Treating depression

Abstract

The 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 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 of dextromethorphan in its free base form or another salt form, for treating a neurological disorder such as pain or depression in a specific patient population.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 342,960, filed May 17, 2022, U.S. Provisional Patent Application No. 63 / 345,396, filed May 24, 2022, U.S. Provisional Patent Application No. 63 / 345,856, filed May 25, 2022, U.S. Provisional Patent Application No. 63 / 346,083, filed May 26, 2022, U.S. Provisional Patent Application No. 63 / 346,269, filed May 26, 2022, and U.S. Provisional Patent Application No. 63 / 347,431, filed May 31, 2022, the entire disclosures of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0002] The 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 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 of dextromethorphan in its free base form or another salt form, for treating a neurological disorder such as pain or depression in a specific patient population. [Brief description of the drawings]

[0003] [Figure 1] FIG. 1 shows a flow chart of subjects in a Phase 2 study (randomized, double-blind, controlled study) of dextromethorphan-bupropion for major depressive disorder in Example 1. [Figure 2A] Figure 1 shows the mean change from baseline in MADRS total score over time for bupropion alone vs. dextromethorphan-bupropion in Example 1. Error bars indicate standard error and p-values ​​are calculated based on least squares means. MADRS = Montgomery-Asberg Depression Rating Scale. [Figure 2B] Figure 1 shows the percentage of patients who achieved remission (MADRS total score < 10) over the course of weeks, comparing bupropion alone with dextromethorphan-bupropion in Example 1. p values ​​are calculated based on least squares means. MADRS = Montgomery-Asberg Depression Rating Scale. [Diagram 3] The study procedure of Example 3 is shown. [Figure 4] FIG. 1 shows time to relapse in weeks for placebo vs. dextromethorphan-bupropion in Example 3. [Diagram 5] 1 shows a plot of the mean reduction in MADRS total score over time, in months, with treatment with dextromethorphan-bupropion in Example 4. [Figure 6] 1 shows plots of the percentage of subjects showing clinical response (≧50% reduction in MADRS) and remission (MADRS≦10) over time in weeks and months with treatment with dextromethorphan-bupropion in Example 4. [Figure 7] FIG. 1 shows plots of the percentage of the proportion of subjects showing a CGI-S response (≧2 category change) over time, weekly and monthly, with treatment with dextromethorphan-bupropion in Example 4. [Figure 8] 1 shows the average loss of SDS over time in months for dextromethorphan-bupropion in Example 4. Error bars indicate standard error. [Figure 9] FIG. 1 shows the proportion (in percentage) of subjects in SDS remission (SDS≦6) over time in weeks and months with treatment with dextromethorphan-bupropion in Example 4. [Figure 10] 1 shows the mean reduction in Hamilton Anxiety Scale (HAM-A) total score over time in months with treatment with dextromethorphan-bupropion in Example 5. [Figure 11]FIG. 1 shows the percentage of patients who achieved remission on the HAM-A (score≦7) over time in weeks and months with treatment with dextromethorphan-bupropion in Example 5. [Figure 12] 1 shows the percentage of patients achieving a HAM-A response (≥50% improvement from baseline) over time in weeks and months with treatment with dextromethorphan-bupropion in Example 5. [Figure 13] FIG. 1 shows the study design of a Phase 3, randomized, double-blind, placebo-controlled, multi-center, US study, Gemini, using dextromethorphan-bupropion or placebo (NCT04019704) in Example 6. [Figure 14] FIG. 1 shows the mean change in MADRS total score from baseline over time in weeks compared to dextromethorphan-bupropion vs. placebo in Example 6. p-values ​​were calculated based on least squares means. [Figure 15] FIG. 13 shows the least squares mean change in MADRS anhedonia subscale over time (weeks) for dextromethorphan-bupropion vs. placebo in Example 6. [Figure 16] FIG. 11 is a comparison of dextromethorphan-bupropion with placebo in Example 6 showing the percentage of responders achieving a 50% or greater reduction in the MADRS anhedonia subscale over time in weeks. [Figure 17] FIG. 1 shows patient disposition for a Phase 3 study of dextromethorphan-bupropion for major depressive disorder in Example 7. [Figure 18A] FIG. 1 shows the mean change in MADRS total score from baseline over time in weeks for dextromethorphan-bupropion vs. placebo in Example 7. MADRS scores range from 0 to 60, with higher scores indicating more severe depression. Results are presented as mean values, with error bars indicating standard error. p-values ​​are calculated based on least squares means. MADRS=Montgomery-Asberg Depression Rating Scale, SE=standard error. [Figure 18B] 1 shows the percentage of patients who achieved remission (MADRS total score ≦10) over time in weeks compared to dextromethorphan-bupropion vs. placebo in Example 7. p-values ​​are calculated via X2 testing. MADRS=Montgomery-Asberg Depression Rating Scale. [Figure 18C] Comparison of dextromethorphan-bupropion vs. placebo in Example 7 showing the percentage of patients achieving clinical response (≥50% reduction in MADRS total score from baseline) over time in weeks. p-values ​​are calculated via X2 testing. MADRS=Montgomery-Asberg Depression Rating Scale. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0004] 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 of dextromethorphan in 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 of dextromethorphan in 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 and 45 mg of dextromethorphan hydrobromide is specifically contemplated.

[0005] Dextromethorphan hydrobromide is a noncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist.

[0006] 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 NO HBr H 2O and has a molecular weight of 370.33. Its structural formula is [ka] It is.

[0007] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and slightly soluble in water.

[0008] Bupropion hydrochloride is an aminoketone and a CYP450 2D6 inhibitor.

[0009] 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] It is.

[0010] Bupropion hydrochloride powder is white and highly soluble in water.

[0011] 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 or round monolayer tablets.

[0012] In some embodiments, each tablet comprising a subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate release formulation. In some embodiments, each tablet comprising a subject combination contains 105 mg of bupropion hydrochloride in a sustained release formulation. In some embodiments, each tablet comprising a subject combination contains 45 mg of dextromethorphan hydrobromide in an immediate release formulation and 105 mg of bupropion hydrochloride in a sustained release formulation.

[0013] 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.

[0014] 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.

[0015] In some embodiments, the starting dose of the subject combination is 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride in one tablet administered once daily in the morning. In some embodiments, after three days, the dosage is increased to one tablet (or one dosage form containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride) administered twice daily, e.g., at least 8 hours apart. In some embodiments, no more than two doses containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride are administered on the same day.

[0016] The subject combinations are administered orally, with or without food, hi some embodiments, the tablets are swallowed whole and are not crushed, split, or chewed.

[0017] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan exhibits nonlinear pharmacokinetics at steady state when coadministered with bupropion, and the AUC and C of dextromethorphan change with varying doses of dextromethorphan (from 30 mg to 60 mg). max The AUC and C of bupropion were greater than proportional to the dose of max is less than dose-proportional.

[0018] 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 accumulation ratios of dextromethorphan at steady state based on C are about 20 and about 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.

[0019] 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. 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 is reached approximately 4 hours after administration and is approximately equal to and approximately 5 times that of bupropion. 0-12 The values ​​are approximately 1.2-fold and 7-fold higher than those of bupropion, respectively.

[0020] The subject combination may be taken with or without food. max and AUC0-12 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.

[0021] The plasma protein binding of dextromethorphan is approximately 60-70%, while that of bupropion is 84%. The extent of protein binding of the hydroxybupropion metabolite is similar to that of bupropion. On the other hand, the extent of protein binding of the threohydroxybupropion metabolite is approximately half that of bupropion.

[0022] Following 8 consecutive 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.

[0023] The mean elimination half-lives for dextromethorphan and bupropion were 22 and 15 hours, respectively. The apparent elimination half-lives for the hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion metabolites were approximately 35, 44, and 33 hours, respectively.

[0024] The subject combination may be used for adjunctive treatment of major depressive disorder or depression.

[0025] In addition to major depressive disorder, the subject combination may be used to treat other disorders in the patient population or condition described herein. For example, the subject combination may be used to treat pain or neurological disorders. Examples of neurological disorders that may be treated with the subject combination include, but are not limited to, affective disorders, psychiatric disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0026] 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 disorders, and emotional lability.

[0027] Depression may present with depressive symptoms. These symptoms include psychological changes such as mood changes, intense sadness, hopelessness, mental slowing, poor concentration, pessimistic worries, agitation, anxiety, irritability, guilt, anger, worthlessness, reckless behavior, suicidal thoughts, suicide attempts, and / or self-deprecation. Physical symptoms of depression include insomnia, loss of appetite, loss of appetite, weight loss, weight gain, reduced energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive problems, and / or abnormal circadian hormone rhythms.

[0028] 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 disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform tendency, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease may also be referred to as dementia of the Alzheimer's type. Other psychobehavioral symptoms of Alzheimer's disease that may be treatable include disinhibition and apathy.

[0029] Agitation in Alzheimer's disease occurs as the disease progresses. The 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, repeated questioning, mood swings, swearing, verbal abuse, physical outbursts, emotional distress, restlessness, shredding, sleep disorders, delusions, hallucinations, pacing, wandering, exploring, searching, repetitive physical movements, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0030] 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, with the number predicted to increase to approximately 14 million by 2050. Agitation has been reported in up to 70% of AD patients and is characterized by emotional distress, aggressive behavior, disruptive irritability, and disinhibition. Management of agitation is a priority in AD. Agitation in AD patients is associated with increased caregiver burden, functional decline, accelerated cognitive decline, earlier nursing home admission, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in AD patients.

[0031] Psychobehavioral symptoms are known to appear during dementia and may be treated with a combination of themes. Caregivers or family members may feel overwhelmed by the patient's behavioral / psychiatric symptoms rather than 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 dementia patients are similar to those of psychiatric illnesses, but with subtle differences from each other. 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.

[0032] Agitation in patients with Alzheimer's disease may be assessed using the Cohen-Mansfield Agitation Inventory or CMAI, which 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 objects or destroying property, making physical sexual advances, pacing, wandering aimlessly, dressing or undressing inappropriately, trying to get to different places, purposely falling, eating / drinking inappropriately, handling objects inappropriately, hiding objects, hoarding objects, repetitive behaviors, general restlessness, screaming, making verbal sexual advances, swearing or verbal aggression, repeating sentences or questions, strange noises (strange laughter or crying), complaining, defiance, and constantly seeking unwarranted attention or help.

[0033] Schizophrenia may be treated with the subject 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.

[0034] Brain dysfunctions that may be treated by the subject combinations include, but are not limited to, disorders involving intellectual disability such as senile dementia, Alzheimer's dementia, memory loss, amnesia / amnesic syndrome, epilepsy, impaired consciousness, coma, impaired attention, speech disorder, vocal spasm, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity disorder, and schizophrenia. Brain dysfunctions also include disorders caused by cerebrovascular disorders including stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., whose symptoms include, but are not limited to, impaired consciousness, senile dementia, coma, impaired attention, and speech disorder.

[0035] Substance abuse addictions that may be treated with the subject combinations include, but are not limited to, drug dependency, 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.

[0036] 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, and Tourette's syndrome, and Wilson's disease.

[0037] 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.

[0038] 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.

[0039] 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-Barre syndrome, and spastic paraplegia.

[0040] Seizure disorders that may be treated with the subject combinations include, but are not limited to, epileptic seizures, non-epileptic 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.

[0041] Types of headaches that may be treated with the subject combination include, but are not limited to, migraines, tension-type headaches, and cluster headaches.

[0042] Other neurological disorders which 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; chemotherapy-induced neurotoxicity, such as diabetic neuropathy, methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0043] In some embodiments, the subject combinations may be used to treat pain, joint pain, pain associated with sickle cell disease, emotion 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.

[0044] 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.

[0045] In some embodiments, the subject combinations are administered to relieve musculoskeletal pain, arthritis pain, and inflammatory pain, including complex regional pain syndrome.

[0046] 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 arthropathy including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

[0047] In some embodiments, the subject combinations are used to treat chronic musculoskeletal pain.

[0048] 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 types 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 hands and feet, which may be accompanied by edema, and autonomic, motor, and sensory changes.

[0049] In some embodiments, the subject compositions may be administered orally to relieve neuropathic pain.

[0050] Examples of neuropathic pain include diabetic peripheral neuropathy or diabetic peripheral neuropathy pain, post-herpetic 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.

[0051] In some embodiments, the subject compositions may be administered to relieve fibromyalgia.

[0052] In some embodiments, the subject combination may reduce relapse of treatment-resistant depression (TRD) in patients. Generally, approximately 40% of patients with MDD are treatment-resistant, defined as failure of a current depressive episode to respond to two or more antidepressants, adequately taken from two different classes. Relapse of MDD is not uncommon for patients with TRD who eventually achieve remission, with over 40% of patients relapsing within four months of treatment. Relapse was defined by one or more of the following: (1) a MADRS total score of 18 or greater on two consecutive assessments, 7-21 days apart; (2) a 2 or more point increase in Clinical Global Impression of Severity (CGI-S) from randomization, with a minimum CGI-S score of 4 on two consecutive assessments, 7-21 days apart; (3) loss of treatment response, such as a) hospitalization due to worsening depression or suicide risk, b) investigator's opinion that additional antidepressant treatment or a change in treatment is required, and c) investigator's opinion that the patient has relapsed.

