Solriamfetol for improving cognitive health in apnea patients

Abstract

Disclosed herein are methods of improving cognitive function, comprising administering solriamfetol to a human patient experiencing excessive daytime sleepiness associated with obstructive sleep apnea.

Description

[0001] SOLRIAMFETOL FOR IMPROVING COGNITIVE HEALTH IN APNEA

[0002] PATIENTS

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional App. No. 63 / 583,552, filed September 18, 2023; and U.S. Provisional App. No. 63 / 613,710, filed December 21, 2023; the entire contents of each of which is incorporated by reference herein in its entirety.

[0005] FIELD

[0006] The present disclosure relates to methods of treating neurological conditions, comprising administering solriamfetol to a human being in need thereof.

[0007] BACKGROUND

[0008] Cognitive health is an aspect of overall well-being, with various factors influencing mental performance and quality of life. For example, as individuals age or face various health conditions, cognitive decline can become a significant concern, impacting memory, atention, and executive functions. For example, sleep disorders, such as obstructive sleep apnea (OSA), can play a role in cognitive impairment, OSA, characterized by repeated interraptions in breathing during sleep, can lead to fragmented sleep and reduced oxygen levels, which can disrupt normal brain function and exacerbate cognitive decline.

[0009] SUMMARY

[0010] The present disclosure relates to a method of improving cognitive function or heal th in human patients, such as human patients with excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea, comprising administering solriamfetol to a human patient experiencing excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea.

[0011] The present, disclosure relates to a method of improving cognitive function, including administering solriamfetol to a human patient experiencing excessive daytime sleepiness associated with obstructive sleep apnea.

[0012] In some embodiments, about 70-80 mg of solriamfetol per day is administered to ths human patient.

[0013] In some embodiments, about 140-160 mg of solriamfetol per day is administered to the human patient. In some embodiments, about 150 mg of solriamfetol per day is administered to the human patient.

[0014] In some embodiments, about 280-320 mg of solriamfetol per day is administered to the human patient.

[0015] In some embodiments, about 300 mg of solriamfetol per day is administered to the human patient.

[0016] In some embodiments, about 70-80 mg of solriamfetol is administered to the human patient daily for three days, and then administering about 140-160 mg of solriamfetol is administered to the human patient daily for fourteen days.

[0017] In some embodiments, about 75 mg of solriamfetol is administered to the human patient daily for three days, and then administering about 150 mg of solriamfetol is administered to the human patient daily for fourteen days.

[0018] In some embodiments, the solriamfetol is administered for at least 7 consecutive days. In some embodiments, the solriamfetol is administered for at least 14 consecutive days. In some embodiments, the solriamfetol is administered for at least 28 consecutive days. In some embodiments, the solriamfetol is administered for at least 35 consecutive days. In some embodiments, the solriamfetol is administered for at least 6 months. In some embodiments, tlie solriamfetol is administered for at least 1 year. In some embodiments, the solriamfetol is administered for at least 2 years. In some embodiments, the solriamfetol is administered for at least 10 years.

[0019] In some embodiments, the human patient is experiencing impaired cognitive functioning.

[0020] The present disclosure relates to a method, the human patient is an adult.

[0021] In some embodiments, the human patient has an age of about 18-55 years.

[0022] In some embodiments, the solriamfetol is administered as a wake -promoting agent.

[0023] In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 5.5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 6. In some embodiments, change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 6.5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7.2. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7,5. In some embodiments, change from baseline in the average post-dose Digrt Symbol Substitution Test in the Repeatable Battery' for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test m the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8.2. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test m tire Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8.5.

[0024] In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -3.5. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -3.6. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -3.7. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -4.0. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -4.2. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory’ (BC-CCI) score is at least about -4.5. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -4.7, In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -5.0. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -5.2. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -5.5.

[0025] In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0.7. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0.75. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0.8. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Seventy (PGI-S) score is at least about -0.85. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about - 0.9. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0.95. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -1. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -1.05.

[0026] In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -2.8. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -2.9. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -3.0. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -3.5. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -3.8. In some embodiments, change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -3.9. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about. -4.0. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4.3, In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4.4. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4.5. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -5.0. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -5.2. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -5.5.

[0027] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients.

[0028] In some embodiments, the solriamtetol is in a dosage form containing no other active pharmaceutical ingredients intended for the treatment of cognitive health or function, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea.

[0029] In some embodiments, no active pharmaceutical ingredients other than the solriamfetol are administered to the human patient for the treatment of cognitive health or function, excessive daytime sleepmess, or excessive daytime sleepiness associated with obstructive sleep apnea.

[0030] In some embodiments, the solriamfetol is administered in the morning.

[0031] In some embodiments, the solriamfetol is administered within one hour of awakening.

[0032] In some embodiments, the solriamfetol is administered more than 9 hours before expected bedtime

[0033] The present disclosure relates to a method of treating cognitive health or function, excessive daytime sleepiness, excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder (SWD), including administering about 140-160 mg of solriamfetol daily to a human patient in need thereof.

[0034] In some embodiments, about 150 mg of solriamfetol is administered daily to a human patient in need thereof.

[0035] The present disclosure relates to a method of treating cognitive health or function, excessive daytime sleepiness, excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder (SWD), including administering about 280-320 mg of solriamfetol daily to a human patient in need thereof.

[0036] In some embodiments, about 300 mg of solriamfetol is administered daily to a human patient in need thereof.

[0037] The present disclosure relates to a method of improving cognitive health or function. treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, wherein the method includes administering, to a human patient in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily.

[0038] In some embodiments, about 75 mg of solriamfetol is administered daily to the human patient for three days, and then about 150 mg of solriamfetol is administered daily to a human patient.

[0039] The present disclosure relates to a method of improving cognitive health or function, including treating disorders associated with cognitive health or function and related conditions, such as, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, wherein the method includes administering, to a human patient in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily for four days, and then administering 280-320 mg of solriamfetol daily.

[0040] In some embodiments, about 75 mg of solriamfetol is administered daily to the human patient for three days, and then about 150 mg of solriamfetol is administered daily to the human patient tor tour days, and then about 300 mg of solriamfetol is administered daily to a human patient.

[0041] These and other aspects of the disclosure are set forth in more detail in the description below.

[0042] BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG. 1 shows the CONSORT flowchart for the study in some embodiments.

[0044] FIG. 2A shows a study design of treatment diagram in some embodiments. FIG. 2B shows a detailed clinical visit structure in some embodiments.

[0045] FIG. 3A shows overall change from baseline in DSST RBANS score in some embodiments.

[0046] FIG. 3B shows change from baseline in DSST RBANS Score by time point in some embodiments.

[0047] FIG. 4 show's change from baseline in overall BC-CCI score in some embodiments.

[0048] FIG. 5 show's overall change from baseline in PGI-S score in some embodiments.

[0049] FIG. 6. shows overall change from baseline in ESS Score (ESS, Epworth Sleepmess Scale; LS, least squares; SE, standard error. **P<0.01).

[0050] DETAILED DESCRIPTION llns disclosure should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. In addition, any references cited herein are incorporated by reference in their entireties.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art to which this disclosure belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. All publications, patent applications, patents, patent publications and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented.

[0052] Unless the context indicates otherwise, it is specifically intended that the various features described herein can be used in any combination.

[0053] Moreover, the present disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted.

[0054] To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. As used in the description and the appended claims, the singular forms “a,” an." and

[0055] “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0056] Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0057] The term “about,” as used herein when referring to a measurable value is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.

[0058] The terms “comprise,” “comprises,” and “comprising” as used herein, specify the presence of the stated 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.

[0059] As used herein, the transitional phrase “consisting essentially of means that the scope of a claim is to be interpreted to encompass the specified materials or steps recited in the claim and those that do not materially affect the basic and novel characterstic(s) of what is claimed. Tims, the term “consisting essentially of when used in a claim or the description is not intended to be interpreted to be equivalent to “comprising.”

[0060] The term “therapeutically effective amount” or “effective amount,” as used herein, includes that amount of a composition, compound, or agent that imparts a modulating effect, which, for example, can be a beneficial effect, to a subject afflicted with a disorder, disease or illness, including improvement in the condition of the subject (e.g., in one or more symptoms), delay or reduction in the progression of the condition, prevention or delay of the onset of the disorder, and / or change in clinical parameters, disease or illness, etc., as would be well known in the art. For example, a therapeutically effective amount or effective amount can include the amount of a composition, compound, or agent that improves a condition in a subject by at least 5%, e.g., 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%.

[0061] “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) includes a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally acceptable and includes a carrier that is acceptable for veterinary and / or human pharmaceutical or therapeutic use. The terms “carrier’ or “pharmaceutically acceptable earner” can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil / water or water / oil emulsion) and / or various types of weting agents. As used herein, the term “carrier” encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.

[0062] The term “modulate,” “modulates,” or “modulation” includes to enhancement (e.g., an increase) or inhibition (e.g., a decrease) m the specified level or activity.

[0063] The term “enhance” or “increase” includes an increase in the specified parameter of at least about 1.25-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 8-fold, 10-fold, twelvefold, or even fifteen-fold and / or can be expressed in the enhancement and / or increase of a specified level and / or activity of at least about 1%, 5%, 10%, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more.

[0064] “Inhibit” or “reduce” or grammatical variations thereof as used herein includes a decrease or diminishment in the specified level or activity of at least about 1, 5, 10, 15%, 25%, 35%, 40%, 50%, 60%, 75%, 80%, 90%, 95% or more. In particular embodiments, the inhibition or reduction results in little or essentially no detectible activity (at most, an insignificant amount, e.g., less than about 10% or even 5%).

[0065] The terms “treating” or “treatment” broadly includes any kind of treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals. Grammatical variations of “administer,” “administration,” and “administering” to a subject include any route of introducing or delivering to a subject an agent. Administration can be earned out by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, mtrastemal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injections or infusion techniques), and the like. “Concurrent administration,” “administration in combination,” “simultaneous administration,” or “administered simultaneously” as used herein, means that the compounds are administered at the same point in time, overlapping in time, or one following the other. In the later case, the two compounds are administered at times sufficiently close that the results observed are indistinguishable from those achieved when the compounds are administered at the same point in time. “Systemic administration” includes the introducing or delivering to a subject an agent via a route which introduces or delivers the agent to extensive areas of the subject's body (e.g., greater than 50% of the body), for example through entrance into the circulatory' or lymph systems. By contrast, “local administration” includes the introducing or delivery' to a subject an agent via a route which introduces or delivers the agent to the area or area immediately adjacent to the point of administration and does not introduce the agent systemically in a therapeutically significant amount. For example, locally administered agents are easily detectable in the local vicinity’ of the point of administration but are undetectable or detectable at negligible amounts in distal parts of the subject's body. Administration includes self-administration and the administration by another.

