzaprine metabolites useful according to the methods of this application are those that have substantially the same or better activity as cyclobenzaprine in alleviating agitation or related symptoms in dementia and / or neurodegenerative states. Cyclobenzaprine metabolites that may be useful according to this application include CBP 10,11-trans-dihydricol, N-desmethyl-2-hydroxycyclobenzaprine, 3-hydroxycyclobenzaprine, N-desmethylcyclobenzaprine, cyclobenzaprine N-oxide, or chiral isomers of these metabolites. Cyclobenzaprine prodrugs are derivatives of cyclobenzaprine that are metabolized in vivo to their active agents. A useful prodrug in accordance with this application is a prodrug having substantially the same or better activity as cyclobenzaprine in treating or preventing agitation, psychosis and / or cognitive decline and associated symptoms in dementia or neurodegenerative states. Methods for preparing prodrugs are readily known in the art (e.g., Balant, et al. 1990; Bund-gaard, H et al. 1991 (as incorporated herein by reference)).

[0037] As used herein, the term “therapeutically effective amount” of cyclobenzaprine means the amount of the compound (as defined herein) that treats or prevents agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states. A physician may readily determine, for example, through clinical observation of the subject or through reports of symptoms by the subject or their caregiver during the course of treatment, when symptoms are treated or prevented. A person skilled in the art may readily determine the amount of cyclobenzaprine to be administered by considering factors such as the subject’s size, weight, age, and sex, the degree or duration of disease penetration and the severity of symptoms, and the route of administration. Generally, therapeutically effective amounts of cyclobenzaprine administered to a subject are between 0.1 mg and 30 mg / day, between 1 and 20 mg / day, less than 10 mg / day, less than 5 mg / day, about 5.6 mg / day, or about 2.8 mg / day. Higher or lower doses are also intended.

[0038] As used herein, the term “about” refers to a value or parameter that includes (and describes) embodiments relating to the value or parameter itself. For example, a statement referring to “about X” refers to the value or parameter X. This includes embodiments relating to the meter itself. As used herein, the term “about” allows for a variation of ±10% within the range of significant figures.

[0039] As used herein, the terms “agent” mean a biological or chemical substance or compound that can be used to treat or prevent a condition in a subject. In some embodiments, the agent is an antibody. The condition may be a symptom of dementia and / or neurodegenerative conditions (including, but not limited to, anxiety, psychosis, cognitive decline, mood swings, agitation, seizures, abnormal neuroscientific phenomena contributing to the pathogenesis of dementia and / or neurodegeneration, and protein aggregation and accumulation contributing to the pathogenesis of dementia and / or neurodegeneration (e.g., amyloid plaque accumulation and abnormal tau deposition)) (see Cummings, 2017).

[0040] As used herein, the term “somatic treatment” refers to an intervention administered to a subject, including but not limited to electroconvulsive therapy, magnetic therapy, transcranial magnetic stimulation, transcranial direct stimulation, cranial electric stimulation, vagus nerve stimulation, epidural electric stimulation, or deep brain stimulation (see Rosa and Lisanby, 2012).

[0041] In some embodiments, the cyclobenzaprine is administered in doses that minimize or reduce any side effects observed at higher doses. These doses include approximately 5.6 mg / day, less than 5 mg / day, or approximately 2.8 mg / day. Even lower doses are also considered. In general, cyclobenzaprine treatment may be given indefinitely to treat or prevent agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states, and the frequency and / or amount of administration may be modified as needed. The duration of treatment should be as long as necessary to treat or prevent agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states. In some embodiments, the cyclobenzaprine is administered at bedtime in an appropriate dose. The dose may be gradually increased or decreased.

[0042] In some embodiments of this application, cyclobenzaprine is administered in combination with one or more agents that can further alleviate agitation, psychosis and / or cognitive decline and associated symptoms in dementia or neurodegenerative states. These agents may be administered sequentially or concurrently with cyclobenzaprine. Examples of these agents include one or more cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, antidepressants, anxiolytics, antipsychotics, anticonvulsants or mood stabilizers, anti-amyloid agents, and anti-tau agents. Examples of cholinesterase inhibitors include, but are not limited to, donepezil, rivastigmine, galantamine, or tacrine. Examples of N-methyl-D-aspartate receptor antagonists include, but are not limited to, amantadine or memantine. Examples of N-antidepressants include, but are not limited to, citalopram, fluoxetine, paroxetine, or sertraline. Examples of anxiolytics include, but are not limited to, lorazepam, oxazepam, or buspirone. Examples of antipsychotics include, but are not limited to, quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone. Examples of anticonvulsants or mood stabilizers include, but are not limited to, carbamazepine, divalproex, or dextromethorphan. Examples of anti-amyloid agents include, but are not limited to, bapineuzumab, solanezumab, or verbecestat. In some embodiments, subjects are administered approximately 1.0 mg / day of lorazepam sequentially or concurrently with the cyclobenzaprine composition of the present disclosure to treat agitation, psychosis and / or cognitive decline and associated breakthrough symptoms in dementia or neurodegenerative states.

