Solliam fetol for the treatment of specific neurological conditions

Abstract

Disclosed here is a method for treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder (SWD) in humans, for example, adults, by administering sorriamfetol to humans suffering from ADHD, MDD, BED, or SWD. Sorriamfetol can be administered in the morning, for example, within one hour of waking. In some embodiments, sorriamfetol is administered more than nine hours before the expected bedtime.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 508,847, filed Jun. 16, 2023; U.S. Provisional Application No. 63 / 582,340, filed Sep. 13, 2023; U.S. Provisional Application No. 63 / 588,966, filed Oct. 9, 2023; U.S. Provisional Application No. 63 / 607,505, filed Dec. 7, 2023; and U.S. Provisional Application No. 63 / 607,536, filed Dec. 7, 2023; the entire contents of each of which are hereby incorporated by reference herein.

[0002] Technical Field The present invention relates to a method of treating a neurological condition, the method comprising administering solriamfetol to a human subject who needs it.

Background Art

[0003] Attention - deficit / hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by persistent patterns of inattention, hyperactivity, or impulsivity that are associated with significant impairment in social, academic, or occupational functioning or development. The etiology of ADHD is not fully determined, but it is thought to represent a stress - vulnerability model, and twin studies have demonstrated that strong heritability, as well as environmental factors in utero or during childhood, such as exposure to toxins and diseases, potentially play a role.

[0004] ADHD symptoms generally appear by age 12 and affect approximately 5% - 10% of school - age children. ADHD is often chronic, with 40% - 60% of cases persisting into adulthood, and approximately 2% - 5% of the adult population suffering from this disorder. Both males and females are affected, but males are diagnosed at twice the frequency. The impairments in cognition appear in attention, planning and problem - solving, working memory, and behavioral inhibition.

Summary of the Invention

[0005] This disclosure relates to a method for treating attention deficit / hyperactivity disorder (ADHD), major depressive disorder / major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder, comprising administering approximately 140-160 mg of souliamfetol daily to a person in need.

[0006] In some embodiments, approximately 150 mg of souliamfetol is administered daily to a person who requires it.

[0007] This disclosure relates to a method for treating attention deficit / hyperactivity disorder (ADHD), major depressive disorder / major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder, comprising administering approximately 280-320 mg of souliamfetol daily to a person in need.

[0008] In some embodiments, approximately 300 mg of souliamfetol is administered daily to a person who requires it.

[0009] In some embodiments, the techniques described herein are methods for treating ADHD, comprising administering to a person in need of such treatment approximately 70-80 mg of souliamfetol daily for three days, and then approximately 140-160 mg of souliamfetol daily.

[0010] In some embodiments, approximately 75 mg of soruliamfetol is administered to humans daily for 3 days, followed by approximately 150 mg of soruliamfetol being administered to humans daily.

[0011] In some embodiments, the techniques described herein are methods for treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder / major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder, comprising administering to a person in need of such treatment approximately 70-80 mg of soluriamfetol daily for 3 days, then approximately 140-160 mg of soluriamfetol daily for 4 days, and then 280-320 mg of soluriamfetol daily.

[0012] In some embodiments, approximately 75 mg of sorriamufetol is administered to humans daily for 3 days, followed by approximately 150 mg of sorriamufetol being administered to humans daily for 4 days, and then approximately 300 mg of sorriamufetol being administered to humans daily.

[0013] In some embodiments, the human being is an adult.

[0014] In some embodiments, the humans are approximately 18 to 55 years old.

[0015] In some embodiments, the person has a primary diagnosis of ADHD based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria, confirmed by an interview conducted by a clinician using the Adult ADHD Clinical Diagnostic Scale, version 1.2 (ACDS v1.2). In some embodiments, the person has the inattentive subtype of ADHD. In some embodiments, the person has the hyperactive subtype of ADHD. In some embodiments, the person has a combined subtype of ADHD (e.g., both inattentive and hyperactive).

[0016] In some embodiments, the diagnosis was made at least six months prior to treatment.

[0017] In some embodiments, a human has a total AISRS score of at least about 26 when evaluated by a health care provider.

[0018] In some embodiments, a human has a total AISRS score of at least about 26 at baseline.

[0019] In some embodiments, a human has a total AISRS score of at least about 26 at the start of treatment.

[0020] In some embodiments, a human has a CGI-S score of at least about 4 when evaluated by a health care provider.

[0021] In some embodiments, a human has a CGI-S score of at least about 4 at baseline.

[0022] In some embodiments, a human has a CGI-S score of at least about 4 at the start of treatment.

[0023] In some embodiments, a human has a QIDS-SR-16 score of less than about 13 when evaluated by a health care provider.

[0024] In some embodiments, a human has a QIDS-SR-16 score of less than about 13 at baseline.

[0025] In some embodiments, a human has a QIDS-SR-16 score of less than about 13 at the start of treatment.

[0026] In some embodiments, a human has a HAM-A score of at least about 21 when evaluated by a health care provider.

[0027] In some embodiments, a human has a HAM-A score of at least about 21 at baseline.

[0028] In some embodiments, the human has a HAM-A score that is at least about 21 on the treatment start date.

[0029] In some embodiments, solriamfetol is present in a dosage form that does not contain other active pharmaceutical ingredients.

[0030] In some embodiments, solriamfetol is present in a dosage form that does not contain other active pharmaceutical ingredients intended for the treatment of ADHD.

[0031] In some embodiments, active pharmaceutical ingredients other than solriamfetol are not administered to humans for the treatment of ADHD.

[0032] In some embodiments, solriamfetol is administered in the morning.

[0033] In some embodiments, solriamfetol is administered within 1 hour of waking.

[0034] In some embodiments, solriamfetol is administered before 9 hours before the expected bedtime.

[0035] In some embodiments, solriamfetol is administered daily for 6 weeks.

[0036] In some embodiments, solriamfetol is administered daily for more than 6 weeks.

[0037] In some embodiments, the total score of the Adult ADHD Investigator Symptom Report Scale (AISRS) for humans is at least 10% lower after solriamfetol has been administered daily to the patient for 6 weeks compared to the AISRS total score on the first day solriamfetol was administered and the AISRS total score before solriamfetol was administered.

[0038] In some embodiments, the total Clinical Global Impression of Severity (CGI-S) score in humans decreases by at least 10% after 6 weeks of daily administration of soruliamufetol to patients, compared to the total CGI-S score on the first day of soruliamufetol administration and the total CGI-S score before soruliamufetol administration.

[0039] In some embodiments, the total Clinical Global Impression of Improvement (CGI-I) score in humans decreases by at least 10% after 6 weeks of daily administration of souliamfetol to patients, compared to the total CGI-I score on the first day of souliamfetol administration and the total CGI-I score before administration of souliamfetol.

[0040] In some embodiments, the total score on the Human Adult Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) decreases by at least 10% after 6 weeks of daily administration of soruliamufetol to the patient, compared to the total BRIEF-A score on the first day of soruliamufetol administration and the total BRIEF-A score before administration of soruliamufetol.

[0041] In some embodiments, the total score on the Adult ADHD Self-Report Scale (ASRS) in humans decreases by at least 10% after 6 weeks of daily administration of soruliamufetol to patients, compared to the total ASRS score on the first day of soruliamufetol administration and the total ASRS score before administration of soruliamufetol.

[0042] In some embodiments, the total score of the Adult ADHD Quality of Life questionnaire (AAQoL) in humans decreases by at least 10% after 6 weeks of daily administration of soruliamufetol to patients, compared to the total AAQoL score on the first day of soruliamufetol administration and the total AAQoL score before administration of soruliamufetol.

[0043] In some embodiments, the total Work Productivity and Activity Impairment (WPAI) score of a person decreases by at least 10% after 6 weeks of daily administration of soruliamfetol to the patient, compared to the total WPAI score on the first day of soruliamfetol administration and the total WPAI score before administration of soruliamfetol.

[0044] These and other aspects of the Disclosure are described in more detail below. [Brief explanation of the drawing]

[0045] Figure 1 shows a summary of a study to evaluate the efficacy and safety of souliamfetol in adults with ADHD in some embodiments. Figure 2 shows the participant flow throughout the trial. It can be seen that four of the patients treated with the active drug souliamfetol had dosing patterns other than 75 mg in week 1 and 150 mg thereafter, while in some embodiments, all subjects in the placebo group increased to 150 mg in week 1. Figure 3 shows the average weekly AISRS total score in some embodiments. Figure 4 shows, in some embodiments, a significant or very significant improvement in CGI scores and a 25% improvement in AISRS scores with Solliam Fetol compared to placebo. Figure 6 shows the clinical visit configuration in some embodiments. Figure 7 shows the results of a coding problem sub-check in some embodiments. Figure 8 shows the change in coding problem subtest scores over time after administration of Solliamfetol and placebo in some embodiments. Figure 9 shows the results from the British Columbia Cognitive Complaints Inventory for Solliamfetol and placebo in some embodiments.

[0046] Detailed explanation This disclosure should not be construed as being limited to the embodiments described herein. Rather, these embodiments are provided so as to fully and completely convey the scope of this disclosure to those skilled in the art. Furthermore, the references cited herein are incorporated in their entirety by reference.

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. The terms used in the descriptions herein are intended solely to describe specific embodiments and are not intended to limit them. All publications, patent applications, patents, patent publications and other references cited herein are incorporated in their entirety by reference for teaching relating to the sentences and / or paragraphs in which the references are presented.

[0048] Unless the context indicates otherwise, the various features described herein are specifically intended to be used in any combination.

[0049] Furthermore, this disclosure is also intended to mean that in some embodiments, any feature or combination of features described herein may be excluded or omitted.

[0050] For example, where this specification states that a complex comprises components A, B, and C, it is specifically intended that any one of A, B, or C, or any combination thereof, may be omitted or discarded individually or in any combination.

[0051] When used in the specification and the attached claims, the singular forms "a," "an," and "the" are intended to include the plural form unless the context indicates otherwise.

[0052] Furthermore, as used herein, “and / or” encompasses any and all possible combinations of one or more related enumerated items, as well as the absence of any combination when interpreted as an alternative ("or").

[0053] As used herein, the term “approximately” means, when referring to a measurable value, to include a variation of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% of the specified quantity.

[0054] The terms “comprise,” “comprises,” and “comprising,” as used herein, identify the presence of the described features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0055] When used herein, the transitional phrase “essentially from” should be interpreted as meaning that the scope of the claim includes the specified material or step described in the claim, as well as any material or step that does not substantially affect the basic and novel features of the claimed. Accordingly, when used in a claim or specification, the term “essentially from” is not intended to be interpreted as equivalent to “includes / contains.”