[0053] In some embodiments, the subject combinations may delay the time to relapse of depressive symptoms compared to placebo in treatment-resistant depression. In some embodiments, the subject combinations may significantly and statistically delay the time to relapse of depressive symptoms compared to placebo in patients with TRD who have achieved stable remission with the subject combination (dextromethorphan and bupropion).

[0054] In some embodiments, patients with TRD continuing treatment with a subject combination may not experience a recurrence of depressive symptoms within about 10 weeks, within about 20 weeks, within about 26 weeks, within about 30 weeks, within about 40 weeks, within about 50 weeks, within about 52 weeks or more, or for at least 6 months or more, of treatment.

[0055] In some embodiments, the subject combinations may significantly reduce the recurrence of depression over at least six months as compared to placebo. In some embodiments, treatment with the subject combinations reduces the likelihood of recurrence as compared to placebo. In some embodiments, the likelihood that a patient will not experience a recurrence of depression following treatment with the subject combinations is at least 30%, about 30-40%, about 40-50%, or about 36%, greater than the percentage of patients who will not experience a recurrence of depression following treatment with a placebo, or any percentage in a range bounded by any of the above values.

[0056] Depressive symptoms may improve rapidly after treatment with the subject combination. The mean change in MADRS total score from baseline may be significant at 1, 2, 4, or 6 weeks. Improvement in depressive symptoms may persist through about 3 months, about 6 months, about 1 year, or more. Clinical response (improvement of 50% or more) with the subject combination may be achieved at 1, 2, 4, or 6 weeks. Remission of MADRS (≦10) with the subject combination may be achieved at 1, 2, 4, or 6 weeks or more. Antidepressant effects with the subject combination may be durable and sustained through 2, 3, 6, 9, or 12 months or more.

[0057] CGI-S response (≧2 category change) with the subject combination treatment may be rapid. CGI-S response (≧2 category change) may be observed at 1, 2, 4, or 6 weeks. CGI-S improvement may be durable through 2, 3, 6, 9, or 12 months or more.

[0058] The mean reduction in SDS with the subject combination treatment may be rapid. The mean reduction in SDS with the subject combination treatment may be significant at 1 week, 2 weeks, 4 weeks, or 6 weeks. The mean reduction in SDS with the subject combination treatment may be durable and sustained through 2 months, 3 months, 6 months, 9 months, or 12 months or more. Remission of SDS (≦6) may be achieved at 1 week, 2 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 6 months, 9 months, or 12 months or more.

[0059] In some embodiments, the human patient is selected as having a HAM-A score of at least 10 or at least 15 prior to treatment.

[0060] The subject combination treatment may improve anxiety symptoms. The reduction in mean HAM-A score from baseline may be significant at 1, 2, 4, or 6 weeks. The improvement in HAM-A may persist through 2, 3, 6, 9, or 12 months or more. The subject combination treatment may rapidly remit anxiety at 1, 2, 4, or 6 weeks. Remission may persist through 2, 3, 6, 9, or 12 months or more.

[0061] HAM-A response (≥50% improvement from baseline) may be achieved in approximately 15%-70% of patients at weeks 1, 2, 4, or 6. Response rates may continue to improve through months 2, 3, 6, 9, or 12 or more.

[0062] In some embodiments, human patients are selected for having a MADRS anhedonia score of at least 15 or at least 19 prior to treatment. In some embodiments, the subject combination may improve anhedonia symptoms of major depressive disorder (MDD) as assessed by the MADRS anhedonia subscale. Anhedonia is one of the central features of MDD. Anhedonia is considered one of the most troublesome aspects of MDD by patients, is associated with decreased functioning, and is a risk factor for non-response to antidepressant treatment. The MADRS anhedonia subscale includes five items: 1) apparent sadness, 2) reported sadness, 3) impaired concentration, 4) fatigue, and 5) inability to feel.

[0063] In some embodiments, the subject combinations may be administered orally to reduce the MADRS anhedonia subscale at week 1, week 2, week 3, week 4, week 5, or week 6 or more. In some embodiments, administration of the subject combinations may result in a mean reduction from baseline in the MADRS anhedonia subscale score of about 4-5, 4-6, 6-8, 6-7, 8-10, 8-9, 9-10, about 4.4, about 6.8, about 8.1, about 9.6, about 9.7, or about 10 or more MADRS anhedonia subscale scores, or any MADRS anhedonia subscale score in a range bounded by any of these values.

[0064] In some embodiments, the mean reduction from baseline in the MADRS Anhedonia subscale when a subject combination is orally administered may be significantly greater than when a placebo is orally administered at weeks 1, 2, 3, 4, 5, or 6 or more. In some embodiments, the mean reduction from baseline in the MADRS Anhedonia subscale when a subject combination is orally administered may be about 30%, about 50%, about 60%, about 20-30%, about 30%-35%, about 30%-50%, about 40%-50%, about 50%-55%, about 50-60%, about 60%-65%, or any percentage within a range bounded by any of these values, when a subject combination is orally administered may be greater than when a placebo is orally administered at weeks 1, 2, 3, 4, 5, or 6 or more.

[0065] In some embodiments, the likelihood of a patient becoming a responder (a 50% or greater reduction in the MADRS Anhedonia subscale) while orally administered a subject combination may be about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 20-25%, about 30-35%, about 40-45%, about 50-55%, about 21%, about 35%, about 42%, about 51%, about 54%, or any likelihood within a range bounded by any of these values ​​at week 1, week 2, week 3, week 4, week 5, or week 6 or more.

[0066] In some embodiments, a subject combination of dextromethorphan and bupropion may result in a statistically significant greater likelihood of a patient being a responder (a 50% or greater reduction in the MADRS anhedonia subscale) at weeks 1, 2, 3, 4, 5, or 6 or more, compared to placebo. In some embodiments, the likelihood of a patient being a responder while being administered a subject combination may be about 10-15%, about 15-20%, about 20-25%, about 13%, about 16%, about 18%, about 20%, about 23%, or any likelihood within a range bounded by any of these values, which is greater than the likelihood of a patient being a responder while taking a placebo at weeks 1, 2, 3, 4, 5, or 6 or more.

[0067] 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.

[0068] Example 1 Efficacy of dextromethorphan-bupropion in major depressive disorder: A randomized, double-blind, controlled trial the purpose: Alterations in glutamatergic neurotransmission have been implicated in the development of major depressive disorder. Dextromethorphan-bupropion is an oral NMDA receptor antagonist and sigma-1 receptor agonist that utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 study evaluated the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder.

[0069] method: This randomized, double-blind, multicenter, parallel-group study evaluated dextromethorphan-bupropion versus an active control, extended-release bupropion, in patients aged 18-65 years diagnosed with major depressive disorder of moderate to severe severity. Patients were randomly assigned to receive dextromethorphan-bupropion (45 mg / 105 mg tablets) or bupropion (105 mg tablets) once daily for the first 3 days and twice daily thereafter for a total of 6 weeks. The primary outcome was a global treatment effect on the Montgomery-Asberg Depression Rating Scale (MADRS) score (mean change from baseline between weeks 1 and 6); all randomized patients had their diagnosis and severity confirmed by an independent assessor, received at least one dose of study medication, and underwent at least one postbaseline assessment.

[0070] result: Of the 97 randomized patients, 17 had no confirmed diagnosis or severity based on independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score (overall treatment effect) through weeks 1 to 6 was significantly greater with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least squares mean difference=-4.9; 95% Cl=-3.1, -6.8). The change in MADRS score with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and all subsequent time points (week 6: -17.3 vs. -12.1 points; least squares mean difference=-5.2, 95% Cl=-1.1, -9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and all subsequent time points (week 6: 46.5% vs. 16.2%; least squares mean difference = 30.3%, 95% Cl = 11.2, 49.4). Response rates (≥ 50% reduction in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least squares mean difference = 19.9%, 95% Cl = -1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

[0071] Conclusion: In patients with major depression, dextromethorphan-bupropion significantly improved depressive symptoms compared with bupropion and was generally well tolerated.

[0072] Major depressive disorder is a prevalent disorder and a leading cause of disability worldwide. Currently approved oral antidepressants act primarily through monoamine pathways. Partial or inadequate responses are common with these medications, and they usually take several weeks to produce clinically meaningful effects. Stepped Treatment Alternatives (STAR) for Relief of Depression ※ D) In ​​trials, approximately two-thirds of patients with depression failed to achieve remission with first-line treatment, and approximately 60% of patients who experienced a clinical response achieved remission after 8 weeks of treatment or more.

[0073] Data from neuroimaging, cellular, and clinical studies suggest the involvement of the glutamatergic system in the pathogenesis of depression. Dextromethorphan is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor (ionotropic glutamate receptor) and a sigma-1 receptor agonist. Blockade of the NMDA receptor and agonism of the sigma-1 receptor modulate glutamatergic signaling in the central nervous system. The clinical usefulness of dextromethorphan is limited by its rapid and extensive metabolism through CYP2D6, resulting in plasma concentrations that are insufficient for therapeutic efficacy. Dextromethorphan-bupropion combination tablets (hereafter dextromethorphan-bupropion) have been formulated to increase the bioavailability and half-life of dextromethorphan and have been developed for the treatment of major depression. The bupropion component acts to increase the plasma concentration of dextromethorphan by inhibiting its metabolism. In March 2019, Breakthrough Drug Designation was granted by the U.S. Food and Drug Administration (FDA) for dextromethorphan-bupropion for the treatment of major depressive disorder. This designation is given to drug candidates that show potential benefits over existing therapies based on preliminary clinical data, and provides providers with greater focused interaction with FDA staff during the development of the drug candidate.

[0074] High rates of failure to achieve signal detection in depression clinical trials are well documented. A large-scale analysis of depression clinical trials submitted for new drug applications over 25 years revealed a nearly 50% trial failure rate and reduced treatment effect (drug-placebo difference) over this period. Reasons for poor signal detection and high failure rates in depression clinical trials identified in the literature include high inflation of placebo response rates, tendency of site assessors to inflate baseline scores, inclusion of less severely symptomatic patients, and failure to exclude patients who are ineligible for study participation. Efforts to address the elevated placebo rate include the design of placebo run-in periods and sequential parallel group comparison designs to exclude subjects with high placebo responses and increase treatment effect. These efforts have been met with repeated failures and successes. Efforts to reduce inclusion of ineligible or unsuitable patients include using a third party to re-interview potential patients to confirm illness severity and eligibility. A limitation of these efforts is that sites are not blinded to the use of independent assessments.

[0075] This pilot study utilized measures that may address issues leading to poor signal detection, including confirmation of disease severity by independent assessment and comprehensive blinding of participating clinical trial sites.

[0076] method research design This was a 6-week randomized, double-blind, active-controlled phase 2 study conducted at four sites in the United States from May 2018 to December 2018. The study used bupropion, an approved antidepressant, as the control since it is a component of dextromethorphan-bupropion.

[0077] To address site assessor bias that could lead to inappropriate patient inclusion, the study assessed efficacy only in patients with a confirmed diagnosis and severity of major depressive disorder based on a clinical review by an independent assessor blinded to treatment allocation. The clinical review utilized only site-collected documentation at screening and baseline, including full medical history and clinician- and patient-reported outcome measures (described below under Efficacy Assessment). The independent assessors had no direct contact with study participants or access to any patient data collected after randomization. To reduce investigator expectation bias and therefore placebo response, sites were blinded to the primary assessment variables and the existence of the independent assessors. Sites were provided with a blinding protocol describing the study as a safety study with exploratory efficacy assessments. Detailed discussion of efficacy analyses was limited to the statistical analysis plan and was not provided to sites.

[0078] All sites were approved by review boards, and all patients provided written informed consent prior to participation. Site investigators collected study data, and the applicant ensured that all individuals administering the rating scales were qualified and appropriately trained. The study was conducted in accordance with the guidelines of the International Conference on Harmonization on Good Clinical Practice, the principles of the Declaration of Helsinki, and all regulatory requirements. This clinical trial appeared on ClinicalTrials.gov (NCT03595579).

[0079] participants This study evaluated patients aged 18-65 years with a confirmed diagnosis of major depressive disorder and a current major depressive episode of moderate or greater severity. Diagnosis was established using the DSM-5 criteria for major depressive disorder without psychotic features based on a structured clinical interview for DSM-5 clinical trials version and investigator assessment of a score of 25 or greater on the Montgomery-Asberg Depression Rating Scale (MADRS) and a score of 4 or greater on the Clinical Global Impression-Severity Scale (CGI-S). Confirmation of the diagnosis of major depressive disorder and a current major depressive episode of moderate or greater severity was performed by blinded independent assessors based on clinical review prior to database lock and unblinding of the study.

[0080] Major exclusion criteria included bipolar disorder, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (defined as failure of at least two adequate antidepressant treatments in a current major depressive episode), substance-related disorders within the past year, lifetime history of psychosis, clinically significant suicide risk, and history of seizure disorder. Patients could be receiving antidepressant treatment prior to study entry but were required to completely discontinue previous treatment, with at least one week or five half-lives of the drug, whichever was longer, washout, prior to the baseline visit and randomization. The screening period was set at up to four weeks to allow for optional tapering and washout of previous medications.

