Bupropion as a modulator of drug activity

Abstract

The present disclosure relates to the administration to a human patient of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion in the free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan in the free base form or another salt form, to treat neurological and psychiatric conditions, such as agitation, associated with Alzheimer's disease and / or to reduce the recurrence of agitation in Alzheimer's disease.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 385,205, filed November 28, 2022, U.S. Provisional Patent Application No. 63 / 589,325, filed October 11, 2023, and U.S. Provisional Patent Application No. 63 / 589,525, filed October 11, 2023, the entire disclosures of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0002] The present disclosure relates to the administration to a human of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of bupropion in its free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of dextromethorphan in its free base form or another salt form (the subject combination).

[0003] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) and / or delaying the time to recurrence of Alzheimer's disease agitation relative to placebo in a human, comprising: i) administering once daily or twice daily to the human patient about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan in the free base form or another salt form, in combination with about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion in the free base form or another salt form, wherein the human patient is experiencing Alzheimer's disease and / or agitation associated with Alzheimer's disease. In some embodiments, the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score that is maintained for at least four consecutive weeks.

[0004] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) and / or delaying the time to relapse of Alzheimer's disease agitation compared to placebo with a combination of dextromethorphan and bupropion in a human, comprising orally administering to the human patient once daily or twice daily a dosage form comprising 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion in combination with 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan. In some embodiments, the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks.

[0005] Some embodiments include a method of treating a human patient with agitation associated with Alzheimer's disease by administering a combination of dextromethorphan and bupropion, comprising orally administering to the human patient once daily or twice daily a dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent of the free base or another salt form of dextromethorphan.

[0006] Some embodiments include a method of reducing the recurrence of agitation in Alzheimer's disease by administering a combination of dextromethorphan and bupropion, comprising orally administering to a human patient once daily or twice daily a dosage form comprising 105 mg of bupropion hydrochloride, or a molar equivalent of the free base or another salt form of bupropion, and 45 mg of dextromethorphan hydrobromide, or a molar equivalent of the free base or another salt form of dextromethorphan.

[0007] Some embodiments include a method of maintaining clinical response in a human patient with agitation associated with Alzheimer's disease, comprising orally administering a dosage form twice daily to the human patient, wherein the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, the sustained clinical response comprising a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, and wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan. In some embodiments, the sustained clinical response further comprises maintaining a Patient Impression of Change in Clinical Outcomes (PGI-C) score of 3 or less for at least four consecutive weeks.

[0008] Some embodiments include a method of reducing the recurrence of agitation in Alzheimer's disease, comprising orally administering a dosage form twice daily to a human patient, wherein the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, the sustained clinical response comprising a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, and wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0009] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient results in rapid improvement in Alzheimer's disease agitation.

[0010] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein the percentage of human patients with agitation relapse is lower upon administration of a subject combination than upon receiving a placebo.

[0011] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient delays the time to recurrence of agitation symptoms compared to placebo.

[0012] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient delays the time to recurrence of agitation symptoms compared to placebo, with about a 3.6-fold lower risk of recurrence.

[0013] Some embodiments include a method of treating agitation associated with Alzheimer's disease (AD) in a human patient, wherein oral administration of a subject combination to the human patient prevents the recurrence of Alzheimer's disease agitation (ADA) relative to placebo. [Brief explanation of the drawings]

[0014] [Figure 1] Figure 1 shows the ACCORD randomized treatment withdrawal study design for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP). a Sustained response consisting of a ≥30% improvement from baseline in the CMAI total score and an improvement in the PGI-C (score ≤3), both maintained for ≥4 consecutive weeks. b Recurrence of agitation, defined as a ≥10-point worsening in the CMAI total score since randomization or a higher CMAI total score than at study entry, or ADA hospitalization or other institutionalization. AD = Alzheimer's disease, ADA = Alzheimer's disease-related agitation, BID = twice daily, BL = baseline, BUP = bupropion, CMAI = Cohen-Mansfield Agitation Scale, DM = dextromethorphan, PGI-C = Patient Impression of Change. [Figure 2A] Shown is the mean change in CMAI from baseline during the open-label period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) over time. ***P<0.001, paired t-test performed at each time point for change from baseline. [Figure 2B] Figure 1 shows the number of open-label period participants with a CMAI response for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) over time. a CMAI response defined as a ≥ 30% reduction from baseline. CMAI = Cohen-Mansfield Agitation Scale. [Figure 3A]Figure 1 shows the agitation-free survival probability over time during the double-blind period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) compared to placebo. [Figure 3B] Figure 1 shows the incidence of agitation relapse over time during the double-blind period for the subject combination of dextromethorphan and bupropion (45 mg DM / 105 mg BUP) compared to placebo. aAgitation relapse defined as a ≥ 10-point worsening (increase) in the CMAI total score since randomization or a CMAI total score higher than at study entry for 2 consecutive weeks. CMAI = Cohen-Mansfield Agitation Inventory; mITT = modified intention to treat. DETAILED DESCRIPTION OF THE INVENTION

[0015] As noted above, the present disclosure relates to the administration of a combination of: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion in its free base form or another salt form; and 2) about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan in its free base form or another salt form. This combination is referred to herein for convenience as the "subject combination." In all instances where the subject combination is referred to herein, a combination of 105 mg of bupropion hydrochloride or a molar equivalent amount of bupropion in its free base form or another salt form with 45 mg of dextromethorphan hydrobromide or a molar equivalent amount of dextromethorphan in its free base form or another salt form is specifically contemplated.

[0016] Dextromethorphan hydrobromide is a non-competitive NMDA receptor antagonist and a sigma-1 receptor agonist.

[0017] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C 18 H 25 It is NO·HBr·HO and has a molecular weight of 370.33. Its structural formula is: [ka] is.