[0043] In another aspect, this application discloses a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine in combination with one or more agents selected from the group consisting of cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, antidepressants, anxiolytics, antipsychotics, anticonvulsants or mood stabilizers, anti-amyloid agents, and anti-tau agents. Generally, the amount of cyclobenzaprine in the pharmaceutical composition is between 0.1 mg and 30 mg, or between 1 mg and 20 mg. Higher or lower doses are also intended. In some embodiments, the amount of cyclobenzaprine is less than 10 mg, less than 5 mg, about 5.6 mg, or about 2.8 mg. Even lower doses are also intended. In some embodiments, cyclobenzaprine is combined with at least one agent that can further alleviate symptoms of agitation, psychosis, and / or cognitive decline in dementia or neurodegenerative states, as well as related symptoms. The drug may be administered sequentially or simultaneously with the cyclobenzaprine composition of the present invention.

[0044] Any suitable route of administration may be used to provide the composition of this application to the subject. For example, sublingual, oral, oral, rectal, vaginal, suppository, parenteral, transdermal, intranasal, inhalation, and thin film administration may be used as appropriate. As used herein, parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrabursal, intrasternal, intrathecal, intrathecal, intralesional, and intracranial administration or other infusion techniques. Useful forms of administration in this application may include: tablets (e.g., scored tablets, coated tablets, or orally dissolving tablets); thin films, powders, caplets, capsules (e.g., hard gelatin capsules), lozenges, sugar-coated tablets, dispersions, suspensions, liquids, patches, etc. (including sustained-release, prolonged-release, delayed-release, and modified-release formulations known in the art). In preferred embodiments, the dosage form is a sublingual tablet, sublingual film, liquid, sublingual powder, or sublingual spray solution.

[0045] As used herein, the term “pharmaceutically acceptable carrier” refers to any diluent or excipient that is compatible with the other components of the above-mentioned formulation and is not harmful to the subject. The pharmaceutically acceptable carrier may be selected based on the desired route of administration in accordance with standard pharmaceutical practice.

[0046] The pharmaceutical compositions of this application for parenteral administration may take the form of aqueous or non-aqueous liquids, dispersions, suspensions, or emulsions. In preparing the pharmaceutical compositions of this application for parenteral administration, cyclobenzaprine may be mixed with a suitable pharmaceutically acceptable carrier (e.g., water, oil (especially vegetable oil), ethanol, physiological saline (e.g., ordinary saline), aqueous dextrose (glucose) and related sugar solutions, glycerol, or glycol (e.g., propylene glycol or polyethylene glycol)). The pharmaceutical compositions of this application for parenteral administration preferably comprise a water-soluble salt of cyclobenzaprine. Stabilizers, antioxidants, and preservatives may also be added to the pharmaceutical compositions for parenteral administration. Suitable antioxidants include sulfites, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol.

[0047] In preparing the pharmaceutical compositions of this application for sublingual administration, cyclobenzaprine may be combined with one or more solid or liquid inert components to form tablets, capsules, pills, powders, granules, sprays, or other suitable sublingual administration forms. For example, cyclobenzaprine may be combined with at least one pharmaceutically acceptable carrier (e.g., solvent, filler, binder, humectant, disintegrant, solution retarder, absorption enhancer, wetting agent, absorbent, or lubricant). In one embodiment, cyclobenzaprine is combined with carboxymethylcellulose calcium, magnesium stearate, mannitol, or starch and formed into tablets by conventional tablet-forming methods. Pharmaceutical compositions suitable for use in this application are described, for example, in WO2013188847.

[0048] The pharmaceutical compositions of this application may be formulated to provide sublingual absorption, including sublingual tablets, sublingual thin film formulations, sublingual powders, and sublingual spray solutions, to provide faster absorption than the oral / GI route and to bypass first-pass hepatic metabolism of cyclobenzaprine by cytochrome P-450 A4 as a CYP3A substrate. Preferably, the controlled-release pharmaceutical compositions of this application may release cyclobenzaprine to a subject at a desired rate to maintain substantially constant or desired pharmacological activity over a predetermined period, reduce or eliminate the effect of food on absorption, and provide elimination of the drug and its metabolites from the body in a reduced final elimination phase. As used herein, “controlled-release component” is a compound (e.g., a lipid or mixture of lipids, liposomes and / or microspheres) that induces controlled release of cyclobenzaprine to the subject upon exposure to certain physiological compounds or conditions. For example, the controlled-release component may be biodegradable or activated by exposure to a specific pH or temperature, by exposure to an aqueous environment, or by exposure to an enzyme. An example of a controlled-release component activated by exposure to a specific temperature is a sol-gel. In this embodiment, cyclobenzaprine is incorporated into a sol-gel matrix that is solid at room temperature. This sol-gel matrix is ​​then transplanted into a subject with a body temperature high enough to induce gel formation of the sol-gel matrix, thereby releasing its active component into the subject.

[0049] The formulation of the pharmaceutically controlled-release compositions of this application is within the scope of the art. Suitable controlled-release formulations for use in this application are, for example, described in U.S. Patent No. 5,674,533 (Liquid Dosage Form), U.S. Patent No. 5,591,767 (Liquid Reservoir Transdermal Patch), U.S. Patent No. 5,120,548 (Device Containing a Swellable Polymer), U.S. Patent No. 5,073,543 (Ganglioside-Liposome Vehicle), and U.S. Patent No. 5,639,476 (Stable Solid Formulation Coated with Hydrophobic Acrylic Polymer) (these disclosures in their entirety are incorporated herein by reference).

