Solriamfetol for the treatment of certain neurological conditions

Abstract

Disclosed herein are methods of treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder (SWD) in human beings, such as in adult human beings, by administering solriamfetol to a human being who is suffering from ADHD, MDD, BED, or SWD. The solriamfetol may be administered in the morning, such as within one hour of awakening. In some embodiments, the solriamfetol is administered more than 9 hours before expected bedtime.

Description

[0001] SOLRIAMFETOL FOR THE TREATMENT OF CERTAIN NEUROLOGICAL CONDITIONS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional App. No. 63 / 508,847, filed June 16, 2023; U.S. Provisional App. No. 63 / 582,340, filed September 13, 2023; U.S. Provisional App. No. 63 / 588,966, filed October 9, 2023; U.S. Provisional App. No. 63 / 607,505, filed December 7, 2023; and U.S. Provisional App. No. 63 / 607,536, filed December 7, 2023; the entire contents of each of which is incorporated by reference herein in its entirety.

[0004] FIELD

[0005] The present disclosure relates to methods of treating neurological conditions, comprising administering solriamfetol to a human being in need thereof.

[0006] BACKGROUND

[0007] Attention Deficit Hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity or impulsivity, associated with significant impairment in social, academic, or occupational functioning or development. The etiology of ADHD has not been fully determined but is believed to represent a stressdiathesis model, with twin studies demonstrating strong heritability, as well as environmental factors such as exposure to toxins and disease in utero or in early childhood potentially playing a role.

[0008] ADHD symptoms generally appear by age 12 and affect approximately 5% to 10% of school age children. ADHD is often chronic with 40% to 60% of cases persisting into adulthood, with approximately 2% to 5% of the adult population afflicted by the disorder. Although both males and females are affected, males are diagnosed twice as often. Impairments in cognition are apparent in attention, planning and problem solving, working memory, and behavioral inhibition.

[0009] SUMMARY

[0010] The present disclosure relates to a method of treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), or shift

[0011] 1

[0012] RECTIFIED SHEET (RULE 91) work disorder, including administering about 140-160 mg of solriamfetol daily to a human being in need thereof.

[0013] In some embodiments, about 150 mg of soleriamfetol is administered daily to a human being in need thereof.

[0014] The present disclosure relates to a method of treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, including administering about 280-320 mg of solriamfetol daily to a human being in need thereof.

[0015] In some embodiments, about 300 mg of soleriamfetol is administered daily to a human being in need thereof.

[0016] In some aspects, the techniques described herein relate to a method of treating ADHD, including 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.

[0017] In some embodiments, about 75 mg of soleriamfetol is administered daily to the human being for three days, and then about 150 mg of soleriamfetol is administered daily to a human being.

[0018] In some aspects, the techniques described herein relate to a method of treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, including 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 four days, and then administering 280-320 mg of solriamfetol daily.

[0019] In some embodiments, about 75 mg of soleriamfetol is administered daily to the human being for three days, and then about 150 mg of soleriamfetol is administered daily to the human being for four days, and then about 300 mg of soleriamfetol is administered daily to a human being.

[0020] In some embodiments, the human being is an adult.

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

[0022] SUBSTITUTE SHEET (RULE 26) In some embodiments, the human being 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 vl.2). In some embodiments, the human being has an inattentive subtype of ADHD. In some embodiments, the human being has a hyperactive subtype of ADHD. In some embodiments, the human being has a combined subtype (e.g., both inattentive and hyperactive) of ADHD.

[0023] In some embodiments, the diagnosis was made at least 6 months prior to treatment.

[0024] In some embodiments, the human being has an AISRS total score that is at least about 26 when evaluated by a health care provider.

[0025] In some embodiments, the human being has an AISRS total score that is at least about 26 at baseline.

[0026] In some embodiments, the human being has an AISRS total score that is at least about 26 on the day treatment starts.

[0027] In some embodiments, the human being has a CGI-S score of that is at least about 4 when evaluated by a health care provider.

[0028] In some embodiments, the human being has a CGI-S score of that is at least about 4 at baseline.

[0029] In some embodiments, the human being has a CGI-S score of that is at least about 4 on the day the treatment starts.

[0030] 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.

[0031] In some embodiments, the human being has a QIDS-SR-16 score that is less than about 13 at baseline.

[0032] In some embodiments, the human being has a QIDS-SR-16 score that is less than about 13 on the day the treatment starts.

[0033] In some embodiments, the human being has a HAM-A score that is at least about 21 when evaluated by a health care provider.

[0034] SUBSTITUTE SHEET (RULE 26) In some embodiments, the human being has a HAM-A score that is at least about 21 at baseline.

[0035] In some embodiments, the human being has a HAM-A score that is at least about 21 on the day the treatment starts.

[0036] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients.

[0037] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients intended for the treatment of ADHD.

[0038] In some embodiments, no active pharmaceutical ingredients other than the solriamfetol are administered to the human being for the treatment of ADHD.

[0039] In some embodiments, the solriamfetol is administered in the morning.

[0040] In some embodiments, the solriamfetol is administered within one hour of awakening.

[0041] In some embodiments, the solriamfetol is administered more than 9 hours before expected bedtime.

[0042] In some embodiments, the solriamfetol is administered daily for 6 weeks.

[0043] In some embodiments, the solriamfetol is administered daily for more than 6 weeks.

[0044] In some embodiments, the Adult ADHD Investigator Symptom Report Scale (AISRS) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0045] In some embodiments, the Clinical Global Impression of Severity (CGI-S) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0046] In some embodiments, the Clinical Global Impression of Improvement (CGI -I) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the CGI-I total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0047] 4

[0048] SUBSTITUTE SHEET (RULE 26) In some embodiments, the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0049] In some embodiments, the Adult ADHD Self-Report Scale (ASRS) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0050] In some embodiments, the Adult ADHD Quality of Life questionnaire (AAQoL) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the AAQoL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0051] In some embodiments, the Work Productivity and Activity Impairment (WPAI) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the WPAI total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0052] These and other aspects of the disclosure are set forth in more detail in the description below.

[0053] BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG. 1 illustrates a study schematic to assess the efficacy and safety of solriamfetol in adults with ADHD in some embodiments.

[0055] FIG. 2 illustrates the flow of participants through the Study -Four of the patients on active solriamfetol treatment were known to have dosing patterns other than 75 mg for the first week and 150 mg thereafter, while all subjects on placebo increased to 150 mg at week 1 in some embodiments.

[0056] FIG. 3 illustrates mean AISRS total score by week in some embodiments.

[0057] FIG. 4 illustrates the CGI score indicating much or very much improved and 25% improvement in AISRS score with solriamfetol versus placebo in some embodiments.

[0058] FIG. 6 illustrates a clinical visit structure in some embodiments.

[0059] 5

[0060] SUBSTITUTE SHEET (RULE 26) FIG. 7 illustrates the results of the Coding Subtest in some embodiments.