[0066] “Pharmaceutically acceptable,” as used herein, includes a material that is not biologically or otherwise unacceptable, i.e., the material can be administered to an individual along with the compositions described herein, without causing unacceptable deleterious biological effects or interacting in an unacceptable manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any unacceptable degradation of the active ingredient and to minimize any unacceptable adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g.. Remington's Pharmaceutical Science; 21st ed. 2005).

[0067] “Concurrently” includes sufficiently close m time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other). In some embodiments, the administration of two or more compounds “concurrently” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two compounds can be administered in the same or different formulations or sequentially. Concurrent administration can be carried out by mixing the compounds prior to administration, or by administering the compounds in two different formulations, for example, at the same point in time but at different anatomic sites or using different routes of administration. A “subject” includes any animal that has or is suspected of having insomnia condition recited herein. Such a subject is generally a mammalian subject (e.g., a laboratory animal such as a rat, mouse, guinea pig, rabbit, primate, etc.), a farm or commercial animal (e.g., a cow, horse, goat, donkey, sheep, etc.), or a domestic animal (e.g., cat, dog, ferret, etc,). In particular embodiments, the subject is a primate subject, a non-human primate subject (e.g., a chimpanzee, baboon, monkey, gorilla, etc.) or a human. Subjects include males and / or females of any age, including neonates, juvenile, mature and geriatric subjects.

[0068] Examples of pharmaceutically acceptable salts include, but are not limited to, acetate, benzene sulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamme, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate, palmitate, panthothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0069] As used herein the term “concomitant administration” or “combination administration” includes administration of one or more compounds described herein with a second drug or agent at such time that both the compound and the second drug or agent will have a therapeutic effect. In some cases, this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e., at the same time), prior, or subsequent administration of the known drag with respect to the administration of a compound described herein. A person of skill in the art, would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compounds described herein.

[0070] “Bioavailability,” as used herein, includes the estimated area under the curve, or AUC of the active drug in systemic circulation after oral administration with a dosage form as disclosed herein when compared with the AUC of the active drag in systemic circulation after intravenous administration of the active drug. The AUC is affected by the extent to which the drug is absorbed in the GI tract. Disclosed herein are methods of treating cognitive health in human patients, such as human patients with excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea, as well as attention~deficit''hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), shift work disorder, or other sleep disorders, in human beings, such as in adult human beings or in children, by administering solriamfetol to a human being who is suffering from any of the foregoing conditions. For example, the solriamfetol may be administered in the morning, such as within one hour of awakening, or in the evening, such as within one hour before the bedtime. In some embodiments, the solriamfetol is administered more than about 1, 2, 3, 4 or 5 hours before expected bedtime.

[0071] In addition to cognitive health, the solriamfetol may be used to treat other diseases in conditions in the patient populations or circumstances described herein. For example, the solriamfetol may be used to treat major depressive disorder, pain or a neurological disorder. Examples of neurological disorders that may be treated with the solriamfetol include, but are not limited to: affective disorders, psychiatric, disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0072] Affective disorders that may be treated by the solriamfetol include, but are not limited to, depression, major depression, treatment resistant depression, treatment resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic, depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder ( ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight-gam, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho- sexual dysfunction, pseudobulbar affect, and emotional lability.

[0073] Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, 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, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and / or abnormal hormonal circadian rhythms.

[0074] Psychiatric disorders that may be treated by the solriamfetol, include, bu t 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 referred to as dementia of the Alzheimer’s type. Other neurobehavioral symptoms of Alzheimer’s disease that may be treated include disinhibition and apathy.

[0075] Agitation in Alzheimer’s disease occurs as the disease progresses. Agitation maypresent itself as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0076] 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 and afflicts an estimated 6 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050. Agitation is reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and dismhibition. Managing agitation is a priorityin AD. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD.

[0077] Neurobehavioral symptoms have been known to appear during dementia and may be treated by tire combination. Caregivers or families may feel more overwhelmed by patients' behavioral / psychological symptoms than by their cognitive impairment. Common forms of the syndrome are Alzheimer's disease, vascular dementia, dementia with Lewy bodies (abnormal aggregates of protein that develop inside nerve cells), and a group of diseases that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms that dementia patients have are similar to those of psychiatric disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsiveness, aggressiveness, compulsion, excessive sex drive, and personality disorders. Neurobehavioral symptoms such as disinhibition may also be found in other conditions such as traumatic brain injury.

[0078] Agitation in patients with Alzheimer’s disease may be assessed using the Cohen Mansfield Agitation Inventory or CMAI. The CMAI assesses various behaviors including, Hitting (including self), Kicking , Grabbing onto people. Pushing, Throwing tilings. Biting , Scratching, Spitting, Hurting self or others. Tearing things or destroying property, Making physical sexual advances. Pacing, aimless wandering, Inappropriate dress or disrobing, Trying to get to a different place. Intentional falling, Eating / drinking inappropriate substances, Handling tilings inappropriately, Hiding things, Hoarding things, Performing repetitive mannerisms. General restlessness, Screaming , Making verbal sexual advances, Cursing or verbal aggression, Repetitive sentences or questions, Strange noises (weird laughter or crying), Complaining, Negativism, Constant unwarranted request for attention or help.

[0079] Schizophrenia may be treated by the combination including positive symptoms and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that may treated include intermittent explosive disorder.

[0080] Cerebral function disorders that may be treated by the solriamfetol include, but are not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer’s type dementia, memory loss, amnesia / amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson’s disease, Lennox- Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders. Substance addiction abuse that may be treated by the solriamfetol includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drags, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and addiction to chewing tobacco.

[0081] Movement disorders that may be treated by the solriamfetol include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, 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 legs syndrome (RLS), tremor, essential tremor, and Tourette’s syndrome, and Wilson’s disease.

[0082] Dementias that may be treated by the solriamfetol include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington’s disease, Wemicke-Korsakoff Syndrome, and Pick’s disease.

[0083] Motor neuron diseases that may be treated by the solriamfetol 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 atrophies, Tay-Sach's disease, Sandoff disease, and hereditary spastic paraplegia.

[0084] Neurodegenerative diseases that may be treated the solriamfetol include, but are not limited to, Alzheimer’s disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson’s disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot- Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barre syndrome, and spastic paraplesia.

[0085] Seizure disorders that may be treated by the solriamfetol include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0086] Types of headaches that may be treated by the solriamfetol include, but are not limited to, migraine, tension, and cluster headaches.

[0087] Other neurological disorders that may be treated by the solriamfetol include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0088] In some embodiments, the solriamfetol may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment resistant depression), disorders related to memory' and cognition, schizophrenia, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Rhett’s syndrome, seizures, cough (including chronic cough), etc.

[0089] In some embodiments, the solriamfetol may be administered orally to relieve musculoskeletal pain including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, sero-negative (non- rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget’s disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc.

[0090] In some embodiments, the solriamfetol may be administered to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and complex regional pain syndrome. Arthritis includes inflammatory' joint diseases that can be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic arthropathies including Charcot’s foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

[0091] In some embodiments, the solriamfetol is used to treat chronic musculoskeletal pain.

[0092] In some embodiments, the solriamfetol may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a ty pe of inflammatory' pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in a limb that can be accompanied by edema, and autonomic, motor, and sensory changes.

[0093] In some embodiments, the solriamfetol may be administered orally to relieve neuropathic pain.

[0094] Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, pain due to multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio- or chemo-therapy associated neuropathy, etc.

[0095] In some embodiments, tire solriamfetol may be administered to relieve fibromyalgia.

[0096] In some embodiments, Solriamfetol may be used to improve cognitive health in human patients, such as human patients with excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea. In some embodiments, the human patient wherein the human patient is experiencing impaired cognitive functioning. For example, the patient may have a Digital Symbold Substitution Test (DSST) score of 90 or less, about 70 or less, about 50 or less, about 40 or less, about 30 or less, about 20 or less, about 10 or less, about 5 or less, with a score as low as e.g., 0-1 or 0-5.

[0097] In some embodiments, about 70-80 mg, about 75 mg, about 80-140-mg, about 140-

[0098] 160 mg, or about 75 mg of solriamfetol, or an equivalent molar amount of a salt of solriamfetol, such as solriamfetol hydrochloride, may be administered per day to the human patient. This may be continued as needed, e.g., for at least about 7 days, at least about 14 days, at least about 28 days, at least about 35 days, or more, such as up to 6 months, up to one year, up to two years, up to five years, up to 10 years, or longer, e.g., for a lifetime of the human patient.

[0099] The present, disclosure includes, in part, methods of using Sunosi® (referred to herein as solriamfetol (also known as (R)-2-amino-3 -phenylpropyl carbamate (APC), and previously known as JZP-210, ADX-N05, R228060, and YKP10A)).

[0100] In some embodiments, solriamfetol structure is given below as formula I:

[0101] In some embodiments, Methods for producing solriamfetol and related compounds can be found in U.S. Pat. Nos. 10,829,443, 5,955,499; 5,705,640; 6,240,532 and 5,756,817. All of the above patents and applications are hereby incorporated by reference in their entireties for all purposes.

[0102] In some embodiments, solriamfetol hydrochloride structure is given below' as formula II:

[0103] Soriamfetol hydrochloride

[0104] In some embodiments, Solriamfetol may be formulated into a tablet that contains inactive ingredients such as hydroxypropyl cellulose and / or magnesium stearate. In addition, a tablet may have film coating that contains, for example, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and / or titanium dioxide. A daily dose of solriamfetol may include about 50-100 mg (or about 0.2-4 mmol), about 100-150 mg (or about 0.4-0.7 mmol), about 150-200 mg (or about 0.7-0.9 mmol), about 200-400 mg (or about 0.8-1 .7 mmol), about 70-80 mg, about 75 mg, about 140-160 mg, about 150 mg, about 280-320 mg, or about 300 mg.

[0105] For some human patients, a dose of about 140-160 nig of solriamfetol, or about 0.6- 0.7 mmoles of solriamfetol (such as 150 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmoles, of another form of solriamfetol) is administered daily to a human being in need thereof. In some instances, it may be desirable to start at a lower dose of solriamfetol, and then increase the dose to a maintenance dose of 140-160 mg, such as 150 mg of solriamfetol. For example, about 70-80 mg of solriamfetol, or about 0.3- 0.35 mmoles of solriamfetol (such as about 75 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.33 mmoles of another form of solriamfetol) may be administered daily for three days. Following this, on the fourth day that solriamfetol is administered, a higher dose, or a maintenance dose, e.g., about 140-160 mg (such as about 150 mg of solriamfetol hydrochloride, or a molar equivalent dose of another form of solriamfetol) of soinamfetoi may be administered daily. The solriamfetol may be administered daily for as long as needed, such as 6 weeks or more.

