Solriamfetol for treating cognitive impairment in a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness

Abstract

The present invention relates to carbamoyl phenylalaninol compounds and methods of using the same to enhance one or more cognitive function in a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness and to treat one or more cognitive impairment in such a patient.

Description

SOLRIAMFETOL FOR TREATING COGNITIVE IMPAIRMENT IN A SUBJECT WITH IMPAIRED COGNITION ASSOCIATED WITH OBSTRUCTIVE SLEEP APNEA AND EXCESSIVE DAYTIME SLEEPINESSField of the Invention

[0001] The present invention relates to carbamoyl phenylalaninol compounds and methods of using the same to enhance one or more cognitive function in a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness and to treat one or more cognitive impairment in such a patient.Background of the Invention

[0002] (R)-2-amino-3-phenylpropyl carbamate (APC; solriamfetol; SUNOSI®) is a phenylalanine analog. Solriamfetol is a dopamine and norepinephrine reuptake inhibitor approved for use in adults in the US, Canada, and select countries in Europe for the treatment of EDS associated with OSA (37.5-150 mg / day) and narcolepsy (75-150 mg / day). Solriamfetol is a Schedule IV WPA with relatively low binding affinity to dopamine and norepinephrine transporters. Baladi MG, Forster MJ, Gatch MB, et al. Characterization of the neurochemical and behavioral effects of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther. 2018;366(2):367-376. Previous studies have demonstrated its short- and long-term efficacy, including improvements in wakefulness, aspects of daily functioning, health-related quality of life, and work productivity. Schweitzer PK, Rosenberg R, Zammit GK, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): a randomized controlled trial. Am J Respir Crit Care Med.2019; 199(11): 1421 -1431 ; Malhotra A, Shapiro C, Pepin JL, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. Sleep. 2020;43(2):zsz220; Weaver TE, Drake CL, Benes H, et al. Effects of solriamfetol on quality of life measures from a 12-week phase 3 randomized trial. Ann Am Thorac Soc. 2020;17(8):998-1007. Weaver TE, Pepin JL, Schwab R, et al.Long-term effects of solriamfetol on quality of life and work productivity in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. J Clin Sleep Med. 2021 ; 17(10): 1995-2007. Preclinical evidence demonstrates solriamfetol has activity at trace amine-associated receptor 1 (TAAR1 ) and serotonin 1A receptors, (Gursahani H, Jolas T, Martin M, Cotier S, Hughes S, Macfadden W. Preclinical pharmacology of solriamfetol: potential mechanisms for wake promotion [abstract 0756], Sleep. 2022;45(suppl 1):A329) and TAAR1 agonists may have beneficial effects on cognitive function. Alnefeesi Y, Tamura JK, Lui LMW, et al. Trace amine-associated receptor 1 (TAAR1): potential application in mood disorders: a systematic review. Neurosci Biobehav Rev. 2021 ;131 :192-210. 18P2 The structure of the free base of APC is given below as formula I.

[0003] Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA). Characterized by recurrent obstruction of the upper airway during sleep, OSA causes episodes of fragmented sleep and intermittent hypoxia and leads to EDS. Zhou J, Camacho M, Tang X, Kushida CA. A review of neurocognitive function and obstructive sleep apnea with or without daytime sleepiness. Sleep Med. 2016;23:99-108. While positive airway pressure (PAP) can improve sleep quality and reduce hypoxic events, residual EDS persists in 10%-28% of PAP-treated patients. Gasa M, Tamisier R, Launois SH, et al. Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure. J Sleep Res. 2013;22(4):389-397; Pepin JL, Viot-Blanc V, Escourrou P, et al.Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study. Eur RespirJ. 2009;33(5): 1062-1067; Bonsignore MR, Pepin JL, Cibella F, et al. Excessive daytime sleepiness in obstructive sleep apnea patients treated with continuous positive airway pressure: data from the European Sleep Apnea Database. Front Neurol. 2021 ;12:690008. Patients with OSA and EDSmay experience impaired occupational and social functioning, increased risk of workplace injuries and motor vehicle accidents, and reduced quality of life.Garbarino S, Guglielmi O, Sanna A, Mancardi GL, Magnavita N. Risk of occupational accidents in workers with obstructive sleep apnea: systematic review and metaanalysis. Sleep. 2016;39(6): 1211-1218; Stepnowsky C, Sarmiento KF, Bujanover S, Villa KF, Li VW, Flores NM. Comorbidities, health-related quality of life, and work productivity among people with obstructive sleep apnea with excessive sleepiness: findings from the 2016 US National Health and Wellness Survey. J Clin Sleep Med. 2019;15(2):235-243. Deficits in cognitive function are troublesome in this population, with up to 68% of patients demonstrating impairment across various cognitive domains, including memory, attention, and executive function. Vasudev P, Arjun P, Azeez AK, Nair S. Prevalence of cognitive impairment in obstructive sleep apnea and its association with the severity of obstructive sleep apnea: a cross-sectional study. Indian J Sleep Med. 2020;15(4):55-59; Werli KS, Otuyama LJ, Bertolucci PH, et al. Neurocognitive function in patients with residual excessive sleepiness from obstructive sleep apnea: a prospective, controlled study. Sleep Med. 2016;26:6-11. The severity of EDS and cognitive impairment is not solely determined by the severity of OSA; impaired cognitive function can persist in patients despite PAP treatment. Gabryelska A, Bialasiewicz P. Association between excessive daytime sleepiness, REM phenotype and severity of obstructive sleep apnea. Sci Rep. 2020; 10(1 ):34; Kendzerska TB, Smith PM, Brignardello-Petersen R, Leung RS, Tomlinson GA. Evaluation of the measurement properties of the Epworth Sleepiness Scale: a systematic review. Sleep Med Rev. 2014; 18(4):321 -331 .