[0081] Randomization and blinding Participants were randomized in a 1:1 ratio to receive treatment with dextromethorphan-bupropion or extended-release bupropion. To ensure that site investigators could not independently confirm diagnoses, all patients deemed eligible by site investigators were randomized to receive study medication and were included in the safety population. Patients whose diagnosis or severity was not confirmed by an independent assessor, as prespecified, were excluded from the efficacy population.

[0082] The dextromethorphan-bupropion tablets and bupropion tablets were identical in appearance. The randomization schedule was computer-generated using a permuted block algorithm that randomly assigned study drugs to randomization numbers. All patients, investigators, and study personnel were blinded to treatment assignment, and no one involved in the conduct of the study had access to the randomization schedule prior to official unblinding of treatment assignment.

[0083] procedure The duration of double-blind treatment was 6 weeks. Patients received their assigned study medication, dextromethorphan-bupropion (45 mg / 105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter. The dose of bupropion in the control group (210 mg daily) was chosen to match the dose included in the dextromethorphan-bupropion to allow for appropriate comparisons. During the treatment period, patients checked their mood daily by completing a visual analog mood scale. Study visits were conducted at weeks 1, 2, 3, 4, and 6 after the baseline visit. A safety follow-up visit was conducted at week 7, 1 week after the last dose of study medication. There were no formal discontinuation criteria, patients could withdraw consent for any reason, and investigators were free to remove patients from the study for safety-related reasons. The dose of dextromethorphan-bupropion was selected based on the results of pharmacokinetic studies and titrated to twice daily. Compliance with study medication was monitored by counting the number of dispensed and returned tablets and by measuring bupropion plasma concentrations at the end of the study.

[0084] Efficacy evaluation The primary efficacy variable was the change from baseline to week 6 in the MADRS total score. The MADRS is a 10-item clinician-rated questionnaire scaled from 0 to 60, with higher scores indicating more severe depression. The primary hypothesis test was the overall treatment effect in MADRS score (mean change from baseline at weeks 1 to 6).

[0085] Secondary outcomes included clinical response (defined as a 50% or greater reduction from baseline in the MADRS total score), remission (defined as a MADRS total score ≤10), scores on the Clinical Global Impression-Improvement scale (CGI-I; range 1 [much improved] to 7 [much worse]), scores on the CGI-S (range 1 [normal] to 7 [extremely severe symptoms]), scores on the 16-item Quick Inventory of Depressive Symptoms (QIDS-SR; range 0-27, with higher scores indicating more severe depression), and scores on the MADRS-6 (a 10-item subscale of the MADRS assessing the core symptoms of depression: apparent sadness, reported sadness, tension, fatigue, inability to feel, and pessimistic thinking).

[0086] Safety was assessed based on the incidence of adverse events and changes in vital signs, clinical laboratory measurements, physical examination, and electrocardiogram, and assessment of suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS).Treatment-emergent adverse events were defined as those occurring from the time of the first dose of dextromethorphan-bupropion or bupropion through 7 days after the last dose.

[0087] statistical analysis Two sets of patients were prespecified for analysis: the safety population included all patients who received at least one dose of study medication. The efficacy population (modified intention-to-treat population) consisted of all patients with a diagnosis of major depressive disorder and a current major depressive episode of moderate or greater severity, confirmed by an independent assessor, who were randomized, received at least one dose of study medication, and had at least one postbaseline assessment.

[0088] The primary efficacy variable was the change from baseline in the MADRS total score, and the primary hypothesis test was the overall treatment effect. The overall treatment effect on MADRS was assessed by averaging the change from baseline at each time point in the study (weeks 1–6). Change from baseline in MADRS was analyzed using a mixed model with repeated measures that included treatment (2-level: 1 indicating active treatment and 2 indicating control treatment), week (5-level: weeks 1–4 and 6), and treatment-by-week interaction as factors, baseline value as a covariate, and control as a random effect. This method was used to analyze all other efficacy variables assessing change from baseline. Missing values ​​were imputed by the last-observation-carried-forward method.

[0089] Overall treatment effects, treatment effects at each postbaseline week, and differences between treatment effects were estimated using least-squares mean estimates and reported with two-sided 95% confidence intervals for the treatment differences. Efficacy variables related to rates (e.g., clinical response rate and remission rate) were analyzed using chi-square tests. CGI-I was analyzed using the Cochran-Mantel-Haenszel test. Analyses were performed using SAS version 9, and all hypothesis tests were performed at a two-sided alpha level of 0.05.

[0090] If the primary hypothesis test of MADRS revealed positive results, other analyses (response, remission) were performed on this variable to examine clinical relevance. As this was a phase 2 pilot study, the secondary efficacy variables were not adjusted for multiplicity and these nominal p-values ​​are presented. The sample size was assumed to be approximately 60 patients (30 in each group) who completed the double-blind period and had a confirmed diagnosis. The sample size for this study was determined based on previous reported experience with trials of similar phase, similar patient population, and similar objectives.

[0091] result Patients and placement A total of 97 patients were randomized (48 to dextromethorphan-bupropion and 49 to bupropion). Of these, the independent assessor's assessment could not confirm the diagnosis or severity of 17 patients, resulting in a total efficacy (modified intention-to-treat) population of 80 patients (43 to the dextromethorphan-bupropion group and 37 to the bupropion group) (Figure 1). Of the 17 patients excluded from the sample, 16 were excluded due to discrepancies in depression severity scores (did not meet criteria for at least moderate depression severity) and 1 was excluded because the patient did not have a primary diagnosis of major depressive disorder.

[0092] Figure 1 shows a flow chart of participants in a Phase 2 trial of dextromethorphan-bupropion for major depressive disorder.

[0093] Baseline demographic and clinical characteristics of patients were largely similar in the dextromethorphan-bupropion and bupropion groups (Table 1). There were higher proportions of women, black or African American patients, and Hispanic or Latino patients in the bupropion group (70.3%, 37.8%, and 29.7%, respectively) compared with the dextromethorphan-bupropion group (58.1%, 27.9%, and 14.0%, respectively). These observed differences were within chance (p>0.15) given the small sample sizes. The number of patients who completed the study in the efficacy population was 34 (79.1%) in the dextromethorphan-bupropion group and 26 (70.3%) in the bupropion group. Completers in the safety population are shown in Figure 1.

[0094] Overall, mean treatment adherence based on pill counts was high across visits in the safety and efficacy populations in both the dextromethorphan-bupropion and bupropion groups (≥90.0% and ≥91.3%, respectively). Consistent with adherence based on pill counts, of the 72 patients in the efficacy population with pharmacokinetic samples, 93.1% had measurable study drug concentrations at the last scheduled study visit.

[0095] efficacy Dextromethorphan-bupropion was associated with a significant reduction in MADRS total score compared with bupropion (Figure 2). The least squares mean change from baseline in MADRS total score (overall treatment effect) at weeks 1–6 was −13.7 points in the dextromethorphan-bupropion group and 28.8 points in the bupropion group (least squares mean difference = −4.9, 95% Cl = −3.1, −6.8; Cohen's d = 1.2; p < 0.001). Improvements in MASRS total score with dextromethorphan-bupropion versus bupropion were observed as early as week 1, with statistically significant differences observed beginning at week 2 (least squares mean difference = −4.7, 95% Cl = −0.6, −8.8; p = 0.024), and significant differences at all time points thereafter. At week 6, dextromethorphan-bupropion was associated with a mean change from baseline in the MADRS total score of -17.3 points compared with -12.1 points for bupropion (least squares mean difference = -5.2, 95% Cl = -1.1, -9.3; Cohen's d = 0.6; p = 0.013). Results of a sensitivity analysis of the primary endpoint (overall treatment effect) using a mixed model for repeated measures without imputation of missing values ​​were consistent with those of the primary analysis (least squares mean difference = -5.1, 95% Cl = -3.1, -7.1; p < 0.001).

[0096] [Table 1]

[0097] Remission, defined as a MADRS total score ≤10, was achieved by a statistically significantly greater proportion of patients in the dextromethorphan-bupropion group than in the bupropion group at week 2 and all time points thereafter (25.6% vs. 2.7%, respectively; least squares mean difference = 22.9%, 95% Cl = 8.8, 36.9; p = 0.004) (Figures 2A and 2B, Table 2). The proportion of patients who achieved remission at week 6 was 46.5% in the dextromethorphan-bupropion group and 16.2% in the bupropion group (least squares mean difference = 30.3%, 95% Cl = 11.2, 49.4; p = 0.004). Clinical response, defined as a ≥50% reduction in MADRS total score, favored the dextromethorphan-bupropion group, with the difference between groups reaching statistical significance at weeks 3 (LSM mean difference = 27.2%, 95% Cl = 7.2, 47.2; p = 0.012) and 4 (LSM mean difference = 23.0%, 95% Cl = 1.7, 44.3; p = 0.040). At week 6, 60.5% of patients in the dextromethorphan-bupropion group achieved a clinical response compared with 40.5% in the bupropion group (LSM mean difference = 19.9%, 95% Cl = -1.6, 41.5; p = 0.075).

[0098] Dextromethorphan-bupropion significantly improved MADRS-6 (core symptoms) scores compared with bupropion. The least squares mean change from baseline in the MADRS-6 from weeks 1 to 6 (overall treatment effect) was -10.1 points in the dextromethorphan-bupropion group and -6.6 points in the bupropion group (least squares mean difference = -3.4, 95% Cl = -2.2, -4.7; p < 0.001) (Table 2). Improvement in MADRS-6 scores with dextromethorphan-bupropion compared with bupropion was observed as early as week 1, with statistically significant differences observed from week 2 to all subsequent time points (least squares mean difference = -3.2, 95% Cl = -0.4, -6.0; p = 0.027).

[0099] Dextromethorphan-bupropion treatment was associated with significantly greater improvements on the CGI-S compared with bupropion. The overall treatment effect on the CGI-S (mean improvement from baseline at weeks 1-6) was -1.6 in the dextromethorphan-bupropion group compared with -1.0 in the bupropion group (LSMD = -0.5, 95% Cl = -0.3, -0.8; p < 0.001) (Table 2). Improvements in the CGI-S with dextromethorphan-bupropion were greater at all time points compared with bupropion, with the between-group difference reaching statistical significance at all subsequent time points, including week 2 (LSMD = -0.9, 95% Cl = 0.0, -1.0; p = 0.049) and week 6 (LSMD = -0.5, 95% Cl = 0.0, -1.1; p = 0.038). The proportion of patients showing moderate to marked improvement on the CGI-I was statistically significantly higher in the dextromethorphan-bupropion group compared with the bupropion group at week 1 (LSM mean difference = 14.3, 95% Cl = 1.5, 28.3; p = 0.045) and week 4 (LSM mean difference = 28.1, 95% Cl = 4.1, 52.1; p = 0.025).

[0100] The dextromethorphan-bupropion group also showed statistically significant improvement compared with the bupropion group on the patient-rated QIDS-SR. The least squares mean change from baseline (overall treatment effect) on the QIDS-SR from weeks 1 to 6 was -6.0 in the dextromethorphan-bupropion group and -4.8 in the bupropion group (least squares mean difference = -1.2, 95% Cl = -0.2, -2.2; p = 0.017). A statistically significantly higher proportion of patients in the dextromethorphan-bupropion group (46.5%) compared with the bupropion group (21.6%) had remission on the QIDS-SR at week 6 (defined as a score ≤ 5) (least squares mean difference = 24.9%, 95% Cl = 4.9, 44.8; p = 0.020).

[0101] Figures 2A and 2B show remission and MADRS total score over time in a Phase 2 study of dextromethorphan-bupropion for major depressive disorder. Figure 2A shows the mean change from baseline in MADRS total score over time, and Figure 2B shows the proportion of patients achieving remission (MADRS total score ≦10) over time. MADRS stands for Montgomery-Asberg Depression Rating Scale. Error bars indicate standard error and p-values ​​are calculated using chi-squared tests.

[0102] [Table 2] a CGI-S5 Clinical Global Impression Severity Scale; LS = least squares; MADRS = Montgomery-Asberg Depression Rating Scale; MADRS-6 = 6-item Montgomery-Asberg Depression Rating Scale; NNT = number needed to treat; ns = not significant. Changes from baseline variables were analyzed using mixed models for repeated measures. This analysis of covariance mixed-effects model for repeated measures includes treatment as factors, week and treatment-by-week interactions, baseline values ​​as covariates, and patient as a random effect. Treatment effects and treatment differences at each time point are assessed using least squares means estimation. Efficacy variables were analyzed via chi-square tests. Hypothesis testing was performed at a 2-sided alpha level of 0.05.

[0103] safety The percentage of patients who experienced any adverse events during the treatment period was 72.9% in the dextromethorphan-bupropion group and 64.6% in the bupropion group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, dry mouth, decreased appetite, and anxiety. The most frequently reported adverse events in the bupropion group were nausea, headache, dry mouth, decreased appetite, and constipation. The majority of adverse events were mild or moderate in severity. Adverse events rated as severe were reported by three patients in the dextromethorphan-bupropion group (dizziness in two patients; somnolence, nausea, and anxiety in one patient each) and one patient in the bupropion group (psychosis). There were no serious adverse events (including hospitalization) in the study. The incidence of adverse events leading to discontinuation of study drug was the same in the dextromethorphan-bupropion and bupropion groups (12.5%). Two patients in the dextromethorphan-bupropion group discontinued the study drug because of dizziness and anxiety, respectively, and one patient in the bupropion group experienced psychosis. Dextromethorphan-bupropion was not associated with an increase in psychotomimetic effects, weight gain, or sexual dysfunction (Table 3).