[0106] For some human patients, a dose of about 280-32.0 mg of solriamfetol, or about 1.2- 1 .4 mmoles of solriamfetol (such as 300 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 1 .3 mmoles, of another form of solriamfetol) is administered daily to a human being in need thereof. In some instances, it may be desirable to start at a lower dose of solriamfetol, and then increase the dose to a maintenance dose of 280-320 mg. For example, about 70-80 mg of solriamfetol (such as about 75 mg of solriamfetol hydrochloride, or a molar equivalent dose of another form of solriamfetol) may be administered daily for three days. Following this, on the fourth day that solriamfetol is administered, a higher dose, e.g., about 140-160 mg (such as about 150 mg of solriamfetol hydrochloride, or a molar equivalent dose of another form of solriamfetol) of solriamfetol may be administered daily for four days (or days 4-7). This may be followed on the eighth day that solriamfetol is administered, by administration of a maintenance dose of about 280-320 mg of solriamfetol (such as 300 mg of solriamfetol hydrochloride, or a molar equivalent dose of another form of solriamfetol) per day. Tire solriamfetol may be administered daily for as long as needed, such as 6 weeks or more. Unless otherwise indicated, any reference to a compound herein, such as solriamfetol, by structure, name, or any other means, includes pharmaceutically acceptable salts, alternate solid forms, such as polymorphs, solvates, hydrates, enantiomers, tautomers, deuterium- modified forms, or any other chemical species, such as precursors, prodrugs, or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0107] Solriamfetol may be administered in a dosage form, such as a tablet, which may contain excipients, vehicles, or other ingredients, including, for example, hydroxypropyl cellulose, magnesium stearate, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, or a combination thereof.

[0108] The present disclosure relates to a method of improving cognitive function or health in human patients, such as human patients with excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea, comprising administering solriamfetol to a human patient experiencing excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea.

[0109] The present disclosure relates to a method of improving cognitive function, including administering solriamfetol to a human patient experiencing excessive daytime sleepiness associated with obstructive sleep apnea.

[0110] In some embodiments, about 70-80 mg of solriamfetol per day is administered to the human patient.

[0111] In some embodiments, about 140-160 mg of solriamfetol per day is administered to the human patient.

[0112] In some embodiments, about 150 mg of solriamfetol per day is administered to the human patient.

[0113] In some embodiments, about 280-320 mg of solriamfetol per day is administered to the human patient.

[0114] In some embodiments, about 300 mg of solriamfetol per day is administered to the human patient. In some embodiments, about 70-80 mg of solriamfetol is administered to the human patient daily for three days, and then about 140-160 mg of solriamfetol is administered to the human patient daily for fourteen days.

[0115] In some embodiments, about 75 mg of solriamfetol is administered to the human patient daily for three days, and then administering about 150 mg of solriamfetol is administered to the human patient daily for fourteen days.

[0116] In some embodiments, the solriamfetol is administered for at least 7 consecutive days. In some embodiments, the solriamfetol is administered for at least 14 consecutive days. In some embodiments, the solriamfetol is administered for at least 28 consecutive days. In some embodiments, the solriamfetol is administered for at least 35 consecutive days. In some embodiments, the solriamfetol is administered for at least 6 months. In some embodiments, the solriamfetol is administered for at least 1 year. In some embodiments, the solriamfetol is administered for at least 2 years. In some embodiments, the solriamfetol is administered for at least 10 years.

[0117] In some embodiments, the human patient is experiencing impaired cognitive functioning.

[0118] The present disclosure relates to a method, the human patient is an adult.

[0119] In some embodiments, the human patient has an age of about 18-55 years.

[0120] In some embodiments, the solriamfetol is administered as a wake-promoting agent.

[0121] In some embodiments, a human patient has an Epworth Sleepiness Scale (ESS) score that is at least about 10, at least about 12, at least about 14, or at least about 16, prior to being treated with solriamfetol.

[0122] In some embodiments, a human patient has an age-corrected scaled score that is less than about 8, less than about 7, or less than about 6 on the Coding subtest, a version of the Digit Symbol Substitution Test (DSST) in the Wechsler Adult Intelligence Scale, 4th Edition (DSST WAIS-IV), prior to being treated with solriamfetol.

[0123] In some embodiments, a human patient has score of at least about 9, at least about 1 1 , or at least about 13 on the British Columbia. Cognitive Complaints Inventory (BC-CCI), prior to being treated with solriamfetol. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 5.5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Batery' for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 6. In some embodiments, change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery- for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 6.5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery' for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7.2. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery for tlie Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7.5. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery' for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8.2. In some embodiments, change from baseline in the average post-dose Digit Symbol Substitution Test in the Repeatable Battery' for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8,5.

[0124] In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -3.5. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -3.6. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -3.7, In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -4.0. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -4.2. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -4.5, In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -4.7. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -5.0. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -5.2. In some embodiments, change from baseline in the average post-dose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -5.5.

[0125] In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0.7. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Seventy' (PGI-S) score is at least about -0.75. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0.8. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity' (PGI-S) score is at least about -0.85. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about - 0.9. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -0,95. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -1. In some embodiments, change from baseline in the average post-dose Patient Global Impression of Severity (PGI-S) score is at least about -1.05.

[0126] In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -2.8. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -2.9. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -3.0. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -3.5. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -3.8. In some embodiments, change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -3.9. In some embodiments, change from baseline m the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4,0. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4.3. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4.4. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -4.5. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -5.0. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -5.2. In some embodiments, change from baseline in the average post-dose Epworth Sleepiness Scale (ESS) score is at least about -5.5.

[0127] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmace uti cal ingredients .

[0128] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients intended for the treatment of cognitive health or function, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea.

[0129] In some embodiments, no active pharmaceutical ingredients other than the solriamfetol are administered to the human patient for the treatment of cognitive health or function, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea.

[0130] In some embodiments, the solriamfetol is administered m the morning

[0131] In some embodiments, the solriamfetol is administered within one hour of awakening.

[0132] In some embodiments, the solriamfetol is administered more than 9 hours before expected bedtime

[0133] The present disclosure relates to a method of treating cognitive health or function, excessive daytime sleepiness, excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MOD), binge eating disorder (BED), or shift work disorder (SWD), including administering about 140-160 mg of solriamfetol daily to a human patient in need thereof.

[0134] In some embodiments, about 150 mg of solriamfetol is administered daily to a human patient in need thereof. The present disclosure relates to a method of treating cognitive health or function, excessive daytime sleepiness, excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder (SWD), including administering about 280-320 mg of solriamfetol daily to a human patient in need thereof.

[0135] In some embodiments, about 300 mg of solriamfetol is administered daily to a human patient in need thereof.

[0136] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, wherein the method includes administering, to a human patient in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily.

[0137] In some embodiments, about 75 mg of solriamfetol is administered daily to the human patient for three days, and then about 150 mg of solriamfetol is administered daily to a human patient.

[0138] The present disclosure relates to a method of improving cognitive health or function, including treating a condition related to cognitive health or function or a related condition, such as excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, wherein the method includes administering, to a human patient in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily for four days, and then administering 280-320 mg of solriamfetol daily.

[0139] In some embodiments, about 75 mg of solriamfetol is administered daily to the human patient for three days, and then about 150 mg of solriamfetol is administered daily to the human patient for four days, and then about 300 mg of solriamfetol is administered daily to a human patient.

[0140] In some embodiments, the human patient to be treated for atention- deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, is an adult, such as a human patient having an age of about 18-100 years, 18-55 years, 55-100 years, or older. However, children, such as children aged 1-17 years, may also be treated.

[0141] In some embodiments, the human being to be treated has a. primary diagnosis of ADHD based on the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria established by a clinician-administered interview using the Adult ADHD Clinical Diagnostic Scale (ACDS v1 .2). In some embodiments, this the diagnosis was made at least 6 months prior to treatment.

[0142] Hie Adult ADHD Clinical Diagnostic Scale, version 1.2. for DSM-5 (ACDS) is a clinician administered retrospective assessment of childhood ADHD symptoms that also includes an expanded assessment of the adult interviewee for recent (past six months) symptoms of adult ADHD. The interview assesses the 9 symptoms of inattention, 9 symptoms of hyperactivity / impulsivity, and additional symptoms not specifically identified in the DSM- 5 but believed to be relevant to adult ADHD. The additional items generally assess difficulties with planning and organization, inattention, and mood lability.

[0143] The AISRS is a clinician -administered rating scale derived from the 18 ADHD symptoms described in the DSM-5 with prompts specifically designed to elucidate the signs of ADHD in adults. Tlie AISRS total score is the sum of the 9-item inattentive symptoms subscale and 9-item hyperactive and impulsive symptoms subscale. Each item is scored as follows: 0=none, l=mild, 2=moderate, and 3=severe. The score for each subscale can range from 0 to

[0144] 27. The total score can range from 0 to 54, with higher scores indicating greater severity.

[0145] In some embodiments, the human being has an AISRS total score that is at least about 26 when evaluated by a health care provider, at baseline, or on the day treatment starts.

[0146] The CGI-S is a clinician-rated scale that measures illness severity. The CGI-S asks the clinician to rate, based on the clinician’s total experience with this particular patient population (i.e., ADHD), the severity of a. subject’s illness, over the past 7 days up to and including the day of the assessment, using the following seven-point scale: bmormal, 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.

[0147] In some embodiments, the human being has a CGI-S score that is at least about 4 when evaluated by a health care provider, at baseline, or on the day the treatment starts. The 16-item QIDS-SR-16, a patient-rated scale, is an abbreviated version of the 30- itern Inventory of Depressive Symptomatology (IDS) and is designed to assess the severity of depressive symptoms. The QIDS-SR-16 assesses criterion symptom domains to diagnose a major depressive episode. lire QIDS-SR-16 may be used to assess the subject’s depressive symptomatology over the past 7 days. Subjects report seventy of symptoms on 10 items assessing sleep, feelings of sadness, appetite, weight change, concentration, self-regard, suicidality, general interest level, energy level, psychomotor retardation, and restlessness. Each item may be scored on a 4-point scale with a score of 0 reflecting no symptoms and a score of 3 reflecting symptoms of maximum severity.

[0148] In some embodiments, the human being has a QIDS-SR-16 score that is less than about 13 when evaluated by a health care provider, at baseline, or on the day the treatment starts.

[0149] In some embodiments, the human being has a HAM-A score that is at least about 21 when evaluated by a health care provider, at baseline, or on the day the treatment starts.