[0050] Biodegradable microparticles may also be used to formulate pharmaceutically controlled-release compositions suitable for use in this application, as described, for example, in U.S. Patent Nos. 5,354,566 and 5,733,566 (these disclosures in their entirety are incorporated herein by reference).

[0051] The compositions of this application may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulations and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0052] The therapeutically effective dose of a composition for the prevention or treatment of agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states varies depending on the type of distress, the severity of the patient's distress, and the route of administration. Its daily dose and frequency of administration also vary according to the individual patient's age, weight, and response. However, its preferred dose is 18 mg or less per day. In a preferred embodiment, the composition is administered in a daily dose at bedtime or several hours before bedtime to promote sleep that achieves depth and recovers from fatigue. Bedtime can be any time of day when a particular individual is drawn into their longest sleep cycle.

[0053] Any of the above treatment methods may be combined with psychotherapeutic behavioral or environmental interventions to improve the outcome of the treatment. Particularly useful are interventions aimed at somehow managing the agitation, including (1) identifying the behavior, (2) understanding the cause of the behavior, and (3) adapting the care environment to alleviate the situation. Precisely identifying what triggers the agitational behavior can often help in selecting the best behavioral intervention. Such interventions may include education and support for family and caregivers, reassurance and socialization of structured routines, supervision, and environmental safety (see Alexopoulos et al, 1998).

[0054] As used herein, the term “genetic sample” refers to a deoxyribonucleic acid (DNA) sample obtained from a subject. For example, such a sample may be collected from tissue or bodily fluids (including, but not limited to, blood, hair, skin, saliva, or oral swabs). A skilled technician may then use methods well known in the art to isolate the DNA from the sample and identify the genetic variations of the cytochrome P450 (CYP) gene present in the subject.

[0055] In another aspect of this application, pharmacogenomic testing measuring the cytochrome CYP3A4, CYP1A2, CYP3A, and CYP2D6 genotypes of subjects suffering from dementia or a neurodegenerative state, or at risk of developing agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or a neurodegenerative state, may be used to estimate the metabolism of cyclobenzaprine by those subjects and, therefore, the preferred dose to be used. Accordingly, one aspect of the disclosure of this application provides a method for obtaining a genetic sample from the subject, using the sample to determine the CYP3A, CYP1A2, CYP3A4, or CYP2D6 genotype of the subject, and selecting a therapeutically effective dose of cyclobenzaprine based on that genotype. The CYP3A, CYP1A2, CYP3A4, or CYP2D6 genotype may be determined, for example, by identifying one or more alleles of the gene using a gene chip or PCR technology. Different CYP alleles metabolize cyclobenzaprine at different rates. Individuals with a cytochrome allele found to metabolize cyclobenzaprine more rapidly should preferably be administered a higher dose of cyclobenzaprine. Individuals with an isoform found to metabolize cyclobenzaprine more slowly should preferably be administered a lower dose of cyclobenzaprine. The genetic testing can be sold as a kit to physician / laboratory testing services along with the above product.

[0056] Examples are provided below to allow for a more complete understanding of this application. These examples are for illustrative purposes only and should not be construed in any way as limiting the scope of this application. The implementation of this application is illustrated by the following non-limiting examples. [Examples]

[0057] Example 1. Cyclobenzapurine sublingual formulation TNX-102 SL One sublingual formulation disclosed in this application (TNX-102 SL) comprises a eutectic complex of cyclobenzaprine hydrochloride (active ingredient) and D-mannitol. It also contains a potassium salt (dibasic). Table 1 shows the composition of TNX-102 SL tablets. [Table 1]

[0058] Example 2. Determination of the safety of the TNX-102 SL formulation in test subjects. To date, a total of 10 clinical trials using TNX-102 SL have been completed to determine the safety of TNX-102 SL formulation in nocturnal administration in human subjects: Five Phase 1 trials in healthy volunteers (data not shown), two Phase 2 trials in patients with FM and PTSD; one Phase 3 trial in patients with FM; and two open-label extension studies in patients with FM and PTSD. In the five completed clinical trials in patients with FM and PTSD, a total of 641 patients received at least one dose of TNX-102 SL administered once daily at bedtime ("combined TNX102 SL safety population"): 197 patients with PTSD and 444 patients with FM. Of the PTSD patients, 50 received 5.6 mg (two sublingual tablets), and the remainder received 2.8 mg (one sublingual tablet) of TNX-102 SL. See Table 2. [Table 2]

[0059] result Combined TNX-102 SL safety group Overall, TNX-102 SL was well-tolerated in both FM and PTSD patients. The most common adverse events (≥ 5% incidence) thought to be associated with TNX-102 SL administration were oral hypoesthesia and oral paresthesia, as well as systemic effects such as somnolence and fatigue. All reported systemic effects were consistent with the adverse effect profile of cyclobenzaprine, but not with commercially available oral formulations (e.g., immediate-release FLEXERIL). (登録商標) and sustained-release AMRIX (登録商標) The frequency was generally lower than that reported in [the relevant study]. No new drug interactions have been identified to date.