[0056] The terms “therapeutic dose” or “effective dose,” as used herein, include an amount of a composition, compound or agent that imparts to a subject suffering from a disorder, disease or illness an improvement in the subject’s condition (e.g., in one or more symptoms), a delay or reduction in the progression of the condition, a prevention or delay in the onset of the disorder, and / or a modulating effect (which may be, for example, a beneficial effect), including changes in clinical parameters, disease or illness, etc. For example, a therapeutic dose or effective dose may include an amount of a composition, compound or agent that improves the condition in the subject by at least 5%, for example, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 200%.

[0057] A “pharmaceutically acceptable carrier” (sometimes referred to as “carrier”) includes carriers or excipients useful for manufacturing pharmaceutical or therapeutic compositions, including carriers that are generally acceptable and acceptable for veterinary and / or human pharmaceutical or therapeutic use. The term “carrier” or “pharmaceutically acceptable carrier” may include, but is not limited to, phosphate-buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions) and / or various types of wetting agents. As used herein, the term “carrier” includes, but is not limited to, any excipients, diluents, fillers, salts, buffers, stabilizers, solubilizers, lipids, stabilizers or other materials known in the art for use in pharmaceutical formulations and as further described herein.

[0058] The terms "modulate," "modulates," or "modulation" include enhancement (e.g., increase) or inhibition (e.g., decrease) at a particular level or activity.

[0059] The terms “enhance” or “increase” include increases of a particular parameter of at least approximately 1.25 times, 1.5 times, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, 12 times or 15 times, and / or can be expressed as enhancement and / or increase of a particular level and / or activity of at least approximately 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more.

[0060] As used herein, “inhibit” or “reduce” or its grammatical variations include a reduction or decrease in a particular level or activity of at least about 1, 5, 10, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95%, or more. In certain embodiments, the inhibition or reduction results in little to no detectable activity (at most a small amount, e.g., less than about 10% or less than 5%).

[0061] The terms “to treat” or “to cure” broadly encompass all therapeutic activities, including the diagnosis, cure, alleviation or prevention of disease in humans or other animals, or any activity that otherwise affects the structure or function of the body of humans or other animals. Grammatical variations of “to administer,” “to administer,” and “administering” to a subject include any route through which the agent is introduced or delivered to the subject. Administration can be performed by inhalation, via an implanted reservoir, or parenterally (e.g., subcutaneous, intravenous, intra-articular, intra-sacral, intramuscular, intra-joint, parenteral, intra-arterial, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intra-lesional, intranasal, rectal, vaginal), by any suitable route including oral, topical, intra-intra-articular, subcutaneous, transdermal, intra-sternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques), by any appropriate route including oral, topical, intra-articular, subcutaneous, transcutaneous, transdermal, intra-sternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques. As used herein, “concurrent administration,” “administration in combination,” “simultaneous administration,” or “administered simultaneously” means that the compounds are administered at the same time, at overlapping times, or one following the other. In the latter case, the two compounds are administered at sufficiently close intervals that the observed results are indistinguishable from the results achieved if the compounds were administered at the same time. “Systemic administration” includes introducing or delivering the agent to a subject via a route that introduces or delivers the agent to a large area of ​​the subject's body (e.g., more than 50% of the body), for example, through an entry point into the circulatory or lymphatic system. In contrast, “local administration” includes introducing or delivering the agent to a subject via a route that introduces or delivers the agent to the area of ​​the administration site or an area directly adjacent to it, and does not introduce the agent systemically in a therapeutically significant amount. For example, a locally administered agent is readily detectable locally near the administration site, but is undetectable or detectable in negligible amounts in distal parts of the subject's body. Administration includes self-administration and administration by another person.

[0062] As used herein, "pharmaceutically acceptable" means a material that is not biologically or otherwise unacceptable; that is, the material can be administered to an individual with the compositions described herein without causing unacceptable adverse biological effects or interacting in an unacceptable manner with any of the other components of the composition in which it is contained. As is well known to those skilled in the art, the material will naturally be selected to minimize unacceptable degradation of the active ingredient and to minimize unacceptable adverse side effects in the subject (see, for example, Remington's Pharmaceutical Science; 21st ed. 2005).

[0063] "Combined administration" includes being sufficiently close in time to produce a combined effect (i.e., a combination can be simultaneous, or two or more events occurring within a short time interval before or after each other). In some embodiments, "combined" administration of two or more compounds means that the two compounds are administered in sufficiently close time intervals that the presence of one alters the biological effect of the other. The two compounds may be administered in the same or different formulations, or sequentially. Combined administration can be achieved by mixing the compounds before administration, or by administering the compounds in two different formulations, for example, at the same time but at different anatomical sites, or using different routes of administration.

[0064] "Subjects" include any animals having or suspected to have any of the insomnia conditions listed herein. Such subjects are generally mammalian subjects (e.g., laboratory animals, e.g., rats, mice, guinea pigs, rabbits, primates, etc.), farm or commercial animals (e.g., cattle, horses, goats, donkeys, sheep, etc.), or domestic animals (e.g., cats, dogs, ferrets, etc.). In certain embodiments, the subjects are primate subjects, non-human primate subjects (e.g., chimpanzees, baboons, monkeys, gorillas, etc.) or humans. Subjects include males and / or females of any age, including newborns, young, middle-aged and elderly subjects.

[0065] Examples of pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, calcium, calcium edetate, cansylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanylate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, and lactic acid. This includes, but is not limited to, salts, lactobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromides, methylnitrates, methyl sulfates, mucates, napsylates, nitrates, oleates, oxalates, pamoates, palmitates, pantothenates, phosphates / diphosphates, polygalacturonic acid, potassium, salicylates, sodium, stearates, basic acetates, succinates, tannates, tartrates, theoclates, tosylates, triethiodies, and valersates.

[0066] As used herein, the terms “concomitant administration” or “combination administration” include the administration of one or more of the compounds described herein with a second drug or agent at a time when the compounds and the second drug or agent have a therapeutic effect. In some cases, this therapeutic effect is synergistic. Such concomitant administration may include simultaneous (i.e., at the same time), prior, or subsequent administration of a known drug to the administration of the compounds described herein. It will not be difficult for a person skilled in the art to determine the appropriate timing, order, and dosage of administration for the particular drugs and compounds described herein.

[0067] "Bioavailability," as used herein, includes the estimated area under the curve or AUC of the active drug in the systemic circulation after oral administration in the dosage forms disclosed herein, compared to the AUC of the active drug in the systemic circulation after intravenous administration of the active drug. The AUC is affected by the extent to which the drug is absorbed in the gastrointestinal tract.

[0068] Disclosed here is a method for treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder, or other sleep disorders in humans, for example, adults or children, by administering sorriamfetol to a person with ADHD. Sorriamfetol can be administered in the morning, for example, within one hour of waking. In some embodiments, sorriamfetol is administered more than nine hours before the expected bedtime.

[0069] In addition to major depressive disorder, Solliamfetol may be used to treat other conditions present in the patient population or circumstances described herein. For example, Solliamfetol may be used to treat pain or neurological disorders. Examples of neurological disorders that may be treated with Solliamfetol include, but are not limited to, affective disorders, psychiatric disorders, brain dysfunction, motor disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0070] Affective disorders that can be treated with Solliamfetol include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymic disorder, 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 (ADHD), bipolar and manic episodes, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, drug addiction or abuse, nicotine addiction, psychogenic dysfunction, dysregulation and emotional instability.

[0071] Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as mood swings, intense sadness, despair, mental numbness, difficulty concentrating, pessimistic worry, restlessness, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, headaches, seizures, digestive problems, and / or circadian rhythm disturbances of hormones.

[0072] Mental disorders that can be treated with Solliamfetl 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-depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. Alzheimer's disease may also be called Alzheimer's type dementia. Other neurobehavioral symptoms of Alzheimer's disease that can be treated include disinhibition and apathy.

[0073] Excitation in Alzheimer's disease occurs as the disease progresses. Excitation can itself manifest as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional responses, attention-seeking, threats, irritability, frustration, shouting, repetitive questioning, mood swings, swearing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, stalking, hitting, scratching, biting, aggressiveness, hyperactivity, and / or kicking.

[0074] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral and psychological symptoms, including agitation. AD is the most common form of dementia, affecting an estimated 6 million people in the United States, a number projected to increase to approximately 14 million by 2050. Agitation is reported to be present in up to 70% of patients with AD and is characterized by emotional distress, aggressive behavior, disruptive hypersensitivity, and disinhibition. Managing agitation is a priority in AD. Agitation in patients with AD is associated with increased caregiver burden, decreased function, accelerated cognitive decline, earlier admission to nursing homes, and increased mortality. Currently, there are no FDA-approved treatments or therapies for treating agitation in patients with AD.

[0075] Neurobehavioral symptoms are known to appear during dementia and can be treated in combination. Caregivers or family members may feel more burdened by the patient's behavioral / psychological symptoms than by their cognitive impairment. Common forms of symptoms include Alzheimer's disease, vascular dementia, Lewy body dementia (abnormal protein aggregates that occur in nerve cells), and the group of disorders that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms experienced by patients with dementia are similar to those of other mental disorders, but some differ slightly from each other. Neurobehavioral symptoms associated with dementia include depression, apathy / apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsivity, aggression, obsessive-compulsive disorder, hypersexuality, and personality disorders. Neurobehavioral symptoms such as disinhibition can also be seen in other conditions such as traumatic brain injury.

[0076] Agitation in patients with Alzheimer's disease can be assessed using the Cohen-Mansfield Agitation Inventory (CMAI). The CMAI assesses a range of behaviors, including hitting (including oneself), kicking, grabbing, pushing, throwing objects, biting, scratching, spitting, harming oneself or others, tearing or ripping objects, physical sexual seduction, pacing, aimless wandering, inappropriate dressing or undressing, trying to go to the wrong place, deliberately falling, ingesting inappropriate substances, improper handling of objects, hiding objects, hoarding objects, repetitively performing distinctive habits, general restlessness, shouting, verbal sexual seduction, insults or verbal aggression, repeating sentences or questions, strange noises (strange laughter or crying), complaining, negativity, and constantly demanding unduly attention or help.

[0077] Schizophrenia can be treated with a combination of positive and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other treatable conditions include intermittent explosive disorder.

[0078] Brain dysfunctions that can be treated with Solliamfetol include, but are not limited to, senile dementia, Alzheimer's disease, memory loss, amnesia / amnesia syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and intellectual disabilities such as schizophrenia. Brain dysfunctions also include, but are not limited to, disorders caused by cerebrovascular diseases, including stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, and their symptoms include impaired consciousness, senile dementia, coma, decreased attention, and speech disorders.

[0079] Drug addictions and abuses that can be treated with Solriamfetol include, but are not limited to, drug dependence and addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, methamphetamine), 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 tobacco, cigars and / or pipes, e-cigarettes or vapes, and chewing tobacco addiction.

[0080] Movement disorders that can be treated with Solliamfetol include, but are not limited to, akathisia, bradykinesia, kinesiology, athetosis, ataxia, ballism, unilateral ballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease chorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless leg syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0081] Dementia that can be treated with Solliamfetol include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0082] Motor neuron diseases that can be treated with Solliamfetl 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, Sandoff disease, and hereditary spastic paraplegia.