[0150] Die HAM-A is a clinician-administered scale which is used to measure tire severity of a patient’s anxiety symptoms. The HAM-A consists of 14 items, each rated on a five- point scale ranging from 0 (not present) to 4 (very severe). The highest possible score is 56, which represents the most severe form of anxiety; the lowest possible score is 0, which represents an absence of anxiety. The rating timeframe is the past 7 days.

[0151] In some embodiments, a subject, such as a human being, being treated for major depressive disorder receives a daily dose of about 140-160 mg of solriamfetol, or about 0.6- 0.7 mmoles of solriamfetol (such as 150 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmoles, of another form of solriamfetol) according to a manner and / or schedule described herein.

[0152] In some embodiments, a subject, such as a human being, being treated for major depressive disorder receives a daily dose of about 280-320 mg of solriamfetol, or about 1.2- 1.4 mmoles of solriamfetol (such as 300 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 1.3 mmoles, of another form of solriamfetol), according to a manner and / or schedule described herein. A binge is eating, in a discrete period of time (e.g., within any 2-hour period), an amount of food that is definitely larger than most people would eat during a similar period of time and under similar circumstances. A binge may also include a lack of control over eating during the episode (e.g., a feeling that one cannot stop eating or control what or how much one is eating). Binge eating includes eating in a discrete period of time an amount of food larger than most people would eat in a similar amount of time under similar circumstances and a send of lack of control over eating, Bing eating disorder includes recurrent binge eating without appropriate compensatory'- behaviors.

[0153] A patient being treated with solriamfetol as described herein may be experiencing binge eating disorder, and may meet one or more, or all of the DSM-5 Criteria for binge eating disorder. The DSM-5 Criteria for Binge Eating Disorder include:

[0154] General presentation:

[0155] * Recurrent episodes of binge eating occurring at least once a week for 3 months

[0156] « Eating a larger amount of food than normal during a short time frame (any tw-o- hour period)

[0157] * A sense of lack of control overeating during the binge episode (feeling you can’t stop eating or control what or how much you are eating)

[0158] Binge eating episodes associated with >3 of the following:

[0159] * Eating until feeling uncomfortably full

[0160] * Eating large amounts of food when not physically' hungry-

[0161] * Eating much more rapidly than normal

[0162] ® Eating alone out of embarrassment over quantity eaten

[0163] « Feeling disgusted, depressed, ashamed, or guilty after overeating

[0164] Additional Characteristics :

[0165] ® Marked distress regarding binge eating is also present

[0166] ® Binge eating is not associated with regular inappropriate compensatory- behavior, such as purging, excessive exercise, etc.

[0167] ® Binge eating does not occur exclusively- during the course of bulimia nervosa or anorexia nervosa

[0168] Binge eating disorder is associated with: * Overeating (night eating, grazing, LOG) and weight gain

[0169] » Obesity, inchiding severe obesity (BMI >40), & obesity-related conditions

[0170] * Mood, anxiety, substance use, impulse control (e.g., ADHD) disorders

[0171] ® 80% have >1 comorbid disorder

[0172] * Reduced quality of life, impairment in functioning

[0173] » (comparable to BN), & increased health care use and costs

[0174] « Marked distress - shame, guilt, self disgust

[0175] A patient being treated with solriamfetol as described herein may meet one or more, or all of the DSM-5 Criteria for binge eating disorder, and a diagnosis may be confirmed by the Eating Disorder Examination Questionaire (EDE-Q).

[0176] In some embodiments, a subject, such as a human being, being treated for binge eating disorder receives a daily dose of about 140-160 mg of solriamfetol, or about 0.6-0.7 mmoles of solriamfetol (such as 150 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmoles, of another form of solriamfetol) according to a manner and / or schedule described herein.

[0177] In some embodiments, a subject, such as a human being, being treated for binge eating disorder receives a daily dose of about 280-320 mg of solriamfetol, or about 1.2- 1 ,4 mmoles of solriamfetol (such as 300 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 1.3 mmoles, of another form of solriamfetol), according to a manner and / or schedule described herein.

[0178] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients, such as no oilier active pharmaceutical ingredients intended for the treatment of any condition described herein. In some embodiments, no active pharmaceutical ingredients other than the solriamfetol are administered to the human being for the treatment of any condition described herein.

[0179] In some embodiments, solriamfetol may be administered to a subject, such as a human subject to treat impaired cognition that is extant to excessive daytime sleepiness associated with obstructive sleep apnea, or to improve cognition in such a subject.

[0180] In some embodiments, a subject, such as a human being, being treated for impaired cognition, or receiving solriamfetol to improve cognition, receives a daily dose of abou t 140- 160 mg of solriamfetol, or about 0.6-0.7 mmoles of solriamfetol (such as 150 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmoles, of another form of solriamfetol) according to a manner and / or schedule described herein.

[0181] In some embodiments, a subject, such as a human being, being treated for impaired cognition, or receiving solriamfetol to improve cognition, receives a daily dose of about 280- 320 mg of solriamfetol, or about 1.2-1.4 mmoles of solriamfetol (such as 300 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 1 ,3 mmoles, of another form of solriamfetol), according to a manner and / or schedule described herein.

[0182] In some embodiments, solriamfetol may be used to treat a subject, such as a human being, who is experiencing shift work disorder. Diagnostic features of shift work disorders include some or all of the following: insomnia during daytime sleep or excessive sleepiness during night work, accompanied by reduced total sleep time; a work schedule that overlaps usual sleep time; symptoms cause clinically significant distress or impairment in important areas of functioning for at least 3 months; symptoms not better explained by another disorder; and overnight and early morning work shifts (starting between 3:00 and 7:00 am) can also cause shift work disorder.

[0183] In some embodiments, a subject, such as a human being, being treated for shift work disorder receives a daily dose of about 140-160 mg of solriamfetol, or about 0.6-0.7 mmoles of solriamfetol (such as 150 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 0.65 mmoles, of another form of solriamfetol) according to a manner and / or schedule described herein.

[0184] In some embodiments, a subject, such as a human being, being treated for shift work disorder receives a daily dose of about 280-320 mg of solriamfetol, or about 1.2- 1 .4 mmoles of solriamfetol (such as 300 mg of solriamfetol hydrochloride, or a molar equivalent dose, i.e., about 1.3 mmoles, of another form of solriamfetol), according to a manner and / or schedule described herein.

[0185] For the purposes of this disclosure, the term “treat,” “treating,” or a similar term (such as “modulating”), includes cure, mitigation, treatment, or prevention of disease in man or other animals, or any other effect that would be associated with a “drug” as defined under 21 USC 321(g). For the purposes of this disclosure, an “active pharmaceutical ingredient” is a compound or substance that meets the statutory- definition of “’drug” as defined under 21 USC 321(g).

[0186] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0187] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0188] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0189] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0190] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol. In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0191] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0192] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering tlie solriamfetol.

[0193] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that tire solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0194] In some embodiments, the AISRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0195] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0196] In some embodiments, the CGI-S total score of the human being is reduced by at least I, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7, after solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0197] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol .

[0198] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0199] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0200] In some embodiments, the CGI-S total score of the human being is reduced by at least

[0201] 1, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7, after solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol .

[0202] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for tour weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0203] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0204] In some embodiments, the CGI-S total score of the human being is reduced by at least

[0205] 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100%, after solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0206] In some embodiments, the CGI-S total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0207] The Clinical Global Impression of Improvement (CGI-I) is a clinician-rated scale that measures how much the patient has improved or worsened relative to baseline. The CGI-I is rated over the past 7 days up to including the day of the assessment, compared to the baseline rating. The CGI-I uses the following seven-point scale: l=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Lower scores indicate improvement.

[0208] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0209] In some embodiments, the CGI-I total score of the human being is reduced by at least

[0210] I, at least 2, at least 3, at least 4, at least 5, up to 5, up to 6, or up to 7, after solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0211] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0212] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0213] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0214] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0215] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0216] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0217] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0218] In some embodiments, the CGI-I total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0219] The Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) is a standardized measure that captures views of an adult’s executive functions or self-regulation in his or her everyday environment. The self-report version may be used. The BRIEF-A consists of 75 items that subjects self-rate on a 3-point Likert scale (1 = behavior is never observed to 3 ~ behavior is often observed). The BRIEF-A has nine non-overlapping subscales; four of them (Inhibit, Shift, Emotional Control, Self-Monitor) combine to yield the Behavioral

[0220] Regulation Index (BRI); the remaining five (Initiate, Working Memory, Plan / Organize, Task Monitor, Organization of Materials) combine to yield the Metacognitive Index (MI). These two indices combine to yield the total score, called the Global Executive Composite (GEC) score.

[0221] Higher scores indicate greater impairment in executive functioning.

[0222] In some embodiments, the BRIEF-A total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0223] In some embodiments, the BRIEF-A total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0224] In some embodiments, the BRIEF-A total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0225] In some embodiments, the BRIEF-A total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0226] In some embodiments, the BRIEF-A total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol. lire Adult ADHD Symptom Rating Scale (ASRS) is a patient-reported outcome rating scale, with a one-week lookback period, derived from the 18 ADHD symptoms described m the DSM-5. The ASRS has shown significant correlation with the clinician administered AISRS.

[0227] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one w'eek (or on the eighth day that tire solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0228] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0229] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0230] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol .

[0231] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0232] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0233] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0234] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for tour weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0235] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0236] In some embodiments, the ASRS total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to tire ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0237] The Adult ADHD Quality of Life Scale (AAQoL) is 29-item, patient-reported, questionnaire that includes 4 domains pertaining to quality of life for adults with ADHD. The 4 domains include l .ric Productivity (1 1 items), Psychological Health (6 items), Life Outlook (7 items), and Relationships (5 items). Scores for individual items range from l=never / not at all to 5=extremely / very often. Higher scores indicate a better quality of life.

[0238] In some embodiments, the AAQOL total score of the human being is increased 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the AAQOL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0239] In some embodiments, the AAQOL, total score of the human being is increased 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the AAQOL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol .

[0240] In some embodiments, the AAQOL total score of the human being is increased 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 solriamfetol is administered daily to the patient tor two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the AAQOL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0241] In some embodiments, the AAQOL, total score of the human being is increased 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 solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the AAQOL. total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0242] In some embodiments, the AAQOL, total score of the human being is increased 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the AAQOL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0243] In some embodiments, the AAQOL total score of the human being is increased 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 solriamfetol is administered daily to the patient for three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the AAQOL, total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0244] In some embodiments, the AAQOL, total score of the human being is increased 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the AAQOL, total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0245] In some embodiments, the AAQOL total score of the human being is increased 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the AAQOL, total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0246] In some embodiments, the A AQOL, total score of the human being is increased 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the AAQoL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0247] In some embodiments, the AAQOL total score of the human being is increased 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the AAQoL, total score on the first day the solriamfetol is administered and prior to administering the solriamfetol. lire Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WP AI:GH) is a validated 6-item self-adm ini stored questionnaire that assesses the impact of disease on -work productivity by measuring time missed and work and activity impairment due to health problems. The time frame is during the past 7 days. The WPAI consists of six questions: I = currently employed; 2 = hours missed due to health problems; 3 = hours missed other reasons; 4 = hours actually worked; 5 = degree health affected productivity while -working (using a 0 to 10 Visual Analogue Scale (VAS)); and 6:::degree health affected productivity in regular unpaid activities (VAS).