[0060] The condition of the local injection site could not be predicted, so it may be a result of the local anesthetic properties of the tricyclic molecule caused by the blockade of sodium channels (Pancrazio et al.). (1998). Aside from its typical mild and transient local administration site conditions, such as occasional reports of mild to moderate oral irritation, tingling, or burning sensation in the mouth, bitterness, and the mild to moderate oral irritation expected with sublingual TNX-102 SL, the overall adverse event profile at both the 2.8 mg and 5.6 mg daily doses was mild.

[0061] The inventors also evaluated the safety profile of blinded safety data (N=71) from an ongoing placebo-controlled phase 3 trial of TNX-102 SL 5.6 mg in patients with military-related PTSD (TNX-CY-P301). As of August 31, 2017, the safety profile of these patients was comparable to the adverse event profile observed in the phase 2 PTSD trial (TNX-CY-P201). There were no unexpected systemic adverse events, including no serious central nervous system-related adverse events, and the most common events (≥ 5% incidence, listed in descending order of incidence) were oral hypoesthesia, somnolence, and dry mouth.

[0062] Incidence of adverse events by age group Patients who received at least one dose of TNX-102 SL ranged in age from 21 to 75 years. As summarized in Table 2, of the 641 patients who received at least one dose of TNX-102 SL, 241 were ≥50 years old and 400 were <50 years old; the majority received the 2.8 mg dose, with only 3 patients ≥50 years old receiving the 5.6 mg dose (age range: 54–59 years). No age-specific safety signs related to the treatment were identified.

[0063] Anticholinergic events Overall, adverse events identified in the TNX-102 SL safety population combined with TNX-102 SL (occurring in >2 patients in either the combined TNX-102 SL safety population or any age group subset, and in the placebo group) that may be partly attributable to anticholinergic effects were somnolence (5.8%) / sedation (2.2%), fatigue (5.0%), and constipation (2.2%) (Note: Somnolence and sedation appeared to represent similar adverse events).

[0064] Safety data from the AtEase trial suggested that somnolence and sedation were dose-related, while constipation and fatigue were not. In both cohorts (TNX-102 SL 2.8 mg or TNX-102 SL 5.6 mg), almost all of these events were mild to moderate in severity. Assuming that plasma cyclobenzaprine concentrations peak 4-5 hours after TNX-102 SL administration, the TNX-102 SL administration regimen (once daily at bedtime) would likely minimize daytime effects such as somnolence, sedation, and fatigue. Among the potentially anticholinergic adverse events associated with TNX-102 SL, only constipation and fatigue had significantly higher incidences in the elderly population compared to the younger population (3.7% and 7.1%, respectively) (approximately 2.8 times and 1.7 times higher, respectively); however, this relatively increased incidence in the elderly group was also observed in the placebo group.

[0065] The following adverse events, which may be considered anticholinergic, did not occur at increased incidence in the combined TNX-102 SL safety population compared to the placebo group: dizziness, lethargy, memory impairment, confusion, disorientation, worsening of balance, dry mouth, thirst, urinary tract infection, and vertigo. Other potential anticholinergic adverse events (including hallucinations, blurred vision, diplopia, delirium, nasal dryness, dry eyes, dysuria, decreased sweating, and decreased saliva) were not reported in the combined TNX-102 SL safety population.

[0066] Other adverse events of concern Certain other adverse events of concern (including syncope, dysphagia, bruising, falls, aggression / aggressive behavior (not reported), agitation (not reported), hypotension (not reported), hypotension (not reported), or any cardiac or hepatic events) did not appear to be associated with TNX-102 SL in any age group.

[0067] Dose-related adverse events The only clinical safety and efficacy study evaluating two different doses of TNX-102 SL (i.e., 2.8 mg and 5.6 mg) is the AtEase Study / P201, conducted in patients with military-related PTSD (see Table 2). In the AtEase Study, safety data are available for 50 PTSD patients who received at least one dose of TNX-102 SL 5.6 mg. The 5.6 mg dose demonstrated good tolerability (83.6% vs. 72.8%, respectively) and a lower incidence of adverse event-related discontinuation (0.0% vs. 3.2%, respectively), as indicated by a higher completion rate in the placebo group. The safety profile of the 5.6 mg dose was comparable to that of the 2.8 mg dose, and the following adverse events suggest a dose-relationship based on numerical differences: somnolence / sedation, headache, and possibly glossodynia. Importantly, there was no evidence of an increased risk of suicidal ideation or behavior associated with TNX-102 SL treatment at any dose.

[0068] Example 3. Safety profile of commercially available oral cyclobenzaprine products To assess the safety profiles of commercially available oral cyclobenzaprine products and potential concerns regarding drug interactions with commercially available Alzheimer's disease therapies, a thorough search was conducted using public databases and literature (including PubMed, NIH Drug Reaction Navigator, Medscape Drug Interaction Checker, Drugs.com, and the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS)). Two types of oral cyclobenzaprine formulations are commercially available: cyclobenzaprine IR (5 mg or 10 mg TID; i.e., FLEXERIL) and cyclobenzaprine ER (15 mg BID or QD or 30 mg QD; i.e., AMRIX). Both formulations are typically administered at doses at least 2 to 3 times higher than TNX-102 SL 5.6 mg, which is sublingually administered once daily at bedtime and is suggested for the treatment of agitation in dementia.