[0018] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and slightly soluble in water.

[0019] Bupropion hydrochloride is an aminoketone and a CYP450 2D6 inhibitor.

[0020] The chemical name of bupropion hydrochloride is (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. Bupropion hydrochloride has the empirical formula C 13 H 18 It is ClNO HCl and has a molecular weight of 276.2. Its structural formula is: [ka] is.

[0021] Bupropion hydrochloride powder is white and highly soluble in water.

[0022] The subject combinations may be included in oral dosage forms, including tablets, such as extended release tablets. In some embodiments, the subject combinations are included in dosage forms for oral administration and are available as round, bilayer tablets.

[0023] In some embodiments, each tablet comprising the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate release formulation. In some embodiments, each tablet comprising the subject combination contains 105 mg of bupropion hydrochloride in a sustained release formulation. In some embodiments, each tablet comprising the subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate release formulation and 105 mg of bupropion hydrochloride in a sustained release formulation.

[0024] In some embodiments, tablets comprising the subject combination comprise L-cysteine ​​hydrochloride monohydrate. In some embodiments, tablets comprising the subject combination comprise carbomer homopolymer. In some embodiments, tablets comprising the subject combination comprise microcrystalline cellulose. In some embodiments, tablets comprising the subject combination comprise colloidal silicon dioxide. In some embodiments, tablets comprising the subject combination comprise crospovidone. In some embodiments, tablets comprising the subject combination comprise stearic acid. In some embodiments, tablets comprising the subject combination comprise magnesium stearate.

[0025] In some embodiments, tablets containing the subject combination contain the following inactive ingredients: L-cysteine ​​hydrochloride monohydrate, carbomer homopolymer, microcrystalline cellulose, colloidal silicon dioxide, crospovidone, stearic acid, and magnesium stearate.

[0026] In some embodiments, the dosage form is one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, for example, administered at least 8 hours apart. In some embodiments, no more than two doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are administered on the same day.

[0027] The subject combinations are administered orally, with or without food. In some embodiments, the tablets are swallowed whole and are not crushed, split, or chewed.

[0028] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan exhibits nonlinear pharmacokinetics at steady state when coadministered with bupropion, with the AUC and C changes observed with varying dextromethorphan doses (30 to 60 mg). max and less than the dose-proportional change with altering the bupropion dose (from 75 to 150 mg).

[0029] When the subject combination is administered, steady-state plasma concentrations of dextromethorphan and bupropion are achieved within 8 days. max and AUC 0-12 The steady-state accumulation ratios of dextromethorphan based on C are approximately 20 and approximately 32, respectively. max and AUC 0-12 The accumulation ratios of bupropion at steady state based on these values ​​are 1.1 and 1.5, respectively.

[0030] After administration of the subject combination, the T of dextromethorphan max The median T of bupropion was approximately 3 hours. max The median time is approximately 2 hours. C max is achieved approximately 3 hours after administration and is approximately 14 times the peak concentration of bupropion. 0-12 is approximately 19 times that of bupropion. The C of the metabolites of erythrohydroxybupropion and threohydroxybupropion max The AUCs of erythrohydroxybupropion and threohydroxybupropion are reached approximately 4 hours after administration and are approximately equal to and approximately 5 times those of bupropion, respectively. 0-12 The values ​​are the AUC of bupropion, 0-12 These are approximately 1.2 and 7 times the values.

[0031] The subject combination can be taken with or without food.max and AUC 0-12 were unchanged and decreased by 14%, respectively, and the C max and AUC 0-12 were increased by 3% and 6%, respectively, when the subject combination was administered with food.

[0032] The plasma protein binding of dextromethorphan is approximately 60-70%, compared with 84% for bupropion. The extent of protein binding of the hydroxybupropion metabolite is similar to that of bupropion, while the extent of protein binding of the threohydroxybupropion metabolite is approximately half that of bupropion.

[0033] After 8 days of administration of the subject combination to extensive metabolizers, the mean elimination half-life of dextromethorphan increased approximately three-fold to approximately 22 hours compared to dextromethorphan administered without bupropion.

[0034] The mean elimination half-lives of dextromethorphan and bupropion were 22 and 15 hours, respectively. The apparent elimination half-lives of the hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites were approximately 35, 44, and 33 hours, respectively.

[0035] Unlike the combination of quinidine and dextromethorphan, the subject combination does not prolong the QT interval to a clinically meaningful extent at a dose of 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide given twice daily. Therefore, electrocardiographic assessment of the QT interval is typically not performed in human patients experiencing agitation associated with Alzheimer's disease and who are at risk for QT prolongation and torsades de pointes.

[0036] In addition to agitation associated with Alzheimer's disease, the subject combinations may be used to treat other disorders in the patient populations or conditions described herein. For example, the subject combinations may be used to treat pain or neurological disorders. Examples of neurological disorders treated with the subject combinations include, but are not limited to, affective disorders, psychiatric disorders, brain dysfunction, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0037] Affective disorders that can be treated with the subject combinations include, but are not limited to, depression, major depression, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (AD / HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, affective dysregulation, and mood lability.

[0038] Depression can present with depressive symptoms. These symptoms include psychological changes such as mood changes, intense sadness, hopelessness, mental slowing, difficulty concentrating, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts, suicide attempts, and / or self-deprecation. Physical symptoms of depression include insomnia, loss of appetite, decreased appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches and pains, headaches, cramps, digestive problems, and / or abnormalities in circadian hormone rhythms.

[0039] Psychiatric disorders that may be treated with the subject combination include, but are not limited to, anxiety disorders, including, but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depression, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform tendencies, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease is also sometimes referred to as dementia of the Alzheimer's type. Other psychobehavioral symptoms of Alzheimer's disease that may be treatable include disinhibition and apathy.