[0248] In some embodiments, the WPAI total score of the human being is reduced 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 solriamfetol is administered daily to the patient for one week (or on the eighth day that the solriamfetol is administered to the patient) as compared to the WPAI total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0249] In some embodiments, the WPAI total score of the human being is reduced by at least

[0250] 10%, at least 20%, at least 30%, at least 50%, and up to 80%, up to 90%, or up to 100%, after solriamfetol is administered daily to the patient for two weeks (or on the fifteenth day that the solriamfetol is administered to the patient) as compared to the WPAI total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0251] In some embodiments, the WPAI total score of the human being is reduced 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 solriamfetol is administered daily to the patient tor three weeks (or on the twenty-second day that the solriamfetol is administered to the patient) as compared to the WPAI total score on the first day the solriamfetol is administered and prior to administering the solriamfetol. In some embodiments, the WPAI total score of the human being is reduced 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 solriamfetol is administered daily to the patient for four weeks (or on the twenty-ninth day that the solriamfetol is administered to the patient) as compared to the WPAI total score on tlie first day the solriamfetol is administered and prior to administering the solriamfetol.

[0252] In some embodiments, the WPAI total score of the human being is reduced 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 solriamfetol is administered daily to the patient for six weeks (or on the forty-third day that the solriamfetol is administered to the patient) as compared to the WPAI total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0253] In some embodiments, solriamfetol provides sustained improvement in objective cognition, reduced participants’ perceived seventy of cognitive impairment, and reduced subjective sleepiness. In some embodiments, solriamfetol is well tolerated. In some embodiments, Solriamfetol can improve cognitive function in patients with cognitive impairment associated with obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS).

[0254] The present disclosure is directed to the effect of on a cognitive function related to obstructive sleep apnea, potentially with excessive daytime sleepiness and cognitive impairment. Characterized by recurrent obstruction of the upper airway during sleep, obstructive sleep apnea (OSA) causes episodes of fragmented sleep and intermittent hypoxia and leads to excessive daytime sleepiness (EDS). Deficits in cognitive function are a troublesome symptom in patients with OSA and EDS, Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA). While positive airway pressure (PAP) can improve sleep quality and reduce hypoxic events, residual EDS persists in 10%-- 28% of PAP-treated patients. Patients with OSA and EDS may experience impaired occupational and social functioning, increased risk of workplace injuries and motor vehicle accidents, and reduced quality of life. Deficits in cognitive function are troublesome in this population, with up to 68% of patients demonstrating impairment across various cognitive domains, including memory’, attention, and executive function. The severity of EDS and cognitive impairment is not solely determined by the severity of OSA; impaired cognitive function can persist in patients despite PAP treatment. In some embodiments, current pharmacological therapeutics fortreatment of EDS can include stimulants and wake-promoting agents (WPAs). The WPA modafinil is approved in the United States (US), Canada, and Australia to improve wakefulness in some sleep disorders, including OSA and EDS, and in select European countries to treat sleepiness associated with narcolepsy. The WPA armodafinil is approved in the US and Australia to improve wakefulness in similar sleep disorders (e.g., OSA and EDS). However, it remains unclear whether modafinil or armodafinil improve cognitive function in this patient population.

[0255] Solriamfetol (Sunosi®) is a dopamine and norepinephrine reuptake inhibitor that may be used for the treatment of EDS associated with OSA (e.g., 37.5-150 mg / day) and narcolepsy (e.g., 75-150 mg / day). Solriamfetol is a Schedule IV WPA with relatively low binding affinity to dopamine and norepinephrine transporters. Solriamfetol may provide short- and long-term efficacy, including improvements in wakefulness, aspects of daily functioning, health-related quality of life, and work productivity. Solriamfetol may have activity at trace amine-associated receptor 1 (TAAR.1) and serotonin 1A receptors, and TAAR1 agonists may have beneficial effects on cognitive function. The study described herein aimed to assess whether solriamfetol improves cognitive function in participants with impaired cognition associated with OSA and EDS.

[0256] In some embodiments, Solriamfetol can be used as a wake-promoting agent.

[0257] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea. In some embodiments, about 70-80 mg, about 75 mg, about 80-140-mg, about 140-160 mg, or about 75 mg of solriamfetol, or an equivalent molar amount of a salt of solriamfetol, such as solriamfetol hydrochloride, may be administered per day to the human patient. This may be continued as needed, e.g., for at least about 7 days, at least about 14 days, at least about 28 days, at least about 35 days, or more, such as up to 6 months, up to one year, up to two years, up to five years, up to 10 years, or longer, e.g., for a lifetime of the human patient.

[0258] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea. including administering from about 100 mg to about 320 mg of solriamfetol daily to a human being in need thereof.

[0259] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, including administering from about 100 mg to about 200 mg of solriamfetol daily to a human being in need thereof.

[0260] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, including administering from about 120 mg to about 180 mg of solriamfetol daily to a human being in need thereof.

[0261] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, including administering from about 140 mg to about 160 mg of solriamfetol daily to a human being m need thereof.

[0262] In some embodiments, about 150 mg of solriamfetol is administered daily to a human being in need thereof.

[0263] The present disclosure relates to a method of improving cogniti ve health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, wherein the method includes administering, to a human being m need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily.

[0264] In some embodiments, about 75 mg of solriamfetol is administered daily to the human being for three days, and then about 150 mg of solriamfetol is administered daily to a human being. In some embodiments, about 75 mg of solriamfetol is administered daily to the human being for three days, and then about 150 mg of solriamfetol is administered daily to a human being for about 2 weeks.

[0265] The present disclosure relates to a method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, wherein the method includes administering, to a human being in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily for about 2 weeks.

[0266] In some embodiments, about 75 mg of solriamfetol is administered daily to the human being for three days, and then about 150 mg of solriamfetol is administered daily to the human being for about 2 weeks.

[0267] In some embodiments, the human being is an adult.

[0268] In some embodiments, the human being has an age of about 18-55 years.

[0269] In some embodiments, solriamefetol may be used to improve cognitive health in human patients, such as human patients with excessive daytime sleepiness, such as excessive daytime sleepiness associated with obstructive sleep apnea. In some embodiments, the human patient wherein the human patient is experiencing impaired cognitive functioning. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of 90 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 70 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 50 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 40 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 30 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 20 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 10 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score of about 5 or less. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score as low as about 0 to about 5. In some embodiments, the patient may have a Digital Symbold Substitution Test (DSST) score as low as about 0 to about 1 . In some embodiments, the solriamfetol is in a dosage form containing no other active pharmace uti cal ingredients .

[0270] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients intended for the treatment of cognitive health or function, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea.

[0271] In some embodiments, no active pharmaceutical ingredients other than the solriamfetol are administered to the human being for the treatment of cognitive health or function, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea.

[0272] In some embodiments, the solriamfetol is administered in the morning.

[0273] In some embodiments, the solriamfetol is administered within one hour of awakening.

[0274] In some embodiments, the solriamfetol is administered more than 9 hours before expected bedtime.

[0275] In some embodiments, the solriamfetol is administered daily' for 2 weeks.

[0276] In some embodiments, the solriamfetol is administered daily for more than 2 weeks.

[0277] In some embodiments, Solriamfetol improves cognitive function in patients with cognitive impairment associated with OSA and EDS. In some embodiments, administering solriamfetol may result in overall improvement in objective cognition on the Battery for the Assessment of Neuropsychological Status (DSST RBANS, DSST, Digit Symbol Substitution Test; and RBANS, Repeatable Battery' tor the Assessment of Neuropsychological Status) scores. In some embodiments, Solriamfetol can be administered for 2 weeks as the treatment period. In some embodiments, administering solriamfetol may result in overall improvement in objective cognition on the DSST RBANS scores when Solriamfetol is administered for 2 weeks as the treatment period. In some embodiments, Solriamfetol can provide improvement in cognitive function in about 2 to 8 hours after dosing. In some embodiments, administering solriamfetol may result in overall improvement in objective cognition on the DSST RBANS scores in about 2 to 8 hours after dosing. In some embodiments, the therapeutic effects of solriamfetol can be maintained throughout an 8-hour day. In some embodiments, administering solriamfetol may result in overall improvement in cognition on the British Columbia Cognitive Complaints Inventory (BC-CC1).

[0278] In some embodiments, solriamfetol can improve EDS relative to placebo. In some mbodiments, solriamfetol can improve Epworth Sleepiness Scale (ESS) scores within 1 week of treatment initiation at the dose of 75 mg / day titrated to 150 mg / day after 3 days. In some embodiments, the wake-promoting effects of solriamfetol can be maintained for up to

[0279] 52 weeks of treatment.

[0280] In some embodiments, solriamfetol can improve subjective sleepiness or objectivi measures of cognitive impairment. For example, in some embodiments, solriamfetol can improve both subjective sleepiness and objective performance.

[0281] In some embodiments, solriamfetol can improve DSST RBANS scores with an effect size of 0.37. In some embodiments, solriamfetol can improve cognition in domains related to memory, processing speed, and attention in patients with cognitive impairment associated with OSA and EDS.

[0282] Solriamfetol is a dopamine and norepinephrine reuptake inhibitor, and increasing noradrenergic and dopaminergic activity may mediate some pro-cognitive effects. In some embodiments, solriamfetol can be an agonist of TA ARI and serotonin 1 A receptors, which is unique to solriamfetol compared with modafinil and bupropion.

[0283] In some embodiments, solriamfetol can improve cognitive function in participants with cognitive impairment associated with OSA and EDS. In some embodiments, solriamfetol can improve EDS in patients with OSA. In some embodiments, solriamfetol can have a favorable safety profile. In some embodiments, solriamfetol can improve cognitive function in patients with cognitive impairment associated with OSA and EDS.

[0284] In some embodiments, about 150 mg of solriamfetol can be administered per day. In some embodiments, about 150 mg of solriamfetol can be administered per day for about 2 weeks.