[0069] It is noteworthy that these safety data are based on administration of higher doses than the preferred cyclobenzaprine 5.6 mg daily dose in this application, and are therefore expected to be associated with increased adverse events. The most commonly reported adverse events for both formulations (FLEXERIL and AMRIX) include drowsiness / somnolence, dry mouth, dizziness, and fatigue, as well as constipation, nausea, and dyspepsia, which were frequently reported, particularly in patients receiving the cyclobenzaprine ER formulation (AMRIX Package Insert, 2016; FLEXERIL Package Inserts, 2013). The incidence of adverse events of particular concern in elderly patients and / or events considered to be anticholinergic in patients receiving FLEXERIL 10 mg, reported in clinical trials or post-marketing, was low. Confusion and blurred vision were reported in 1%–3% of patients. The following were reported in <1% of patients: cardiovascular events (tachycardia, arrhythmia, vasodilation, palpitations, and hypotension), neurological and psychiatric adverse events (e.g., seizure, agitation, vertigo, disorientation, excitement, hallucinations, and diplopia), and urinary retention (AMRIX Package Inserts, 2016; FLEXERIL Package Inserts, 2013). Notably, in a post-marketing study conducted in 1980 (N=6,311) after 20 years of experience and more than 100,000,000 prescriptions of cyclobenzaprine 10 mg, the incidence of hallucinations was found to be 0.2% (mostly in elderly patients), and the event was attributed to 5 mg TID (FLEXERIL). (登録商標) In patients who ingested the OTC Switch (NDA 21079, FDA Safety Review: July 20, 1999), the effects were mostly reversible and likely dose-related, as no cases were reported.

[0070] These findings indicate that the preferred TNX-102 SL formulation has minimal side effects in elderly populations with agitation, psychosis, and / or cognitive decline and related symptoms in dementia or neurodegenerative states.

[0071] Example 4. Testing of cyclobenzaprine in elderly patients The effects of cyclobenzaprine IR 5 mg on psychomotor function were investigated in a crossover study of cyclobenzaprine IR 5 mg TID, diphenhydramine 50 mg TID, and placebo in elderly healthy volunteers (62–80 years old, N=17) (Lines et al., 1997). Each treatment was administered in 10 doses over 4 days. There was no evidence of drowsiness or impaired cognitive test performance in this patient population. Notably, less sedation and cognitive impairment were observed in this elderly population compared to the younger population in previous studies. Consistent with these findings, results from psychomotor function tests conducted by the manufacturer (Merck; FLEXERIL® OTC Switch NDA 21079 FDA Safety Review: July 20, 1999) also showed no consistent pattern of psychomotor function impairment when measured by computerized test batteries, including the assessment of driving-related skills in older patients (≥ 65 years old, N=32), and the results were similar to those in younger populations (21–49 years old).

[0072] Precautions for the use of anticholinergics and muscle relaxants in elderly patients There are recommendations for potentially inappropriate drug use in older adults (e.g., the Beers Criteria; American Geriatric Society, 2015). Anticholinergic drugs, which are muscle relaxants, are listed as potentially inappropriate, primarily due to their effects on cognitive function and neurological effects, as well as secondary adverse events (e.g., falls). Cyclobenzaprine (IR 5-10 mg TID and ER 15 mg BID / QD-30 mg QD) is given a score of 2 on the anticholinergic load scale out of 3, primarily due to its anticholinergic activity and long half-life (Rudolph et al., 2008). It should be noted that these recommendations are based on higher doses than the TNX-102 SL dose proposed in this application, which studies a target population with caregivers. The most commonly reported anticholinergic adverse event associated with cyclobenzaprine administration is dose-related dry mouth; this is considered tolerable given the potential clinical benefits of TNX-102 SL and is of minimal clinical importance. All other potential anticholinergic effects in patients receiving cyclobenzaprine IR 10 mg were reported at low incidence: tachycardia (<1%), urinary retention (<1%), confusion (1%–3%), and blurred vision (1%–3%). Data are not available for cyclobenzaprine 5 mg IR. Overall, adverse central nervous system effects and poor cognitive and functional outcomes associated with high anticholinergic load scores were generally not observed with cyclobenzaprine (i.e., incidence <1%–3%).

[0073] Drug-drug interactions For the treatment of agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states, most patients are likely taking one of the four current prescription drugs for dementia (donepezil, rivastigmine, galantamine, and memantine). Three of these drugs (donepezil, rivastigmine, and galantamine) have anticholinesterase activity as their mechanism of action. Therefore, their product labels recommend avoiding co-administration with anticholinergics due to opposing activity. Cyclobenzaprine was not specifically mentioned in searches for drug interactions between cyclobenzaprine and these four drugs in PubMed, NIH Drug Reaction Navigator, Medscape Drug Interaction Checker, and Drugs.com, and no reports of interactions were found.