[0104] Mean changes from baseline in clinical laboratory parameters and vital signs were small and similar between treatment groups. Two patients in the dextromethorphan-bupropion group experienced weight loss and one patient in the bupropion group experienced an increase in blood pressure, both of which resolved. The weight loss adverse event was mild rather than serious.

[0105] The study found no indication of increased suicidality as assessed by change from baseline on the C-SSRS. At baseline, five patients (10.4%) in the dextromethorphan-bupropion group and four patients (8.2%) in the bupropion group had a positive response to item 1 of the C-SSRS (wish to die). At week 1, only two patients in the dextromethorphan-bupropion group had a positive response to item 1, compared with five patients in the bupropion group. At week 6, one patient in each treatment group had a positive response to item 1 of the C-SSRS.

[0106] [Table 3] a The safety population included all randomized patients who received at least one dose of dextromethorphan-bupropion or bupropion. Treatment-emergent adverse events were defined as those that began or worsened after the first dose of dextromethorphan-bupropion or bupropion up to 7 days after the last dose. b A serious adverse event was defined as any adverse event that resulted in death, was immediately life-threatening, resulted in hospitalization or prolonged hospitalization, or resulted in persistent or clinically significant impairment or incapacity. c A serious adverse event was defined as any event that disrupted usual activities of daily living or had a significant impact on clinical status or required intensive therapeutic intervention.

[0107] Discussion In this randomized controlled clinical trial, dextromethorphan-bupropion demonstrated rapid, substantial, and statistically significant antidepressant efficacy compared with the active control bupropion in the primary efficacy variable (MADRS total score) and numerous other clinician- and patient-reported measures of depression severity. Given the known challenges in achieving signal detection in clinical trials for depression, design features were implemented in this study to increase assay sensitivity and ensure evaluation of an appropriate patient population. To address potential site-rater bias regarding inclusion of inappropriate patients, the study assessed only patients whose diagnosis and severity of major depressive disorder were confirmed by a blinded, independent rater based on clinical review. Another important design feature implemented to increase the power to detect efficacy signals in this phase 2 trial was blinding site investigators to the efficacy objectives of the study to reduce expectancy bias.

[0108] Dextromethorphan-bupropion rapidly reduced depressive symptoms, with statistically significant differences over bupropion observed as early as week 1 and at all time points from week 2 onward, as measured by MADRS total score. The treatment difference in MADRS (change in dextromethorphan-bupropion minus change in bupropion) was substantial and consistent over time, approximately 5 points at each time point from week 2 through week 6 (range, 4.5-5.6 points). This treatment effect over active control compares favorably with a mean difference of approximately 2.5 points over placebo seen at weeks 6-8 in studies of antidepressants in the FDA database.

[0109] Symptom remission is considered a desirable goal in depression treatment because it is associated with better daily functioning and better long-term prognosis. Remission rates on the MADRS (total score ≤ 10) were statistically significantly higher in the dextromethorphan-bupropion group from week 2 (p = 0.004) and at all time points thereafter. At week 6, remission rates on the patient-rated QIDS-SR (total score ≤ 5) also favored dextromethorphan-bupropion (p = 0.020), demonstrating consistency between clinician- and patient-reported outcomes.

[0110] Because it has been suggested that core symptoms may be more sensitive to change with antidepressant treatment, the MADRS core symptoms subscale (MADRS-6) was assessed. Results of the MADRS-6 were consistent with those of the 10-item MADRS, demonstrating greater improvement among patients in the dextromethorphan-bupropion group compared with those in the bupropion group, with both measures achieving statistical significance at week 2 and all subsequent time points.

[0111] Results of clinician global assessments were consistent with those of the symptom-specific scales in favor of dextromethorphan-bupropion. Clinicians reported more rapid and consistently greater reductions in illness severity as measured by the CGI-S with dextromethorphan-bupropion compared with bupropion, beginning at week 2 (p=0.049) and remaining statistically significant at all time points thereafter, including week 6 (p=0.038).

[0112] Despite the small sample size of the study, dextromethorphan-bupropion showed a rapid onset of effect on depression symptoms and global measures, with statistically significant improvements observed on some measures beginning at week 2 compared with bupropion. Dextromethorphan-bupropion demonstrated a statistically significant reduction in MADRS total score from baseline compared with bupropion beginning at week 2 (p=0.024). Remission rates on the MADRS were statistically significantly better in the dextromethorphan-bupropion group than in the bupropion group beginning at week 2 (26% vs. 3%; p=0.004). Global measures showed rapid improvement with dextromethorphan-bupropion, with statistically significant changes observed at week 1 on the CGI-1 (p=0.045) and week 2 on the CGI-S (p=0.049).

[0113] This study is the first controlled trial of dextromethorphan-bupropion in patients with depression. Marrow et al. reported the results of a combination of dextromethorphan and quinidine in patients with treatment-resistant depression. However, it was an open-label trial without a control group, limiting interpretation. Development of a combination of deuterated dextromethorphan and quinidine for the treatment of major depression was discontinued because the results of a phase 2 placebo-controlled trial (NCT02153502) in this condition did not provide sufficient evidence of efficacy to justify continued development. In this phase 2 trial, the bupropion arm (210 mg / day) showed the expected effect, producing a substantial reduction from baseline (12 points) in the MADRS total score at week 6. By comparison, in an 8-week randomized placebo-controlled trial of 362 patients, treatment with bupropion at doses of 150 mg / day or 300 mg / day resulted in a reduction from baseline of approximately 10 points on the Hamilton Depression Scale (HAM-D) at week 8 for each of the two doses. This 10-point change in the HAM-D translated into an approximately 12-point change in the MADRS, which is consistent with the results of bupropion in this Phase 2 study. The dose of bupropion in this study was chosen to be consistent with the dose contained in dextromethorphan-bupropion, allowing for a proper comparison. This dose is lower than the usual target dose of 300 mg / day for monotherapy as stated in the FDA prescribing information for bupropion.

[0114] In this study, dextromethorphan-bupropion was safe and well tolerated. The incidence of adverse events was broadly similar between the two groups, except for dizziness, which was reported in 20.8% of the dextromethorphan-bupropion group compared with 4.2% in the bupropion group. A larger study was conducted to estimate the approximate incidence of dizziness with dextromethorphan-bupropion (ClinicalTrials.gov identifier: NCT04019704). Discontinuation rates due to adverse events were similar in the two treatment groups.

[0115] Unlike other NMDA receptor antagonists, dextromethorphan-bupropion has not been associated with psychotomimetic effects. This tolerability profile may be related to the significantly faster rate of unblocking of the NMDA receptor channel reported with dextromethorphan compared to other NMDA antagonists. In this study, dextromethorphan-bupropion was not associated with abuse-related adverse events. While dosing in this study lasted only 6 weeks, dextromethorphan-bupropion has been administered for up to 1 year in a long-term open-label safety study (ClinicalTrials.gov Identifier: NCT04039022). In this and other larger controlled studies, dextromethorphan-bupropion has not been associated with abuse to date. In this 6-week study, dextromethorphan-bupropion was not associated with increased weight gain or sexual dysfunction.

[0116] Limitations of this study include the exclusion of patients with inappropriate symptom severity, psychosis or other psychiatric disorders, substance use disorders, clinically significant suicide risk, or significant medical comorbidities. These exclusions and the prohibition of certain concomitant medications may limit the generalizability of the study findings. In addition, treatment by specialized clinicians at experienced study sites based on a study protocol with frequent clinical evaluations may not reflect general treatment. While most secondary outcomes favored dextromethorphan-bupropion over bupropion, confidence intervals for the differences between groups were not adjusted for multiple comparisons. A greater number of patients were excluded by independent assessment in the bupropion group compared with the dextromethorphan-bupropion group, which may affect the overall results. Imputation of missing values ​​via methods that impute the most recent data for missing time series data may affect the results of categorical variables such as response and remission. Finally, the duration of the study was limited to 6 weeks. The effects of long-term treatment with dextromethorphan-bupropion have also been evaluated in other studies. In this phase 2 randomized clinical trial, treatment with dextromethorphan-bupropion produced clinically meaningful and statistically significant improvements in depressive symptoms and was well tolerated compared with the active control bupropion. Reductions in dextromethorphan-bupropion symptoms were statistically significant compared with bupropion alone at 2 weeks and all subsequent time points.

[0117] Example 2 Dextromethorphan-Bupropion Achieves Primary and Key Secondary Endpoints in the MERIT Phase 2 Trial for Treatment-Resistant Depression Dextromethorphan-bupropion significantly delayed the time to relapse of depression compared with placebo (p=0.002, primary endpoint). Dextromethorphan-bupropion significantly prevented relapse of depression over at least 6 months compared with placebo (p=0.004, key secondary endpoint). Dextromethorphan-bupropion, a novel, oral, investigational NMDA receptor antagonist with multimodal activity, met its primary and key secondary endpoints in the Phase 2 MERIT (Mechanisms of Response Evaluation in TRD) trial, providing a substantial and statistically significant prevention of depressive relapse compared with placebo in patients with treatment-resistant depression (TRD). MERIT is a randomized, double-blind, placebo-controlled, relapse prevention, multicenter, US study that evaluated 44 patients with TRD. Patients who achieved stable remission after treatment with dextromethorphan-bupropion were randomized to continue treatment with dextromethorphan-bupropion or to discontinue dextromethorphan-bupropion and switch to placebo.

[0118] Dextromethorphan-bupropion met its primary endpoint by substantially and statistically significantly delaying the time to relapse of depressive symptoms compared with placebo (p=0.002), with no relapses observed with dextromethorphan-bupropion over at least 6 months of double-blind treatment, and dextromethorphan-bupropion met its key secondary endpoint of relapse prevention based on relapse rate during the double-blind treatment period (0.0% of patients on dextromethorphan-bupropion vs 36.4% of patients switching from dextromethorphan-bupropion to placebo, p=0.004).

[0119] Dextromethorphan-bupropion was well tolerated in this study. No treatment-emergent adverse events were reported in more than one patient in the dextromethorphan-bupropion group. One patient in the dextromethorphan-bupropion group experienced two serious adverse events (gout and bacteremia), neither of which were deemed related to study drug.

[0120] About the MERIT Study MERIT was a phase 2, randomized, double-blind, placebo-controlled, multicenter study evaluating dextromethorphan-bupropion compared with placebo for preventing relapse of depressive symptoms in patients with treatment-resistant depression (TRD). Treatment resistance was defined as continued depressive symptoms despite treatment with ≥2 conventional antidepressants during the current major depressive episode. TDR patients were enrolled in MERIT from a long-term, open-label, phase 3 study and were required to be in stable remission before randomization. Stable remission was defined as a score of ≤12 on the Montgomery-Asberg Depression Rating Scale (MADRS) on at least two consecutive occasions, at least 4 weeks apart.

[0121] A total of 44 TDR patients who experienced stable remission after up to 12 months of open-label treatment with dextromethorphan-bupropion (45 mg dextromethorphan, 105 mg bupropion) tablets twice daily were randomized 1:1 in a double-blind fashion to continue dextromethorphan-bupropion or to discontinue dextromethorphan-bupropion and switch to placebo for at least 26 weeks or until depressive relapse occurred. Relapse was defined in the study by one or more of the following: MADRS total score ≥ 18 on two consecutive assessments; increase in Clinical Global Impression of Severity of Depression of ≥ 2 points from randomization on two consecutive assessments; hospitalization due to worsening depression or suicide risk; or investigator decision to relapse or add antidepressant or change treatment.

[0122] The primary outcome of the study was time from randomization to recurrence, calculated by Kaplan-Meier estimates and hazard ratios. The main secondary outcome to assess recurrence prevention was the proportion of patients free of recurrence.

[0123] About Major Depressive Disorder Major depressive disorder (MDD) is a debilitating, chronic, biologically-based disorder characterized by low mood, inability to experience pleasure, feelings of guilt and worthlessness, reduced energy, and other emotional and physical symptoms that impair social, occupational, educational, or other important functioning. In severe cases, MDD may lead to suicide. According to the National Institutes of Health, it is estimated that 7% of adults in the United States, or approximately 19 million people, experience MDD annually. According to the World Health Organization (WHO), depression is the leading cause of disability worldwide and a major contributor to the overall global burden of disease. Nearly two-thirds of diagnosed and treated patients do not experience an adequate therapeutic response to currently available first-line treatments, highlighting the need for add-on therapies with novel mechanisms of action. The majority of initial failures also fail second-line treatments. Patients diagnosed with MDD are defined as having treatment-resistant depression (TRD) if they have failed to respond to two or more antidepressant treatments.

[0124] About Dextromethorphan-Bupropion Dextromethorphan-bupropion is a novel, oral, patent-protected, investigational NMDA receptor antagonist with multimodal activity being developed for the treatment of major depressive disorder and other central nervous system (CNS) disorders. Dextromethorphan-bupropion utilizes a unique formulation and dosage of dextromethorphan and bupropion, and Applicant's metabolic inhibition technology modulates the delivery of the components. The dextromethorphan component of dextromethorphan-bupropion is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, also known as a glutamate receptor modulator, with a novel mechanism of action that works differently from currently approved oral treatments for major depressive disorder. Additionally, the dextromethorphan component of dextromethorphan-bupropion is a sigma-1 receptor agonist. The bupropion component of dextromethorphan-bupropion works by increasing the bioavailability of dextromethorphan, a norepinephrine and dopamine reuptake inhibitor. Dextromethorphan-bupropion has been granted Breakthrough Drug Designation by the U.S. Food and Drug Administration (FDA) for the treatment of MDD and agitation in Alzheimer's disease.