[0285] EXAMPLES

[0286] EXAMPLE 1. PHASE 4 CLINICAL TRIAL TO OF THE EFFECT OF THE WAKEPROMOTING AGENT SOLRIAMFETOL ON COGNITIVE JUNCTION

[0287] Study Design SHARP was a phase IV randomized, double-blind, placebo-controlled, crossover trial that evaluated the efficacy and safety of solriamfetol in participants with cognitive impairment associated with EDS and OS A (NCT04789174; EudraCT: 2020-004243-92). The study was conducted from May 2021 to September 2022 at 28 sites in North America (US, Canada) and Europe (United Kingdom, Netherlands, Spain, Italy) (e-Appendix 1) and in accordance with the Declaration of Helsinki and the International Conference on

[0288] Harmonization Guidelines. Study enrollment ended following a change in sponsor in May

[0289] 2022. Prior to database lock, the study protocol was amended August 2022, changing the primary DSST-RBANS endpoint from the average of the 2- and 4-hour post-dose assessments to the average of the 2-, 4-, 6-, and 8-hour post-dose assessments.

[0290] Participants

[0291] Participants were 18- to 65-year-old males and females diagnosed with OSA per the

[0292] International Classification of Sleep Disorders 3rd Edition criteria. Associated EDS was defined as anEpworth Sleepiness Scale (ESS) score >10 at screening and baseline. Impaired cognitive function was defined as an age-corrected scaled score <8 on the Coding subtest, a version of the Digit Symbol Substitution Test (DSST) in the Wechsler Adult Intelligence Scale, 4th Edition (DSST WAIS-IV) at screening and a score >9 on the British Columbia Cognitive Complaints Inventory (BC-CCI) at screening and baseline.

[0293] FIG. 1 shows the CONSORT flowchart for the study in some embodiments. Participants were included if they were consistent in the number of hours of PAP use on >5 nights / week for >1 month prior to baseline: had no current PAP therapy for >1 month prior to baseline but a history of attempted PAP use for >1 month with >1 adjustments intended to optimize therapy; or a history of surgical intervention intended to treat OSA symptoms. Usual bedtime later than 1:00 AM; shift work; use of over-the-counter or prescription medications that could affect EDS; any contraindication for solriamfetol; use of PAP machine without downloadable adherence data; diagnosis of a sleep disorder other than OSA; positive urine drug screen during the study; excessive caffeine use (>600 mg / day) I week prior to screening or anticipated during the study; and history or current diagnosis of any clinically relevant medical, behavioral, or psychiatric disorder associated with impaired cognitive function were exclusionary. Table 1. Summary of Reasons for Screen Failures

[0294] This study was designed for an intra-participant comparison between solriamfetol and placebo on cognitive function. Because excessive daytime sleepiness (EDS) associated with obstructive sleep apnea (OSA) and cognitive impairment are chronic conditions, they are amenable to evaluation with a crossover study design. Solriamfetol is meant to alleviate symptoms typical of the condition. A crossover study design achieves higher statistical power and requires fewer participants to evaluate hypotheses relative to a parallel study design.

[0295] The washout period of 1 week was considered sufficient to avoid carryover effects. Solriamfetol is rapidly absorbed with a mean elimination half-life of approximately 6 to 7 hours, suggesting that at 1 week after the final dose of solriamfetol, plasma levels would be negligible. Further, previous findings in patients with narcolepsy treated with solriamfetol in a crossover study design that did not include a washout period between treatments suggest no carry' over effects.

[0296] Participants were excluded from the study if they had a history of regular THC use. In addition, participants who used any over the counter (OTC) or prescription medications that could affect the evaluation of excessive daytime sleepiness within a time period prior to the baseline visit corresponding to at least 5 half-lives of the drug(s) or planned use of such dmg(s) at some point throughout the duration of the study were excluded. Examples include OTC sleep aids, stimulants, sodium oxybate, pemoline, pitolisant, bupropion, trazodone, vortioxetine, duloxetine, tricyclic antidepressants, hypnotics, benzodiazepines, pseudoephedrine, barbiturates, and opioids. In addition, patients with a history or presence of any other clinically relevant medical, behavioral, or psychiatric disorder other than OSA that is associated with an impact on cognitive function were excluded, including history' or presence of neurodegenerative condition (eg, mild cognitive impairment due to Alzheimer’s), autism, vascular dementia, active suicidal ideation, that could affect the safety of the participant or interfere with study efficacy, safety, conduct or the ability of the participant to complete the trial based on the judgment of the investigator; the presence of bipolar disorder, bipolar related disorders, schizophrenia, schizophrenia spectrum disorders, or other psychotic disorders according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria were also exclusionary'.

[0297] Randomization and Al location Procedures

[0298] A computer-generated list of random numbers used to allocate participants was created by Endpoint Clinical. Participants v / ere randomly assigned to 1 of 2 treatment sequences using random block sizes of 4. Randomization occurred centrally through the use of an interactive response technology (IRT) system; randomization numbers could not be reused. Specifications as well as dummy and randomization lists were reviewed and approved by Jazz Pharmaceuticals.

[0299] Treatment

[0300] At the baseline visit, participants were randomized 1: 1 to treatment with oral solriamfetol (75 mg / day' for 3 days, then 150 mg / day) or matching placebo each morning for 2 weeks. After a 1-week washout period, participants crossed over to receive the opposite treatment for 2 weeks. FIG. 2A shows a study design of treatment diagram in some embodiments.

[0301] Assessments

[0302] Objective cognition was assessed with the Coding subtest, a variation of the DSST in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS), an objective measure of cognitive function sensitive to pharmacologic intervention. Based on the DSST WAIS-IV, the DSST RBANS is a symbol-digit test that measures attention, processing speed, and executive functions (eg, working memory'); participants were asked to match symbols to numbers in accordance with a key. To avoid practice effects, a practice test followed by rotating versions of the DSST RBANS were administered during screening and each assessment visit (Supplemental Material). The DSST RBANS score was the number of correct symbol-digit pairings within 90 seconds.

[0303] Subjective cognition was assessed with the BC-CCI, a validated 6-item questionnaire that assessed self-reported problems with concentration, memory', expressing thoughts, word finding, thinking, and solving problems. Each item had four response options and was scored from 0 to 3, with higher scores indicating greater cognitive impairment. The BC-CCI score was the total score across items.

[0304] Perceived severity of problems with concentration, memory, and thinking skills was measured with the Patient Global Impression of Severity (PGI-S). Participants rated severity of problem over the last week from ‘"none” (0) to “ven' severe” (4).

[0305] EDS was assessed with the ESS, a validated 8-item, self-report questionnaire that measures the likelihood of falling asleep in various activities. Each item had four response options and was scored 0-3, with higher scores indicating greater EDS. Tire ESS score was tlie total score across items. FIG. 2B shows a detailed clinical visit structure in some embodiments (AEs, adverse events; BC-CCI, British Columbia Cognitive Complaints Inventory; Con Meds, concomitant medications; Columbia-Suicide Severity Rating Scale (C- SSRS), Columbia-Suicide Seventy Rating Scale; DSST, Digit Symbol Substitution Test; DSST RBANS, the Coding subtest, a variation of the DSST in the Repeatable Battery for the Assessment of Neuropsychological Status; DSST WAIS-IV, the Coding subtest, a version of the DSST in the Wechsler Adult Intelligence Scale, 4th Edition; EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; PGI-S, Patient Global Impression of Severity; WAIS-IV, Wechsler Adult Intelligence Scale, 4th Edition).

[0306] Outcomes

[0307] The primary efficacy endpoint was change from baseline to the end of each treatment period in tire DSST RBANS scores averaged over the 2-, 4-, 6-, and 8-hour post-dose timepoints. A key secondary endpoint was the change from baseline to the end of each treatment period in BC-CCI scores. Other secondary' endpoints included change from baseline to the end of each treatment period for the ESS and PGI-S and for the timepoint-specific DSST RBANS scores.

[0308] Safety and tolerability were assessed based on treatment-emergent adverse events (TEAEs) and vital signs. TEAEs were defined as any adverse event that started between treatment initiation (placebo or solri am fetal) up to 7 days after the last dose of study drug in each treatment period. Suicidal ideation was evaluated at screening, baseline, and each study visit using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0309] Assessments — Additional Information on DSST RBANS

[0310] The DSST is a validated, widely used assessment known for brevity, reliability, and generalizability across languages, cultures, and educational levels, and provides an objective means of evaluating cognitive deficits in patients with cognitive impairment. Unlike the DSST WAIS-IV, the DSST RBANS is unique in its capacity to avoid learning effect following repeated testing, malting it amenable for testing every 2. hours. In this context, multiple versions of the DSST RBANs were administered during clinical visits at baseline and at the end of each treatment period; patients were given an initial practice test followed by a different version of the DSST RBANS every 2 hours over the 8-hour visit. Thus, learning effect was minimized m 3 ways: (1) initial learning effect was saturated by repeated exposure to the DSST RBANS during screening visit, (2) within-day learning effect was minimized using a different order of 4 rotating versions of the DSST RBANS at each study visit after screening, and (3) across-day learning effect was minimized with an initial practice test upon arrival at each study visit after screening.

[0311] Participants were asked to consume the same amount of caffeine and / or tobacco / mcotine during each visit, and caffeine was limited to 200 mg before 9 AM. Tobacco and nicotine were disallowed within I hour of cognitive assessments.

[0312] Outcomes

[0313] The primary efficacy endpoint was change from baseline to the end of each treatment period in the DSST RBANS scores averaged over the 2-, 4-, 6-, and 8-hour post-dose timepoints. A key secondary endpoint was the change from baseline to the end of each treatment period in BC-CCI scores. Other secondary' endpoints included change from baseline to the end of each treatment period for the ESS and PGI-S and for the timepoint-specific DSST RBANS scores.

[0314] Safety and tolerability were assessed based on treatment-emergent adverse events

[0315] (TEAEs) and vital signs. TEAEs were defined as any adverse event that started between treatment initiation (placebo or solriamfetol) up to 7 days after the last dose of study drug in each treatment period. Suicidal ideation was evaluated at screening, baseline, and each study visit using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0316] Statistical Analysis and Power Calculation

[0317] Demographics, baseline clinical characteristics, and safety outcomes were summarized descriptively and were analyzed for the safety population (randomized participants who received >1 dose of the study drug). Efficacy outcomes were analyzed for the modified intent-to-treat population, (participants who received >1 dose of the study drug and had DSST RBANS scores at baseline and from at least 1 treatment period).

[0318] As the primary endpoint, average post-dose DSST RBANS scores were analyzed with a repeated-measures regression model estimating treatment effects with baseline as a covariate and controlling for treatment period, treatment sequence, and subject. The treatment effect and the two-sided 95% confidence interval (CI) of the treatment difference (solriamfetol - placebo) are presented. Period and sequence effects were evaluated; carryover effect was not examined, considering the duration of the washout period. A secondary analysis was conducted on the DSST RBANS scores of each individual time point (2, 4, 6, and 8 hours post-dose).