[0061] FIG. 8 illustrates conding subtest change score over time post-dose for Solriamfetol and placebo in some embodiments.

[0062] FIG. 9 indicates the results of British Columbia Cognitive Complaints Inventory Change Score for Solriamfetol and placebo in some embodiments.

[0063] DETAILED DESCRIPTION

[0064] This 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.

[0065] 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.

[0066] Unless the context indicates otherwise, it is specifically intended that the various features descnbed herein can be used in any combination.

[0067] Moreover, the present disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein can be excluded or omitted.

[0068] 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.

[0069] As used in the description and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0070] 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”).

[0071] 6

[0072] SUBSTITUTE SHEET (RULE 26) 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.

[0073] 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.

[0074] 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. Thus, the term “consisting essentially of when used in a claim or the description is not intended to be interpreted to be equivalent to “comprising.”

[0075] 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%.

[0076] “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 carrier” 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 t pes of wetting 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.

[0077] 7

[0078] SUBSTITUTE SHEET (RULE 26) The term “modulate,” “modulates,” or “modulation” includes to enhancement (e.g., an increase) or inhibition (e.g., a decrease) in the specified level or activity.

[0079] 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.

[0080] “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%).

[0081] 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 carried 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, intrastemal, 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 latter 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

[0082] 8

[0083] SUBSTITUTE SHEET (RULE 26) 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.

[0084] “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).

[0085] “Concurrently” includes sufficiently close in 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.

[0086] 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 pnmate 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.

[0087] 9

[0088] SUBSTITUTE SHEET (RULE 26) Examples of pharmaceutically acceptable salts include, but are not limited to, acetate, benzenesulfonate, 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, hydrabamine, 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.

[0089] 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 drug 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.

[0090] “Bioavailability,” as used herein, includes the estimated area under the curve, or AUG 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 drug 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.

[0091] Disclosed herein are methods of treating 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 ADHD. The solriamfetol may be administered in the morning, such as within one hour of awakening. In some embodiments, the solriamfetol is administered more than 9 hours before expected bedtime.

[0092] 10

[0093] SUBSTITUTE SHEET (RULE 26) In addition to major depressive disorder, 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 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.

[0094] 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-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho- sexual dysfunction, pseudobulbar affect, and emotional lability.

[0095] 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.

[0096] Psychiatric disorders that may be treated by the solriamfetol, include, but are not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post- traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer’s disease, agitation, and agitation in Alzheimer’s disease. Alzheimer’s disease may also be referred to as dementia of the Alzheimer’s type. Other neurobehavioral symptoms of Alzheimer’s disease that may be treated include disinhibition and apathy.

[0097] 11

[0098] SUBSTITUTE SHEET (RULE 26) Agitation in Alzheimer’s disease occurs as the disease progresses. Agitation may present 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.

[0099] 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 disinhibition. Managing agitation is a priority in 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.

[0100] Neurobehavioral symptoms have been known to appear during dementia and may be treated by the 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.

[0101] 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 things, Biting ,

[0102] 12

[0103] SUBSTITUTE SHEET (RULE 26) 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 things 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.

[0104] 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.

[0105] 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.

[0106] 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 drugs, 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.

[0107] 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.

[0108] 13

[0109] SUBSTITUTE SHEET (RULE 26) 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, Wernicke-Korsakoff Syndrome, and Pick’s disease.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] Types of headaches that may be treated by the solriamfetol include, but are not limited to, migraine, tension, and cluster headaches.

[0114] 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

[0115] 14

[0116] SUBSTITUTE SHEET (RULE 26) 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.

[0117] 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.

[0118] 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.

[0119] In some embodiments, the solriamfetol may be administered to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and complex regional pain syndrome.

[0120] 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.

[0121] In some embodiments, the solriamfetol is used to treat chronic musculoskeletal pain.

[0122] 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 type 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.

[0123] In some embodiments, the solriamfetol may be administered orally to relieve neuropathic pain.

[0124] 15

[0125] SUBSTITUTE SHEET (RULE 26) 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.

[0126] In some embodiments, the solriamfetol may be administered to relieve fibromyalgia.

[0127] 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)). In certain embodiments, solriamfetol structure is given below as formula I:

[0128] 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.

[0129] Possible treatments for ADHD include stimulant medications, which are considered the mainstay of treatment for adults wi th ADHD, and non-stimulant medications. Limitations of these treatments include inadequate or non-response in a substantial proportion of patients, variable tolerability, being highly scheduled because of the potential for abuse and diversion (stimulants), and reduced and delayed treatment effects for non-stimulants compared to stimulants. There is therefore a need for new, effective, safe, and well tolerated treatments for ADHD.

[0130] Some individuals with attention-deficit / hyperactivity disorder (ADHD) may not tolerate or adequately respond to currently available treatments. In some embodiments, solriamfetol has a pattern of effects and tolerability as a treatment for ADHD in adults.

[0131] Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) which is currently approved in the U.S. and the E.U. for the treatment of excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea in adults. The effects of solriamfetol on

[0132] 16

[0133] SUBSTITUTE SHEET (RULE 26) dopamine and norepinephrine are relevant since these neurotransmitters systems are implicated in the pathophysiology' of ADHD. In addition, some treatments for ADHD, including the stimulants methylphenidate and mixed amphetamine salts, and the nonstimulant atomoxetine, are thought to work in part through the dopamine and norepinephrine pathways.

[0134] Pharmacology studies have also identified agonist activity at the trace amine- associated receptor 1 (TAAR1) for solriamfetol. In some embodiments, it has been demonstrated that solriamfetol activates human TAAR1 in vitro at potencies that are within the clinically relevant plasma concentration range and overlap with observed dopamine and norepinephrine transporter inhibitory potencies. TAAR1 is a G-protein coupled receptor with affinity for the trace amines, and, in some embodiments, TAAR1 agonists have demonstrated pro-cognitive and wake-promoting effects in rodents and primates. Animal behavioral studies have also shown that TAAR1 modulates motor activity, cognition, and anxiety-like behavior in spontaneously hypertensive hats (SHR), considered the most validated animal model of ADHD. In some embodiments, the effects of solriamfetol on TAAR1 is relevant to the treatment of ADHD.

[0135] Solriamfetol is also a serotonin 1A receptor (or 5-HTIA receptor) agonist.

[0136] For example, in some embodiments, solriamfetol is associated with significant improvement over placebo in maintenance of wakefulness test performance and self-reported sleepiness in individuals with narcolepsy and obstructive sleep apnea, with benefits identifiable at week 1. In some embodiments, Solriamfetol exposure can be well tolerated and can also be associated with greater reduction of ADHD symptoms as rated on our primary outcome measure, the Adult ADHD Investigator Symptom Rating Scale (AISRS). In some embodiments, individuals on solriamfetol treatment have a higher rate of achieving our a priori definition of clinical improvement: at least 25% reduction in ADI ID symptoms and a Clinical Global Impressions scale (CGI) rating of much or very much improved.