[0125] Example 3 Efficacy and safety of the oral NMDA receptor antagonist dextromethorphan-bupropion in preventing relapse in patients with treatment-resistant depression: Results of the MERIT, double-blind, placebo-controlled relapse prevention trial introduction Major depressive disorder (MDD) is a serious disorder: it is a chronic, disabling, pervasive, biologically-based disorder and a leading cause of suicide. Treatment-resistant depression (TRD): Approximately 40% of patients with MDD are treatment-resistant, defined as failure of the current depressive episode to respond to two or more antidepressants, taken precisely from two different classes. Relapse of MDD is not uncommon in TRD patients who eventually achieve remission, with over 40% of patients relapsing within 4 months of treatment. Need for new mechanistic approaches: Currently approved oral antidepressants act primarily through monoaminergic mechanisms. Glutamate hypothesis of MDD: Clinical and preclinical evidence implicates dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD and suggests a role for NMDA receptor antagonism in the treatment of MDD. There is an urgent clinical need for new, more effective, faster acting, mechanistically novel and well-tolerated treatments for MDD.

[0126] Dextromethorphan-bupropion is a novel, oral, investigational NMDA receptor antagonist with multimodal activity. Dextromethorphan - The dextromethorphan component of bupropion is an NMDA receptor antagonist, an ionotropic glutamate receptor, and a sigma-1 receptor agonist. These actions modulate glutamatergic neurotransmission. The bupropion component of dextromethorphan-bupropion primarily works to increase the bioavailability of dextromethorphan, and is a norepinephrine and dopamine reuptake inhibitor.

[0127] Objective of the MERIT Study MERIT (Mechanisms of Response Evaluation in TRD) was a phase 2, randomized, double-blind, placebo-controlled relapse prevention study designed to evaluate dextromethorphan-bupropion compared with placebo in preventing relapse of depressive symptoms in patients with TRD. This trial is registered with ClinicalTrials.gov (NCT044608396).

[0128] Study Procedure Patients with TRD in stable remission after treatment with dextromethorphan-bupropion (N=44) were randomized to continue treatment with dextromethorphan-bupropion or to discontinue dextromethorphan-bupropion and switch to placebo for up to 52 weeks or until relapse. Patients with TRD who achieved stable remission in an open-label, long-term study of dextromethorphan-bupropion ('COMET') were eligible to be enrolled in MERIT. Stable remission was defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 12 or less on at least two consecutive occasions, separated by at least 4 weeks. FIG. 3 shows the study procedure.

[0129] Eligibility Criteria Key specifications: Stable responders were defined as a MADRS score of 12 or less on at least two consecutive occasions, separated by at least 4 weeks. The depression of the controls before participating in COMET was treatment-resistant; Pre-registration of a study evaluating dextromethorphan-bupropion in patients with pre-defined TRD (NCT02741791), or This was defined as subjects enrolled in COMET who had taken ≥2 prior antidepressants during a major depressive episode prior to participating in COMET.

[0130] Key exclusion criteria: Have received electroconvulsive therapy, vagus nerve stimulation, transcranial magnetic stimulation, or any experimental central nervous system therapy during the current episode or within the past 6 months; Schizophrenia, bipolar disorder, obsessive-compulsive disorder, and Psychiatric symptoms secondary to any other general medical condition.

[0131] Efficacy evaluation Primary endpoint: Time from randomization to recurrence calculated by Kaplan-Meier estimates Subjects who discontinued for reasons other than recurrence were considered not to have recurred and were censored. Key secondary endpoint: Proportion of recurrence-free controls Recurrence was defined as one or more of the following: A total MADRS score of 18 or greater on two consecutive assessments, 7 to 21 days apart; an increase in Clinical Global Impression of Severity (CGI-S) score of ≥2 from randomization on two consecutive assessments, 7 to 21 days apart, with a minimum CGI-S score of 4; Loss of therapeutic response, including: (i) Hospitalization due to worsening depression or suicide risk. (ii) the need for additional antidepressant treatment or treatment change as determined by the investigator. (iii) Patient relapse in the opinion of the investigator.

[0132] result Demographics and baseline characteristics Table 4 shows demographic and baseline characteristics.

[0133] [Table 4] CGI-S=Clinical Global Impression of Severity; values ​​are means (SD) unless otherwise noted; DM=dextromethorphan; BUP=bupropion. A total of 22 subjects were randomly selected from each treatment group. The mean age in both treatment groups was approximately 50 years. The majority of subjects were white and female. Subjects were in remission as defined by a mean MADRS score <6 and a CGI-S score <2.

[0134] Primary endpoint: Time from randomization to recurrence FIG. 4 shows time to recurrence in weeks. As shown in FIG. 4, the following was observed: Dextromethorphan-bupropion met its primary endpoint of delaying the time to relapse of depressive symptoms. Subjects who continued treatment with dextromethorphan-bupropion demonstrated a substantially and statistically delayed time to relapse of depressive symptoms compared with those randomized to placebo (p=0.0023).

[0135] Key secondary endpoint: Proportion of patients free of recurrence The proportions of relapse-free patients in the dextromethorphan-bupropion and placebo groups are shown in Table 5 .

[0136] [Table 5]

[0137] Treatment with dextromethorphan-bupropion prevented relapse in a statistically significantly greater proportion of subjects compared with placebo.

[0138] None of the subjects treated with dextromethorphan-bupropion had a relapse during the evaluation period compared with eight subjects (36.4%) who received placebo, a difference in relapse rate of 36.4% (p=0.004).

[0139] Proportion of subjects meeting each recurrence criterion The recurrence criteria are shown in Table 6.

[0140] [Table 6]

[0141] The most common reason for relapse in the placebo group was a MADRS score of 18 or greater on two consecutive visits. No subject in the dextromethorphan-bupropion group reached the MADRS relapse criterion or any other endpoint criterion. Seven subjects in the dextromethorphan-bupropion group increased by 2 points on the CGI-S but did not meet relapse criteria because their score did not exceed 3 ("mildly depressed") and / or the deviation was transient (not persisted at two consecutive assessments).

[0142] Safety and Tolerability Table 7 shows treatment-emergent adverse events (TEAEs).

[0143] [Table 7]

[0144] Long-term treatment with dextromethorphan-bupropion was well tolerated. One subject in the dextromethorphan-bupropion group experienced two serious adverse events (gout, positive staphylococcus test), both of which were judged to be unrelated to study drug, and one subject in the dextromethorphan-bupropion group had a TEAE that led to discontinuation of study drug (anxiety).

[0145] conclusion Dextromethorphan-bupropion substantially and statistically significantly delayed the time to relapse of depressive symptoms compared with placebo in patients with TRD who achieved stable remission on dextromethorphan-bupropion. No relapses were observed in dextromethorphan-bupropion patients who continued double-blind treatment for at least 6 months. Dextromethorphan-bupropion was well tolerated in the study, and no new safety signals were observed. These data support the continued development of dextromethorphan-bupropion in TRD and provide additional evidence for the long-term efficacy of dextromethorphan-bupropion in the treatment of MDD.

[0146] Example 4 Dextromethorphan-bupropion improves depression symptoms and functioning in patients with prior treatment failure, according to the EVOLVE long-term, open-label study.

[0147] introduction Major depressive disorder (MDD) is a serious disorder; MDD is a chronic, disabling, pervasive, biologically-based disorder and a leading cause of suicide. MDD is difficult to treat, and the largest open-label trial conducted, STAR ※ In D, only about one-third of people with MDD achieved remission with up to 12 weeks of treatment with the SSRI citalopram. Secondary treatment: STAR ※ In D, the remission rate on second-line treatment was approximately 25%, regardless of the switching strategy employed: switching to a different SSRI (sertraline), switching to an SNRI (venlafaxine), or switching to an NDRI (bupropion) after non-remission with an SSRI.

[0148] The need for mechanistically new approaches: STAR ※ The lower remission rates in D may be partly explained by the lack of pharmacological diversity between different treatments, e.g. all antidepressants used are generally thought to act in the same way, i.e. by monoamine modulation. Glutamate hypothesis of MDD: Clinical and preclinical evidence implicates dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD and suggests a role for NMDA receptor antagonism in the treatment of MDD. There is an urgent clinical need for new, more effective, faster acting, mechanistically novel and well-tolerated treatments for MDD.

[0149] the purpose The objective was to evaluate the safety and efficacy of dextromethorphan-bupropion for previously treated MDD patients in a current major depressive episode.

[0150] Research design: EVOLVE EVOLVE (Evaluation of NMDA Modulation of Depressive Episodes) was an open-label, US study in which patients were treated with dextromethorphan-bupropion (45 mg dextromethorphan HBr-105 mg bupropion HCl) twice daily for up to 15 months. Eligible patients either came after completion of a previous study of dextromethorphan-bupropion (MERIT) or were directly enrolled and had a DSM-5 diagnosis of MDD, a MADRS score of 25 or greater, and had been previously treated with at least one antidepressant in their current major depressive episode. A total of 186 patients were enrolled, consisting of 35 carryovers and 146 direct enrollments. Here, we present the results of the direct enrollments. Newly enrolled subjects who did not achieve a 25% or greater reduction in MADRS score at week 6 were discontinued from the study.

[0151] Efficacy Outcome Measures: The primary efficacy analyses were change from baseline to week 6 (primary time point) and to weeks 1 and 2 (key secondary time points). 1) Montgomery-Asberg Depression Rating Scale (MADRS), clinical response (≥50% reduction in MADRS total score); and clinical remission (≤10 MADRS total score of 10). 2) Sheehan Disability Scale (SDS), functional clinical response (≤ SDS total score of 12); SDS remission (≤6 total score).

[0152] Statistical analysis: Efficacy analyses were performed on the mlTT population, consisting of all patients who received at least one dose of dextromethorphan-bupropion and were provided with at least one post-baseline efficacy measurement. Safety analyses were performed on the safety population, which included all patients who received at least one dose of dextromethorphan-bupropion. Changes from baseline p-values ​​were analyzed using paired t-tests. Table 8 shows the main inclusion and exclusion criteria.

[0153] [Table 8]

[0154] Table 9 shows demographic and baseline characteristics.

[0155] [Table 9]

[0156] Baseline illness severity represents a moderate to severely depressed population.

[0157] result FIG. 5 shows rapid improvement in symptoms of depression. Table 10 shows the mean improvement from baseline MADRS total score with treatment with dextromethorphan-bupropion. As shown in Table 10, the following was observed: Depressive symptoms improved rapidly following treatment with dextromethorphan-bupropion. The mean change from baseline of 32.2 in MADRS total score was -9.1 ± 7.64 (p < 0.001), 13.3 ± 8.58 (p < 0.001), and -20.4 ± 7.79 (p < 0.001) points at weeks 1, 2, and 6, respectively. Improvement in depressive symptoms was sustained for one year.

[0158] [Table 10]

[0159] Clinical response and remission FIG. 6 shows clinical response and remission over time. As shown in FIG. 6, the following was observed: Clinical response (≥50% improvement) was achieved by 17.7% of patients at week 1, 39.0% at week 2, and 74.2% at week 6. MADRS (≦10) remission was achieved by 5.7%, 16.2%, and 46.0% of patients at weeks 1, 2, and 6, respectively. The effects of the antidepressant were durable and sustained over 12 months.

[0160] CGI-S scores correlate highly with change in the MADRS over time. FIG. 7 shows the CGI-S response over time. As shown in FIG. 7, the following was observed: Responses (≥2 category change) on the CGI-S were rapid, with 19.1% of patients responding at week 1, 38.2% at week 2, and 71.0% at week 6. Improvement in the CGI-S was sustained, with up to 77.9% of patients responding at 6 months and 79.5% of patients responding at 12 months.

[0161] Rapid improvement in function and SDS remission FIG. 8 shows the average decrease in SDS over time. FIG. 9 shows the percentage of subjects in remission from SDS over time. The baseline SDS score was 17.5±6.08. The mean reduction in SDS total score was 2.9±5.39, 5.0±5.78, and 8.3±6.71 at weeks 1, 2, and 6, respectively (all p<0.001) (FIG. 8). SDS remission (≦6) was achieved in 8.5% of patients at week 1, 18.4% at week 2, and 38.5% at week 6 (FIG. 9). The improvement in SDS was durable and sustained over 12 months (Figure 9).

[0162] Safety and Tolerability Table 11 shows adverse events (AEs) occurring in ≥5.0% of patients.

[0163] [Table 11]

[0164] Long-term treatment with dextromethorphan-bupropion was well tolerated. COVID-19 infection, nausea, and headache were the most common adverse events (AEs) (Table 11). Discontinuation due to AEs occurred in 8.9% of patients. The incidence of serious adverse events after long-term treatment with dextromethorphan-bupropion was low (5 patients; 3.4%), with no SAEs occurring in more than one patient.