[0040] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation itself may manifest as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior may include, but is not limited to, babbling, inappropriate emotional responses, demands for attention, threats, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, verbal abuse, physical outbursts, emotional distress, restlessness, shredding, sleep disturbances, delusions, hallucinations, pacing, wandering, exploring, rummaging, repetitive body movements, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0041] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia, affecting an estimated 6 million people in the United States, a number predicted to increase to approximately 14 million by 2050. Agitation is reported in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. Managing agitation is a priority in AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home placement, and increased mortality. Currently, there are no FDA-approved therapies for the treatment of agitation in AD patients.

[0042] Psychobehavioral symptoms are known to appear during dementia and may be treated with the present combination. Caregivers or family members may feel more overwhelmed by the patient's behavioral / psychiatric symptoms than by the patient's cognitive impairment. Common forms of the syndrome include Alzheimer's disease, vascular dementia, Lewy body dementia (aggregates of abnormal proteins expressed in nerve cells), and a group of diseases that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). Symptoms of patients with dementia are similar to those of psychiatric illnesses, but there are subtle differences between them. Psychobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, compulsivity, excessive sexual desire, and personality disorders. Psychobehavioral symptoms, such as disinhibition, may also be seen in other conditions, such as traumatic brain injury.

[0043] Agitation in patients with Alzheimer's disease may be assessed using the Cohen-Mansfield Agitation Inventory, or CMAI. The CMAI assesses a variety of behaviors, including hitting (including at oneself), kicking, grabbing at people, pushing, throwing objects, biting, scratching, spitting, injuring oneself or others, tearing up or destroying property, making physical sexual advances, pacing, wandering aimlessly, inappropriate dressing or undressing, trying to get to different locations, intentionally falling, eating / drinking inappropriately, handling objects inappropriately, hiding objects, hoarding objects, engaging in repetitive behaviors, general restlessness, screaming, making verbal sexual advances, cursing or verbal aggression, repeating sentences or questions, strange noises (such as strange laughter or crying), complaining, defiance, and constantly seeking unwarranted attention or help.

[0044] Schizophrenia may be treated with the combination, including the positive and / or negative symptoms of schizophrenia, or the residual symptoms of schizophrenia. Other conditions that may be treated include intermittent explosive disorder.

[0045] Brain dysfunction disorders that may be treated with the subject combinations include, but are not limited to, disorders involving intellectual disability such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnestic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, vocal spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity disorder, and schizophrenia. Brain dysfunction also includes disorders caused by cerebrovascular disorders, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., the symptoms of which include impaired consciousness, senile dementia, coma, decreased attention, and speech disorders.

[0046] Substance abuse addictions that may be treated with the subject combinations include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and chewing tobacco.

[0047] Movement disorders that may be treated with the subject combinations include, but are not limited to, akathisia, akinesia, dyskinesia, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's chorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0048] Dementias that may be treated with the subject combinations include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0049] Motor neuron diseases that may be treated with the subject combinations include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0050] Neurodegenerative diseases that may be treated with the subject combinations include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0051] Seizure disorders that may be treated with the subject combinations include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsy partialis continua; generalized seizures, including but not limited to generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0052] Types of headaches that may be treated with the subject combination include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0053] Other neurological disorders that may be treated with the subject combinations include Rett syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; dysphonia due to uncontrollable laryngeal muscle spasms, including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscle tension dysphonia, and voice tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0054] In some embodiments, the subject combinations may be used to treat pain, joint pain, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and cognition disorders, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0055] In some embodiments, the subject combinations may be administered orally to relieve musculoskeletal pain, including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthropathies, non-articular rheumatism, periarticular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, and the like.

[0056] In some embodiments, the subject combinations are administered to relieve musculoskeletal pain, arthritis pain, and inflammatory pain, including complex regional pain syndrome.

[0057] Arthritis refers to inflammatory joint diseases that may be associated with pain. Examples of arthritic pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathies including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

[0058] In some embodiments, the subject combination is used to treat chronic musculoskeletal pain.

[0059] In some embodiments, the subject compositions may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or other forms of CRPS. CRPS is a type of inflammatory pain. CRPS may also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the extremities, which may be accompanied by edema, and autonomic, motor, and sensory changes.

[0060] In some embodiments, the subject compositions may be administered orally to relieve neuropathic pain.

[0061] Examples of neuropathic pain include diabetic peripheral neuropathy or diabetic peripheral neuropathy pain, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, pain due to central pain, pain due to multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radiation or chemotherapy-associated neuropathy, etc.

[0062] In some embodiments, the subject compositions may be administered to alleviate fibromyalgia.

[0063] The terms "therapy" or "treatment" include the diagnosis, care, mitigation, treatment, or prevention of disease in humans or other animals, or any other activity affecting the structure or any function of the body of humans or other animals.

[0064] In some embodiments, the subject combinations may reduce the CMAI (Cohen-Mansfield Agitation Inventory) total score from baseline by at least 5, or by about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, or about 30-35, or any value delimited therein or between these ranges, after oral administration of the subject combinations to a human patient for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.

[0065] In some embodiments, after a sustained clinical response is achieved as a result of receiving the combination of bupropion and dextromethorphan (a sustained clinical response comprising a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least 4 consecutive weeks), the subject combination is administered twice daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 2 years, at most 1 year, at most 2 years, at most 3 years, at most 4 years, at most 5 years, at most 10 years, or longer.

[0066] In some embodiments, the percentage of human patients having a CMAI response or the likelihood of a CMAI response (wherein a CMAI response is defined as a ≥ 30% reduction from baseline) can be at least 20%, or about 20-40%, about 40-60%, about 60-80%, about 80-90%, about 90-95%, about 80-100%, about 40%, about 50-55%, about 60%, about 70%, about 60-70%, about 70-80%, about 22%, about 54%, about 61%, about 79%, about 91%, about 93%, about 95%, or any value delimited therewith or between these ranges, after oral administration of a subject combination to human patients for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.