[0083] Neurodegenerative diseases that can be treated with Solliamfetol include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar spinal muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, and Shii-Drei's disease. This includes Garr syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, autosomal dominant cerebral arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0084] Seizure disorders that can be treated with Solliamfetol include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, and febrile convulsions; but are not limited to, partial seizures including simple partial seizures, Jacksonian seizures, complex partial seizures, and persistent partial epilepsy; but are not limited to, generalized seizures including generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0085] The types of headaches that can be treated with Solliam Fetol include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0086] Other neurological disorders that can be treated with Solliamfetol include Rett syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and vocal cord tremor; neurotoxicity due to chemotherapy, such as diabetic neuropathy and methotrexate neurotoxicity; incontinence, including stress-induced urinary incontinence, urge urinary incontinence, and fecal incontinence, but not limited to these; and erectile dysfunction.

[0087] In some embodiments, Solliamfetol may be used to treat pain, joint pain, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and cognitive impairments, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), and the like.

[0088] In some embodiments, Solliamufetol may be administered orally to relieve lower back pain and musculoskeletal pain, including pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatic) arthritis, non-rheumatoid arthritis, periarthritis, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral comminuted fractures, osteoporosis, etc.

[0089] In some embodiments, Solliamfetol may be administered to alleviate musculoskeletal pain, arthritis pain, and inflammatory pain, including complex regional pain syndrome.

[0090] Arthritis includes inflammatory joint diseases that may be associated with pain. Examples of arthritis pain include osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatic) arthritis, non-rheumatic arthritis, periarthritis, neuropathic arthritis including Charcot foot, axial spondyloarthritis including ankylosing spondylitis, and pain associated with SAPHO syndrome.

[0091] In some embodiments, Solliam Fetol is used to treat chronic musculoskeletal pain.

[0092] In some embodiments, Solliamfetol may be administered to alleviate complex regional pain syndromes 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 also has a neurological component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the limbs, which may be accompanied by edema, autonomic, motor, and sensory changes.

[0093] In some embodiments, Solliamfetol is administered to alleviate neuropathic pain.

[0094] Examples of neuropathic pain include pain or diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, simple nerve root compression, phantom limb pain, central pain, and pain due to multiple sclerosis. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and neuropathy associated with radiotherapy or chemotherapy.

[0095] In some embodiments, Solliamfetol may be administered to alleviate fibromyalgia.

[0096] This disclosure is in part with respect to Sunosi (登録商標) The method includes using (referred to herein as Solliamufetol (also known as (R)-2-amino-3-phenylpropylcarbamate (APC), and previously known as JZP-210, ADX-N05, R228060 and YKP10A)). In certain embodiments, the structure of Solliamufetol is shown below as Formula I:

[0097] [ka] Methods for producing solliamfetol and related compounds can be found in U.S. Patents 10,829,443, 5,955,499; 5,705,640; 6,240,532 and 5,756,817. All of the above patents and applications are incorporated herein by reference in their entirety for all purposes.

[0098] Possible treatments for ADHD include stimulant and non-stimulant medications, which are considered the mainstays of treatment for adults with ADHD. Limitations of these treatments include insufficient or no response in a significant proportion of patients, variability in tolerability, high scheduling classification due to the potential for abuse and misuse (stimulants), and reduced and delayed therapeutic effects of non-stimulants compared to stimulants. Therefore, there is a need for novel, effective, safe, and well-tolerated treatments for ADHD.

[0099] Some individuals with attention-deficit / hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. In some embodiments, Solliam fetol has a pattern of efficacy and tolerability as a treatment for ADHD in adults.

[0100] Solliamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) currently approved in the United States and the European Union for the treatment of excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea in adults. The effects of Solliamfetol on dopamine and norepinephrine are related because these neurotransmitter systems are involved in the pathophysiology of ADHD. Furthermore, several treatments for ADHD, including the stimulants methylphenidate and mixed amphetamine salts as well as the non-stimulant atomoxetine, are thought to act in part through the dopamine and norepinephrine pathways.

[0101] Pharmacological studies have also identified agonist activity of soruliamfetol at trace amine-associated receptor 1 (TAAR1). In some embodiments, soruliamfetol has been demonstrated to activate human TAAR1 in vitro with efficacy within clinically appropriate plasma concentration ranges, overlapping with observed dopamine and norepinephrine transporter inhibitory efficacy. TAAR1 is a G protein-coupled receptor with affinity for trace amines, and in some embodiments, TAAR1 agonists have shown facilitative and arousal-promoting effects in rodents and primates. Behavioral studies have also shown that TAAR1 modulates motor activity, cognition, and anxiety-like behavior in spontaneously hypertensive rats (SHR), considered the most effective animal model for ADHD. In some embodiments, the effects of soruliamfetol on TAAR1 are relevant to the treatment of ADHD.

[0102] Solliamfetol also has serotonin 1A receptors (or 5-HT receptors). 1A It is also a receptor agonist.

[0103] For example, in some embodiments, Soluriamfetol is associated with significant improvements over placebo in wakefulness maintenance test performance and self-reported sleepiness in individuals with narcolepsy and obstructive sleep apnea, and the benefit can be confirmed at week 1. In some embodiments, Soluriamfetol exposure may be well-tolerated and may be associated with a greater reduction in ADHD symptoms as assessed by our primary outcome measure, the Adult ADHD Investigator Symptom Rating Scale (AISRS). In some embodiments, individuals undergoing Soluriamfetol treatment have a higher percentage of achieving our primary definition of clinical improvement: at least a 25% reduction in ADI-ID symptoms and a significantly or very significantly improved rating on the Clinical Global Impressions scale (CGI).

[0104] Daily doses of Solliamufetol may include approximately 50-100 mg (or approximately 0.2-4 mmol), approximately 100-150 mg (or approximately 0.4-0.7 mmol), approximately 150-200 mg (or approximately 0.7-0.9 mmol), approximately 200-400 mg (or approximately 0.8-1.7 mmol), approximately 70-80 mg, approximately 75 mg, approximately 140-160 mg, approximately 150 mg, approximately 280-320 mg, or approximately 300 mg.

[0105] For some human patients, a dose of approximately 140–160 mg of souliamfetol, or approximately 0.6–0.7 mmol of souliamfetol (e.g., 150 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., approximately 0.65 mmol of another form of souliamfetol), is administered daily to those who require it. In some cases, it may be desirable to start with a lower dose of souliamfetol and then increase that dose to a maintenance dose of 140–160 mg, e.g., 150 mg of souliamfetol. For example, approximately 70–80 mg of souliamfetol, or approximately 0.3–0.35 mmol of souliamfetol (e.g., approximately 75 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., approximately 0.33 mmol of another form of souliamfetol), can be administered daily for three days. Following this, on the fourth day of administration of sorriamfetol, a higher dose or maintenance dose, such as approximately 140-160 mg (e.g., approximately 150 mg of sorriamfetol hydrochloride, or another form of sorriamfetol in molar equivalent doses), may be administered daily. Sorriamfetol may be administered daily for the required period, for example, for six weeks or more.

[0106] For some human patients, a dose of approximately 280–320 mg of souliamfetol, or approximately 1.2–1.4 mmol of souliamfetol (e.g., 300 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., approximately 1.3 mmol of another form of souliamfetol), is administered daily to those who require it. In some cases, it may be desirable to start with a lower dose of souliamfetol and then increase that dose to a maintenance dose of 280–320 mg. For example, approximately 70–80 mg of souliamfetol (e.g., approximately 75 mg of souliamfetol hydrochloride, or a molar equivalent dose of another form of souliamfetol) can be administered daily for three days. Following this, on the fourth day of administration of sorriamufetol, a higher dose of sorriamufetol, for example, about 140-160 mg (e.g., about 150 mg of sorriamufetol hydrochloride, or another form of sorriamufetol in molar equivalent doses) may be administered daily for four days (days 4-7). After this, on the eighth day of administration of sorriamufetol, a maintenance dose of about 280-320 mg of sorriamufetol per day (e.g., about 300 mg of sorriamufetol hydrochloride, or another form of sorriamufetol in molar equivalent doses) may be administered. Sorriamufetol can be administered daily for the required period, for example, for six weeks or more.

[0107] Unless otherwise stated, any references or mentions of a compound herein, such as soluriamphetol, by structure, name or any other means, include pharmaceutically acceptable salts, alternative solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium-modified / deuterated forms, or any other chemical species, such as precursors, prodrugs, or any other chemical species that can be rapidly converted to the compound described herein under the conditions under which the compound is used as described herein.

[0108] Solliamufetol may be administered in dosage forms, such as tablets, which may contain excipients / additives, media / vehicles, or other components, including, for example, hydroxypropylcellulose, magnesium stearate, yellow iron oxide, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, or combinations thereof.

[0109] Typically, human patients treated for attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder are adults, e.g., those aged approximately 18–100 years, 18–55 years, 55–100 years, or older. However, children, e.g., those aged 1–17 years, may also be treated.

[0110] In some embodiments, the person being treated has a primary diagnosis of ADHD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, confirmed by an interview conducted by a clinician using the Adult Clinical Diagnostic Scale for ADHD (ACDS v1.2). In some embodiments, this diagnosis was made at least six months prior to treatment.

[0111] The Adult ADHD Clinical Diagnostic Scale, version 1.2 for DSM-5 is a clinician-administered retrospective assessment of childhood ADHD symptoms, which also includes an expanded assessment of adult interviewees' recent (past 6 months) symptoms of adult ADHD. The interview assesses nine symptoms of inattention, nine symptoms of hyperactivity / impulsivity, and additional symptoms not specifically identified in DSM-5 but thought to be associated with adult ADHD. Additional items generally assess planning and organizing difficulties, inattention, and mood instability.

[0112] The AISRS is a clinician-administered assessment scale derived from 18 ADHD symptoms listed in the DSM-5, with prompts specifically designed to identify signs of ADHD in adults. The AISRS total score is the sum of a 9-item inattentive symptoms subscale and a 9-item hyperactivity and impulsivity symptoms subscale. Each item is scored as follows: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Scores for each subscale can range from 0 to 27. The total score can range from 0 to 54, with higher scores indicating greater severity.

[0113] In some embodiments, a person has an AISRS total score of at least about 26 when assessed by a healthcare provider at baseline or on the day of treatment initiation.

[0114] The Clinical Guidance Indicator (CGI-S) is a clinician assessment scale for measuring the severity of a disorder. The CGI-S asks clinicians to assess the severity of the disorder over the past seven days (including the assessment day) using the following seven-point scale, based on their overall experience with this particular patient population (i.e., ADHD): 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill patients.

[0115] In some embodiments, a human has a CGI-S score of at least about 4 when assessed by a healthcare provider at baseline or on the day of treatment initiation.