[0074] Furthermore, a preliminary search of the FDA's Adverse Event Reporting System (FAERS) was conducted to identify all reported AEs during the first quarter of 2017 in which both an AD drug and cyclobenzaprine were reported as suspected drugs. The following product active ingredients were used to retrieve AD drug-related events from the FAERS database as either the primary or secondary suspected drug: donepezil, rivastigmine, galantamine, and memantine. These events were then filtered to select those involving cyclobenzaprine as some suspected cause. Of the 296 specific cases retrieved using the above search criteria and filters, only one case was identified in which both cyclobenzaprine and an AD drug (galantamine) were listed as suspected drugs. None of the drugs were the primary suspected drug in this patient, as she was receiving multiple therapies. Further details of this case are provided below. A 77-year-old female patient (Case ID: 13227232) receiving multiple therapies was identified. The reported adverse events included balance disorders, cognitive impairment, constipation, falls, hypotension, multiple drug therapy, orthostatic hypotension, sedation, and toxicity to various drugs. In the patient, morphine sulfate was identified as the primary suspected drug for the reported adverse events, and cyclobenzaprine and galantamine were identified as secondary suspected drugs, in addition to 23 other drugs.

[0075] Guidelines for the use of cyclobenzaprine in the elderly Pharmacokinetic data showed that plasma concentrations of cyclobenzaprine were increased in elderly subjects compared to younger subjects (up to 1.7 times and 1.4 times higher for IR and ER formulations, respectively). Therefore, for cyclobenzaprine IR, it is recommended to start treatment with a 5 mg dose, while having the option of slow upward titration. Furthermore, the product labeling for cyclobenzaprine IR should note that "given that elderly patients may be at greater risk of central nervous system adverse events such as hallucinations and confusion, falls or other sequelae, drug-drug interactions, and cardiac events resulting from drug-disease interactions, cyclobenzaprine IR should only be used when clearly necessary" (FLEXERIL package insert, 2013). However, administration of sustained-release cyclobenzaprine (AMRIX 30 mg or 15 mg capsules) is not recommended in elderly patients because its administration flexibility is more limited due to its once-daily dosing regimen (AMRIX package insert, 2016).

[0076] conclusion To date, the safety profiles of TNX-102 SL and other commercially available cyclobenzaprine products (particularly those at typical low doses for the elderly, e.g., cyclobenzaprine 5 mg IR TID, twice as high as the preferred dose of TNX-102 SL for agitation in dementia) have been favorable and well-tolerated, along with a very low incidence of systemic anticholinergic effects. As summarized above, the safety profiles of cyclobenzaprine at daily doses up to 30 mg have been mostly mild to moderate and well-tolerated. Furthermore, the unique formulation of TNX-102 SL, which allows for rapid transmucosal absorption, bypass of first-pass hepatic metabolism, and reduced production of norcyclobenzaprine, an active metabolite with a long half-life, minimizes daytime effects when administered once daily at bedtime.

[0077] The most commonly reported adverse events associated with commercially available cyclobenzaprine products include drowsiness / somnolence, dry mouth, dizziness, and fatigue, whereas the most commonly reported drug-related events associated with TNX-102 SL are local administration site conditions (e.g., oral hypoesthesia and paresthesia), as well as systemic effects such as drowsiness / sedation and headache. Dizziness (which can be of particular concern to the elderly) was not reported at an increased incidence in the TNX-102 SL treatment group compared to the placebo group.

[0078] An analysis of the incidence of anticholinergic events and other events of particular concern in the elderly among patients treated with TNX-102 SL, broken down by age group, revealed that only constipation and fatigue were considered to be related to TNX-102 SL, and even though the incidence was relatively low, it was shown to be relatively higher in patients aged ≥50 years compared to patients aged <50 years (approximately 2.8 times and 1.7 times higher, respectively).

[0079] No drug interactions have been identified between cyclobenzaprine and currently approved dementia medications related to the management of agitation in dementia, thereby allowing patients to continue with their standard care.

[0080] The preferred dose of TNX-102 SL for the treatment of agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states is approximately 5.6 mg (2 x approximately 2.8 mg tablets), which is more than twice as low as the lowest recommended cyclobenzaprine administration regimens (e.g., cyclobenzaprine IR 5-10 mg TID or cyclobenzaprine ER 15 mg BID / QD-30 mg QD). Safety data from its marketed cyclobenzaprine drug products and the TNX-102 SL clinical trials described herein support a favorable safety profile for once-daily administration of TNX-102 SL 5.6 mg used at bedtime in a patient population of dementia and / or neurodegenerative states aged over 50 years.

[0081] Example 5. Efficacy, safety, and tolerability of TNX-102 SL for the treatment of agitation, psychosis, and / or cognitive decline and associated symptoms in dementia or neurodegenerative states. A randomized, double-blind, placebo-controlled trial of a fixed dose of TNX-102-SL for the treatment of agitation (AAD) in Alzheimer's disease will be conducted over 8 weeks. The efficacy of TNX-102-SL 5.6 mg (2 x 2.8 mg tablets) will be tested in subjects aged 50–90 years who are likely diagnosed with Alzheimer's disease and experiencing clinically significant, moderate or severe agitation as defined by the International Society for Geriatric Psychiatry's Working Group on Agitation Definitions (Cummings et al, 2015). Subjects will have a Clinical Global Impression (CGIS) score of 4 or higher (moderately diseased) at screening and baseline. Subjects may be currently receiving pharmacotherapy for the treatment of Alzheimer's disease (e.g., donepezil, rivastigmine, galantamine, memantine), provided that the dose has been stable for at least 3 months prior to randomization in the trial. TNX-102-SL (two 2.8 mg tablets taken sublingually at bedtime each day) will be compared to placebo over an 8-week evaluation period.