[0137] 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.

[0138] For some human patients, a 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

[0139] 17

[0140] SUBSTITUTE SHEET (RULE 26) 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 solriamfetol may be administered daily. The solriamfetol may be administered daily for as long as needed, such as 6 weeks or more.

[0141] For some human patents, a 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) 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. The solriamfetol may be administered daily for as long as needed, such as 6 weeks or more.

[0142] 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.

[0143] 18

[0144] SUBSTITUTE SHEET (RULE 26) 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.

[0145] Typically, the human patient to be treated for attention-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.

[0146] 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 vl.2). In some embodiments, this the diagnosis was made at least 6 months prior to treatment.

[0147] The 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.

[0148] 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. The 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 27. The total score can range from 0 to 54, with higher scores indicating greater severity.

[0149] 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.

[0150] 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

[0151] 19

[0152] SUBSTITUTE SHEET (RULE 26) (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: l=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.

[0153] 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.

[0154] The 16-item QIDS-SR-16, a patient-rated scale, is an abbreviated version of the 30- item 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.

[0155] The QIDS-SR-16 may be used to assess the subject’s depressive symptomatology over the past 7 days. Subjects report severity 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.

[0156] 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.

[0157] 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.

[0158] The HAM-A is a clinician-administered scale which is used to measure the 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.

[0159] 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.

[0160] 20

[0161] SUBSTITUTE SHEET (RULE 26) 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.

[0162] 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.

[0163] 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:

[0164] General presentation:

[0165] • Recurrent episodes of binge eating occurring at least once a week for 3 months

[0166] • Eating a larger amount of food than normal during a short time frame (any two- hour period)

[0167] • 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)

[0168] Binge eating episodes associated with >3 of the following:

[0169] • Eating until feeling uncomfortably full

[0170] • Eating large amounts of food when not physically hungry

[0171] • Eating much more rapidly than normal

[0172] • Eating alone out of embarrassment over quantity eaten

[0173] • Feeling disgusted, depressed, ashamed, or guilty after overeating

[0174] Additional Characteristics:

[0175] • Marked distress regarding binge eating is also present

[0176] 21

[0177] SUBSTITUTE SHEET (RULE 26) • Binge eating is not associated with regular inappropriate compensatory behavior, such as purging, excessive exercise, etc.

[0178] • Binge eating does not occur exclusively during the course of bulimia nervosa or anorexia nervosa

[0179] Binge eating disorder is associated with:

[0180] • Overeating (night eating, grazing, LOC) and weight gain

[0181] • Obesity, including severe obesity (BMI >40), & obesity-related conditions

[0182] • Mood, anxiety, substance use, impulse control (e.g., ADHD) disorders

[0183] • 80% have >1 comorbid disorder

[0184] • Reduced quality of life, impairment in functioning

[0185] • (comparable to BN), & increased health care use and costs

[0186] • Marked distress - shame, guilt, self disgust

[0187] 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).

[0188] In some embodiments, a subj ect, 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.

[0189] In some embodiments, a subj ect, 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.

[0190] In some embodiments, the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients, such as no other 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.

[0191] 22

[0192] SUBSTITUTE SHEET (RULE 26) 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.

[0193] 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 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 23

[0199] SUBSTITUTE SHEET (RULE 26) 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).

[0200] 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).

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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

[0206] 24

[0207] SUBSTITUTE SHEET (RULE 26) 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.

[0208] 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.

[0209] 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.

[0210] 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 the solriamfetol.

[0211] 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 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.

[0212] 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.

[0213] 25

[0214] SUBSTITUTE SHEET (RULE 26) 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.

[0215] 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 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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 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.

[0220] 26

[0221] SUBSTITUTE SHEET (RULE 26) 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 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.

[0222] 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.

[0223] 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 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 27

[0228] SUBSTITUTE SHEET (RULE 26) 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 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 28

[0235] SUBSTITUTE SHEET (RULE 26) 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.

[0236] 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.

[0237] 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.

[0238] 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 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. Higher scores indicate greater impairment in executive functioning.

[0239] 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.

[0240] 29

[0241] SUBSTITUTE SHEET (RULE 26) 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] The 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 in the DSM-5. The ASRS has shown significant correlation with the clinician administered AISRS.

[0246] 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 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.

[0247] 30

[0248] SUBSTITUTE SHEET (RULE 26) 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 31

[0255] SUBSTITUTE SHEET (RULE 26) 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 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.

[0256] 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.

[0257] 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 the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0258] 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 Life Productivity (11 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.

[0259] 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.

[0260] 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.

[0261] 32

[0262] SUBSTITUTE SHEET (RULE 26) 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 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 33

[0269] SUBSTITUTE SHEET (RULE 26) 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 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.

[0270] 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.

[0271] The Work Productivity and Activity Impairment Questionnaire: General Health V2.0 (WPALGH) is a validated 6-item self-administered 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: 1 = 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)

[0272] 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.

[0273] 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 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.

[0274] 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 three weeks (or on the twenty-second day

[0275] 34

[0276] SUBSTITUTE SHEET (RULE 26) 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.

[0277] 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 the first day the solriamfetol is administered and prior to administering the solriamfetol.

[0278] 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.

[0279] In some embodiments, Solriamfetol provide sustained improvement in objective cognition, reduced participants’ perceived severity of cognitive impairment, and reduced subjective sleepiness. In some embodiments, solriamfetol is well tolerated. In some embodimetns, Solriamfetol can improve cognitive function in patients with cognitive impairment associated with OSA and EDS.

[0280] EXAMPLES

[0281] Example 1. Phase 3 Clinical Trial to assess Efficacy and Safety

[0282] A Phase 3, multi-center, randomized, double-blind, placebo-controlled, parallel-group trial to assess the efficacy and safety of solriamfetol in adults with ADHD is conducted. The study consists of a screening period of up to 5 weeks, a 6-week double-blind treatment period, and a follow-up visit 1 week after the last dose of the study drug. The primary efficacy endpoint is the change from baseline to Week 6 in the AISRS. Secondary endpoints include the change from baseline to Week 6 in the CGI-S, CGI-I, BRIEF-A, ASRS, AAQoL questionnaire, and WPAI questionnaire.

[0283] During screening, eligible subjects have 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 vl.2) during screening, and no exclusionary diagnoses as assessed by the Mini

[0284] 35

[0285] SUBSTITUTE SHEET (RULE 26) International Neuropsychiatric Interview (MINI). Subjects must have an AISRS total score > 26 at screening and baseline.

[0286] Eligible subjects are randomized in a 1 : 1 : 1 ratio to be treated with solriamfetol titrated to 150 mg, solriamfetol titrated to 300 mg, or placebo, once daily, for 6 weeks. Subjects randomized to the 150 mg dose receive 75 mg from Day 1 through Day 3, and 150 mg on Day 4 and thereafter. Subjects randomized to the 300 mg dose receive 75 mg from Day 1 through Day 3, 150 mg from Day 4 through Day 7, and 300 mg from Day 8 and thereafter.