[0116] The 16-item QIDS-SR-16 is a patient rating scale, a simplified version of the 30-item Inventory of Depressive Symptomatology (IDS), designed to assess the severity of depressive symptoms. The QIDS-SR-16 assesses the criterion symptom domains for diagnosing a major depressive episode.

[0117] The QIDS-SR-16 can be used to assess a subject's depressive symptoms over the past seven days. Subjects report the severity of symptoms across 10 items, which assess sleep, feelings of sadness, appetite, weight change, concentration, self-regard, suicidality, general interest level, energy level, psychomotor retardation, and restlessness. Each item can be scored on a 4-point scale, with a score of 0 representing no symptoms and a score of 3 representing the most severe symptom.

[0118] In some embodiments, humans have a QIDS-SR-16 score of less than approximately 13 when assessed by a healthcare provider at baseline or on the day of treatment initiation.

[0119] In some embodiments, a person has a HAM-A score of at least about 21 when assessed by a healthcare provider at baseline or on the day of treatment initiation.

[0120] The HAM-A is a clinician-administered scale used to measure the severity of a patient's anxiety symptoms. The HAM-A consists of 14 items, each rated on a 5-point scale from 0 (absent) to 4 (very severe). The highest possible score is 56, representing the most severe form of anxiety, while the lowest possible score is 0, representing no anxiety. The assessment timeframe is the past 7 days.

[0121] In some embodiments, a subject being treated for major depressive disorder, e.g., a human, receives a daily dose of about 140–160 mg of souliamfetol, or about 0.6–0.7 mmol of souliamfetol (e.g., 150 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmol of another form of souliamfetol), in accordance with the methods and / or schedule described herein.

[0122] In some embodiments, a subject being treated for major depressive disorder, e.g., a human, receives a daily dose of about 280–320 mg of souliamfetol, or about 1.2–1.4 mmol of souliamfetol (e.g., 300 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., about 1.3 mmol of another form of souliamfetol), in accordance with the methods and / or schedule described herein.

[0123] Binge eating is eating significantly more food than most people would eat in a similar amount of time under similar circumstances, within a clearly defined time period (for example, within any two-hour window). Binge eating may also include an inability to control eating during the episode (for example, an inability to stop eating or an inability to control the type or amount of food eaten). Binge eating includes eating more food than most people would eat in a similar amount of time under similar circumstances, within a clearly defined time period, as well as an inability to control eating. Binge eating disorder includes recurrent binge eating without appropriate compensatory behaviors.

[0124] Patients being treated with Solliam Fetol as described herein may be experiencing bulimia and may meet one, more, or all of the DSM-5 criteria for bulimia. The DSM-5 criteria for bulimia include: Typical clinical presentation: • Recurrent episodes of binge eating occurring at least once a week for three months. • Eating a larger-than-usual amount of food in a short period of time (for example, within any two-hour period) During an episode of overeating, there is a feeling of being unable to control overeating (for example, a feeling of being unable to stop eating, or being unable to control the type or amount of food eaten). Overeating episodes related to three or more of the following: • Eat until you're uncomfortably full. • Eating large amounts of food even when not physically hungry • Eat very quickly • I feel ashamed of the amount I eat, so I eat alone. • Feeling disgusted, depressed, ashamed, or guilty after overeating. Additional features: • There is also significant distress related to overeating. • The overeating is not accompanied by habitual inappropriate compensatory behaviors such as purging or excessive exercise. • Overeating does not only occur during bulimia nervosa or anorexia nervosa. Bulimia is accompanied by the following: • Overeating (eating at night, snacking, LOC) and weight gain • Obesity (including severe obesity (BMI ≥ 40) and obesity-related conditions) • Mood, anxiety, substance use, and impulse control disorders (e.g., ADHD) • 80% have one or more comorbidities • Decreased quality of life, functional impairment • (Equivalent to BN) & Increased medical use and medical expenses • Significant distress - shame, guilt, self-loathing

[0125] Patients treated with Solliamfetol as described herein may meet one, more, or all of the DSM-5 criteria for bulimia nervosa, and the diagnosis can be confirmed by the Eating Disorder Examination Questionnaire (EDE-Q).

[0126] In some embodiments, a subject being treated for bulimia, e.g., a human, receives a daily dose of about 140–160 mg of souliamfetol, or about 0.6–0.7 mmol of souliamfetol (e.g., 150 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmol of another form of souliamfetol), in accordance with the methods and / or schedule described herein.

[0127] In some embodiments, a subject being treated for bulimia, e.g., a human, receives a daily dose of about 280–320 mg of souliamfetol, or about 1.2–1.4 mmol of souliamfetol (e.g., 300 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., about 1.3 mmol of another form of souliamfetol), in accordance with the methods and / or schedule described herein.

[0128] In some embodiments, solliamfetol is present in a dosage form that does not contain other active pharmaceutical ingredients, for example, other active pharmaceutical ingredients intended for the treatment of the conditions described herein. In some embodiments, no active pharmaceutical ingredients other than solliamfetol are administered to humans for the treatment of the conditions described herein.

[0129] In some embodiments, Solliamfetol may be administered to subjects, such as human subjects, to treat cognitive impairment present in excessive daytime sleepiness associated with obstructive sleep apnea, or to improve cognition in such subjects.

[0130] In some embodiments, a subject, e.g., a human, who is being treated for cognitive impairment or receiving souriamufetol to improve cognition, receives a daily dose of about 140–160 mg of souriamufetol, or about 0.6–0.7 mmol of souriamufetol (e.g., 150 mg of souriamufetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmol of another form of souriamufetol), in accordance with the methods and / or schedule described herein.

[0131] In some embodiments, a subject, e.g., a human, who is being treated for cognitive impairment or receiving souriamufetol to improve cognition, receives a daily dose of about 280–320 mg of souriamufetol, or about 1.2–1.4 mmol of souriamufetol (e.g., 300 mg of souriamufetol hydrochloride, or a molar equivalent dose, i.e., about 1.3 mmol of another form of souriamufetol), in accordance with the methods and / or schedule described herein.

[0132] In some embodiments, Solliamfetol can be used to treat subjects, such as humans, who are experiencing a shift work disorder. Diagnostic features of shift work disorder include some or all of the following: insomnia during daytime sleep or excessive sleepiness during nighttime shifts, accompanied by a reduction in total sleep time; work schedules that overlap with normal sleep time; symptoms causing clinically significant distress or impairment in a significant functional area for at least three months; symptoms not better explained by another disorder; and overnight and early morning shifts (starting between 3 a.m. and 7 a.m.) may also cause shift work disorder.

[0133] In some embodiments, a subject being treated for a shift work disorder, e.g., a human, receives a daily dose of about 140–160 mg of souliamfetol, or about 0.6–0.7 mmol of souliamfetol (e.g., 150 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmol of another form of souliamfetol), in accordance with the methods and / or schedule described herein.

[0134] In some embodiments, a subject being treated for a shift work disorder, e.g., a human, receives a daily dose of approximately 280–320 mg of souliamfetol, or approximately 1.2–1.4 mmol of souliamfetol (e.g., 300 mg of souliamfetol hydrochloride, or a molar equivalent dose, i.e., approximately 1.3 mmol of another form of souliamfetol), in accordance with the methods and / or schedule described herein.

[0135] For the purposes of this disclosure, the terms “to treat,” “to treat,” or similar terms (e.g., “modulating”) include any other effect relating to the cure, mitigation, treatment or prevention of a disease in humans or other animals, or to a “drug” as defined in 21 USC 321(g).

[0136] For the purposes of this disclosure, “active pharmaceutical ingredient” is a compound or substance that meets the statutory definition of “drug” in 21 USC 321(g).

[0137] In some embodiments, the total AISRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamufetol daily for one week (or on the 8th day of administration of sorriamufetol) compared to the total AISRS score on the first day of administration of sorriamufetol and the total AISRS score before administration of sorriamufetol.

[0138] In some embodiments, the human AISRS total score decreases by at least 3, at least 6, at least 10, at least 15, at least 20, at least 25, up to 20, up to 30, up to 40, up to 50, or up to 54 after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0139] In some embodiments, the human AISRS total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0140] In some embodiments, the human AISRS total score decreases by at least 3, at least 6, at least 10, at least 15, at least 20, at least 25, up to 20, up to 30, up to 40, up to 50, or up to 54 after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0141] In some embodiments, the human AISRS total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0142] In some embodiments, the human AISRS total score decreases by at least 3, at least 6, at least 10, at least 15, at least 20, at least 25, up to 20, up to 30, up to 40, up to 50, or up to 54 after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0143] In some embodiments, the human AISRS total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered to the patient), compared to the AISRS total score on the first day of souriamfetol administration and the AISRS total score before souriamfetol administration.

[0144] In some embodiments, the human AISRS total score decreases by at least 3, at least 6, at least 10, at least 15, at least 20, at least 25, up to 20, up to 30, up to 40, up to 50, or up to 54 after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered to the patient), compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0145] In some embodiments, the total AISRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after 6 weeks of daily administration of sorriamfetol to the patient (or on the 43rd day of administration of sorriamfetol) compared to the total AISRS score on the first day of administration of sorriamfetol and the total AISRS score before administration of sorriamfetol.

[0146] In some embodiments, the human AISRS total score decreases by at least 3, at least 6, at least 10, at least 15, at least 20, at least 25, up to 20, up to 30, up to 40, up to 50, or up to 54 after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day when souriamfetol is administered to the patient), compared to the AISRS total score on the first day of administration of souriamfetol and the AISRS total score before administration of souriamfetol.

[0147] In some embodiments, the human CGI-S total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0148] In some embodiments, the human CGI-S total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0149] In some embodiments, the human CGI-S total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0150] In some embodiments, the human CGI-S total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 2 weeks (or on the 15th day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0151] In some embodiments, the human CGI-S total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0152] In some embodiments, the human CGI-S total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0153] In some embodiments, the human CGI-S total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered to the patient), compared to the CGI-S total score on the first day of souriamfetol administration and the CGI-S total score before souriamfetol administration.

[0154] In some embodiments, the human CGI-S total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered to the patient), compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0155] In some embodiments, the human CGI-S total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day of administration of souriamfetol) compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0156] In some embodiments, the human CGI-S total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day when souriamfetol is administered to the patient), compared to the CGI-S total score on the first day of administration of souriamfetol and the CGI-S total score before administration of souriamfetol.

[0157] The Clinical Global Impression of Improvement (CGI-I) is a clinician-assessed scale that measures how much a patient has improved or worsened compared to baseline. The CGI-I is assessed over the past seven days, including the assessment day, compared to the baseline assessment. The CGI-I uses a 7-point scale: 1 = Very significant improvement, 2 = Significant improvement, 3 = Minimal improvement, 4 = No change, 5 = Minimal deterioration, 6 = Significant deterioration, 7 = Very significant deterioration. A lower score indicates improvement.