[0082] Efficacy endpoint The primary efficacy endpoint is the mean change from baseline in the Cohen-Mansfield Agitation Assessment Scale (CMAI) 8 weeks after treatment (measured at baseline and at each outpatient visit). Key secondary efficacy endpoints include: (1) the overall clinical impression of changes in the Revised Alzheimer's Disease Collaborative after 8 weeks of treatment in the agitation domain score (mADCS-CGIC-agitation); (2) the mean change from baseline in the CMAI overall score after 4 weeks of treatment; (3) the mean change from baseline in the CMAI overall score after 2 weeks of treatment; (4) the mean change from baseline in the CMAI physical / aggressive subscale score after 8 weeks of treatment; (5) the mean change from baseline in the CMAI physical / non-aggressive subscale score after 8 weeks of treatment; (6) the mean change from baseline in the CMAI verbal / aggressive subscale score after 8 weeks of treatment; and (7) the mean change from baseline in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score after 8 weeks of treatment. The sequential testing procedure can be applied to the above secondary endpoints to adjust for redundancy and control the overall Type I error.

[0083] Exploratory efficacy endpoints include: (1) Neuropsychiatric symptom assessment questionnaire after 8 weeks of treatment. (1) Change from baseline in the (NPI) agitation / aggression domain score after 8 weeks of treatment, (2) Change from baseline in the NPI irritability / distress domain score after 8 weeks of treatment, (3) Change from baseline in the NPI caregiver burden score after 8 weeks of treatment, (4) CGIS agitation domain score after 8 weeks of treatment, (5) Zarit burden scale (ZBI), (6) ADCS-CGIC overall score after 8 weeks of treatment, (7) CGIS-agitation change from baseline to 8 weeks, (8) Percentage of patients using rescue drug therapy (recorded in drug therapy administration records or caregiver diaries), (9) Overall impression of patient change after 8 weeks of treatment (PGIC-caregiver-assessed) score, (10) Change from baseline in the Sleep Disorders Inventory (SDI) score after 8 weeks of treatment, (11) Change from baseline activity level and change from baseline sleep parameters as monitored by the ActiGraph device after 8 weeks of treatment, and (12) Alzheimer's disease collaborative research Activities of Daily Living Questionnaire 19 items (ADCS-ADL 19 Changes from baseline in activities of daily living, as assessed by ).

[0084] safety Safety will be assessed throughout the duration of the trial by adverse events (AEs) and serious adverse events (SAEs), and may include detailed assessments of: oral AEs, changes from baseline in laboratory findings, changes from baseline in vital signs (including, but not limited to, body temperature and weight), changes from baseline in electrocardiogram (ECG) parameters, changes from baseline in Columbia Suicide Severity Scale (C-SSRS) scores, changes from baseline in Mini-Mental State Examination (MMSE) scores, changes from baseline in ADAS-Cog scores, and Delirium Rating Scale-Revised-98 (DRS-R-98) scores (Trzepacz). Changes from baseline in 2001), and anticholinergic adverse events as defined in the protocol for the particular purpose, including orthostatic blood pressure changes of >20 mmHg (systolic) or >10 mmHg (diastolic), acute cognitive changes consistent with the DSM-5 diagnosis of delirium, clinically relevant cognitive deterioration, confusion, falls, hallucinations, decreased sweating, and fever.

[0085] Pharmacokinetic endpoints Determine the blood levels of cyclobenzaprine and norcyclobenzaprine after daily treatment for 3 and 8 weeks.

[0086] Pharmacological Genomics Endpoints Potential genetic determinants of treatment response will be tested by studying functional modifiers of several genes related to treatment outcomes. Excitation and other neurobehavioral disorders in Alzheimer's disease have long been known to be associated with dysregulation of monoaminergic neurotransmission. Genetic modifiers of several genes involved in the monoaminergic pathway, including serotonin and dopamine, have been associated with excitement in dementia (Pritchard et al., 2007; Proitsi et al., 2012). Genetic modifiers of the 5-HT2A and 5-HT2C receptors have been associated with the treatment response of excitement to citalopram treatment in Alzheimer's disease (Peters, et al., (2016). In this study, the inventors investigated potential genetic determinants of treatment response by studying functional variants of several genes related to treatment outcome. These genetic variants include, but are not limited to, the following: 5-HT2A serotonin receptor (HTR2A-T102C), 5-HT2C serotonin receptor (HTR2C-Cys23Ser), serotonin transporter (5HTT-LPR), brain-derived neurotrophic factor (BDNF-Val66-Met), and apolipoprotein E (ε2, ε3, ε4 variants).

[0087] A single blood sample is obtained at baseline (outpatient visit 2) from a patient who has signed a separate informed consent form regarding the analysis of potential genetic variants and associated biomarkers.

[0088] statistical methods All subjects receiving at least one dose of the study drug will be analyzed in the safety evaluation. All randomized subjects, at least at baseline and at least one post-baseline CMAI assessment, will be evaluated and analyzed in the revised intention-based analysis (mITT) evaluation. All randomized subjects receiving at least one dose of TBX-102 SL and for which evaluable pharmacokinetic (PK) blood samples are available will be analyzed in the PK evaluation.