[0287] Screening Penod

[0288] Subjects taking ADHD medications at screening undergo a washout of at least 2 weeks or 5 half-lives, whichever is longer, prior to the Baseline Visit (Visit 2).

[0289] Subjects are rescreened once if insufficient medication washout, or if other procedural reasons, after discussion with the Sponsor and Medical Monitor; however, subjects are not rescreened who did not meet ADHD diagnosis criteria.

[0290] Treatment Period

[0291] Subjects who successfully complete Screening are randomly assigned at the Baseline Visit (Visit 2) in a 1: 1 : 1 ratio to treatment with solriamfetol titrated to 150 mg, solriamfetol titrated to 300 mg, or placebo, once daily, for 6 weeks. Study drug sre titrated as follows:

[0292] • Solriamfetol 150 mg group: 75 mg once daily on Day 1 through Day 3, then 150 mg once daily on Day 4 and thereafter.

[0293] • Solriamfetol 300 mg group: 75 mg once daily on Day 1 through Day 3, then 150 mg once daily from Day 4 through Day 7, then 300 mg once daily on Day 8 and thereafter.

[0294] • Placebo: Matching placebo once daily on Day 1 and throughout the study.

[0295] The first dose of study drug is taken in the clinic after baseline assessments are completed. Thereafter, subjects are instructed to take a single oral daily dose of study drug within one hour of awakening in the morning, except at Visits 4, 6, and 8, where the study drug dose is taken in the clinic. Subjects are contacted by phone 1 week after the last dose of study drug for a follow up visit. Study visits occur at screening (Visit 1), baseline (Day 1, Visit 2), Day 4 (Visit 3 phone call), Days 8, 15, 22, 29, 43 (Visits 4 - 8), and Day 50 (Visit 9

[0296] 36

[0297] SUBSTITUTE SHEET (RULE 26) follow-up). Subjects who prematurely discontinue the study are encouraged to complete Visit 8. Study procedures and assessments are performed during study visits as outlined in the Schedule of Assessments. Assessments include safety parameters, AISRS, CGI-S, CGI-I, BRIEF-A, ASRS, AAQoL, and WPAI.

[0298] Blood samples for measurement of the concentrations of solriamfetol are collected at each post-dose in-clinic study visit.

[0299] FIG. 1 illustrates a study schematic to assess the efficacy and safety of solriamfetol in adults with ADHD.

[0300] Example 2. Assessment of Efficacy and Safety

[0301] Individuals who were at least 18 years old and younger than 65 years old were included. Participants enrolled and participated from August 2021 through January 2023. The principal investigator, a board-certified psychiatrist trained in neuropsychiatry' and an expert administrator of the AISRS, determined eligibility by a systematic virtual visit interview that included administration of the AISRS and review of current and past mental health symptoms. This systematic interview, which explored presence of symptom criteria for all major Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mental health conditions, was supplemented by review of self-reported symptom patterns on the Adult Self-Report (ASR) to increase the chance of identifying exclusionary comorbid conditions. Participants met DSM-5 criteria for ADHD and had an AISRS score of at least 20. Individuals were excluded if there were with any of the following attributes: solriamfetol intolerance, conditions that obscured determination of an ADHD diagnosis, renal insufficiency / impairment, pregnancy, currently nursing an infant, unwillingness to use a reliable contraceptive method or methods during the trial, or cancer in the last 5 years. Individuals were excluded if they are with major unstable medical illness. Individuals were excluded if they were with specific conditions that a sympathomimetic agent might exacerbate: current or past psychotic or bipolar disorder, current affective or anxiety disorder with more than mild symptoms, untreated hypertension (> 140 / 90 mm Hg), narrow-angle glaucoma, drug abuse, or drug dependence (other than to nicotine). FDA-approved ADHD treatments and catecholaminergic medications were excluded, such as duloxetine, venlafaxine, and bupropion, during the study for 5 half-lives prior to study participation, or longer if needed to assess eligibility. Less than twice-a-week use of benzodiazepines or sedative-hypnotics was allowed.

[0302] 37

[0303] SUBSTITUTE SHEET (RULE 26) Subjects were randomized in double-blind fashion to solriamfetol 75 mg or placebo capsules and instructed to take doses in the morning. Over 6 weekly (defined as 7±3 days) visits, safety and effectiveness measures were obtained. All subjects took 1 capsule in the morning between baseline and the following visit a week later. At each subsequent visit, the study investigator reviewed the following variables to determine dosing recommendations: change in blood pressure and heart rate, spontaneously reported adverse events, the amount of improvement on the AISRS rating scale, and CGI-Improvement scores. If the study agent was well tolerated, subjects were instructed to increase to 2 capsules in the morning at this first post-baseline weekly visit. At this first weekly visit, if there were adverse experiences greater than mild in severity and possibly or probably attributable to the study agent, participants were asked to remain on 1 capsule for the next week. At subsequent visits, if an individual had been held at 1 capsule in the prior week and was tolerating it well, the dose was increased to 2 capsules.

[0304] Dose could also be dropped from 2 capsules to 1 capsule at any of the study visits if doing so might improve tolerability. If a subject was on 1 capsule and rated with a CGI rating of very much improved, and had nearly no ADHD symptoms on the AISRS, they were given the option of staying on 1 capsule for the next week of the study. The investigator also prioritized a goal of stable dosing for the last 4 weeks of the study, but only if a subject was tolerating the dose well. Subjects were never told to take more than 2 capsules. Data were collected from August 2021 to January' 2023. Subjects were trained to operate an OMRON model 7200 automatic blood pressure cuff (OMRON Healthcare, Inc) and took readings at screening and twice at each study visit. Women with childbearing potential had urine pregnancy tests at baseline and endpoint.

[0305] Weekly assessments included our primary outcome, the AISRS; Global Assessment of Functioning (GAF); CGI for ADHD; and spontaneous adverse experience reports. Subjects completed the following baseline and endpoint self-ratings: the 18-item ASRS with item order modified (MASRS) to alternate between inattentive and impulsive-hyperactive items, the Behavior Rating Inventory of Executive Function- Adult Form (BRIEF-A), the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). The ASRS has been validated as having high internal consistency and high concurrent validity with a rater- administered ADHD symptom interview, the ADHD-RS, which is similar to the AISRS. In this validation, the item order of the ASRS used an alternating pattern of inattentive and impulsive hyperactive items, so we deployed this format; we highlight this small difference

[0306] 38

[0307] SUBSTITUTE SHEET (RULE 26) by using the label MASRS. Pill counts were conducted visually by staff at weeks 2, 4, and 6 and upon return of pill bottles.