[0158] In some embodiments, the total CGI-I score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the total CGI-I score on the first day of administration of souriamfetol and the total CGI-I score before administration of souriamfetol.

[0159] In some embodiments, the human CGI-I total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the CGI-I total score on the first day of administration of souriamfetol and the CGI-I total score before administration of souriamfetol.

[0160] In some embodiments, the total CGI-I score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the total CGI-I score on the first day of administration of souriamfetol and the total CGI-I score before administration of souriamfetol.

[0161] In some embodiments, the human CGI-I total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 2 weeks (or on the 15th day of administration of souriamfetol) compared to the CGI-I total score on the first day of administration of souriamfetol and the CGI-I total score before administration of souriamfetol.

[0162] In some embodiments, the total CGI-I score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol), compared to the total CGI-I score on the first day of administration of souriamfetol and the total CGI-I score before administration of souriamfetol.

[0163] In some embodiments, the human CGI-I total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the CGI-I total score on the first day of administration of souriamfetol and the CGI-I total score before administration of souriamfetol.

[0164] In some embodiments, the total CGI-I score in humans decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after 4 weeks of daily administration of sorriamfetol to the patient (or on the 29th day of administration of sorriamfetol) compared to the total CGI-I score on the first day of administration of sorriamfetol and the total CGI-I score before administration of sorriamfetol.

[0165] In some embodiments, the human CGI-I total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered to the patient), compared to the CGI-I total score on the first day of administration of souriamfetol and the CGI-I total score before administration of souriamfetol.

[0166] In some embodiments, the total CGI-I score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day when souriamfetol is administered to the patient), compared to the total CGI-I score on the first day of administration of souriamfetol and the total CGI-I score before administration of souriamfetol.

[0167] In some embodiments, the human CGI-I total score decreases by at least 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7 after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day when souriamfetol is administered to the patient), compared to the CGI-I total score on the first day of administration of souriamfetol and the CGI-I total score before administration of souriamfetol.

[0168] The Behavior Rating Inventory of Executive Function—Adult Version (BRIEF-A) is a standardized scale that captures aspects of an adult's executive function or self-control in their everyday environment. A self-report version is available. The BRIEF-A consists of 75 items that are self-rated on a 3-point Likert scale (1 = behavior not observed, to 3 = behavior frequently observed). The BRIEF-A has nine non-overlapping subscales, four of which (inhibition, shifting, emotional control, self-monitoring) are combined to produce the Behavioral Regulation Index (BRI), and the remaining five (initiation, working memory, planning / organizing, task monitoring, tool organization) are combined to produce the Metacognitive Index (MI). Combining these two indices yields a total score called the Global Executive Composite (GEC) score. A higher score indicates greater executive function impairment.

[0169] In some embodiments, the human BRIEF-A total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamfetol daily for one week (or on the 8th day of administration of sorriamfetol) compared to the BRIEF-A total score on the first day of administration of sorriamfetol and the BRIEF-A total score before administration of sorriamfetol.

[0170] In some embodiments, the human BRIEF-A total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamfetol daily for two weeks (or on the 15th day of administration of sorriamfetol) compared to the BRIEF-A total score on the first day of administration of sorriamfetol and the BRIEF-A total score before administration of sorriamfetol.

[0171] In some embodiments, the human BRIEF-A total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the BRIEF-A total score on the first day of administration of souriamfetol and the BRIEF-A total score before administration of souriamfetol.

[0172] In some embodiments, the human BRIEF-A total score decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamufetol daily for 4 weeks (or on the 29th day when sorriamufetol is administered to the patient), compared to the BRIEF-A total score on the first day of administration of sorriamufetol and the BRIEF-A total score before administration of sorriamufetol.

[0173] In some embodiments, the total BRIEF-A score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamufetol daily for 6 weeks (or on the 43rd day of administration of sorriamufetol) compared to the total BRIEF-A score on the first day of administration of sorriamufetol and the total BRIEF-A score before administration of sorriamufetol.

[0174] The Adult ADHD Symptom Rating Scale (ASRS) is a patient-reported outcome assessment scale based on 18 ADHD symptoms described in the DSM-5, with a one-week lookback period. The ASRS showed a significant correlation with the AISRS administered by clinicians.

[0175] In some embodiments, the total ASRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0176] In some embodiments, the total ASRS score of a human patient decreases by at least 2, at least 4, at least 6, at least 8, at least 10, up to 8, up to 10, up to 14, or up to 18 after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0177] In some embodiments, the total ASRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0178] In some embodiments, the total ASRS score of a human patient decreases by at least 2, at least 4, at least 6, at least 8, at least 10, up to 8, up to 10, up to 14, or up to 18 after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0179] In some embodiments, the total ASRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0180] In some embodiments, the total ASRS score of a human patient decreases by at least 2, at least 4, at least 6, at least 8, at least 10, up to 8, up to 10, up to 14, or up to 18 after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0181] In some embodiments, the total ASRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered) compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0182] In some embodiments, the total ASRS score of a human patient decreases by at least 2, at least 4, at least 6, at least 8, at least 10, up to 8, up to 10, up to 14, or up to 18 after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered to the patient), compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0183] In some embodiments, the total ASRS score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after 6 weeks of daily administration of soruliamfetol to the patient (or on the 43rd day of administration of soruliamfetol) compared to the total ASRS score on the first day of administration of soruliamfetol and the total ASRS score before administration of soruliamfetol.

[0184] In some embodiments, the total ASRS score of a human patient decreases by at least 2, at least 4, at least 6, at least 8, at least 10, up to 8, up to 10, up to 14, or up to 18 after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day when souriamfetol is administered to the patient), compared to the total ASRS score on the first day of administration of souriamfetol and the total ASRS score before administration of souriamfetol.

[0185] The Adult ADHD Quality of Life Scale (AAQoL) is a 29-item patient-reported questionnaire covering four domains / areas related to the quality of life of adults with ADHD. The four domains are: life productivity (11 items), psychological health (6 items), life outlook (7 items), and relationships (5 items). The scores for each item range from 1 = never / never to 5 = extremely / very frequently. A higher score indicates a better quality of life.

[0186] In some embodiments, the total AAQOL score of a human increases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamfetol daily for one week (or on the 8th day of administration of sorriamfetol) compared to the total AAQOL score on the first day of administration of sorriamfetol and the total AAQOL score before administration of sorriamfetol.

[0187] In some embodiments, the total AAQOL score of a human increases by at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, up to 30, or up to 40 after the patient has been administered sorriamfetol daily for one week (or on the 8th day of administration of sorriamfetol) compared to the total AAQOL score on the first day of administration of sorriamfetol and the total AAQOL score before administration of sorriamfetol.

[0188] In some embodiments, the total AAQOL score of a human increases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol), compared to the total AAQOL score on the first day of administration of souriamfetol and the total AAQOL score before administration of souriamfetol.

[0189] In some embodiments, the total AAQOL score of a human increases by at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, up to 30 or up to 40, after the patient has been administered solliamfetol daily for two weeks (or on the 15th day that solliamfetol is administered to the patient), compared to the total AAQOL score on the first day of administration of solliamfetol and the total AAQOL score before administration of solliamfetol.

[0190] In some embodiments, the total AAQOL score of a human increases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol), compared to the total AAQOL score on the first day of administration of souriamfetol and the total AAQOL score before administration of souriamfetol.

[0191] In some embodiments, the total AAQOL score of a human increases by at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, up to 30, or up to 40 after the patient has been administered sorriamfetol daily for 3 weeks (or on the 22nd day of administration of sorriamfetol) compared to the total AAQOL score on the first day of administration of sorriamfetol and the total AAQOL score before administration of sorriamfetol.

[0192] In some embodiments, the total AAQOL score of a human increases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered sorriamfetol daily for 4 weeks (or on the 29th day when sorriamfetol is administered to the patient), compared to the total AAQOL score on the first day of administration of sorriamfetol and the total AAQOL score before administration of sorriamfetol.

[0193] In some embodiments, the total AAQOL score of a human increases by at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, up to 30 or up to 40, after the patient has been administered solliamfetol daily for 4 weeks (or on the 29th day when solliamfetol is administered to the patient), compared to the total AAQOL score on the first day of administration of solliamfetol and the total AAQOL score before administration of solliamfetol.

[0194] In some embodiments, the total AAQOL score of a human increases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 6 weeks (or on the 43rd day when souriamfetol is administered to the patient), compared to the total AAQOL score on the first day of administration of souriamfetol and the total AAQOL score before administration of souriamfetol.

[0195] In some embodiments, the total AAQOL score of a human increases by at least 8, at least 12, at least 16, at least 20, at least 24, at least 28, up to 30, or up to 40 points after the patient has been administered sorriamfetol daily for 6 weeks (or on the 43rd day when sorriamfetol is administered to the patient), compared to the total AAQOL score on the first day of administration of sorriamfetol and the total AAQOL score before administration of sorriamfetol.

[0196] The Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPAI:GH) assesses the impact of illness on work productivity by measuring the time lost and work and activity impairments caused by health problems. The time frame is the past 7 days. The WPAI consists of six questions: 1=Are you currently employed?; 2=Time taken off due to health problems; 3=Time taken off for other reasons; 4=Time actually worked; 5=To what extent did health affect productivity while working (using a Visual Analogue Scale (VAS) from 0 to 10); and 6=To what extent did health affect productivity in non-work daily activities?

[0197] In some embodiments, the total WPAI score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for one week (or on the 8th day of administration of souriamfetol) compared to the total WPAI score on the first day of administration of souriamfetol and the total WPAI score before administration of souriamfetol.

[0198] In some embodiments, the total WPAI score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for two weeks (or on the 15th day of administration of souriamfetol) compared to the total WPAI score on the first day of administration of souriamfetol and the total WPAI score before administration of souriamfetol.

[0199] In some embodiments, the total WPAI score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 3 weeks (or on the 22nd day of administration of souriamfetol) compared to the total WPAI score on the first day of administration of souriamfetol and the total WPAI score before administration of souriamfetol.

[0200] In some embodiments, the total WPAI score of a human patient decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after the patient has been administered souriamfetol daily for 4 weeks (or on the 29th day when souriamfetol is administered) compared to the total WPAI score on the first day of administration of souriamfetol and the total WPAI score before administration of souriamfetol.

[0201] In some embodiments, the total WPAI score in humans decreases by at least 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100% after 6 weeks of daily administration of sorriamfetol to the patient (or on the 43rd day of administration of sorriamfetol) compared to the total WPAI score on the first day of administration of sorriamfetol and the total WPAI score before administration of sorriamfetol.