[0067] Agitation recurrence is defined as a worsening (increase) of ≥ 10 points in the CMAI total score higher than at study entry for two consecutive weeks. In some embodiments, the percent probability of agitation recurrence-free survival in human patients treated with a subject combination may be higher than those receiving placebo. In some embodiments, the percent probability of agitation-free survival upon treatment with a subject combination may be at least 80%, at least 85%, at least 90%, about 90-95%, about 95-100%, about 90-92%, about 92-94%, about 94-96%, about 96-98%, or any value delimited therewith or between these ranges, following oral administration of a subject combination to a human patient for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 15-20 weeks, about 20 weeks, about 20-25 weeks, about 25 weeks, about 26 weeks, or longer. In some embodiments, the risk of relapse is at least about 2-fold lower, at least 3-fold lower, 3-4-fold lower, about 3-fold lower, about 4-fold lower, about 3.6-fold lower, or about 4-5-fold lower for the subject combination compared to placebo.

[0068] In some embodiments, the percentage of human patients experiencing agitation relapse may be substantially lower with the subject combination than with placebo, hi some embodiments, the percentage of human patients experiencing agitation relapse may be extremely low, such as less than 10%, about 5-10%, about 5%, about 5-6%, about 5-8%, about 7.5%, about 6-8%, or about 7-8%.

[0069] In some embodiments, the subject combinations may substantially delay the time to recurrence of agitation symptoms compared to placebo, hi certain embodiments, the subject combinations may delay the time to recurrence of agitation symptoms compared to placebo, with about half, about one-third, about one-quarter, about three-quarters, about four-fifths, or about 3.6 times lower risk of recurrence compared to placebo.

[0070] In some embodiments, the subject combination may significantly prevent relapse of Alzheimer's disease agitation (ADA) compared to placebo.

[0071] In some embodiments, treatment with the subject combination may result in rapid and sustained improvement in Alzheimer's disease agitation.

[0072] The subject combinations may be used to treat any disease or condition identified as treatable by a combination of bupropion and dextromethorphan in any of the following U.S. Patent Nos., which are incorporated herein by reference in their entireties for their disclosure of diseases that may be treated by a combination of bupropion and dextromethorphan, including the specific embodiments and combinations set forth therein: 8569328, 9168234, 9189905, 9205083, 9238032, 9278095, 9314462, 9370513, 9375429, 9408815, 9421176, 9457023, 9457025, 9474731, 94 86450, 9700528, 9700553, 9707191, 9763932, 9861595, 9867819, 9968568, 10058518, 10064857, 10080727, 10092560, 10092561, 10105327, 10105361, 10251879, 10463634, 10512643, 10548 857, 10596167, 10772850, 10780064, 10780066, 10786469, 10786496, 10799497, 10806710, 10864209, 10874663, 10874664, 10874665, 10881624, 10881657, 10894046, 10894047, 10898453.

[0073] Example 1 Efficacy and safety of DM / BUP (dextromethorphan-bupropion) for agitation associated with Alzheimer's disease: Results from the ACCORD Phase 3 double-blind, placebo-controlled relapse prevention trial Dextromethorphan-bupropion, i.e., DM / BUP, e.g., 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride, is a novel, oral, investigational N-methyl-D-aspartate (NMDA) receptor antagonist with multimodal activity that is being developed for the treatment of Alzheimer's disease (AD) agitation and other central nervous system (CNS) disorders.

[0074] DM / BUP utilizes a proprietary formulation, doses of dextromethorphan and bupropion, and Axsome's metabolic inhibition technology to regulate delivery of ingredients. DM / BUP's dextromethorphan component is an uncompetitive NMDA receptor antagonist, also known as a glutamate receptor modulator, and a sigma-1 receptor agonist. DM / BUP's bupropion component serves to increase the bioavailability of dextromethorphan and is a norepinephrine and dopamine reuptake inhibitor.

[0075] DM / BUP tablets are formulated for oral administration. They are round, bilayer tablets. Each tablet contains 45 mg of dextromethorphan hydrobromide (equivalent to 32.98 mg of dextromethorphan free base) in an immediate-release formulation and 105 mg of bupropion hydrochloride (equivalent to 91.14 mg of bupropion free base) in a sustained-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, L-cysteine ​​hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and / or yellow iron oxide.

[0076] (introduction) Alzheimer's disease (AD) is the most common cause of dementia, affecting 6.7 million Americans as of 2023, a number predicted to increase to 13.8 million by 2060 due to the aging population. AD-associated agitation (ADA) is reported in up to 70% of individuals with AD and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. ADA and other behavioral symptoms are associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home placement, and increased mortality. Non-pharmacological treatments for ADA are not always effective, and the only U.S. Food and Drug Administration (FDA)-approved treatment for agitation in dementia due to AD is brexpiprazole, an antipsychotic medication with a boxed warning for use in dementia-associated psychosis due to an increased risk of death.

[0077] DM / BUP (dextromethorphan-bupropion, extended-release tablets) is a novel oral N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist approved by the FDA for the treatment of major depressive disorder in adults. Neurotransmitter imbalances in individuals with AD contribute to agitation, and these neurotransmitters may be modulated by DM / BUP treatment.