[0165] conclusion Dextromethorphan-bupropion produced rapid and sustained improvement in depressive symptoms and functioning in patients with a current major depressive episode who had previously failed 1 antidepressant. High clinical response and tolerability rates in the MADRS and functional response rates in the SDS were achieved and maintained up to 12 months of treatment. These data provide further support for dextromethorphan-bupropion in the treatment of patients with depression, including those who have previously received one during a major depressive episode.

[0166] Example 5 Improvement in anxiety symptoms in depressed patients treated with dextromethorphan-bupropion: Results from the EVOLVE open-label long-term study introduction Major depressive disorder (MDD) is a serious disorder; MDD is a chronic, disabling, pervasive, biologically-based disorder and a leading cause of suicide. MDD is difficult to treat, and the largest open-label trial conducted, STAR ※ In D, only about one-third of people with MDD achieved remission with up to 12 weeks of treatment with the SSRI citalopram. Anxiety in MDD: Anxiety is reported in up to 50% of people with depression and is associated with making depression more difficult to treat. Secondary treatment: STAR ※ In D, the remission rate on second-line treatment was approximately 25%, regardless of the switching strategy employed: switching to a different SSRI (sertraline), switching to an SNRI (venlafaxine), or switching to an NDRI (bupropion) after non-remission with an SSRI. There is a need for mechanistically new approaches: STAR ※ The lower remission rates in D may be partly explained by the lack of pharmacological diversity between different treatments, e.g. all antidepressants used are generally thought to act in the same way, i.e. by monoamine modulation. Glutamate hypothesis of MDD: Clinical and preclinical evidence implicates dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD and suggests a role for NMDA receptor antagonism in the treatment of MDD. There is an urgent clinical need for new, more effective, faster acting, mechanistically novel and well-tolerated treatments for MDD.

[0167] the purpose The objective was to evaluate the effect of dextromethorphan-bupropion (45 mg dextromethorphan HBr-105 mg bupropion HCl) on anxiety in patients with MDD who had been previously treated with at least one antidepressant in a current major depressive episode.

[0168] Research design: EVOLVE EVOLVE (Evaluation of NMDA Modulation of Depressive Episodes) was an open-label, US study in which patients were treated with dextromethorphan-bupropion twice daily for up to 15 months. Eligible patients had either come after completion of a previous dextromethorphan-bupropion study or were directly enrolled. All patients had a DSM-5 diagnosis of MDD, a MADRS score ≥ 25, and had been previously treated with at least one antidepressant in a current major depressive episode. A total of 186 patients were enrolled, 35 were continuations from the previous dextromethorphan-bupropion study (MERIT), and 146 were direct enrollments. Here, we present the results of the direct enrollments. Newly enrolled subjects who did not achieve a 25% or greater reduction in MADRS score at week 6 were discontinued from the study.

[0169] Efficacy Outcome Measures: 1) Montgomery-Asberg Depression Rating Scale (MADRS), 2) Hamilton Anxiety Scale (HAM-A) score, and 3) Sheehan Disability Scale (SDS).

[0170] Statistical analysis: Efficacy analyses were performed on the mlTT population, consisting of all patients who received at least one dose of dextromethorphan-bupropion and were provided with at least one post-baseline efficacy measurement. Safety analyses were performed on the safety population, which included all patients who received at least one dose of dextromethorphan-bupropion. Changes from baseline p-values ​​were analyzed using paired t-tests. Table 12 shows the main inclusion and exclusion criteria.

[0171] [Table 12]

[0172] Demographics and baseline characteristics (mlTT population) Table 13 shows the demographics and baseline characteristics (mlTT population).

[0173] [Table 13]

[0174] Baseline depression severity represents a population with moderate to severe depression. Baseline anxiety severity represents mild to moderate anxiety.

[0175] result FIG. 10 and Table 14 show the reduction in Hamilton Anxiety Scale (HAM-A) scores over time.

[0176] [Table 14]

[0177] As shown in Figure 10 and Table 14, the following was observed: Treatment with dextromethorphan-bupropion significantly improved anxiety symptoms. The mean HAM-A score was below 7 at week 6, indicating remission of anxiety symptoms. The reductions from baseline to weeks 1, 2, and 6 were 3.4±5.34 (p<0.001), 5.5±5.81 (p<0.001), and 8.6±5.75 (p<0.001), respectively. Improvement in HAM-A was sustained through 6 months (-10.2 ± 6.47; p < 0.001) and 12 months (-10.2 ± 6.33; p < 0.001).

[0178] FIG. 11 shows the percentage of patients who achieved remission of HAM-A (score ≦7) over time. As shown in Figure 11, the following was observed: Treatment with dextromethorphan-bupropion resulted in rapid rates of anxiety remission. By the fourth week, over 50% of patients achieved remission of anxiety symptoms. Remission was durable, with 74.7% of patients in remission at 6 months and 78.3% in remission at 12 months.

[0179] FIG. 12 shows the percentage of patients achieving a HAM-A response (≧50% improvement from baseline) over time. As shown in Figure 12, the following was observed: HAM-A responses were achieved in 18.4%, 27.9% and 62.1% of patients at weeks 1, 2 and 6, respectively. Response rates continued to improve through 6 months (73.7%) and 12 months (77.1%).

[0180] Safety and Tolerability Table 15 shows adverse events (AEs) occurring in ≥5% of patients.

[0181] [Table 15]

[0182] Long-term treatment with dextromethorphan-bupropion was well tolerated. COVID-19 infection, nausea, and headache were the most common adverse events. The discontinuation rate due to adverse events was 8.9%. After chronic treatment with dextromethorphan-bupropion, the incidence of serious adverse events (5 patients; 3.4%) was low. No SAEs occurred in more than one patient.

[0183] conclusion Treatment with dextromethorphan-bupropion reduced anxiety symptoms in patients with MDD. Response and remission from anxiety symptoms was achieved as early as one week after initiating treatment with dextromethorphan-bupropion. These data are consistent with pooled data from controlled trials of dextromethorphan-bupropion, showing reduced scores on the MADRS internal tension item at week 1 compared with controls. Long-term treatment with dextromethorphan-bupropion was generally safe and well tolerated. These data provide additional evidence for the efficacy of dextromethorphan-bupropion in MDD, including in previously treated patients and those with anxiety traits.

[0184] Example 6 Effects of oral NMDA receptor dextromethorphan-bupropion on anhedonia in major depressive disorder introduction Major depressive disorder (MDD) is a serious disorder; MDD is a chronic, disabling, pervasive, biologically-based disorder and a leading cause of suicide. MDD is difficult to treat, with 63% of patients with MDD experiencing an inadequate response to current first-line oral treatments (STAR ※ D study results), the majority of these inadequate responders also failed second-line therapy (69%). Anhedonia is one of the core features of major depressive disorder (MDD) and is present in up to 75% of individuals diagnosed with MDD. Anhedonia is considered one of the most distressing aspects for patients, is associated with decreased functioning, and is a risk factor for non-response to antidepressant treatment. Response to treatment takes time, and current oral antidepressants are associated with long times to clinically significant response (up to 6–8 weeks). Need for new mechanistic approaches: Currently approved oral antidepressants act primarily through monoaminergic mechanisms. Glutamate hypothesis of MDD: Clinical and preclinical evidence implicates dysfunctional glutamatergic neurotransmission in the pathophysiology of MDD and suggests a role for NMDA receptor antagonism in the treatment of MDD. There is an urgent clinical need for new, more effective, faster acting, mechanistically novel and well-tolerated treatments for MDD.

[0185] the purpose GEMINI was a phase 3, randomized, double-blind, placebo-controlled, multicenter, US study in which 327 adult patients with confirmed moderate-to-severe MDD were randomized to dextromethorphan-bupropion or placebo (NCT04019704). Post hoc analyses were conducted to determine the effect of dextromethorphan-bupropion compared with placebo on the 5-item MADRS anhedonia subscale. The objective was to evaluate the efficacy of dextromethorphan-bupropion compared with placebo in improving anhedonic symptoms of MDD as assessed by the MADRS anhedonia subscale.

[0186] Research design: GEMINI Figure 13 shows the GEMINI study design.

[0187] Primary endpoint: Change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6. Key secondary endpoints: change from baseline and change in MADRS at weeks 1 and 2. MADRS Anhedonia Subscale: Response rate and change from baseline measured by the five-item MADRS Anhedonia Subscale. 1) Obvious sadness 2) reported sadness 3) Decreased concentration 4) Fatigue 5) The inability to feel.

[0188] Previous studies have demonstrated that the MADRS Anhedonia subscale correlates highly with the Snaith-Hamilton Pleasure Scale, a valid measure of hedonic states. Table 16 shows the main inclusion and exclusion criteria. Table 17 shows the demographics and baseline characteristics.

[0189] [Table 16]

[0190] [Table 17]

[0191] Baseline illness severity represents a population with moderate to severe depression. Demographics were similar in both the dextromethorphan-bupropion and control groups.

[0192] result FIG. 14 shows the mean change from baseline in MADRS total score for dextromethorphan-bupropion compared to placebo. As shown in FIG. 14 and Table 18, the following was observed: Primary endpoint - A statistically significant reduction from baseline in MADRS total score at week 6 compared to placebo (-16.6 vs -11.9, p=0.002) was achieved. Compared to placebo, there was a rapid and statistically significant reduction in MADRS total score at week 1, first measurement time point (p=0.007), week 2 (p<0.001) and all subsequent time points. Table 18 shows the change in MADRS total score from baseline at weeks 1 and 2.

[0193] [Table 18]

[0194] FIG. 15 shows the least squares mean (LS mean) change in the MADRS anhedonia subscale for dextromethorphan-bupropion compared to placebo over time. As shown in FIG. 15, the following was observed: At week 1 (first measurement time point), dextromethorphan-bupropion treatment resulted in a statistically significant mean reduction from baseline in MADRS anhedonia subscale score of 4.44 points compared with 2.69 points for placebo (p<0.001). By week 6, the mean reduction from baseline in MADRS anhedonia subscale score was 9.70 with dextromethorphan-bupropion compared with 7.22 with placebo (p=0.001). FIG. 16 shows the percentage of responders who achieved a 50% or greater reduction in the MADRS anhedonia subscale. As shown in FIG. 16, response rates (≥50% improvement in the MADRS anhedonia subscale) were statistically significantly higher for dextromethorphan-bupropion compared to placebo at week 1 (p<0.001) and all time points thereafter. By week 6, 54% of patients receiving dextromethorphan-bupropion were responders compared with 36% of patients receiving placebo at week 6 (p=0.002).

[0195] Safety and Tolerability Table 19 shows adverse events (AEs) for dextromethorphan-bupropion compared to placebo.

[0196] [Table 19]

[0197] The most commonly reported adverse events (AEs) were dizziness, nausea, and headache. Discontinuation rates due to AEs were 6.2% for dextromethorphan-bupropion and 0.6% for placebo.

[0198] conclusion Dextromethorphan-bupropion, a novel oral NMDA receptor antagonist, produced rapid and statistically significant improvements in depressive symptoms at weeks 1 and 2. Treatment with dextromethorphan-bupropion produced rapid and significant reductions in anhedonic symptoms and overall depressive symptoms. Dextromethorphan-bupropion was generally safe and well tolerated. These data support the efficacy of dextromethorphan-bupropion for a broad range of symptoms in patients with MDD.

[0199] Example 7 Efficacy and safety of dextromethorphan-bupropion in patients with major depressive disorder: A phase 3 randomized clinical trial (GEMINI) excerpt Objective: The development of depression has been implicated in alterations in glutamatergic neurotransmission. This study assessed the efficacy of oral N-methyl-D-aspartate (NMDA) receptor antagonists and σ-receptor antagonists in the treatment of major depressive disorder (MDD). 1 We evaluated the efficacy and safety of the receptor agonist dextromethorphan-bupropion.

[0200] METHODS:This double-blind, phase 3 study was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg to 105 mg tablets) or placebo orally (once daily on days 1-3, then twice daily thereafter) for 6 weeks. The primary outcome measure was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy outcomes and variables included change from baseline in the MADRS at weeks 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician and patient global assessments, Brief Self-Rating Depressive Symptoms Scale, Sheehan Disability Scale, and quality of life scale.

[0201] RESULTS: A total of 327 patients were randomized, 163 to dextromethorphan-bupropion and 164 to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total scores was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [Cl], -1.39 to -6.36; p = 0.002). Dextromethorphan-bupropion was superior to placebo in improving MADRS at all time points, including week 1 (p = 0.007) and week 2 (p < 0.001). At week 6, remission was achieved by 39.5% of patients on dextromethorphan-bupropion versus 17.3% on placebo (treatment difference, 20.0%; 95% Cl, 8.4% vs. 31.6%; p<0.001), and clinical response was achieved by 54.0% vs. 34.0%, respectively (treatment difference, 20.0%; 95% Cl, 8.4% vs. 31.6%; p<0.001). Results of most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (e.g., CGI-S least-squares mean difference at week 6, -0.48; 95% Cl, -0.48 to -0.79; p=0.002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.

[0202] Conclusions: In this phase 3 study in patients with MDD, treatment with dextromethorphan-bupropion significantly improved depressive symptoms compared with placebo after 1 week of treatment and was generally well tolerated.