[0202] In some embodiments, Soluriamfetol results in sustained improvement in objective cognition, a reduction in the perceived severity of cognitive impairment by participants, and a reduction in subjective drowsiness. In some embodiments, Soluriamfetol is well-tolerated. In some embodiments, Soluriamfetol can improve cognitive function in patients with cognitive impairment associated with OSA and EDS. [Examples]

[0203] example Example 1. Phase 3 clinical trial to evaluate efficacy and safety A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial will be conducted to evaluate the efficacy and safety of souliamfetol in adults with ADHD. The trial will consist of a screening period of up to 5 weeks, a double-blind treatment period of 6 weeks, and a follow-up visit 1 week after the final dose of the study drug. The primary efficacy endpoint is the change from baseline to week 6 on the AISRS. Secondary endpoints include changes from baseline to week 6 on the CGI-S, CGI-I, BRIEF-A, ASRS, AAQoL questionnaire, and WPAI questionnaire.

[0204] During the screening period, eligible subjects must have a primary diagnosis of ADHD based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, confirmed by an interview conducted by a clinician using the Clinical Diagnostic Scale for Adult ADHD, Version 1.2 (ACDS v1.2), and must not have any exclusion diagnoses as assessed by the Mini International Neuropsychiatric Interview (MINI). Subjects must have an AISRS total score of 26 or higher at screening and baseline.

[0205] Eligible subjects will be randomized in a 1:1:1 ratio to receive either souliamfetol adjusted to a dose up to 150 mg, souliamfetol adjusted to a dose up to 300 mg, or placebo, once daily for 6 weeks. Subjects randomized to the 150 mg dose will receive 75 mg on days 1-3 and 150 mg from day 4 onward. Subjects randomized to the 300 mg dose will receive 75 mg on days 1-3, 150 mg on days 4-7, and 300 mg from day 8 onward.

[0206] Screening period Participants taking ADHD medication at the time of screening will undergo a washout of at least two weeks or five half-lives, whichever is longer, before their baseline visit (second visit).

[0207] Participants will be rescreened after consultation with the sponsor and medical monitor if drug washout is insufficient or for other procedural reasons; however, participants who do not meet the ADHD diagnostic criteria will not be rescreened.

[0208] Treatment period Participants who successfully complete the screening will be randomly assigned in a 1:1:1 ratio at their baseline visit (second visit) to receive either 150 mg of soliamfetol, 300 mg of soliamfetol, or placebo once daily for 6 weeks. The study drug will be dose-adjusted as follows: • Soluliamfetor 150mg group: 75mg once daily from day 1 to day 3, followed by 150mg once daily from day 4 onwards. • Soluliamfetor 300mg group: 75mg once daily from day 1 to day 3, then 150mg once daily from day 4 to day 7, and then 300mg once daily from day 8 onwards. • Placebo: A placebo will be administered once daily, matched on day 1 and throughout the entire study.

[0209] The initial dose of the study drug will be administered in the hospital after the baseline assessment is completed. Thereafter, subjects will be instructed to take a single daily oral dose of the study drug within one hour of waking in the morning, except for visits 4, 6, and 8. The study drug will be administered in the hospital. Subjects will be contacted by telephone one week after the final dose of the study drug for follow-up visits. Study visits will be conducted at screening (visit 1), baseline (day 1, visit 2), day 4 (visit 3), days 8, 15, 22, 29, and 43 (visits 4-8), and day 50 (visit 9 follow-up). Subjects who discontinue the study early are encouraged to complete visit 8. Study procedures and evaluations will be conducted during study visits as outlined in the evaluation schedule. Evaluations will include safety parameters, AISRS, CGI-S, CGI-I, BRIEF-A, ASRS, AAQoL, and WPAI.

[0210] Blood samples will be collected each time the patient visits the hospital for in-hospital trials after medication administration to measure the concentration of Solliamufetol.

[0211] Figure 1 shows a summary of a study to evaluate the efficacy and safety of souliamfetol in adults with ADHD.

[0212] Example 2. Evaluation of efficacy and safety Individuals were at least 18 years of age and included those under 65 years of age. Participants were enrolled and participated from August 2021 to January 2023. Eligibility was determined by a systematic online consultation interview, including the administration of the AISRS and a review of current and past mental health symptoms, conducted by the principal investigator, a board-certified psychiatrist trained in neuropsychiatry and an expert administrator of the AISRS. This systematic interview, which examined the presence of symptom criteria for all major Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mental health conditions, was supplemented by a review of self-reported symptom patterns on the Adult Self-Report (ASR) to increase the likelihood of identifying exclusionary comorbidities. Participants met the DSM-5 criteria for ADHD and had at least 20 AISRS scores. Individuals were excluded if they had any of the following attributes: intolerance to soluriamfetol, a condition that impairs the determination of an ADHD diagnosis, renal failure / renal impairment, pregnancy, currently breastfeeding an infant, unwillingness to use reliable contraception during the study period, or a history of cancer in the past five years. Individuals were excluded if they had a significant and unstable medical condition. Individuals were excluded if they had certain conditions that sympathomimetic agents may exacerbate: current or past psychotic or bipolar disorder, current affective or anxiety disorder with symptoms greater than mild, untreated hypertension (>140 / 90 mm Hg), narrow-angle glaucoma, substance abuse, or substance dependence (other than nicotine). FDA-approved ADHD treatments and catecholamine agonists (e.g., duloxetine, venlafaxine, and bupropion) were not permitted for five half-lives prior to participation in the study, or longer if necessary to assess eligibility. Use of benzodiazepines or sedatives less than twice a week was permitted.

[0213] Participants were randomized in a double-blind manner to receive either Solliamfetol 75 mg or placebo capsules, and were instructed to take the dose in the morning. Safety and efficacy measures were obtained at weekly visits (defined as 7 ± 3 days) for 6 weeks. All participants took one capsule in the morning at baseline and until the next visit one week later. At each subsequent visit, the principal investigator considered the following variables to determine the recommendation for medication: changes in blood pressure and heart rate, spontaneously reported adverse events, the amount of improvement on the AISRS rating scale, and the CGI improvement score. If the study drug was well tolerated, participants were instructed to increase to two capsules in the morning at this first weekly visit after baseline. If, at this first weekly visit, a participant experienced an adverse event of mild or greater severity that was possibly attributable to the study drug, the participant was asked to remain on one capsule for the following week. If an individual maintained one capsule the previous week and tolerated it well, the dose was increased to two capsules at a subsequent visit.

[0214] Furthermore, if there was a possibility of improving tolerability, the dose could be reduced from two capsules to one capsule at any of the trial visits. If a subject was on one capsule, assessed with a very significant improvement in CGI, and had few ADHD symptoms on the AISRS, the subject was given the option to remain on one capsule for the following week of the trial. The principal investigator also prioritized the goal of stable medication for the final four weeks of the trial, only if the subject was well tolerable to that dosage. Subjects were not instructed to take more than two capsules. Data were collected from August 2021 to January 2023. Subjects were trained to operate an OMRON Model 7200 automated blood pressure cuff (OMRON Healthcare, Inc.) and performed readings twice: at screening and at each trial visit. Women of childbearing potential underwent urine pregnancy testing at baseline and at the endpoint.

[0215] Weekly assessments included our primary outcome AISRS; Global Assessment of Functioning (GAF); CGI for ADHD; and voluntary adverse experience reporting. Participants completed the following baseline and endpoint self-assessments: the 18-item ASRS (MASRS) with alternating item order to alternate inattention and impulsivity-hyperactivity items; the Adult Executive Function and Behavior Assessment Scale Form (BRIEF-A); the Pittsburgh Sleep Quality Index (PSQI); and the Epworth Sleepiness Scale (ESS). The ASRS has been shown to have high internal consistency and high concurrent validity with the rater-administered ADHD Symptom Interview (ADHD-RS), which is similar to the AISRS. In this validation, we adopted the ASRS format because it used an alternating pattern of inattention and impulsivity-hyperactivity items. This minor difference is highlighted by using the label MASRS. Pill counting was visually performed by staff at weeks 2, 4, and 6, as well as upon return of the pill bottle.

[0216] Statistical analysis: AISRS total score data from each trial visit were analyzed using a linear mixed-effects regression model with fixed effects for treatment group, trial visit number (as a 7-level categorical variable), and group × visit number interaction, as well as patient random effects. Unbiased estimates of the differences for weekly missing data were obtained using maximum likelihood estimation. Differences between groups were similarly modeled with two-level fixed effects between trial visits 0 and 6 for the following: AISRS total and subscale scores, GAF score, MASRS total score, BRIEF-A index and subscale T score, PSQI total and subscale scores, ESS score, and cardiovascular measurements. Using Fisher's exact test, the following were assessed: proportion of patients showing >25% and >50% improvement on AISRS; AISRS total score <18 and <12 at week 6; CGI assessment at week 6 being “significantly improved” or “very significantly improved”; >25% improvement in AISRS score in either of these latter CGI assessments at week 6; adverse event (AE) patterns included in any of the categories, moderate or severe AEs in some categories, and recurrent AEs in some categories; a 0.5 standard deviation reduction in BRIEF-A index / subscale scores, and the rate of improvement in BRIEF-A index / subscale scores. The proportion of patients with poor quality sleep (PSQI total score >5) and excessive daytime sleepiness (ESS score >11) was assessed at baseline and at the endpoint. Effect sizes for AISRS, MASRS, and BRIEF-A scores were estimated as the difference between treatment groups in the mean change between baseline and week 6, divided by the standard deviation of the baseline score. Patients were counted in each AE category for which they had previously reported an AE and placed in the severity category corresponding to the most severe reported severity. Cardiovascular analysis was based on the mean of two weekly vital sign measurements and included data from all early dropout participants.

[0217] The analysis was performed using SAS v9.4. The two-sided significance level was 0.05 for all analyses, and no adjustment for multiple comparisons was made, given the preliminary nature of this pilot study.

[0218] result Of the 60 participants, one in the placebo group discontinued the trial in week 2 due to personal preference; another in the placebo group deviated from the protocol by taking a stimulant during week 4, and the principal investigator requested that they terminate their participation in the trial. Figure 2 shows the participant flow throughout the trial. It can be seen that four of the subjects in the active drug solliamfetol treatment had a dosage pattern other than 75 mg in week 1 and 150 mg thereafter, while all of the placebo subjects increased to 150 mg in week 1. The dosing patterns of these four subjects in active treatment were described: blood pressure monitoring and complications delayed the increase to 150 mg at week 4; another subject was reduced to 75 mg after receiving 150 mg for one week due to the end of daytime irritability by a second visit at 150 mg; another subject delayed the increase to 150 mg at week 2 for no attributable reason; and another subject preferred to remain at 75 mg daily, having experienced insomnia at 150 mg between weeks 1 and 2 and having experienced a meaningful benefit. Furthermore, assessment of pill counts suggested that the four subjects in active treatment and the four subjects in placebo were likely missing exposure by more than a few days during either trial week.

[0219] Table 1 shows the demographic characteristics of the study participants.