[0089] Efficacy analysis (mITT population) - Endpoint The primary efficacy endpoint is the change in the composite CMAI score from baseline to 8 weeks. The primary efficacy analysis will be performed using a mixed-model repeated measures (MMRM) approach, comparing patients treated with TNX-102 SL with those treated with concurrent placebo. The model will include all patients in the mITT population, and its dependent variable will be the observed change from baseline in the total CMAI score at each post-randomization visit. Covariates in the model will include fixed category effects of treatment, site, location type (nursing home or community), visit, and treatment-by-visit interaction, as well as continuous fixed covariates of baseline CMAI score and baseline score-by-visit interaction.

[0090] Sequential secondary efficacy endpoint analysis is performed using the MMRM methodology, and the analysis is based on the mITT population. Significance tests for treatment differences are performed at two-sided 0.05 levels, and the corresponding 95% confidence intervals are calculated. To adjust for multiplicity and control for overall type I error, sequential testing procedures are applied to the secondary efficacy endpoints.

[0091] Safety analysis (safety group) Adverse events are coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) and grouped overall and by preferred terminology and organ-specific categories. Adverse events are also grouped by severity and relevance to the study drug. Serious AEs and AEs resulting in discontinuation of the study drug are also grouped. Actual values ​​and changes from baseline regarding laboratory results, vital signs measurements, ADAS-Cog, DRS-R-98, and MMSE scores are grouped by endpoint using descriptive statistics (n, mean, SD, median, minimum, and maximum). Oral examinations are performed to assess the safety of sublingual administration, and pregnancy tests are performed in women of potential pregnancy.

[0092] Sample size prediction Approximately 160 subjects in total (i.e., 80:80 subjects for the TNX-102 SL 5.6 mg and placebo groups) will be enrolled in the trial through 1:1 randomization. The sample size of 80 patients per arm will enable the determination of the effect size for the design of the final confirmation trial.

[0093] Blood sample collection Blood samples will be collected at baseline, and at weeks 3 and 8, for population pharmacokinetic and pharmacogenetic analysis.

[0094] Predicted results TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) is safe, well-tolerated, and effective in treating AAD over an 8-week study period.

[0095] Example 6. Long-term safety and tolerance of TNX-102 SL for the treatment of AAD. The long-term safety and tolerability of TNX-102 SL will be evaluated in an open-label, multicenter, fixed-dose study up to 44 weeks for the treatment of agitation in subjects with Alzheimer's disease (n=160; aged 50–90 years; men and women with AAD). Subjects who safely complete the double-blind study (see Example 5) without any serious adverse events related to the study drug will be eligible for the open-label extension study. Subjects who likely continue to meet the criteria for Alzheimer's disease and have a reliable caregiver willing to adhere to the study procedures will remain in the study. Patients who, in the opinion of the principal investigator or medical monitor, have a serious medical condition that could interfere with the safety assessment will be excluded from the study. At baseline visits, all subjects will receive open-label TNX-102 SL. Receive 5.6 mg at bedtime.

[0096] The primary efficacy endpoint for evaluating the long-term efficacy of TNX-102 SL is the mean change from baseline in CMAI. Important secondary efficacy endpoints include evaluation of the NPI excitability / aggression domain and mADCS-CGIC-excitability. The safety and tolerability of TNX-102 SL will be assessed by reported adverse events (AEs), physical and neurological examinations, vital signs (including orthostatic blood pressure), laboratory assessments, resting 12-lead ECG, S-STS, and MMSE. Daytime somnolence will be assessed by MTRSS. Regular, intensive oral examinations will be performed to assess the safety of sublingual administration of the study drug. Pregnancy tests will be performed in women of potential pregnancy.

[0097] The exploratory efficacy endpoints to be evaluated include: (1) change from baseline in the Neuropsychiatric Symptom Scale (NPI) agitation / aggression domain score, (2) change from baseline in the NPI irritability / instability domain score, (3) change from baseline in the NPI caregiver burden score, (4) CGIS agitation domain score, (5) Zarit burden scale (ZBI), (6) ADCS-CGIC overall score, (7) CGIS-agitation change from baseline to 44 weeks, (8) percentage of patients using rescue medication (recorded in medication administration records or caregiver diaries), (9) overall impression of patient change after 44 weeks of treatment (PGIC-caregiver-assessed) score, (10) change from baseline in the Sleep Disorders Inventory (SDI) score after 44 weeks of treatment, (11) change from baseline activity level and change from baseline sleep parameters as monitored by the ActiGraph device after 44 weeks of treatment, and (12) Alzheimer's disease collaborative study Activities of Daily Living Questionnaire 19 items (ADCS-ADL 19 Changes from baseline in activities of daily living, as assessed by ).

[0098] Predicted results TNX-102 SL 5.6 mg (2 x 2.8 mg tablets) is safe, well-tolerated, and effective in treating AAD over a 44-week study period.

[0099] All references cited herein are provided in part for informational purposes only. This application may be embodied in other specific forms without departing from its intent or essential characteristics, and references should be made to the appended claims as an indication of the scope of this application rather than to the foregoing specification. References [ka] [ka] [ka]

Claims

[Claim 1] The method described in the specification.

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