[0078] (Methods and research design) The main inclusion and exclusion criteria for participants entering the study with probable AD and clinically significant agitation are shown in Table 1. [Table 1] Note: AD, Alzheimer's disease; IPA, International Psychogeriatric Association; MMSE, Mini-Mental State Examination; NIA-AA, National Institute of Aging-Alzheimer Association

[0079] The ACCORD (Assessing Clinical Outcomes in Alzheimer's Disease Agitation; NCT04797715) study was a phase 3, randomized, treatment-withdrawal, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of DM / BUP for the treatment of Alzheimer's disease agitation (ADA) in patients with ADA (Figure 1). Patients with a diagnosis of probable Alzheimer's disease and clinically meaningful agitation associated with their disease participated in a 9-week, open-label period during which they were treated with DM / BUP and monitored for sustained clinical response. Sustained clinical response was defined as a ≥30% improvement from baseline in the Cohen-Mansfield Agitation Inventory (CMAI) total score and an improvement in the PGI-C (score ≤3), both maintained for at least four consecutive weeks.

[0080] Patients who experienced a sustained clinical response during the open-label treatment period were randomly assigned (1:1) in a double-blind manner to continue treatment with DM / BUP or switch to placebo treatment for up to 26 weeks. Treatment was continued until the recurrence of agitation symptoms or the end of the 26-week double-blind period, whichever occurred first. Relapse was defined as a ≥10-point worsening in the CMAI total score since randomization or a CMAI total score higher than at study entry, or hospitalization or other institutionalization due to Alzheimer's disease-related agitation.

[0081] A total of 178 patients participated in the open-label period and were treated with DM / BUP, with 108 patients randomly assigned to continue DM / BUP (n=53) or switch to placebo (n=55). The mean Cohen-Mansfield Agitation Inventory (CMAI) total score at baseline study entry was 70.9. The mean CMAI total scores at randomization were 43.7 (DM / BUP) and 44.9 (placebo). The minimum score on the CMAI was 29, corresponding to the complete absence of symptoms, with higher scores corresponding to more severe agitation.

[0082] The primary endpoint of the study was the time from randomization (during the double-blind period) to relapse of Alzheimer's disease agitation, calculated from the Kaplan-Meier estimator and hazard ratio. The key secondary endpoint for assessing relapse prevention was the percentage of patients who relapsed. The primary time point for open-label efficacy evaluation was week 5, and the key secondary time point was week 2. P values ​​for the open-label period were calculated relative to baseline.

[0083] In Figure 1, AD stands for Alzheimer's disease, ADA stands for Alzheimer's disease-related agitation, BID stands for twice daily, BL stands for baseline, BPU stands for bupropion, CMAI stands for Cohen-Mansfield Agitation Scale, DM stands for dextromethorphan, and PGI-C stands for Patient Impression of Change.

[0084] (Patient population) Participants had moderately severe AD dementia based on the Mini-Mental State Examination (MMSE). Baseline demographic and clinical characteristics were similar between groups during the double-blind period (Table 2). During the double-blind period, 54.2% of participants completed the study, with sponsor-initiated study discontinuation being the most common cause of treatment discontinuation (22.4%). [Table 2] aNPI-AA total score, n=49 participants in both the DM / DUP and placebo groups; CGI-S, Clinical Global Impression-Severity Scale; CMAI, Cohen-Mansfield Agitation Inventory; ITT, Intent to Treat; MMSE, Mini-Mental State Examination; NPI-AA, Neuropsychiatric Inventory-Agitation and Aggression domain.

[0085] (Open-label efficacy prior to randomized treatment discontinuation) A total of 178 patients were treated with open-label DM / BUP for up to 9 weeks and evaluated for efficacy. The primary time point for open-label efficacy evaluation was 5 weeks, and the primary secondary time point was 2 weeks. P values ​​were calculated relative to baseline. The mean CMAI total score was 70.9 at baseline.

[0086] The mean change from baseline in CMAI score during the open-label period and the number of participants with a CMAI response are shown in Figures 2A and 2B. In Figure 2A, a paired t-test was performed at each time point for the change from baseline, with P<0.001. CMAI stands for Cohen-Mansfield Agitation Scale, and a CMAI response is defined as a ≥30% reduction from baseline.

[0087] As shown in Figures 2A and 2B, statistically significant improvements in Cohen-Mansfield Agitation Scale total scores were observed at all time points during the open-label period, beginning as early as week 1 (Figure 2A), with response rates increasing over time (Figure 2B). More detailed results from the open-label period are summarized below.

[0088] Treatment with DM / BUP was associated with a mean reduction from baseline in CMAI total scores of 6.7 points at week 1, 11.0 points at week 2, and 20.6 points at week 5 (p<0.001 for all) (Figure 2A).

[0089] Clinical response (defined as a ≥30% reduction from baseline) in CMAI after treatment with DM / BUP was achieved in 21.8% of patients at week 1, 40.4% of patients at week 2, and 70.0% of patients at week 5 ( Figure 2B ).

[0090] Treatment with DM / BUP was also associated with improvements in all CMAI subscales, including the physical aggression subscale, at all time points (p<0.001).

[0091] Improvement in Alzheimer's disease agitation, assessed using the clinician-rated mADCS-CGIC, was achieved in 47.1% of patients at week 1, 66.3% at week 2, and 86.3% at week 5 after treatment with DM / BUP.

[0092] Improvement in Alzheimer's disease agitation, assessed using the caregiver-rated PGI-C, was achieved in 51.2% of patients at week 1, 67.5% at week 2, and 89.3% at week 5 after treatment with DM / BUP.

[0093] Caregiver distress, assessed using the NPI Agitation and Aggression caregiver burden score, was significantly reduced after treatment with DM / BUP (p<0.001 at weeks 4 and 8).

[0094] Caregiver burden, assessed using the ZBI, was significantly reduced after treatment with DM / BUP (p=0.006 at week 4 and p=0.003 at week 8).

[0095] Patients' quality of life, assessed using the caregiver-rated QoL-AD scale, significantly improved after treatment with DM / BUP (p<0.001 at week 4, p=0.013 at week 8).

[0096] Depressive symptoms, assessed using the CSDD, were significantly reduced after treatment with DM / BUP (p<0.001 at weeks 4 and 8).