[0319] A fixed hierarchical testing sequence controlling for multiplicity was employed for the secondary endpoints, focusing on change in score from baseline to the end of each treatment period in 1) BC-CCI, 2) PGI-S, and 3) ESS. The testing sequence was stopped when the two-sided P value was no longer significant (ie, P>0.05). Results are presented as least squares (LS) mean change from baseline and its standard error (SE). Effect sizes (Cohen’s d) were determined for the change from baseline to the end of each treatment period in DSST RBANS, BC-CCI, PGI-S, and ESS scores.

[0320] Exploratory analyses included Pearson correlation between change from baseline to end of treatment period, stratified by treatment condition and controlling for treatment sequence, in ESS and DSST RBANS scores, ESS and BC-CCI scores, and ESS and PGI-S scores. lire original sample size determination was based on a >3.0 point mean difference between solriamfetol and placebo in the change from baseline to the end of each double-blind treatment period in DSST RBANS scores at 2 and 4 hours post-dose, with a Standard Deviation (SD) <9.0 points. This was informed by previous randomized, parallel, placebo- controlled trials of vortioxetine; additional details on the original primary outcome prior to study amendment are presented in the present disclosure. Because the primary efficacy outcome for the present study was the average of DSST RBANS scores at 2, 4, 6, and 8 hours post-dose (ie, twice as many time points), an overall SD of 6.9 points was assumed. Using a two-group t-test for the crossover design of the present study and assuming a correlation of 0.5 between treatment periods, the sample size needed to detect an equivalent effect size with at least 90% power at a two-sided type I error rate of 0.05 would be 29 participants per treatment sequence, or 58 participants overall.

[0321] Statistical Analysis of Original Primary Endpoint

[0322] As the primary endpoint prior to study amendment, DSST RBANS were averaged over 2 and 4 hours post-dose and analyzed using a mixed model for repeated measures; the model included sequence, treatment (solriamfetol and placebo), period as fixed effects, and the baseline average of the scores as the co variate. Subject within sequence was included as a repeated measurement; covariances were unstructured. A sensitivity analysis was conducted using the same model with the addition of actual sequence. The treatment effect and the two- sided 95% confidence interval (CI) of the treatment difference (solriamfetol - placebo) is presented in Table 2 below.

[0323] Table 2. Change from Baseline in DSST RBANS Score Using Average Over 2 to 4 Hour Post-Dose Assessments

[0324] Power Calculation Prior to Protocol. A mendment Tire original primary outcome examined the mean difference between solriamfetol and placebo in the change from baseline to the end of each double-blind treatment period in DSST RBANS scores at 2 and 4 hours post-dose. A sample size of 49 participants per treatment sequence for a total sample size of 98 will provide 90% power to detect a difference of 3 points in means for the change from baseline to week 2 on the DSST RBANS scores between solriamfetol and placebo, assuming a standard deviation (SD) of 9 points in the change in DSST; the cross over analysis of variance (ANOVA) root mean squared error (RMSE) is 6.36. The sample size estimates are based on the results from randomized, parallel, placebo-controlled trials of vortioxetme that examined DSST outcomes in patients with major depressive disorder; one study included participants with self-reported cognitive decline, and both had similar DSST scores at baseline. The change from baseline to week 8 resulted in an estimated delta on DSST performance score of 1.8-4.3 (average 3.4) and SD of 6.6-8.6. In addition, a crossover study was referenced and included 5 dosages of MK-0249, modafinil 200 mg, and placebo; each treatment period was 2 weeks, and the RMSEs were estimated from 4.4-5.7. Here, RMSE was increased to 6.36 to account for uncertainty in sample size assumptions. A 1 -sided significance level of 0.025 using a 2-group t-test (crossover AM OVA) was used in the sample size calculation. Assuming a correlation of 0.5 between periods on DSST, a delta of 3.0, a standard deviation of 9, and a 15% dropout rate, a total of 116 (58 participants per treatment sequence) were required for randomization. Research protocols and amendments were approved by each institution’s ethics committee or institutional review board. All participants provided written informed consent.

[0325] EXAMPLE 2. RESULTS - PARTICIPANT POPULATION

[0326] Participant Population

[0327] Of the 173 participants screened for this study, 59 were enrolled and randomly assigned to one of the two treatment sequences. Referring to FIG. 1 , the safety population included 59 (solriamfetol / placebo, n:::3(); placebo / solriamfetol, n:::29) participants. Two participants (one in each treatment sequence) did not complete the study; one completed the first period efficacy visit, resulting in 58 participants in the modified intent-to-treat population with data available for analysis of efficacy outcomes. Baseline demographic and clinical characteristics were similar between treatment groups, including PAP use (e.g., see Table 1 below). Overall, PAP was used by 42 (71 .2%) participants, most of whom (n=34) were adherent users (defined as >4 hours of PAP use per night for >70% of nights in any given time frame). Mean -.t standard deviation (SD) baseline PAP use per night among all users was 6.3 ± 2.5 hours.

[0328] Table 1. Baseline Demographic and Clinical Characteristics

[0329] EXAMPLE 3. RESULTS - EFFICACY AND SAFETY

[0330] FIG. 3 A shows overall change from baseline in DSST RBANS score in some embodiments. Referring to FIG. 3A, the primary endpoint of change from baseline to the end of treatment in average DSST RBANS scores showed a statistically significant difference between solriamfetol and placebo. Mean (SE) change from baseline after solriamfetol treatment (6.49 [0.65]) was significantly greater (ie, improved) compared with placebo (4.74 [0.65]); the mean difference (solriamfetol vs placebo) was 1 .75 (95% CI: 0.46, 3.04; P=0.009; effect size: <A:().37). Post hoc analysis of the change in average of the 2- and 4-hour DSST RBAN S (original primary endpoint prior to study amendment) was consistent with the current primary’ endpoint. (See, e.g., Table 2).

[0331] FIG. 3B show's change from baseline in DSST RBANS Score by time point in some embodiments (L.S, least squares; DSST, Digit Symbol Substitution Test; DSST RBANS, the Coding subtest, a variation of the DSST in the Repeatable Batten' for the Assessment of Neuropsychological Status; SE, standard error. *P<0.05, **P<0.01.). Referring to FIG. 3B, When evaluated at each 2-hour time point, DSST RB ANS scores significantly improved with solriamfetol relative to placebo at 2, 6, and 8 hours after dosing. Mean differences at 2, 4, 6, and 8 hours were 1.91 (95% CI: 0.16, 3.65; P ==0.033), 1.38 (95% CI: -0.22, 2,97; P-0.089), 2.33 (95% CI: 0.78, 3.88; P-0.004), and 1.58 (95% CI: 0.23. 2.93; P-0.022), respectively. There was no significant effect of period (P-0.274) or sequence (P-0,915),

[0332] FIG. 4 shows change from baseline in overall BC-CCI score in some embodiments (BC-CCI, British Columbia Cognitive Complaints Inventory; LS, least squares; SE, standard error. **P<0.01.). Referring to FIG. 4, The mean (SE) change from baseline to end of each treatment period on the BC-CCI showed a significantly greater decrease (ie, improvement) of -4.7 (0.48) after solriamfetol treatment compared with -3.1 (0.48) after placebo, with a mean difference of -1.58 (95% CI: -2.53, -0.63; P-0.002); effect size: <7=0.45.

[0333] FIG. 5 shows overall change from baseline in PGI-S score in some embodiments (LS, least squares; PGI-S, Patient Global Impression of Severity; SE, standard error. *P<0.05). Referring to FIG. 5, the mean change from baseline on the PGI-S showed a significantly greater decrease (ie, improvement) of -0.90 (0.10) after solriamfetol treatment compared with -0.61 (0.10) after placebo, with a mean difference of -0.29 (95% CI: -0.57, -0.02; P-0.034; effect size: J-0,2.9).

[0334] FIG. 6. shows overall change from baseline in ESS Score (ESS, Epworth Sleepiness Scale; LS, least squares; SE, standard error. **P<0.01). Referring to FIG. 6, Solriamfetol significantly improved EDS as measured by ESS scores. The mean (SE) change from baseline to end of solriamfetol treatment was —4.41 (0.57), compared with —2.31 (0.56) for placebo; the mean difference was -2.10 (95% CI: -3.51, -0.68; P-0.004; effect size: <7=0.40).

[0335] The change from baseline to the end of each treatment period in ESS scores had statistically significant correlations, controlling for treatment sequence, with day-average DSSTRBANS scores (solriamfetol , BC-CCI scores (solriamfetol, r=0.54, P<0.001; placebo, r=0,60, P<0.001), and PGI-S scores (solriamfetol, r=0.56, P<0.001 ; placebo, r=0.46, P<0.001). In all cases, a greater drop in ESS corresponded with a greater improvement in cognitive outcomes. There were no deaths, serious TEAEs, or TEAEs that led to discontinuation of the study. Overall, 16 of 59 patients (27.1%) in the safety population experienced any TEAE throughout the study; all were mild or moderate in severity. The incidence of any TEAE with solriarnfetol (19.0%) was higher than with placebo (10.3%; see, e.g., Table 2 below). The most common TEAEs with solriarnfetol were nausea (7%) and anxiety (3%). No participants had suicidal thoughts or behaviors as determined by the C-SSRS.

[0336] Table 2. Treatment-Emergent Adverse Events g y p

[0337] The change from baseline in diastolic blood pressure was greater with solriarnfetol (LS mean [SEj: 2.0 [0.6] mmHg, SD: 4.7 mmHg) than with placebo (0.5 [0.6] mmHg, SD: 4.6 mmHg, P=0.033). There were no significant differences between solriamfetol and placebo in change from baseline in systolic blood pressure (solriarnfetol: 1.0 [0.8] mmHg, SD: 6.3 mmHg; placebo: pulse rate (solriarnfetol: 0.1 [1.0] bpm, SD: 7.1 bpm; placebo: -0.6 [1.0 bpm], SD: 7.1 bpm, P=0.396), or weight (solriamfetol: 0.03 [0.19] kg, SD: 1.40 kg; placebo: 0.27 [0.19] kg, SD: 1.38 kg, P-0.252).

[0338] DISCUSSION

[0339] Solriamfetol unexpectedly and significantly improved cognitive function in patients with cognitive impairment associated with OSA and EDS. The overall improvement in objective cognition on the DSST RBANS scores demonstrated efficacy of solriamfetol over placebo over a 2-week treatment period. Results from the analysis of the original primary endpoint were similar. This unexpected effect was generally consistent overtime (2 to 8 hours after dosing), indicating the therapeutic effects of solriamfetol were maintained throughout an 8-hour day. Participants reported tin overall improvement in subjective cognitive function with solriamfetol on the BC-CCI. Taken together, these results indicate solriamfetoTs efficacy over placebo in both objective and subjective measures of cognitive function.