[0220] [Table 1]

[0221] Compared to participants in the soruliamfetol group, participants randomly assigned to the placebo group had a higher proportion of white / Caucasian individuals (15 percentage points higher), a higher proportion of those with a bachelor's or nursing degree (17 percentage points higher), and a higher average income (21 percentage points higher). More women than men were exposed to soruliamfetol. Baseline concomitant psychopharmacological prescriptions included zolpidem, citalopram, escitalopram, gabapentin, alprazolam (1 participant each), trazodone (2 participants), escitalopram (3 participants), fluoxetine, and sertraline (5 participants each). Cardiovascular prescriptions included tamsulosin, telmisartan (1 participant each), losartan (3 participants), and spironolactone (2 participants). None of the 16 subjects in the soruliamfetol group and none of the 11 participants in the placebo group had previously received stimulant therapy. Of the group that had never received stimulants, three in each of the active drug group and the placebo group had previously received treatment with a non-stimulant (either atomoxetine or bupropion) that had potential ADHD effects.

[0222] At baseline, the ADHD CG1 severity assessment was moderate for most participants (see Table 1). There was a difference of less than 10% between the active treatment group and the placebo group in the percentage of individuals scoring in the disorder domain for all mental health subcategories of the ASR. At baseline, the mean (SD) AISRS total score was 25.5 (4.7) in the Solliamfetol group and 24.4 (4.2) in the placebo group. At baseline, all but one participant met the survey definition of executive dysfunction, i.e., having two or more subscales assessed at 1.5 standard deviations from the mean norm score of the BRIEF-A.

[0223] There were no significant differences in vital signs between the treatment and placebo groups during the study period. Comparing the mean vital signs of Solliamfetol and placebo from baseline to week 6, the following was found: heart rate: +3.7 vs. +2.2 bpm (P=.5609), systolic blood pressure: +2.4 vs. +1.5 mm Hg (P=.6474), diastolic blood pressure: +1.1 vs. +1.5 mm Hg (P=0.8117). Three subjects in the placebo group and four subjects in the treatment group met our definition of clinically meaningful hypertension, defined as two consecutive measurements (>140 / 90 mm Hg) over two consecutive visits. No subjects reported abnormal heart rates (>100 bpm) over two consecutive study visits.

[0224] All adverse events were analyzed regardless of their potential relevance to the trial. With the exception of syncope episodes occurring in patients in the placebo group, all were of mild or moderate severity. Adverse events were categorized by the affected physical system. Table 2 shows a comparison of the proportion of adverse events between the groups.

[0225] [Table 2]

[0226] There was no statistically significant therapeutic effect for the occurrence of events in these categories (Table 2), for the occurrence of repeated events in these categories (occurring in two or more visits in a single subject) (P-values ​​ranging from 0.1068 to 1.0000), or for the occurrence of events classified as having moderate or greater severity (P-values ​​ranging from 0.2294 to 1.0000). The following categories were observed at least 10 percentage points higher among treatment participants than among placebo participants: decreased appetite, headache, gastrointestinal issues, insomnia, increased vitality, cardiovascular and nervous system issues. The only category observed at least 10 percentage points higher among placebo participants than among treatment participants was dermatological issues. Examination of patterns of repeated classified adverse events showed that the rate of decreased appetite was the most differentiated (occurring in 3 patients in the Soluliamfetol treatment group, compared to none in the placebo group). Adverse events led to dose adjustments or discontinuation in 10 subjects in the active drug treatment group and 4 subjects in the placebo group, and one subject experienced skin itching during active drug treatment with souliamfetol, which led to discontinuation of treatment (at week 6).

[0227] The remote online diagnostic-based clinical trial format was also well tolerated by participants. For participants living in geographically diverse areas of Massachusetts, the trial was less time-consuming than if it required travel for in-person visits. No adverse experiences directly attributable to the remote nature of the trial occurred.

[0228] The mean improvement in total AISRS scores was significantly greater in individuals in the Soluliamfetol treatment group than in the placebo group from week 3 (mean difference was -3.4 (95% CI, -6.7 to -0.1; P=0.0439)) to the end of the study at week 6. By week 6, the mean difference in AISRS scores was -4.3 (95% CI, -7.7 to -1.0; P=.0106). Figure 3 shows the mean total AISRS scores by week. Referring to Figure 3, the mean improvement in total AISRS scores by the week 6 visit was -7.6 in the active drug participants and -2.1 in the placebo group (P=.0012; effect size=1.09). Similar patterns were observed in the AISRS inattention subscale (treatment showed a mean improvement of 4.0 points greater than placebo; P=.001; effect size=1.59) and the AISRS impulsivity-hyperactivity subscale (treatment showed a 1.4 point greater improvement than placebo; P=.024; effect size=0.34).

[0229] By week 6, 52% of individuals in the Soluriamfetol treatment group showed a 25% improvement in their AISRS total score, compared to 17% in the placebo group (P=.0119). By week 6, 28% of individuals in the Soluriamfetol treatment group showed a 50% improvement in their AISRS total score, compared to 3.4% in the placebo group (P=.0253). By week 6, significantly more individuals in the Soluriamfetol treatment group than in the placebo group met the remission AISRS total score definition of 12 (24% of Soluriamfetol treatment participants vs. 3% of placebo participants; P=0.0517) or 18 (59% of Soluriamfetol treatment participants vs. 21% of placebo participants; P=.0067). By week 6, significantly more individuals (45%, 13 / 29) in the soruliamfetol treatment group showed substantial or very substantial improvement in CGI assessment compared to the placebo group (6%, 2 / 31) (P=.0020). Figure 4 demonstrates a 25% improvement in CGI scores and AISRS scores with soruliamfetol compared to placebo, indicating substantial or very substantial improvement. Referring to Figure 4, further breakdown revealed the following distributions: in active treatment, substantial improvement = 24% (7 participants), very substantial improvement = 20% (6 participants); within placebo treatment, substantial improvement = 3% (1 participant), very substantial improvement = 3% (1 participant). 45% of participants in the treatment group and 6.9% in the placebo group were considered responders / responders according to our pre-defined criteria (P=.0020).

[0230] To enable a more direct comparison with several prior trials of adult ADHD treatment, outcomes were adjusted with slightly different post-hoc improvement and response definitions, focusing on a 30% improvement. By week 6, 48% of individuals in the Soluriamfetol treatment group had a 30% improvement in their AISRS total score, compared to 14% in the placebo group (-.0096). Responses based on this amount of improvement in the CGI assessment, with significant or very significant improvement, occurred in 41% of individuals in the Soluriamfetol treatment group and in 6.9% of individuals in the placebo group (P=.0046). The mean GAF score was significantly more significantly improved in the treatment group (-4.8 points; 95% CI, 3.1~6.6 vs. -0.3 points; 95% CI, -1.4~2.1; P=.0006).

[0231] Self-reported executive function abilities using BRIEF-A were assessed. Significantly more individuals in active treatment (69%) than in placebo (34%) had a 0.5 standard deviation improvement in T-scores in BRIEF-A Global Executive Function (GEC) ( / '=.0173), metacognitive indices (66% vs 34%, P=.0348), shift subscale (69% vs 34%, P=.0173), and initiation subscale (62% vs 31%, P=.0343). Solliamfetl was associated with significantly larger changes between baseline and week 6 compared to placebo for the following BRIEF-A subscales: Global Executive Function, Behavioral Regulation Indices, Metacognitive Indices, Shift Subscale, Emotional Control Subscale, Initiation Subscale, Working Memory Subscale, Planning / Organizing Subscale, and Task Monitor Subscale (each with moderate to high effect size). The subscales for inhibition, self-monitoring, and tool organization did not show significant changes compared to placebo.

[0232] Between baseline and week 6, the treatment group showed the mean MASRS total score reported by subjects (treatment group mean = -11.1; 95% CI, -14.6 to -7.7; placebo group mean = -3.9; 95% CI, -7.4 to -0.5; P = .0047; effect size = 1.23), MASRS inattention score (treatment group mean = -5.9; 95% CI, -7.7 to -4.0; placebo group mean = -1.7; 95% CI, -1.7 to -3.5; P = .0022; effect size = 1.30), and MASRS hyperactivity (treatment group mean = -5.2; 95% CI). A significantly larger reduction was observed in the CI (-7.1 to -3.4; placebo group mean = -2.4; 95% CI, -4.3 to -0.6; P = 0.0366; effect size = 0.55).

[0233] When evaluating the overall or subscale PSQI score changes from baseline to week 6, no significant differences were observed among participants in the treatment group. The mean sleepiness score on the ESS was significantly more improved in the treatment group (-2.4 points; P=.0056). We analyzed the change from baseline in the total AISRS score within the ESS subgroups for normal daytime sleepiness and excessive daytime sleepiness, and found that the improvement in AISRS was not mitigated by the change in the ESS assessment of sleepiness (P=0.3735).

[0234] We also assessed the shift from good sleep to poor sleep (defined as a PSQI score > 5) and vice versa between baseline and the end of the study, assigning participants to a trend toward improvement, no change, or deterioration in sleep quality. Overall, 24.1% in the active treatment group and 20.7% in the placebo group showed improvement in sleep, while 6.9% in the active treatment group and 10.3% in the placebo group showed deterioration in sleep. A combined 69% in both the active treatment and placebo groups remained in the same sleep category.

[0235] The effects of sorriamfetol in adults with ADHD described in this disclosure are unexpected and, to our knowledge, novel. Furthermore, this example is based on the first remotely conducted psychopharmacological clinical trial in adults with ADHD. Sorriamfetol was well-tolerated and was associated with significantly greater improvement than placebo, with a robust effect size based on both ADHD clinician and participant measurements, as well as participant self-reported executive function.

[0236] The effect size of soluriamfetol for ADHD symptom improvement in adults was similar to that of stimulant administration in previous trials where the effect size for symptom improvement was also calculated. A particularly low placebo response was observed in this trial, which may have contributed to a larger effect size estimate. While there is no established mean clinical importance difference (MCID) for the AISRS based on data from the same controlled 6-week trial, an analysis based on 6-month exposure to atomoxetine suggests that the AISRS change level, distinguishing individuals with a 1-point difference in ADHD CGI severity from those with no change in ADHD CGI severity, was -10.1. By examining response patterns, we found that 10 subjects in our trial who received active treatment showed improvement greater than 10 points, compared to only one subject in the placebo group.

[0237] In the atomoxetine trial where MCID was estimated, a one-point change in CGI severity correlated with at least a 30% improvement on the AISRS rating scale. Since we found that 48% of individuals in Solliamfetol had such a significant improvement on the AISRS rating, we believe further research is needed to clarify how MCID is best estimated with respect to AISRS in trials like the pilot study we present. For example, we note that the AISRS baseline scores were significantly higher in the atomoxetine trial used to estimate this MCID: 38.5 in the active group and 39.2 in the placebo group. This suggests that the two populations may not have been equivalent in terms of the possible changes in AISRS. While comparisons with in-person trials would be necessary to understand how participants' characteristics and outcomes differ specifically, several clinical trials have opened up the feasibility, usefulness, and efficacy of fully remote clinical trials.