[0097] (Efficacy during the double-blind period) A total of 108 patients were randomized to continue treatment with DM / BUP (53) and switch to placebo (55). The mean CMAI total scores at randomization were 43.7 and 44.9 for the DM / BUP and placebo groups, respectively.

[0098] The agitation relapse-free survival probability and relapse incidence rate during the double-blind period are shown in Figure 3A and Figure 3B. In Figure 3A or 3B, agitation relapse is defined as a worsening (increase) of ≥10 points in the CMAI total score after randomization or a CMAI total score higher than that at study entry for two consecutive weeks. CMAI stands for Cohen-Mansfield Agitation Assessment Scale, and mITT stands for modified intention to treat.

[0099] As shown in Figures 3A and 3B, DM / BUP met the primary endpoint by substantially and statistically increasing the time to recurrence of agitation symptoms compared with placebo (hazard ratio, 0.275, P = 0.014) (Figure 3A). The risk of recurrence was 3.6 times lower with DM / BUP compared with placebo.

[0100] DM / BUP also met the key secondary endpoint by significantly preventing relapse of Alzheimer's disease agitation compared to placebo (7.5% vs. 25.9% of participants, respectively, p = 0.018) ( Figure 3B ).

[0101] The incidence of adverse events during the double-blind period was 28.3% in the DM / BUP group and 22.2% in the placebo group. Treatment discontinuation due to adverse events during the double-blind period was low (0% in the DM / BUP group and 1.9% in the placebo group).

[0102] (safety) Treatment-emergent adverse events are summarized in Table 3. There were no treatment-emergent sedative adverse events with DM / BUP. No clinically meaningful cardiovascular changes were observed with DM / BUP. There was no evidence of cognitive decline in participants treated with DM / BUP based on MMSE (mean change from baseline to week 8 of the open-label period, 0.4; P = 0.421). No deaths occurred in the DM / BUP group during any period. [Table 3] a Died of cardiac arrest. b TEAEs were reported as preferred terms: TEAE, treatment-emergent adverse event;

[0103] One serious adverse event (phaecologic event) was reported in the DM / BUP group, which was determined by the investigator to be unrelated to the study drug; two serious adverse events (cardiac arrest, femur fracture) were reported in the placebo group. Four patients in the DM / BUP group reported falls, none of which were associated with serious adverse events and all of which were determined by the investigator to be unrelated to the study drug; two patients in the placebo group reported falls, one of which involved a femur fracture. One death was reported in the placebo group. Patients treated with DM / BUP showed no signs of cognitive decline, as measured by the Mini-Mental State Examination (MMSE), a widely used measure of global cognitive function. DM / BUP treatment was not accompanied by sedation.

[0104] (Conclusion) DM / BUP significantly increased the time to recurrence of agitation symptoms compared with placebo during the double-blind period.

[0105] Improvement in agitation symptoms with DM / BUP was rapid and sustained during the initial open-label period.

[0106] Overall, DM / BUP was generally well tolerated without any new safety signals identified in the previous phase 2 trial.

[0107] No treatment-emergent adverse events of sedation, clinically significant cardiovascular changes, or signs of cognitive decline were observed in participants treated with DM / BUP in this study.

[0108] Therefore, DM / BUP is a promising candidate for the treatment of agitation in patients with Alzheimer's disease.

[0109] Furthermore, rapid and sustained improvements in Alzheimer's disease agitation have been reported by both clinicians and caregivers based on global measures. Clinicians reported improvement in agitation in 66.3% of patients at week 2 and 86.3% at week 5 after treatment with DM / BUP, as assessed using the modified Alzheimer's Disease Cooperative Study-Agitation Clinical Global Impression of Change (mADCS-CGIC). Caregivers reported improvement in agitation in 67.5% of patients at week 2 and 89.3% at week 5 after treatment with DM / BUP, as assessed using the Patient Global Impression of Change (PGI-C).

[0110] Caregiver burden and burden, patient quality of life, and depressive symptoms all statistically significantly improved compared to baseline after patients received open-label DM / BUP treatment. Caregiver burden was assessed using the NPI Agitation Caregiver Burden score (p<0.001 at weeks 4 and 8). Caregiver burden was assessed using the Zarit Caregiver Burden Scale (ZPI) (p=0.006 at week 4, p=0.003 at week 8). Patient quality of life was assessed using the Caregiver-Rated Alzheimer's Disease Quality of Life (QoL-AD) scale (p<0.001 at week 4, p=0.013 at week 8). Depressive symptoms were assessed using the Cornell Scale for Depression in Dementia (CSDD) (p<0.001 at weeks 4 and 8).

[0111] In conclusion, DM / BUP statistically significantly delayed the time to relapse of Alzheimer's disease agitation compared with placebo (p = 0.014, primary endpoint), statistically significantly reduced relapse of Alzheimer's disease agitation compared with placebo (p = 0.018, key secondary endpoint), and statistically significantly improved Alzheimer's disease agitation as measured by the CMAI total score, beginning at week 1, with open-label DM / BUP (p < 0.001 vs. baseline at all time points). Improvement in Alzheimer's disease agitation, as assessed by the modified Alzheimer's Disease Cooperative Investigative Committee-CGIC scale, was achieved by 66% of patients at 2 weeks and 86% at 5 weeks. Improvement in Alzheimer's disease agitation, as assessed by the Prospective Patient Geriatrics and Cardiac Surgery-Combined Criteria (PGI-C) scale, was achieved by 68% of patients at 2 weeks and 89% at 5 weeks.