[0203] Trial registration: ClinicalTrials.gov Identifier: NCT04019704 Major depressive disorder (MDD) is a pervasive, incapacitating, chronic, biologically-based disorder that impairs social, occupational, and educational functioning. It is a leading cause of disability worldwide and is associated with increased suicide risk, morbidity, and mortality. Currently approved oral antidepressants act primarily through monoamine pathways. Partial or inadequate responses are common with these medications, and they usually take several weeks to produce clinically meaningful effects. Stepped Treatment Alternatives for Relief of Depression (STAR) ※ D) In ​​trials, approximately two-thirds of patients with depression failed to achieve remission with first-line treatment, and approximately 60% of patients who experienced a clinical response achieved remission after 8 weeks of treatment or more.

[0204] Data from neuroimaging, cellular, and clinical studies implicate the glutamatergic system in the pathogenesis of depression. This evidence includes the discovery of abnormal glutamate levels in the cortex of depressed patients using magnetic resonance spectroscopy, the observation of abnormal N-methyl-D-aspartate (NMDA) receptor expression and signaling in postmortem cortical specimens from depressed patients, and the demonstration of antidepressant efficacy in studies of parenterally administered NMDA receptor antagonist ketamine.

[0205] Dextromethorphan is a noncompetitive antagonist of the NMDA receptor (ionotropic glutamate receptor) and a sigma 1 receptor agonist. Blockade of the NMDA receptor and agonism of the sigma 1 receptor modulate glutamate signaling in the central nervous system. The clinical utility of dextromethorphan is limited in humans by its rapid and extensive metabolism through cytochrome P450 (CYP) 2D6, which results in plasma levels that are insufficient for therapeutic benefit. Dextromethorphan-bupropion combination tablets (hereafter dextromethorphan-bupropion), formulated to increase the bioavailability and half-life of dextromethorphan, have been developed for the treatment of MDD. The bupropion component acts to increase the plasma concentration of dextromethorphan by inhibiting its metabolism. Breakthrough drug designation was granted by the U.S. Food and Drug Administration (FDA) for dextromethorphan-bupropion for the treatment of MDD in March 2019. The objective of this phase 3 study was to evaluate the efficacy and safety of dextromethorphan-bupropion compared with placebo in treating patients with MDD.

[0206] Clinical Points Currently available oral antidepressants act primarily via monoamine pathways, may be associated with partial or inadequate responses, and usually take several weeks to produce clinically meaningful effects. In this large randomized controlled trial, dextromethorphan-bupropion, an orally administered NMDA receptor antagonist and sigma-1 receptor agonist, rapidly reduced depressive symptoms and induced remission in patients with major depressive disorder. Dextromethorphan-bupropion was well tolerated.

[0207] method Study Design and Management The GEMINI (Glutamate and Monoaminergic Modulation in Depression) trial was a phase 3, randomized, double-blind, placebo-controlled, 6-week study conducted at 40 centers in the United States from June 2019 to December 2019. The study was conducted in accordance with the International Conference on Harmonization guidelines and the principles of the Declaration of Helsinki. Site investigators collected study data and the instructor ensured that all individuals administering the rating scales were qualified and appropriately trained. All sites had review board approval, and all patients provided written informed consent prior to participation.

[0208] Patient population Patients were males or females aged 18–65 years who had a primary diagnosis of MDD, had experienced a major depressive episode lasting at least 4 weeks, and had a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 25 or more, with higher scores indicating more severe depression, corresponding to moderate or greater severity. Patients were also required to have a Clinical Global Impression Severity Scale (CGI-s) scale score of 4 or more (range, 1–7, with higher scores indicating greater severity of illness). The diagnosis of depression was established based on a structured clinical interview using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for MDD without psychotic features, which has been shown to diagnose MDD more conservatively than other structured interviews. As part of the screening process, an independent assessor confirmed each patient's eligibility and symptom severity. The evaluation consisted of a complete medical history and a clinical review of all available documentation, including clinician- and patient-reported outcome measures.

[0209] Key exclusion criteria included bipolar disorder, psychosis, panic disorder, obsessive-compulsive disorder, treatment-resistant depression (defined as failure of two or more adequate antidepressant treatments in a current major depressive episode), alcohol / substance use disorder within the past year, clinically significant suicide risk, and seizure disorder.

[0210] Test Design and Procedures Eligible patients were randomly assigned in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg to 105 mg) or placebo orally for 6 weeks. Randomization was performed by a central web-based automated response system. Study medications were provided by the study sponsor and were identical in form and appearance, and all investigators, patients, and study personnel involved in the study were blinded to the study treatment. Patients took their assigned study medication once daily for 3 days and twice daily thereafter. Study visits were conducted at 1, 2, 3, 4, and 6 weeks after the baseline visit. A safety follow-up visit was conducted at week 7, 1 week after the last dose of study medication. There were no formal discontinuation criteria, patients could withdraw consent for any reason, and investigators were free to remove patients from the study for safety-related reasons. The dose of dextromethorphan-bupropion was selected based on the results of a pharmacokinetic study and titrated to twice daily. This clinical trial was described on ClinicalTrials.gov (NCT04019704).

[0211] Evaluation items The primary outcome was the change from baseline to week 6 in the MADRS total score. The MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores indicating more severe depression. Key secondary outcomes were change from baseline in the MADRS total score at week 1, change from baseline in the MADRS total score at week 2, remission defined as a MADRS total score of 10 or less, and a 50% or greater reduction in the MADRS total score at week 6.

[0212] Other secondary outcomes were the Clinical Global Impression-Improvement scale (CGI-I; scores range from 1 [much improved] to 7 [much worse]). 19, CGI-S (scores range from 1 [normal] to 7 [most severe illness]), Patient Global Impression-Improvement (PGI-I; scores range from 1 [much improved] to 7 [much worse]), Brief Depressive Symptoms Scale-Self-Rating (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating more severe depression), Sheehan Disability Scale (SDS; scores range from 0 to 30, with higher scores indicating more severe disability), Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF; scores are based on a percentage of the maximum total score, with higher percentages indicating more satisfaction), and MADRS-6 (a 10-item subscale of the MADRS assessing core symptoms of depression [overt sadness, reported sadness, inner tension, fatigue, inability to feel, and pessimistic thinking]).

[0213] Safety was assessed based on the incidence of adverse events; changes in vital signs, clinical laboratory measurements, physical examinations, and electrocardiograms; assessment of suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS); and assessment of withdrawal-related symptoms using a physician-administered withdrawal checklist. Treatment-period adverse events were defined as those occurring from the time of the first dose of dextromethorphan-bupropion or placebo through 7 days after the last dose.

[0214] statistical analysis The safety analysis set included all patients who received at least one dose of study drug. Efficacy analyses were performed in the modified intent-to-treat population, which consisted of all patients who were randomized, received at least one dose of study drug, and had at least one post-baseline efficacy assessment. The primary efficacy variable, change from baseline in MADRS, was analyzed using a mixed model for repeated measures. The analysis of covariance mixed-effects model for repeated measures included treatment, week and treatment-by-week interactions as factors, baseline value as a covariate, and patient as a random effect. All other changes from baseline efficacy variables were analyzed using this method. Treatment effects and treatment differences at each time point were estimated using least squares mean estimates. Percentage-related efficacy (e.g., clinical response and remission rates, CGI-I, PGI-I) was performed on the basis of observed cases and was calculated using the X-ray method. 2 Analyses were performed using SAS version 9.4, and all hypothesis tests were performed at a 2-sided α level of 0.05.

[0215] If the results were found to be positive for the MADRS primary endpoint, other analyses (response, remission) were performed on this variable to examine its clinical relevance. To adjust for multiplicity, if a primary endpoint was established, the key secondary endpoints were tested using hierarchical hypothesis testing in a prespecified fixed-order procedure in the following order (which would stop after reaching a non-significant result): change in MADRS total score from baseline to week 2; proportion of patients achieving remission defined as a MADRS total score ≤ 10 at week 2; change in MADRS total score from baseline to week 1; proportion of patients achieving a clinical response defined as a ≥ 50% reduction in MADRS total score at week 6; CGI-I at week 6; change in CGI-S from baseline to week 6; CGI-I at week 1; proportion of patients achieving remission at week 1; and change in SDS from baseline to week 6. For all other secondary endpoints, no adjustment for multiplicity was performed and these nominal p values ​​are presented.

[0216] Missing data for primary or secondary endpoints were not imputed.Sensitivity analyses for the main efficacy variables were performed based on random permutation and tipping point methods.

[0217] With a sample size of approximately 150 patients per treatment group, there would be 90% power to detect a treatment difference for the primary efficacy variable, change in MADRS, assuming an effect size of 0.31, at a two-sided significance level of 0.05.

[0218] result Patient characteristics A total of 617 patients were examined, of whom 327 were randomly assigned in a 1:1 ratio to receive dextromethorphan-bupropion (163 patients) or placebo (164 patients) (Figure 17). The modified intention-to-treat population consisted of 156 patients in the dextromethorphan-bupropion group and 162 patients in the placebo group. Baseline demographic and clinical characteristics were largely similar between the two study groups (Table 20). There were more males in the dextromethorphan-bupropion group than in the placebo group (39.1% vs. 27.8%; p=0.033). At baseline, the mean MADRS total score was 33.6 in the dextromethorphan-bupropion group and 33.2 in the placebo group, and the mean CGI-S score was 4.6 in both groups. The number of patients who completed the study was 123 in the dextromethorphan-bupropion group and 147 in the placebo group.

[0219] FIG. 17 shows patient disposition in a Phase 3 trial of dextromethorphan-bupropion for major depressive disorder.

[0220] [Table 20]

[0221] Effectiveness Dextromethorphan-bupropion significantly reduced MADRS total scores compared with placebo at all time points assessed (Figures 18A, 18B, and 18C). The least squares mean change from baseline to week 6 in MADRS total scores was -15.9 points in the dextromethorphan-bupropion group and -12.0% in the placebo group (least squares mean difference, -3.87; 95% confidence interval [Cl], -1.39 to -6.36; p=0.002). Results of a sensitivity analysis of the change in MADRS total scores from baseline to week 6 were also statistically significant in favor of dextromethorphan-bupropion, with a treatment difference of similar magnitude as the primary analysis. At the first time point, week 1, the least squares mean change from baseline in the MADRS total score was -7.20 points in the dextromethorphan-bupropion group and -4.97 points in the placebo group (least squares mean difference, -2.23; 95% Cl, -0.60 to -3.86; p=0.007). At week 2, the least squares mean change from baseline in the MADRS total score was -11.09 points in the dextromethorphan-bupropion group and -7.66 points in the placebo group (least squares mean difference, -3.44; 95% Cl, -1.40 to -5.47; p<0.001).

[0222] FIG. 18A shows the change from baseline in MADRS total score over time. MADRS scores range from 0 to 60, with higher scores indicating more severe depression. Results are displayed as mean values, with error bars indicating standard error. p-values ​​are calculated based on least squares means. FIG. 18B shows the proportion of patients who achieved remission (MADRS total score ≦10) over time. p-values ​​are expressed as x 2 Figure 18C shows the proportion of patients who achieved a clinical response (≥50% reduction from baseline in MADRS total score) over time. p values ​​are calculated using the X 2 The scores are calculated via the test. MADRS stands for Montgomery-Asberg Depression Rating Scale, and SE indicates standard error.

[0223] A significantly higher proportion of patients in the dextromethorphan-bupropion group than in the placebo group achieved remission, defined as a MADRS total score of 10 or less, at week 2 (16.9% vs. 7.5%, respectively; treatment difference, 9.4%; 95% Cl, 1.9% to 16.8%; P = .013) and at all time points thereafter. At week 6, 39.5% of patients in the dextromethorphan-bupropion group achieved remission compared with 17.3% in the placebo group (treatment difference, 22.2%; 95% Cl, 11.7% to 32.7%; P < .001). A significantly higher proportion of patients in the dextromethorphan-bupropion group than in the placebo group achieved clinical response, defined as a 50% or greater reduction in the MADRS total score, at all time points. At week 6, the proportion of patients achieving a clinical response was 54.0% in the dextromethorphan-bupropion group and 34.0% in the placebo group (treatment difference, 20.0%; 95% Cl, 8.4% to 31.6%; p<0.001) (Table 21).

[0224] [Table 21] a Changes from baseline variables were analyzed using mixed models for repeated measures. This analysis of covariance mixed-effects model for repeated measures included treatment as factors, week and treatment-by-week interaction, baseline value as a covariate, and patient as a random effect. Treatment effects and treatment differences at each time point were assessed using least squares means estimation. Efficacy variables were calculated using the X 2 All hypothesis tests were performed at a two-sided alpha level of 0.05. bThe MADRS is a 10-item clinician-rated questionnaire ranging from 0 to 60, with higher scores indicating more severe depression. CGI-I scores range from 1 (much improved) to 7 (much worse). CGI-S scores range from 1 (normal) to 7 (most severe illness). The MADRS-6 is a 10-item MADRS subscale assessing the core symptoms of depression (overt sadness, reported sadness, inner tension, fatigue, inability to feel, and pessimistic thinking). QIDS-SR-16 scores range from 0 to 27, with higher scores indicating more severe depression. PGI-I scores range from 1 (much improved) to 7 (much worse). Q-LES-Q-SF scores are based on a percentage of the maximum total score, with higher percentages indicating greater well-being. SDS scores range from 0 to 30, with higher scores indicating more severe impairment. c Nominal P value. Abbreviations: CGI-I=Clinical Global Impression-Improved, CGI-S=Clinical Global Impression of Severity, Cl=confidence interval, MADRS-6=6-item Montgomery-Asberg Depression Rating Scale, LS mean=least squares mean, PGI-I=Patient Global Impression-Improved, QIDS-SR-16=Brief Depressive Symptoms Scale-Self-Rating, Q-LES-Q-SF=Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form, SDS=Sheehan Disability Scale, SE=standard error.