[0308] Statistical Analysis

[0309] AISRS total score data at each study visit were analyzed by a linear mixed-effects regression model comparing mean scores, with fixed effects for treatment group, study visit number (as a 7-level categorical variable), and a group-by-visit number interaction as well as a random patient effect. Maximum likelihood estimation obtained unbiased estimates of the weekly missing data differences. Differences between groups were similarly modeled with a 2-level fixed effect between study visits 0 and 6 for the following: AISRS total and subscale scores, GAF score, MASRS total score, BRIEF-A index and subscale T-scores, PSQI total and subscale scores, ESS score, and cardiovascular measures. Fisher exact test was used to evaluate the following: proportions of patients with > 25% and > 50% improvement on the AISRS; week 6 AISRS total scores < 18 and < 12; CGI “much improved” or “very' much improved" week 6 ratings; either of these latter CGI ratings at week 6 with > 25% improved AISRS scores; adverse event (AE) patterns including in any category, moderate or severe AE in a category, and repeated AEs in a category; and a 0.5 -standard deviation reduction in BRIEF-A index / subscale scores and the rate of improvement in BRIEF-A index / subscale scores. Proportions of poor sleep quality (PSQI total score > 5) and excessive daytime sleepiness (ESS score >11) were evaluated at baseline and endpoint. Effect size for AISRS, MASRS, and BRIEF-A scores was estimated as the difference between the treatment groups in the mean change between baseline and week 6, divided by the standard deviation of the baseline scores. Patients were counted in each AE category for which they ever reported an AE and included in the severity category corresponding to the highest severity reported. Cardiovascular analyses were based on a mean of the 2 weekly vital sign measurements and included all early drop participant data.

[0310] Analysis was performed using SAS v9.4. The 2-sidcd significance level was .05 for all analyses, without adjustment for multiple comparisons given the preliminary nature of this pilot study.

[0311] Results

[0312] Of 60 participants, 1 individual on placebo dropped out of the trial at week 2 by personal preference; another individual on placebo deviated from protocol by taking a

[0313] 39

[0314] SUBSTITUTE SHEET (RULE 26) stimulant medication dunng the fourth week, and the investigator asked them to end study participation. FIG. 2 illustrates the flow of participants through the Study-Four of the patients on active solriamfetol treatment were known to have dosing patterns other than 75 mg for the first week and 150 mg thereafter, while all subjects on placebo increased to 150 mg at week 1. The dosing patterns of these 4 subjects on treatment with active agent were described: blood pressure readings and concurrent illness delayed increase to 150 mg to week 4; another returned to 75 mg after receiving 150 mg for 1 week because of end of day irritability by visit 2 on 150 mg; another delayed increase to 150 mg at week 2 for no attributable reason; and another subject experienced insomnia while on 150 mg between week 1 and week 2 and preferred to stay at 75 mg daily as they were experiencing meaningful benefit. In addition, evaluating pill counts suggested that 4 subjects on active treatment and 4 on placebo were likely to have missed more than few days of exposure during any study week.

[0315] Table 1 presents demographic characteristics of study participants.

[0316] Table 1. Patient Characteristics at Baseline

[0317] Treatment Group

[0318] Characteristic Solriamfetol Placebo

[0319] Total enrolled, n 29 31

[0320] Age, y

[0321] Mean 36.2 36.9

[0322] Minimum 19.0 22.1

[0323] Maximum 61.0 60.0

[0324] Gender, n (%)

[0325] Male 10 (34.5) 17 (54.8)

[0326] Female 17 (58.6) 12 (38.7)

[0327] Other 2 (6.9) 2 (6.5)

[0328] Race, n (%)

[0329] White / Caucasian 19 (65.5) 25 (80.6)

[0330] Black / African American 2 (6.9) 2 (6.5)

[0331] Asian 3 (10.3) 2 (6.5)

[0332] Native Hawaiian / Pacific Islander 5 (17.2) 2 (6.5)

[0333] Ethnicity, n (%)

[0334] Hispanic or Latino 4 (13.8) 2 (6.5)

[0335] Not Hispanic or Latino 25 (86.2) 29 (93.5)

[0336] Highest education, n (%)

[0337] High school graduate 1 (3.2) 0 (0)

[0338] Some college but no college degree 4 (13.8) 2 6.5)

[0339] Associate degree 2 (6.9) 3 (9.7)

[0340] Bachelor or RN degree 10 (34.5) 16 (51.6)

[0341] Some graduate school but no graduate degree 2 (6.9) 2 (6.5)

[0342] Master’s degree 3 (10.3) 2 (6.5)

[0343] Doctoral or law degree 7 (24.1) 6 (19.4)

[0344] SUBSTITUTE SHEET (RULE 26) Marital status, n (%)

[0345] Married 13 (44.8) 12 (38.7)

[0346] Unmarried 16 (55.2) 19 (61.3)

[0347] Socioeconomic status*: estimated annual income, 98,349 119,593 mean (SD), $ (31,349) (33,612)

[0348] CGI Severity score (baseline), n (%)

[0349] Moderately ill 22 (75.9) 25 (80.6)

[0350] Markedly ill 7 (24.1) 6 (19.4)

[0351] GAF score (baseline)

[0352] Mean (SD) 63.8 (1.9) 63.8 (1.5)

[0353] Minimum 60.0 61.0

[0354] Maximum 68.0 66.0

[0355] *Median income was estimated based on the median household of the zip code that the participant listed.

[0356] Abbreviations: CGI=Clinical Global Impressions scale, GAF=Global Assessment of Functioning.

[0357] The participants randomized to placebo, compared to those on solriamfetol, had a higher (by 15 percentage points) rate of being White / Caucasian, a higher (by 17 percentage points) rate of receiving education at the bachelor or nursing degree level, and a higher mean income (by 21 percentage points). More women than men were exposed to solriamfetol. Concomitant psychopharmacology at baseline included zolpidem, citalopram, escitalopram, gabapentin, alprazolam (1 participant each), trazodone (2 participants), escitalopram (3 participants), fluoxetine, and sertraline (5 participants each). Cardiovascular medications included tamsulosin, telmisartan (1 participant each), losartan (3 participants), and spironolactone (2 participants). Sixteen subjects on solriamfetol treatment and 11 subjects on placebo had never been on treatment with a stimulant previously. Among this stimulant-naive group, 3 individuals each in both active and placebo groups had been on treatment with a nonstimulant with potential ADHD effects in the past (either atomoxetine or bupropion).

[0358] At baseline, the ADHD CGl-Severity rating was moderate for most participants (see Table 1). There was less than a 10% difference in the percentage of individuals scoring in the impaired range on every mental health subcategory of the ASR between the active and placebo groups. At baseline, mean (SD) AISRS total scores were 25.5 (4.7) in the solriamfetol group and 24.4 (4.2) in the placebo group. At baseline, all but 1 subject met a research definition of executive function impairment, having 2 or more subscales of the BRIEF-A rated at 1.5 standard deviations from normed mean BRIEF-A scores.