[0112] According to Jeffrey Cummings, MD, ScD, Director Emeritus of the Lou Ruvo Center for Brain Health at the Cleveland Clinic and Chambers Professor of Neuroscience at the University of Nevada, Las Vegas, "agitation is one of the most troublesome and significant aspects of Alzheimer's disease for patients and their caregivers, as it is associated with earlier nursing home placement, accelerated cognitive decline, and increased mortality. Results from the ACCORD trial demonstrate the robust clinical activity of DM / BUP for Alzheimer's disease agitation, based on both a significant delay in symptom relapse and a reduction in relapse compared with placebo. Treatment with DM / BUP during the open-label phase in a large patient cohort resulted in rapid and clinically meaningful improvements in Alzheimer's disease agitation. This improvement was particularly notable because it was also observed in the aggressive symptom subscale of the Agitation Scale. Agitation occurs in a large proportion of patients with Alzheimer's disease, and there are currently no approved treatments for this symptom." Based on the observed positive efficacy, favorable safety, and tolerability results, [DM / BUP], if approved, is believed to have the potential to fulfill this significant unmet medical need for patients and their caregivers.

[0113] Unless otherwise indicated, all numerical values ​​expressing properties such as quantities, amounts, and proportions of ingredients used in the specification and claims are understood to be generally understood as being both the exact value stated and the modified term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the scope of the claims by the doctrine of equivalents, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0114] Any use of the term "comprising" or "comprises" herein contemplates the use, in that context, of "consisting essentially of," "consists essentially of," "consisting of," or "consists of."

[0115] Any affirmative mention of an element anywhere in this specification should be understood to contemplate both the inclusion and exclusion of that element.

[0116] Terms such as "a," "an," "the," and similar referents, when used in the context of describing embodiments (particularly in the context of the claims below), are to be construed to include both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended solely to better clarify the embodiments and does not pose a limitation on the scope of any claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of a claim.

[0117] The classification of alternative elements or embodiments disclosed herein is not to be construed as limiting. Elements of each group may be referenced or claimed individually or in any combination with other elements of the group or other elements described herein. It is anticipated that one or more elements of a group may be included in, or deleted from, a group for reasons of convenience and / or speed of prosecution. When such inclusion or deletion occurs, the specification is deemed to include the modified group, which thereby satisfies the description of all Markush groups as used in the appended claims.

[0118] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in these arts upon reading the foregoing description. The inventors intend the claimed embodiments to be practiced other than as expressly described herein, expecting those skilled in the art to adopt such variations as necessary. Accordingly, the claims include all modifications and equivalents of the claimed subject matter permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0119] Finally, it is understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, and not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Therefore, the claims are not limited to the precise embodiments as shown and described.

[0120] [Note] [Appendix 1] 1. A method of maintaining clinical response in a human patient with agitation associated with Alzheimer's disease, comprising orally administering a dosage form twice daily to the human patient, wherein the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, and wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0121] [Appendix 2] 2. The method of claim 1, wherein said sustained clinical response further comprises maintaining a Patient Impression of Change in Clinical Trials (PGI-C) score of 3 or less for at least 4 consecutive weeks.

[0122] [Appendix 3] 1. A method for reducing the recurrence of agitation in Alzheimer's disease, comprising orally administering a dosage form twice daily to a human patient, wherein the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, and wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

[0123] [Appendix 4] 4. The method of any one of claims 1 to 3, wherein the dosage form comprising 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the patient twice daily.

[0124] [Appendix 5] 5. The method of any one of claims 1 to 4, wherein the dosage form is administered twice daily for at least four weeks.

[0125] [Appendix 6] 6. The method of any one of claims 1 to 5, wherein the dosage form is administered twice daily for at least three months.

[0126] [Appendix 7] 7. The method of any one of claims 1 to 6, wherein the dosage form is administered twice daily for at least 6 months.

[0127] [Appendix 8] 8. The method of any one of claims 1 to 7, wherein the dosage form is a solid dosage form.

[0128] [Appendix 9] 9. The method of claim 8, wherein the solid dosage form further comprises a carbomer homopolymer.

[0129] [Appendix 10] 10. The method of claim 8 or 9, wherein the solid dosage form further comprises colloidal silicon dioxide.

[0130] [Appendix 11] 11. The method of any one of claims 8 to 10, wherein the solid dosage form further comprises crospovidone.

[0131] [Appendix 12] 12. The method of any one of claims 8 to 11, wherein the solid dosage form further comprises glyceryl monocaprylocaprate.

[0132] [Appendix 13] 13. The method of any one of claims 8 to 12, wherein the solid dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

[0133] [Appendix 14] 14. The method of any one of claims 8 to 13, wherein the solid dosage form further comprises magnesium stearate.

[0134] [Appendix 15] 15. The method of any one of claims 8 to 14, wherein the solid dosage form further comprises microcrystalline cellulose.

[0135] [Appendix 16] 16. The method of any one of claims 8 to 15, wherein the solid dosage form further comprises polyvinyl alcohol.

[0136] [Appendix 17] 17. The method of any one of claims 8 to 16, wherein the solid dosage form further comprises red iron oxide.

[0137] [Appendix 18] 18. The method of any one of claims 8 to 17, wherein the solid dosage form further comprises sodium lauryl sulfate.

[0138] [Appendix 19] 19. The method of any one of claims 8 to 18, wherein the solid dosage form further comprises stearic acid.

[0139] [Appendix 20] 20. The method of any one of claims 8 to 19, wherein the solid dosage form further comprises talc.

[0140] [Appendix 21] 21. The method of any one of claims 8 to 20, wherein the solid dosage form further comprises titanium dioxide.

[0141] [Appendix 22] 22. The method of any one of claims 8 to 21, wherein the solid dosage form further comprises yellow iron oxide.

[0142] [Appendix 23] 23. The method of any one of claims 8 to 22, wherein the solid dosage form is a tablet.

[0143] [Appendix 24] 24. The method of claim 23, wherein the tablet is a bilayer tablet.