[0238] Example 3: Effects of Soluliamfetol on cognitive function The effects of Solliamfetol on cognitive function were evaluated in participants with cognitive impairment associated with excessive daytime sleepiness related to obstructive sleep apnea.

[0239] Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA). It can persist in 10%–28% of patients even with primary airway therapy. Patients with OSA-related EDS may have performance deficits in several cognitive domains.

[0240] Solliamfetol (Sunosi®) is a dopamine and norepinephrine reuptake inhibitor with agonist properties at trace amine-related receptor 1 (TAAR1) and serotonin 1A receptors. Solliamfetol (37.5–150 mg / day) is approved in the United States, Canada, and select European countries for the treatment of EDS associated with OSA.

[0241] A randomized, double-blind, placebo-controlled, crossover phase IV trial was conducted to evaluate whether Solliamfetol improves cognitive function in patients with OSA-related EDS and to assess pre-existing cognitive impairment. Figure 4 shows a summary of the randomized, double-blind, placebo-controlled, crossover trial process. Referring to Figure 4, the trial consisted of a screening period of approximately 2–4 weeks, a first 2-week double-blind treatment period, a second 2-week double-blind treatment period, and a follow-up visit approximately 4–10 days after the final dose of the study drug.

[0242] Participants who successfully complete the screening will be randomized to receive treatment in double-blind periods 1 and 2 at their baseline visit (third visit). The investigational drug will be dose-adjusted as follows: Take 75mg once a day from day 1 to day 3, then 150mg once a day from day 4 onwards. • Placebo: A placebo will be administered once daily, matched on day 1 and throughout the entire study.

[0243] Figure 6 shows the clinical visitor composition. Table 3 shows baseline demographic and clinical characteristics. Of the 173 screened participants, 59 were enrolled and 57 completed the study. Among participants using positive airway pressure, the average usage time was 6 hours or more per night.

[0244] [Table 3]

[0245] The study measured the change in objective cognitive function from baseline to end of treatment using the Coding Subtest (a variation of the Numerical Code Substitution Test) of the Repeatable Battery for the Assessment of Neuropsychological Status (average across all post-administration time points). Figure 7 shows the results of the Coding Subtest. Referring to Figure 7, Solliamfetol significantly improved objective cognitive function compared to placebo. The mean difference was 1.75 (95%, Cl: 0.46, 3.04) (Cohen's d: 0.36).

[0246] Changes in objective cognitive function from baseline to the end of treatment were measured using a repeatable battery coding subtest (a variation of the digit substitution test) for assessing neuropsychological state (at each post-dosing time point). Figure 8 shows the change in coding subtest scores over time after administration for sorriamfetol and placebo. Referring to Figure 8, sorriamfetol significantly improved objective cognitive function compared to placebo at 2, 6, and 8 hours after administration. The mean difference (95% Cl) was 1.91 (0.16, 3.65) at 2 hours, 1.38 (-0.22, 2.97) at 4 hours, 2.33 (0.78, 3.88) at 6 hours, and 1.58 (0.23, 2.93) at 8 hours.

[0247] Changes in subjective cognitive function from baseline to the end of treatment were measured using the British Columbia Cognitive Complaints Inventory. Figure 9 shows the results from the British Columbia Cognitive Complaints Inventory for Solliamfetol and placebo. Referring to Figure 9, Solliamfetol significantly improved subjective cognitive function compared to placebo. The mean difference was -1.58 (95%Cl: -2.53, -.063) (Cohen's d: 0.43).

[0248] Table 4 shows the findings from the safety study. All adverse events (TEAEs) that occurred during treatment were mild or moderate in severity. There were no deaths, serious TEAEs, or TEAEs that led to the discontinuation of the study.

[0249] [Table 4]

[0250] Solliamfetol resulted in sustained improvements in objective cognition, reduced severity of cognitive impairment as perceived by participants, and reduced subjective drowsiness. The adverse event profile and high trial completion rate suggest that Solliamfetol was well-tolerated. Solliamfetol has the potential to improve cognitive function in patients with OSA and EDS-related cognitive impairment.

Claims

1. A method for treating attention deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder (SWD), comprising administering approximately 140 to 160 mg of souliamfetol daily to a person in need thereof.

2. The method according to claim 1, wherein approximately 150 mg of souliamfetol is administered daily to a person requiring the method.

3. A method for treating attention deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder (SWD), comprising administering approximately 280 to 320 mg of souliamfetol daily to a person in need thereof.

4. The method according to claim 1, wherein approximately 300 mg of souliamfetol is administered daily to a person requiring the method.

5. A method for treating ADHD, comprising administering approximately 70-80 mg of souliamfetol daily for three days to a person in need, and then administering approximately 140-160 mg of souliamfetol daily.

6. The method according to claim 1, wherein approximately 75 mg of soruliamfetol is administered to the human being daily for three days, and then approximately 150 mg of soruliamfetol is administered to the human being daily.

7. A method for treating attention deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), bulimia nervosa (BED), or shift work disorder, comprising administering to a person in need of such treatment approximately 70-80 mg of soruliamfetol daily for three days, then approximately 140-160 mg of soruliamfetol daily for four days, and then 280-320 mg of soruliamfetol daily.

8. The method according to claim 1, wherein approximately 75 mg of soruliamfetol is administered to the human being daily for 3 days, then approximately 150 mg of soruliamfetol is administered to the human being daily for 4 days, and then approximately 300 mg of soruliamfetol is administered to the human being daily.

9. The method according to any one of claims 1 to 8, wherein the person is an adult.

10. The method according to claim 9, wherein the person is approximately 18 to 55 years of age.

11. The method according to any one of claims 1 to 10, wherein the person has a primary diagnosis of ADHD based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed by an interview conducted by a clinician using the Adult ADHD Clinical Diagnostic Scale v1.2 (ACDS v1.2).

12. The method according to claim 11, wherein the diagnosis was made at least six months prior to treatment.

13. The method according to any one of claims 1 to 12, wherein the person has an AISRS total score of at least about 26 when assessed by a healthcare provider.

14. The method according to any one of claims 1 to 13, wherein the person has an AISRS total score of at least about 26 at baseline.

15. The method according to any one of claims 1 to 14, wherein the human has an AISRS total score of at least about 26 on the day the treatment was initiated.

16. The method according to any one of claims 1 to 15, wherein the person has a CGI-S score of at least about 4 when assessed by a healthcare provider.

17. The method according to any one of claims 1 to 16, wherein the human has a CGI-S score of at least about 4 at baseline.

18. The method according to any one of claims 1 to 17, wherein the human has a CGI-S score of at least about 4 on the day the treatment was initiated.

19. The method according to any one of claims 1 to 18, wherein the person has a QIDS-SR-16 score of less than approximately 13 when assessed by a healthcare provider.

20. The method according to any one of claims 1 to 19, wherein the person has a QIDS-SR-16 score of less than approximately 13 at baseline.

21. The method according to any one of claims 1 to 20, wherein the person has a QIDS-SR-16 score of less than approximately 13 on the day the treatment was initiated.

22. The method according to any one of claims 1 to 21, wherein the person has a HAM-A score of at least about 21 when assessed by a healthcare provider.

23. The method according to any one of claims 1 to 22, wherein the person has a HAM-A score of at least about 21 at baseline.

24. The method according to any one of claims 1 to 23, wherein the human has a HAM-A score of at least about 21 on the day the treatment was initiated.

25. The method according to any one of claims 1 to 24, wherein the solliamfetol is present in a dosage form that does not contain other active pharmaceutical ingredients.

26. The method according to any one of claims 1 to 25, wherein the solliamfetol is present in a dosage form that does not contain other active pharmaceutical ingredients intended for the treatment of ADHD.

27. The method according to any one of claims 1 to 26, wherein no active pharmaceutical ingredient other than Soluliamfetol is administered to humans for the treatment of ADHD.

28. The method according to any one of claims 1 to 27, wherein the Soluliamfetor is administered in the morning.

29. The method according to any one of claims 1 to 28, wherein the Solliamfetor is administered within one hour of wakefulness.

30. The method according to any one of claims 1 to 29, wherein the solliamfetol is administered more than nine hours before the expected time to go to bed.

31. The method according to any one of claims 1 to 30, wherein the solliam fetol is administered daily for six weeks.

32. The method according to any one of claims 1 to 31, wherein the solliamfetol is administered daily for more than six weeks.

33. The method according to any one of claims 1 to 32, wherein the total score of the Adult ADHD Detector Symptom Report Scale (AISRS) in the aforementioned human adult ADHD is reduced by at least 10% after the patient has been administered soruliamfetol daily for 6 weeks, compared to the total AISRS score on the first day of administration of soruliamfetol and the total AISRS score before administration of soruliamfetol.

34. The method according to any one of claims 1 to 33, wherein the total Clinical Global Impression of Severity (CGI-S) score of the person is reduced by at least 10% after the patient has been administered souliamfetol daily for 6 weeks, compared to the total CGI-S score on the first day of administration of souliamfetol and the total CGI-S score before administration of souliamfetol.

35. The method according to any one of claims 1 to 34, wherein the total Clinical Global Impression of Improvement (CGI-I) score of the person is reduced by at least 10% after the patient has been administered souliamfetol daily for 6 weeks, compared to the total CGI-I score on the first day of administration of souliamfetol and the total CGI-I score before administration of souliamfetol.

36. The method according to any one of claims 1 to 35, wherein the total score of the Human Adult Behavior Rating Inventory of Executive Function-Adult Version (BRIEFF-A) decreases by at least 10% after the patient has been administered solliamfetol daily for 6 weeks, compared to the total BRIEF-A score on the first day of administration of solliamfetol and the total BRIEF-A score before administration of solliamfetol.

37. The method according to any one of claims 1 to 36, wherein the total score of the Adult ADHD Self-Report Scale (ASRS) in the person is reduced by at least 10% after the patient has been administered soruliamfetol daily for 6 weeks, compared to the total ASRS score on the first day of administration of soruliamfetol and the total ASRS score before administration of soruliamfetol.

38. The method according to any one of claims 1 to 37, wherein the total score of the Adult ADHD Quality of Life Questionnaire (AAQoL) in the aforementioned human is reduced by at least 10% after the patient has been administered solliamfetol daily for 6 weeks, compared to the total AAQoL score on the first day of administration of solliamfetol and the total AAQoL score before administration of solliamfetol.

39. The method according to any one of claims 1 to 38, wherein the total Work Productivity and Activity Impairment (WPAI) score of the person is reduced by at least 10% after the patient has been administered souliamfetol daily for 6 weeks, compared to the total WPAI score on the first day of administration of souliamfetol and the total WPAI score before administration of souliamfetol.

40. The method according to any one of claims 1 to 39, wherein the person is experiencing ADHD.

41. The method according to any one of claims 1 to 39, wherein the person is in a state of experiencing MDD.

42. The method according to any one of claims 1 to 39, wherein the person is in a state of experiencing BED.

43. The method according to any one of claims 1 to 39, wherein the person is in a state of experiencing SWD.

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