[0359] There were no significant differences in changes in vital signs over the course of the study between the treatment and placebo groups. Comparing solriamfetol and placeb mean

[0360] 41

[0361] SUBSTITUTE SHEET (RULE 26) vital sign changes from baseline to week 6, we found the following: heart rate, +3.7 versus +2.2 bpm (P=.5609); systolic blood pressure, +2.4 versus +1.5 mm Hg (P=. 474y. diastolic blood pressure, +1.1 versus +1.5 mm Hg P= .8117). There were 3 subjects in the placebo group and 4 in the treatment group who met our definition of clinically meaningful high blood pressure readings, defined as 2 readings (> 140 / 90 mm Hg) in a row during any 2 consecutive visits. No subjects had abnormal heart rates (> 100 bpm) at 2 consecutive study visits.

[0362] All adverse events were analyzed regardless of likelihood of attribution to the study.

[0363] All were mild or moderate in severity, except a syncope episode that occurred in a patient on placebo. We grouped adverse events into body system categories impacted. Table 2 shows the comparison of rates of adverse events between groups.

[0364] 42

[0365] SUBSTITUTE SHEET (RULE 26) Table 2. Comparison of Rates of Adverse Events (Regardless of Severity) Between Groups.

[0366] Adverse Effect Solriamfetol Placebo P Value

[0367] (n=29), (n=31), n (%) n (%)

[0368] Cold / infection / allergy 13 (45) 17 (55) .6058

[0369] Increased appetite 0 (0) 1 (3) 1.0000

[0370] Decreased appetite 5 (17) 2 (6) .2472

[0371] Headache 14 (48) 9 (29) .1844

[0372] Nausea / vomiting / diarrhea 7 (24) 2 (6) .0756

[0373] (gastrointestinal)

[0374] Insomnia 9 (31) 5 (16) .2271

[0375] Sedation 3 (10) 1 (3) .3455

[0376] Increased energy 4 (14) 1 (3) .1877

[0377] Cardiovascular 5 (17) 1 (3) .0977

[0378] Tense / jittery 1 (3) 0 (0) .4833

[0379] Agitated / irritable 3 (10) 2 (6) .6658

[0380] Anxious / worried 0 (0) 1 (3) 1.0000

[0381] Mucosal dryness 3 (10) 4 (13) 1.0000

[0382] Dizzy / lightheaded 1 (3) 0 (0) .4833

[0383] Neurologic 4 (14) 1 (3) .1877

[0384] Musculoskeletal 7 (24) 7 (23) 1.0000

[0385] Genitourinary 3 (10) 2 (6) .6658

[0386] Dermatologic 1 (3) 4 (13) .3547

[0387] Other 1 (3) 3 (10) .6128

[0388] There was no statistically significant treatment effect on occurrence of events in these categories (Table 2), on occurrence of repeated (occurring at 2 or more visits in a single subject) events in these categories (P values ranged from .1068 to 1.0000), or on occurrence of events categorized as having moderate or worse severity (P values ranged from .2294 to 1.0000). The following categories were represented among treatment participants at a rate of at least 10 percentage points higher than among placebo participants: decreased appetite, headache, gastrointestinal, insomnia, increased energy, cardiovascular, and neurologic. The only category of event to occur in participants on placebo at a rate at least 10 percentage points higher than in patients than on treatment was dermatologic. Review of patterns of repeated categorized adverse events showed that rate of decreased appetite was the most differentiating, occurring in 3 individuals on solriamfetol treatment and none on placebo. Adverse events led to dose adjustment or interruption in 10 subjects on active treatment and 4 on placebo and led to discontinuation (at week 6) in 1 subject, who had skin itching while on active solriamfetol treatment.

[0389] 43

[0390] SUBSTITUTE SHEET (RULE 26) The remote virtual visit-based clinical trial format was also very well tolerated by participants. The time burden for the participants, who lived in geographically diverse areas of Massachusetts, was less than if the study had required travel to in-person visits. There were no adverse experiences that occurred that were attributed directly to the remote nature of the study.

[0391] Mean improvement in total AISRS ratings was significantly greater for individuals on solriamfetol treatment than for those on placebo from week 3, for which the difference in means was -3.4 (95% Cl, -6.7 to -0.1; P= .0439), through the end of the study at week 6. By week 6, the difference in mean AISRS score was -4.3 (95% CI, -7.7 to -1.0; = 0106). FIG. 3 illustrates mean AISRS total score by week. Referring to FIG. 3, The mean total improvement in AISRS score by the week 6 study visit was -7.6 for active study drug participants, and -2.1 for individuals on placebo (P= 0012; effect size = 1.09) . Similar patterns were evident for the AISRS inattentive subscale (mean improvement greater for treatment than for placebo by 4.0 points; P= .001; effect size = 1.59) and AISRS impulsive- hyperactive subscale (improvement greater for treatment than for placebo by 1.4 points; P= .024; effect size = 0.34).

[0392] Total AISRS score improved 25% by week 6 in 52% of individuals on solriamfetol treatment versus 17% of individuals on placebo (P= .0119). Total AISRS score improved 50% by week 6 in 28% of individuals on solriamfetol treatment versus 3.4% receiving placebo ( = .0253). By week 6, significantly more individuals on solriamfetol treatment than on placebo met remission AISRS total score definitions of 12 (24% of participants on solriamfetol treatment and 3% of participants on placebo; P=.05V ) or 18 (59% of participants on solriamfetol treatment and 21% on placebo; P= .0067 on the AISRS. By week 6, CGI ratings of much or very much improved occurred for significantly more individuals on solriamfetol treatment (45%, 13 / 29) than on placebo (6%, 2 / 31) (P= .0020). FIG. 4 illustrates the CGI score indicating much or very much improved and 25% improvement in AISRS score with solriamfetol versus placebo. Referring to FIG. 4, breaking this down further, the following distributions were noted: for active treatment: much improved=24% (7 individuals), very much improved = 20% (6 individuals); within placebo treatment: much improved = 3% (1 individual), very much improved = 3% (1 individual). Forty-five percent of participants in the treatment group and 6.9% in the placebo group were considered responders by our a priori definition (P= .0020).

[0393] 44

[0394] SUBSTITUTE SHEET (RULE 26) Outcome aligned with a slightly different post hoc improvement and response definition focused on 30% improvement to allow more direct comparison to some prior studies of adult ADHD treatments was also evaluated. Total AISRS score improved 30% by week 6 in 48% of individuals on solriamfetol treatment versus 14% of individuals on placebo Response, based on this amount of improvement with CGI ratings of much or very much improved occurred in 41% of individuals on solriamfetol treatment and 6.9% of those on placebo (P= .0046). Mean GAF scores improved significantly more in the treatment group (-4.8 points; 95% CI, 3.1 to 6.6 vs-0.3 points; 95% CI, -1.4 to 2.1; =.0006).