[0144] [Appendix 25] 25. The method of any one of claims 1 to 24, wherein the dextromethorphan hydrobromide is in an immediate release formulation.

[0145] [Appendix 26] 26. The method of any one of claims 1 to 25, wherein the bupropion hydrochloride is in a sustained release formulation.

[0146] [Appendix 27] 27. The method of any one of claims 1 to 26, wherein oral administration of the dosage form to the human patient results in rapid improvement in Alzheimer's disease agitation.

[0147] [Appendix 28] 28. The method of any one of claims 1 to 27, wherein the percentage of human patients with agitation relapse is lower in the human patients administered the dosage form than in the human patients receiving a placebo.

[0148] [Appendix 29] 29. The method of any one of claims 1-28, wherein oral administration of the dosage form to the human patient delays the time to recurrence of agitation symptoms compared to placebo.

[0149] [Appendix 30] 30. The method of any one of claims 1-29, wherein oral administration of the dosage form to the human patient delays the time to recurrence of agitation symptoms compared to placebo, with about a 3.6-fold lower risk of recurrence.

[0150] [Appendix 31] 31. The method of any one of claims 1 to 30, wherein oral administration of the dosage form to the human patient reduces the risk of relapse of Alzheimer's disease agitation (ADA) compared to placebo.

Claims

1. 1. A method of maintaining clinical response in a human patient with agitation associated with Alzheimer's disease, comprising orally administering a dosage form twice daily to the human patient, wherein the human patient has experienced a sustained clinical response as a result of receiving a combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, and wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

2. 10. The method of claim 1, wherein the sustained clinical response further comprises maintaining a Patient Impression of Change in Clinical Outcomes (PGI-C) score of 3 or less for at least four consecutive weeks.

3. 1. A method for reducing the recurrence of agitation in Alzheimer's disease, comprising orally administering a dosage form twice daily to a human patient, wherein the human patient has experienced a sustained clinical response as a result of receiving the combination of bupropion and dextromethorphan, wherein the sustained clinical response comprises a 30% or greater improvement from baseline in the human patient's Cohen-Mansfield Agitation Inventory (CMAI) total score maintained for at least four consecutive weeks, and wherein the dosage form comprises 105 mg of bupropion hydrochloride or a molar equivalent of the free base or another salt form of bupropion and 45 mg of dextromethorphan hydrobromide or a molar equivalent of the free base or another salt form of dextromethorphan.

4. 4. The method of any one of claims 1 to 3, wherein the dosage form containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide is orally administered to the patient twice daily.

5. 5. The method of any one of claims 1 to 4, wherein the dosage form is administered twice daily for at least four weeks.

6. 6. The method of any one of claims 1 to 5, wherein the dosage form is administered twice daily for at least three months.

7. 7. The method of any one of claims 1 to 6, wherein the dosage form is administered twice daily for at least six months.

8. 8. The method of any one of claims 1 to 7, wherein the dosage form is a solid dosage form.

9. 10. The method of claim 8, wherein the solid dosage form further comprises a carbomer homopolymer.

10. 10. The method of claim 8 or 9, wherein the solid dosage form further comprises colloidal silicon dioxide.

11. 11. The method of any one of claims 8 to 10, wherein the solid dosage form further comprises crospovidone.

12. 12. The method of any one of claims 8 to 11, wherein the solid dosage form further comprises glyceryl monocaprylocaprate.

13. 13. The method of any one of claims 8 to 12, wherein the solid dosage form further comprises L-cysteine ​​hydrochloride monohydrate.

14. 14. The method of any one of claims 8 to 13, wherein the solid dosage form further comprises magnesium stearate.

15. 15. The method of any one of claims 8 to 14, wherein the solid dosage form further comprises microcrystalline cellulose.

16. 16. The method of any one of claims 8 to 15, wherein the solid dosage form further comprises polyvinyl alcohol.

17. 17. The method of any one of claims 8 to 16, wherein the solid dosage form further comprises red iron oxide.

18. 18. The method of any one of claims 8 to 17, wherein the solid dosage form further comprises sodium lauryl sulfate.

19. 19. The method of any one of claims 8 to 18, wherein the solid dosage form further comprises stearic acid.

20. 20. The method of any one of claims 8 to 19, wherein the solid dosage form further comprises talc.

21. 21. The method of any one of claims 8 to 20, wherein the solid dosage form further comprises titanium dioxide.

22. 22. The method of any one of claims 8 to 21, wherein the solid dosage form further comprises yellow iron oxide.

23. 23. The method of any one of claims 8 to 22, wherein the solid dosage form is a tablet.

24. 24. The method of claim 23, wherein the tablet is a bilayer tablet.

25. 25. The method of any one of claims 1 to 24, wherein the dextromethorphan hydrobromide is in an immediate release formulation.

26. 26. The method of any one of claims 1 to 25, wherein the bupropion hydrochloride is in a sustained release formulation.

27. 27. The method of any one of claims 1 to 26, wherein oral administration of the dosage form to the human patient results in rapid improvement in Alzheimer's disease agitation.

28. 28. The method of any one of claims 1 to 27, wherein the percentage of human patients with agitation relapse is lower in the human patients administered the dosage form than in the human patients receiving a placebo.

29. 29. The method of any one of claims 1 to 28, wherein oral administration of the dosage form to the human patient delays the time to recurrence of agitation symptoms compared to placebo.

30. 30. The method of any one of claims 1 to 29, wherein oral administration of the dosage form to the human patient delays the time to recurrence of agitation symptoms compared to placebo with about a 3.6-fold lower risk of recurrence.

31. 31. The method of any one of claims 1 to 30, wherein oral administration of the dosage form to the human patient reduces the risk of relapse of Alzheimer's disease agitation (ADA) compared to placebo.

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