[0340] Solriamfetol improved EDS relative to placebo. This is consistent with findings from the solriamfetol pivotal trial, in which solriamfetol improved ESS scores within 1 week of treatment initiation at the same dose as this study (75 mg / day titrated to 150 mg / day after 3 days). A long-term open-label extension study demonstrated that the wake-promoting effects of solriamfetol were maintained for up to 52 weeks of treatment.

[0341] Research in patients with OSA, with and without PAP treatment, has revealed that dissociations between subjective sleepiness and objective measures of cognitive impairment are common m this population. While solriamfetol improved both subjective sleepiness and objective performance outcomes compared with placebo, these effects may be distinct. This possibility is supported by the relatively strong correlations observed between the subjective outcomes and more modest correlations for subjective outcomes versus objective DSST RBANS performance. Preclinical evidence showing that solriamfetol may be a TAAR1 agonist, with anticipated beneficial effects on cognitive function, is also consistent with the idea that solriamfetol may mitigate cognitive impairment in OSA with EDS beyond its wakepromoting effect.

[0342] The tolerability of solriamfetol in this study was consistent with its known safety profile. There were no serious TEAEs, and no participants withdrew from the study due to TEAEs related to the study drug. The most common TEAEs were nausea and anxiety. While this study had a short duration of solriamfetol exposure, the long-term safety and tolerability of solriamfetol in patients with EDS associated with OSA has been demonstrated. In a 52- week open-label study (n=417 patients with OSA), common TEAEs were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory’ infection; most TEAEs were mild or moderate in severity. In addition, there was no evidence of tolerance, rebound hypersomnia, or withdrawal after sudden discontinuation of long-term solriamfetol use.

[0343] In murine models of cognitive impairment associated with OSA and EDS, significant improvements in cognitive function (ie, explicit memory) and / or anxiety-like behavior were observed with solriamfetol (200 mg / kg) but not modafinil (200 mg / kg). Human studies of WPAs other than solriamfetol have shown mixed results on cognitive measures, including the Cognitive Drug Research battery-, in patients with OSA and EDS. Here, solriamfetol improved DSST RD ANS scores with an effect size of 0.37. For comparison, an effect size of 0.2.5 led to the conclusion that vortioxetine significantly improved DSST performance compared with placebo in major depressive disorder. When combined wdth the clinical utility of DSST outcomes related to effect sizes in similar populations, the present study suggests that solriamfetol meaningfully improves cognition in domains related to memory, processing speed, and attention in patients with cognitive impairment associated with OSA and EDS.

[0344] The precise mechanism of action of solriamfetol’ s wake-promoting properties is not clear. Solriamfetol is a dopamine and norepinephrine reuptake inhibitor, and increasing noradrenergic and dopaminergic activity may mediate some pro-cognitive effects. Preclinical evidence show's solriamfetol is an agonist of TA ARI and serotonin 1A receptors, which is unique to solriamfetol compared with modafinil and bupropion. TAAR1 has been identified as a potential therapeutic target for several psychiatric disorders, and preclinical studies suggest it may impact cognitive function. More research is needed to better understand the role of these mechanisms on cognitive function in patients with OSA and EDS.

[0345] One limitation of this study was the 5-week study duration, which precludes conclusions on sustained effects on cognitive function over longer durations. The moderate sample size drawn from a predominantly older (mean age 52.2), male (64.4%), and Caucasian (72.9%) population limits generalizability of the results. In addition, the study design did not include direct comparisons with other WPAs. Research is needed to evaluate cognitive improvements from solriamfetol compared with oilier WPAs. A strength of this study was the randomized, placebo-controlled, double-blind, repeated-measures, crossover design, in which participants served as their own controls. This design reduced confounders and was efficient in terms of statistical power. Furthermore, the study included both objective and subjective measure of cognitive function. Follow-up studies should evaluate additional cognitive endpoints. INTERPRETATION

[0346] Thss study found that solriamfetol, compared with placebo, improved cognitive function in participants with cognitive impairment associated with OSA and EDS. Hie results of the DSST RBANS showed that solriamfetol improved cognition objectively. Participants perceived an improvement in cognitive function and EDS, as indicated by the results of the BC-CCI and ESS. Solriamfetol was well tolerated in this study. These results support previous findings that solriamfetol improves EDS in patients with OSA, has a favorable safety profile, and has the potential to improve cognitive function in patients with cognitive impairment associated with OSA and EDS.

Claims

CLAIMS1 . A method of improving cognitive function, comprising administering solriamfetol to a human patient experiencing excessive daytime sleepiness associated with obstructive sleep apnea.

2. The method of claim 1, wherein about 70-80 mg of solriamfetol per day is administered to the human patient.

3. The method of claim 1, wherein about 140-160 mg of solriamfetol per day is administered to the human patient.

4. Hie method of claim 1, wherein about 150 mg of solriamfetol per day is administered to the human patient.

5. The method of claim 1, wherein about 280-320 mg of solriamfetol per day is administered to the human patient.

6. The method of claim 1, wherein about 300 mg of solriamfetol per day is administered to the human patient.

7. The method of claim 1 , wherein about 70-80 mg of solriamfetol is administered to the human patient daily for three days, and then administering about 140-160 mg of solriamfetol is administered to the human patient daily for fourteen days.

8. The method of claim 1, wherein about 75 mg of solriamfetol is administered to the human patient daily for three days, and then administering about 150 nig of solriamfetol is administered to the human patient daily for fourteen days.

9. The method of any of claims 1-6, wherein the solriamfetol is administered for at least 7 consecutive days.

10. The method of any of claims 1-6, wherein the solriamfetol is administered for at least 14 consecutive days.11 . The method of any of claims 1-6, wherein the solriamfetol is administered for at least 28 consecutive days.

12. The method of any of claims 1-6, wherein the solriamfetol is administered for at least 35 consecutive days.

13. The method of any of claims 1-6, wherein the solriamfetol is administered for at least6 months.

14. The method of any of claims 1-6, wherein the solriamfetol is administered for at least1 year.

15. The method of any of claims 1-6, wherein the solriamfetol is administered for at least2 years.

16. The method of any of claims 1-6, wherein the solriamfetol is administered for at least 10 years.

17. The method of any of claims 1-16, wherein tire human patient is experiencing impaired cognitive functioning.

18. lire method of any of claims 1-17, the human patient is an adult.

19. The method of claim 18, wherein the human patient has an age of about 18-55 years.

20. The method of any of claims 1-19, wherein the solriamfetol is administered as a wakepromoting agent.

21. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test m the Repeatable Batten’ for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 5.

22. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 5.5.

23. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Batery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 6.

24. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Batten- for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 6.5.

25. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7.

26. The method of any of claims 1 -20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7.2.

27. The method of any of clasms 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 7,5.

28. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8.

29. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8.2.

30. The method of any of claims 1-20, wherein change from baseline in the average postdose Digit Symbol Substitution Test in the Repeatable Batten,’ for the Assessment of Neuropsychological Status (DSST RBANS) score is at least about 8.5.

31. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -3.5.

32. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least, about -3.6.

33. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -3.7.

34. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -4.0.

35. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -4.2.

36. The method of any of claims 1 -30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -4.5.

37. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory' (BC-CCI) score is at least about -4.7.

38. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inv entory (BC-CCI) score is at least about -5.0.

39. The method of any of claims 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory’ (BC-CCI) score is at least about -5.2.

40. The method of any of clasms 1-30, wherein change from baseline in the average postdose British Columbia Cognitive Complaints Inventory (BC-CCI) score is at least about -5.5.

41. The method of any of claims 1 -40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -0.7.

42. The method of any of claims 1-40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -0.75.

43. The method of any of claims 1-40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -0.8.

44. The method of any of claims 1-40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -0,85.

45. The method of any of claims 1-40, wherein change from baseline in the average postdose Patient Global Impression of Severity' (PGI-S) score is at least about -0.9.

46. The method of any of claims 1 -40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -0.95.

47. The method of any of claims 1-40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -1.

48. The method of any of claims 1 -40, wherein change from baseline in the average postdose Patient Global Impression of Severity (PGI-S) score is at least about -1 .05.

49. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -2.8.

50. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -2.9,51. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -3.0.

52. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -3.5.

53. The method of any of claims 1 -48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -3.8.

54. The method of any of clasms 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -3.9.

55. The method of any of claims 1 -48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -4.0.

56. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -4.3.

57. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -4.4.

58. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -4.5.

59. The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -5.0.

60. The method of any of claims 1 -48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -5.2.61 . The method of any of claims 1-48, wherein change from baseline in the average postdose Epworth Sleepiness Scale (ESS) score is at least about -5.5.

62. The method of any of claims 1 -61, wherein the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients.

63. The method of any of claims 1-62, wherein the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients intended for the treatment of cognitive health or function, excessive daytime sleepiness, or excessive daytime sleepiness associated with obstructive sleep apnea.

64. The method of any of claims 1-63, wherein no active pharmaceutical ingredients other than the solriamfetol are administered to the human patient for the treatment of cognitive health or function, excessive daytime sleepmess, or excessive daytime sleepiness associated with obstructive sleep apnea.

65. The method of any of claims 1-64, wherein the solriamfetol is administered in the morning.

66. The method of any of claims 1-65, wherein the solriamfetol is administered within one hour of awakening.

67. The method of any of claims 1-66. wherein the solriamfetol is administered more than9 hours before expected bedtim<68. A method of treating impaired cognitive health or function, excessive daytime sleepiness, excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder (SWD), comprising administering about 140-160 mg of solriamfetol daily to a human patient in need thereof69. The method of claim 68, wherein about 150 mg of solriamfetol is administered daily to a human patient in need thereof.

70. A method of treating impaired cognitive health or function, excessive daytime sleepiness, excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder (SWD), comprising administering about 280-320 mg of solriamfetol daily to a human patient in need thereof.

71. The method of claim 70, wherein about 300 mg of solriamfetol is administered daily to a human patient in need thereof.

72. A method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, comprising administering, to a human patient in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily.

73. The method of claim 72, wherein about 75 mg of solriamfetol is administered daily to the human patient for three days, and then about 150 mg of solriamfetol is administered daily to a human patient.

74. A method of improving cognitive health or function, treating a condition related to cognitive health or function, treating excessive daytime sleepiness, or treating excessive daytime sleepiness associated with obstructive sleep apnea, major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, comprising administering, to a human patient in need thereof, about 70-80 mg of solriamfetol daily for three days, and then administering about 140-160 mg of solriamfetol daily for four days, and then administering 280-320 mg of solriamfetol daily.

75. The method of claim 75, wherein about 75 mg of solriamfetol is administered daily to the human patient for three days, and then about 150 mg of solriamfetol is administered daily to the human patient for four days, and then about 300 mg of solriamfetol is administered daily to a human patient.

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