[0225] A significantly higher proportion of patients in the dextromethorphan-bupropion group achieved marked or moderate improvement in the CGI than in the placebo group at all time points assessed (Table 21). The proportion of patients who achieved marked or moderate improvement in the CGI-I at week 6 was 57.6% in the dextromethorphan-bupropion group and 43.0% in the placebo group (treatment difference, 14.6%; 95% Cl, 2.9% to 26.4%; p=0.016). Dextromethorphan-bupropion produced significantly lower CGI-S scores compared with placebo at all time points assessed. The least-squares mean change from baseline to week 6 in CGI-S score was -1.69 points in the dextromethorphan-bupropion group and -1.29 points in the placebo group (least-squares mean difference, -0.48; 95% Cl, -0.48 to -0.79; p = 0.002).

[0226] At all time points tested, the least squares mean improvements from baseline in the QIDS-SR-16, the MADRS-6 subscales, and the Q-LES-Q-SF were statistically significantly greater in the dextromethorphan-bupropion group than in the placebo group, and the proportion of patients with a substantially or very substantially improved PGI-I was statistically significantly greater in the dextromethorphan-bupropion group than in the placebo group. The least squares mean improvements from baseline in the SDS were statistically significantly greater in the dextromethorphan-bupropion group than in the placebo group at week 2 and all time points thereafter (Table 21). The p values ​​for these endpoints are nominal due to the lack of adjustment for multiplicity of these results.

[0227] safety The proportion of patients who experienced adverse events during the treatment period was 61.7% in the dextromethorphan-bupropion group and 45.1% in the placebo group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, headache, somnolence, and dry mouth. There was one serious adverse event in the study, pancreatitis in the dextromethorphan-bupropion group, which was determined by the investigator to be unrelated to the study drug. One adverse event rated as severe (migraine) was observed in the dextromethorphan-bupropion group, and two adverse events rated as severe (back pain, finger fracture repair) were reported in the placebo group. Adverse events leading to discontinuation of the study drug occurred in 6.2% of patients in the dextromethorphan-bupropion group and 0.6% of patients in the placebo group. Dextromethorphan-bupropion was not associated with an increase in psychotomimetic effects, weight gain, or sexual dysfunction (Table 22). There were no suicide-related adverse events or suicidal behaviors on the C-SSRS in either treatment group. One patient in each treatment group reported nonintental suicidal ideation on the C-SSRS at week 6. There were no signs of withdrawal following discontinuation of dextromethorphan-bupropion.

[0228] [Table 22]

[0229] Consideration In this randomized, placebo-controlled trial, dextromethorphan-bupropion demonstrated statistically significant antidepressant efficacy across multiple symptom-specific and global measures, as well as across the majority of primary and secondary endpoints. Treatment with dextromethorphan-bupropion resulted in a statistically significant greater reduction in MADRS total score compared with placebo, beginning at week 1 and at all subsequent time points. Drug-placebo differences in change in MADRS for dextromethorphan-bupropion were real at all time points, ranging from approximately 2-3 points at weeks 1 and 2 to increasing to approximately 4-5 points at weeks 4 and 6. This treatment effect compares favorably with the mean difference from placebo of approximately 2.5 points observed at 6 to 8 weeks in antidepressant studies in the FDA database.

[0230] Symptom remission is considered a desirable goal in the treatment of depression because it leads to improved daily functioning and long-term prognosis. Dextromethorphan-bupropion treatment achieved early and significant remission of MADRS (total score ≤ 10) and demonstrated statistically significant separation from placebo at week 2 and all subsequent time points. At week 6, 39.5% of patients in the dextromethorphan-bupropion group achieved remission compared with 17.3% in the placebo group (p = 0.004). Also, early and statistically significant clinical response (≥ 50% reduction from baseline) in MADRS compared with placebo was observed at week 1 and all subsequent time points. At week 6, 54.0% of patients in the dextromethorphan-bupropion group achieved clinical response compared with 34.0% in the placebo group (p < 0.001).

[0231] The early efficacy of dextromethorphan-bupropion was further demonstrated in many other clinically relevant measures, including MADRS-6, CGI-S, CGI-I, PGI-I, QIDS-SR-16, and Q-LES-Q-SF, with statistically significant advantages versus placebo at week 1 and all subsequent time points. Early improvements in functional impairment were also observed, achieving statistical significance on the SDS at week 2 and all subsequent time points.

[0232] In this study, dextromethorphan-bupropion was safe and well tolerated, with a low rate of discontinuation due to adverse events. The magnitude of the difference in adverse event rates and rates of discontinuation due to adverse events between the two treatment arms in the study may reflect a much lower than expected rate of these events in the placebo group. For example, the overall rate of adverse events of 61.7% in the dextromethorphan-bupropion group is consistent with the average of 76.4% reported for antidepressant groups in a large meta-analysis of placebo-controlled depression trials. In comparison, the placebo adverse event rate of 45.1% in this study is lower than the average of 63.0% reported for placebo groups in the same meta-analysis. Similarly, the discontinuation rate due to adverse events of 6.2% in the dextromethorphan-bupropion group is consistent with the average of 7% reported for antidepressant groups in another large meta-analysis of placebo-controlled depression trials. In contrast, the placebo discontinuation rate due to adverse events of 0.6% in our study was significantly lower than the average of 4% reported in the placebo group in the same meta-analysis. Unlike other NMDA receptor antagonists, dextromethorphan-bupropion was not associated with psychotomimetic effects. This tolerability profile may be related to the much faster rate of unblocking of the NMDA receptor channel reported with dextromethorphan compared with other NMDA antagonists. Dextromethorphan-bupropion was not associated with increased weight gain or sexual dysfunction.

[0233] Limitations of this study include the exclusion of patients with psychosis or other psychiatric disorders, alcohol / substance use disorders, clinically significant risk of suicide, or significant medical comorbidities. These exclusions, along with the prohibition of certain concomitant medications, may limit the generalizability of the study findings. In addition, treatment at experienced trial sites by specialized clinicians under a study protocol with frequent clinical evaluations may not reflect typical treatment. The discontinuation rate of 24.1% in the dextromethorphan-bupropion group is roughly twice that of placebo. However, this rate is consistent with the 24.3% reported in antidepressant groups in a large meta-analysis of published placebo-controlled depression trials. In contrast, the discontinuation rate of 10.4% for placebo in this study was substantially lower than the average of 24.0% reported in placebo groups in the same meta-analysis. Multiplicity adjustment was applied only to the primary secondary efficacy endpoint, whereas nominal p values ​​for most other secondary endpoints were <.05. Finally, the duration of the study was limited to 6 weeks. The effects of long-term treatment with dextromethorphan-bupropion are being evaluated in other studies.

[0234] In conclusion, this study demonstrated that treatment with dextromethorphan-bupropion produced clinically meaningful and statistically significant improvements in depressive symptoms compared with placebo in patients with MDD from week 1 and was well tolerated. The efficacy of dextromethorphan-bupropion was supported by significant improvements compared with placebo in multiple clinically relevant outcome measures across symptom-specific global measures, demonstrating the internal consistency of the study findings.

[0235] Unless otherwise indicated, all numerical values ​​expressing properties such as amounts, quantities, percentages of ingredients, and the like used in the specification and claims are understood to be in each instance indicated both by the exact value set forth and by the modified term "about." Thus, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations and may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0236] The terms "a," "an," "the," and similar referents, as 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 otherwise clearly contradicted by context. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any examples or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the embodiments and does not cause 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 the claims.

[0237] The categorization of alternative elements or embodiments disclosed herein is not to be construed as limiting. The elements of each group may be referred to 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, thereby satisfying the description of all Markush groups as they are used in the appended claims.

[0238] 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 expect skilled artisans to adopt such variations as necessary, and intend that the claimed embodiments may be practiced other than as expressly described herein. Accordingly, the claims include all modifications and equivalents of the claimed subject matter as 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.

[0239] Finally, it is understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted 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. Thus, the claims are not limited to the precise embodiments as shown and described.

[0240] (Additional Note) (Appendix 1) Selecting a human patient experiencing anxiety and major depressive disorder; The human patient is 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt of dextromethorphan or dextromethorphan in free base form; 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion; administering a combination of Including, A method for treating anxiety in a human patient experiencing a major depressive disorder.

[0241] (Appendix 2) The human patient is selected by having a Hamilton Anxiety Rating Scale (HAM-A) score of at least 10 prior to treatment. The method described in Appendix 1.

[0242] (Appendix 3) The human patient is selected by having a HAM-A score of at least 15 prior to treatment. The method described in Appendix 2.

[0243] (Appendix 4) one week after the treatment, the human patient's HAM-A score is reduced by about 3 to about 4; The method according to any one of appendix 1 to 3.

[0244] (Appendix 5) After two weeks of treatment, the human patient's HAM-A score is reduced by about 5 to 6. 5. The method according to any one of claims 1 to 4.

[0245] (Appendix 6) After 6 weeks of treatment, the human patient's HAM-A score is reduced by about 8 to 9. 6. The method according to any one of claims 1 to 5.

[0246] (Appendix 7) After one or more weeks of treatment, the human patient achieves remission of anxiety based on the human patient's HAM-A score. 7. The method according to any one of claims 1 to 6.

[0247] (Appendix 8) Selecting a human patient experiencing anhedonia and major depressive disorder; The human patient is 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt of dextromethorphan or dextromethorphan in free base form; 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion; administering a combination of Including, A method for treating anhedonia in a human patient experiencing a major depressive disorder.

[0248] (Appendix 9) Prior to treatment, the human patient is selected by having a CGI-S score of at least 4. The method described in Appendix 8.

[0249] (Appendix 10) The human patient is selected by having a Montgomery-Asberg Depression Rating Scale (MADRS) anhedonia score of at least 15 prior to treatment. 10. The method according to claim 8 or 9.

[0250] (Appendix 11) The human patient is selected by having a MADRS anhedonia score of at least 19 prior to treatment. 10. The method according to claim 8 or 9.

[0251] (Appendix 12) After one week of treatment, the human patient's MADRS anhedonia score is reduced by about 4 to about 5. 12. The method according to claim 8, 9, 10 or 11.

[0252] (Appendix 13) After 6 weeks of treatment, the human patient's MADRS anhedonia score is reduced by about 9 to about 10. 13. The method according to claim 8, 9, 10, 11 or 12.

[0253] (Appendix 14) The combination is administered twice daily. 14. The method according to any one of claims 1 to 13.

[0254] (Appendix 15) Prior to treatment, the human patient is selected by having a MADRS score of at least 25. 15. The method according to any one of claims 1 to 14.

Claims

1. Selecting a human patient experiencing anxiety and major depressive disorder; The human patient is 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt of dextromethorphan or dextromethorphan in free base form; 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion; administering a combination of Including, A method for treating anxiety in a human patient experiencing a major depressive disorder.

2. The human patient is selected by having a Hamilton Anxiety Rating Scale (HAM-A) score of at least 10 prior to treatment. The method of claim 1.

3. The human patient is selected as having a HAM-A score of at least 15 prior to treatment. The method of claim 2.

4. one week after treatment, the human patient's HAM-A score is reduced by about 3 to about 4; The method according to any one of claims 1 to 3.

5. After two weeks of treatment, the human patient's HAM-A score is reduced by about 5 to 6. The method according to any one of claims 1 to 4.

6. After 6 weeks of treatment, the human patient's HAM-A score is reduced by about 8 to 9. The method according to any one of claims 1 to 5.

7. After one or more weeks of treatment, the human patient achieves remission of anxiety based on the human patient's HAM-A score. The method according to any one of claims 1 to 6.

8. Selecting a human patient experiencing anhedonia and major depressive disorder; The human patient is 45 mg of dextromethorphan hydrobromide, or a molar equivalent of another salt of dextromethorphan or dextromethorphan in free base form; 105 mg of bupropion hydrochloride, or a molar equivalent of another salt or free base form of bupropion; administering a combination of Including, A method for treating anhedonia in a human patient experiencing a major depressive disorder.

9. Prior to treatment, the human patient is selected by having a CGI-S score of at least 4. The method according to claim 8.

10. The human patient is selected by having a Montgomery-Asberg Depression Rating Scale (MADRS) anhedonia score of at least 15 prior to treatment.

10. The method according to claim 8 or 9.

11. Prior to treatment, the human patient is selected by having a MADRS anhedonia score of at least 19.

10. The method according to claim 8 or 9.

12. After one week of treatment, the human patient's MADRS anhedonia score is reduced by about 4 to about 5.

12. The method of claim 8, 9, 10 or 11.

13. After 6 weeks of treatment, the human patient's MADRS anhedonia score is reduced by about 9 to about 10.

13. The method of claim 8, 9, 10, 11 or 12.

14. The combination is administered twice daily. The method according to any one of claims 1 to 13.

15. Prior to treatment, the human patient is selected by having a MADRS score of at least 25. The method according to any one of claims 1 to 14.

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