[0395] Self-report of executive functioning capacities using the BRIEF -A was evaluated. Significantly more individuals on active treatment (69%) than placebo (34%) had a 0.5- standard deviation improvement in T-score on the BRIEF-A Global Executive Composite (GEC) ( / ’= .0173), Metacognition Index (66% vs 34%, P= .0348), Shift subscale (69% vs 34%, P= .0173), and Initiate subscale (62% vs 31%, P= .0343). Solriamfetol was associated with significantly more change than placebo between baseline and week 6 for the following BRIEF-A subscales: Global Executive Composite, Behavioral Regulation Index, Metacognition Index, Shift subscale, Emotional Control subscale, Initiate subscale, Working Memory subscale, Plan / Organize subscale, and the Task Monitor subscale, with moderate to high effect sizes for each. The Inhibit, Self-Monitor, and Organization of Materials subscales showed no significant change relative to placebo.

[0396] Between baseline and week 6, the treatment group had a significantly greater reduction in the subject-reported mean MAS RS total scores (treatment group mean = -11.1; 95% Cl, -14.6 to -7.7; placebo group mean = -3.9; 95% CI, -7.4 to -0.5; P= .0047; effect size = 1.23), MASRS inattentive scores (treatment group mean = -5.9; 95% CT, -7.7 to -4.0; placebo group mean = -1.7; 95% CI, -1.7 to -3.5; P= .0022; effect size = 1.30), and MASRS hyperactivity (treatment group mean = -5.2; 95% CI. -7. 1 to -3.4; placebo group mean = -2.4; 95% CI, -4.3 to -0.6; P= .0366; effect size = 0.55).

[0397] Evaluating change in the PSQI overall or subscale scores from baseline to week 6, there was no significant difference between participants in the treatment groups. Mean sleepiness scores on the ESS improved significantly more for the treatment group (-2.4 points; P= 0056). We ran an analysis on change from baseline in AISRS total score within the ESS subgroups of normal daytime sleepiness and excessive daytime sleepiness and found that AISRS improvement was not moderated by changes in ESS ratings of sleepiness (P= .3735).

[0398] 45

[0399] SUBSTITUTE SHEET (RULE 26) We also evaluated shifts from good sleep to bad (defined as PSQI score > 5) sleep and vice versa between baseline and end of study to assign study participants to improved, unchanged, or worsened sleep quality trends. Overall, 24.1% in the active group and 20.7% in the placebo group showed improved sleep, and 6.9% in the active group and 10.3% in the placebo group showed worsened sleep. A total of 69% of both active and placebo groups remained in the same sleep category.

[0400] The effects of solriamfetol in adults with ADHD in the present disclosure were unexpected results, and are, to our knowledge, novel. Additionally, this example is based on the first remotely conducted clinical psychopharmacology trial in adults with ADHD. Solriamfetol was well tolerated and was associated with significantly greater improvement than placebo with robust effect sizes based on both clinician and participant measures of ADHD as well as participant self-report of executive function.

[0401] The effect size of solriamfetol for ADHD symptom improvement in adults was like that of stimulant medications in prior studies that also calculated effect sizes for symptom improvement. There was notably a low placebo response in this study, which could contribute to the larger effect size estimates. While there is no mean clinically important difference (MCID) established for the AISRS grounded in data from an identical controlled 6-week study, analysis based on a 6-month exposure to atomoxetine suggests that the AISRS change level which discriminated individuals with a 1 -point difference in ADHD CGI severity from those with no change in ADHD CGI severity was -10.1 Inspecting response patterns, we found that 10 of the subjects receiving active treatment in our study had greater than a 10- point improvement, while only 1 subject on placebo had this much improvement.

[0402] In the atomoxetine study that estimated MCID, a 1 -point change in CGI severity correlated with at least 30% improvement on the AISRS rating scale. Because we found that 48% of individuals on solriamfetol had this much improvement in AISRS ratings, we believe that future research is needed to clarify how MCID for the AISRS may be best estimated in studies like the pilot one we present. For example, we note that AISRS baseline scores were much higher in the atomoxetine study used to estimate this MCID: 38.5 in the active group and 39.2 in the placebo group. This means the populations may not be comparable in the amount of AISRS change that was possible. Some clinical trials have explored effects of feasibility, utility, and efficacy of an all-remote clinical trial, although comparison to an in-

[0403] 46

[0404] SUBSTITUTE SHEET (RULE 26) person study would be necessary to understand specifically how participant characteristics or outcomes would be different.

[0405] Example 3. Effects of Solriamfetol on Cognitive Function

[0406] Effects of solriamfetol on cognitive function in participants with cognitive impairment associated with excessive daytime sleepiness in obstructive sleep apnea were assessed.

[0407] Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA). It can persist in 10%— 28% of patients, despite use of primary airway therapy. Patients with EDS associated with OSA may have performance deficits in several cognitive domains.

[0408] Solriamfetol (Sunosi®) is a dopamine and norepinephrine reuptake inhibitor with agonistic properties at trace amine-associated receptor 1 (TAAR1) and serotonin 1 A receptors Solriamfetol (37.5-150 mg / day) is approved in United States, Canada, and select European countries to treat EDS associated with OSA.

[0409] A phase IV, randomized, double-blind, placebo-controlled, crossover trial was conducted to assess whether solriamfetol improves cognitive function in patients with EDS associated with OSA and extant impaired cognition was assessed. FIG. 4 illustrates a summarized process of the randomized, double-blind, placebo-controlled, crossover trial. Referring to FIG. 4, the study consisted of a screening period of about 2 to 4 weeks, a first 2- week double-blind treatment period, a second 2 weeks double-blind treatment period, and a follow-up visit about 4 to about 10 days after the last dose of the study drug.

[0410] Subjects who successfully complete Screening are assigned at the Baseline Visit (Visit 3) in atreatment for double-blind treatment periods 1 and 2. Study drug are titrated as follows:

[0411] • 75 mg once daily on Day 1 through Day 3, then 150 mg once daily on Day 4 and thereafter.

[0412] • Placebo: Matching placebo once daily on Day 1 and throughout the study.

[0413] FIG. 6 illustrates a clinical visit structure. Table 3 indicates baseline demographics and clinical characteristics. Of 173 participants screened, 59 were enrolled, and 57 completed the study. Among participants using positive airway pressure, average use was >6 hours per night.

[0414] 47

[0415] SUBSTITUTE SHEET (RULE 26) Table 3. Baseline Demographics and Clinical Characteristics.

[0416] From the trial, change from baseline to end of treatment in objective cognitive function was measured with the Coding Subtest (a variation of the Digit Symbol Substitution Test) of the Repeatable Battery for the Assessment of Neuropsychological Status (average across all post-dose timepoints). FIG. 7 illustrates the results of the Coding Subtest. Referring to FIG. 7, Solriamfetol significantly improved objective cognitive function compared with placebo. Mean difference was 1.75 (95%, Cl: 0.46, 3.04) (Cohen’s d: 0.36).

[0417] Change from baseline to end of treatment in objective cognitive function was measured with the Coding Subtest (a variation of the Digit Symbol Substitution Test) of the Repeatable Battery for the Assessment of Neuropsychological Status (at each post-dose timepoint). FIG. 8 illustrates coding subtest change score overtime post-dose for Solriamfetol and placebo. Referring to FIG. 8, Solriamfetol significantly improved objective cognitive function compared with placebo at 2, 6, and 8 hours after dosing. The mean differences (95% Cl) was 1.91 (0.16, 3.65) at 2 hour, 1.38 (-0.22, 2.97) at 4 hour, 2.33 (0.78, 3.88) at 6 hour, and 1.58 (0.23, 2.93) at 8 hour.

[0418] SUBSTITUTE SHEET (RULE 26) Change from baseline to end of treatment in subjective cognitive function was measured with the British Columbia Cognitive Complaints Inventory. FIG. 9 indicates the results of British Columbia Cognitive Complaints Inventory Change Score for Solriamfetol and placebo. Referring to FIG. 9, Solriamfetol significantly improved subjective cognitive function compared with placebo. Mean difference was -1.58 (95% Cl: -2.53, -.063) (Cohen’s d 0.43).

[0419] Table 4 indicates study findings on safety. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity. There were no deaths, serious TEAEs, or TEAEs that led to discontinuation of the study.

[0420] Table 4. Studying Findings on Safety.

[0421] Common TEAEs (reported by >2 participants)

[0422] Solriamfetol provided sustained improvement in objective cognition, reduced participants’ perceived severity of cognitive impairment, and reduced subjective sleepiness. The adverse event profile and high study completion rate suggest solriamfetol was well tolerated. Solriamfetol has the potential to improve cognitive function in patients with cognitive impairment associated with OSA and EDS.

[0423] 49

[0424] SUBSTITUTE SHEET (RULE 26)

Claims

CLAIMS1. A method of treating attend on-deficit / hyperactivity disorder (ADHD), 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 being in need thereof.

2. The method of claim 1, wherein about 150 mg of soleriamfetol is administered daily to a human being in need thereof.

3. A method of treating attend on-deficit / hyperactivity disorder (ADHD), 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 being in need thereof.

4. The method of claim 1, wherein about 300 mg of soleriamfetol is administered daily to a human being in need thereof.

5. A method of treating ADHD, comprising 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.

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

7. A method of treating attention-deficit / hyperactivity disorder (ADHD), major depressive disorder (MDD), binge eating disorder (BED), or shift work disorder, comprising 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 four days, and then administering 280-320 mg of solriamfetol daily.

8. The method of claim 1, wherein about 75 mg of soleriamfetol is administered daily to the human being for three days, and then about 150 mg of soleriamfetol is administered daily to the human being for four days, and then about 300 mg of soleriamfetol is administered daily to a human being.

9. The method of claims 1-8, the human being is an adult.50SUBSTITUTE SHEET (RULE 26)10. The method of claim 9, wherein the human being has an age of about 18-55 years.

11. The method of any preceding claim, wherein the human being 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 vl.2).

12. The method of claim 11, wherein the diagnosis was made at least 6 months prior to treatment.

13. The method of any preceding claim, wherein the human being has an AISRS total score that is at least about 26 when evaluated by a health care provider.

14. The method of any preceding claim, wherein the human being has an AISRS total score that is at least about 26 at baseline.

15. The method of any preceding claim, wherein the human being has an AISRS total score that is at least about 26 on the day treatment starts.

16. The method of any preceding claim, wherein the human being has a CGI-S score of that is at least about 4 when evaluated by a health care provider.

17. The method of any preceding claim, wherein the human being has a CGI-S score of that is at least about 4 at baseline.

18. The method of any preceding claim, wherein the human being has a CGI-S score of that is at least about 4 on the day the treatment starts.

19. The method of any preceding claim, wherein the human being has a QIDS-SR-16 score that is less than about 13 when evaluated by a health care provider.

20. The method of any preceding claim, wherein the human being has a QIDS-SR-16 score that is less than about 13 at baseline.

21. The method of any preceding claim, wherein the human being has a QIDS-SR-16 score that is less than about 13 on the day the treatment starts.

22. The method of any preceding claim, wherein the human being has a HAM-A score that is at least about 21 when evaluated by a health care provider.

23. The method of any preceding claim, wherein the human being has a HAM-A score that is at least about 21 at baseline.51SUBSTITUTE SHEET (RULE 26)24. The method of any preceding claim, wherein the human being has a HAM-A score that is at least about 21 on the day the treatment starts.

25. The method of any preceding claim wherein the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients.

26. The method of any preceding claim, wherein the solriamfetol is in a dosage form containing no other active pharmaceutical ingredients intended for the treatment of ADHD.

27. The method of any preceding claim, wherein no active pharmaceutical ingredients other than the solriamfetol are administered to the human being for the treatment of ADHD.

28. The method of any preceding claim, wherein the solriamfetol is administered in the morning.

29. The method of any preceding claim, wherein the solriamfetol is administered within one hour of awakening.

30. The method of any preceding claim, wherein the solriamfetol is administered more than 9 hours before expected bedtime.

31. The method of any preceding claim, wherein the solriamfetol is administered daily for 6 weeks.

32. The method of any preceding claim, wherein the solriamfetol is administered daily for more than 6 weeks.

33. The method of any preceding claim, wherein the Adult ADHD Investigator Symptom Report Scale (AISRS) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the AISRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

34. The method of any preceding claim, wherein the Clinical Global Impression of Severity (CGI-S) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the CGI-S total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

35. The method of any preceding claim, wherein the Clinical Global Impression of Improvement (CGI-I) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the CGI-I total52SUBSTITUTE SHEET (RULE 26)score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

36. The method of any preceding claim, wherein the Behavior Rating Inventory of Executive Function- Adult Version (BRIEF -A) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the BRIEF-A total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

37. The method of any preceding claim, wherein the Adult ADHD Self-Report Scale (ASRS) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the ASRS total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

38. The method of any preceding claim, wherein the Adult ADHD Quality of Life questionnaire (AAQoL) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the AAQoL total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

39. The method of any preceding claim, wherein the Work Productivity and Activity Impairment (WPAI) total score of the human being is reduced by at least 10% after solriamfetol is administered daily to the patient for six weeks as compared to the WPAI total score on the first day the solriamfetol is administered and prior to administering the solriamfetol.

40. The method of any preceding claim, wherein the human being is experiencing ADHD.

41. The method of any one of claims 1-39, wherein the human being is experiencing MDD.

42. The method of any one of claims 1-39, wherein the human being is experiencing BED.

43. The method of any one of claims 1-39, wherein the human being is experiencing SWD.53SUBSTITUTE SHEET (RULE 26)

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