[0004] Current pharmacological therapeutics for treatment of EDS include stimulants and wake-promoting agents (WPAs). Abad VC, Guilleminault C. Solriamfetol for the treatment of daytime sleepiness in obstructive sleep apnea. Expert Rev Respir Med. 2018; 12(12): 1007-1019; Gandhi KD, Mansukhani MP, Silber MH, Kolla BP. Excessive daytime sleepiness: a clinical review. Mayo Clin Proc. 2021 ;96(5): 1288- 1301 ; Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. J Clin Sleep Med. 2021 ; 17(12):2543-2555. The WPA modafinil is approved in the United States (US), Canada, and Australia to improvewakefulness in some sleep disorders, including OSA and EDS, and in select European countries to treat sleepiness associated with narcolepsy. Modafinil [summary of product characteristics], 2011 . Available at:produc characterjstics- packa e--ieafset en pdf. Accessed: October 14,2021 ;Prmar-modafinil [product monograph]. Ottawa, Ontario: Marcan Pharmaceuticals Inc.; 2017. Modavigil. 2023. Available at:Accessed: 10 July 2023. The WPA armodafinil is approved in the US and Australia to improve wakefulness in similar sleep disorders (eg, OSA and EDS). Nuvigil [package insert]. North Wales, PA: Teva Pharmaceuticals; 2018. Armodafinil for sleep disorders. Aust Prescr. 2016;39:221-222. However, it remains unclear whether modafinil or armodafinil improve cognitive function in this patient population. Avellar AB, Carvalho LB, Prado GF, Prado LB. Pharmacotherapy for residual excessive sleepiness and cognition in CPAP-treated patients with obstructive sleep apnea syndrome: A systematic review and meta-analysis. Sleep Med Rev. 2016;30:97-107; Kuan YC, Wu D, Huang KW, et al. Effects of modafinil and armodafinil in patients with obstructive sleep apnea: A meta-analysis of randomized controlled trials. Clin Ther. 2016;38(4):874-888. (18P2)

[0005] Cognitive impairment is a broad term used to describe some degree of difficulty with cognitive functioning. Impairment can range in intensity and may involve problems with memory, concentration, language, perceptual-motor skills, decision making, and learning. Cognitive impairment is prevalent in our increasingly aging population, with approximately 16% of the population over the age of 70 experiencing some type of mild cognitive impairment. There are currently no FDA-approved treatment for cognitive impairment.

[0006] The present invention overcomes shortcomings in the art by evaluating whether solriamfetol improves cognitive function in participants with impaired cognition associated with OSA and EDS.Summary of the Invention

[0007] The present invention relates to the development of methods for enhancing one or more cognitive function in patients with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness.

[0008] Accordingly, one aspect of the present invention relates to a method of enhancing one or more cognitive function, said method comprising administering to a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof.

[0009] Another aspect of the invention relates to a method of treating one or more cognitive impairment, said method comprising administering to a subject with obstructive sleep apnea and excessive daytime sleepiness which has resulted in one or more cognitive impairment a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof.

[0010] A further aspect of the invention relates to a method of delaying or slowing an increase in one or more cognitive impairment, said method comprising administering to a subject having or at risk of having said one or more cognitive impairment resultingfrom obstructive sleep apnea and excessive daytime sleepiness a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof, thereby treating one or more cognitive impairment in the subject.

[0011] In some embodiments, the compound is the compound of formula Ior a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the hydrochloride salt of the compound of formula II or I.

[0012] These and other aspects of the invention are set forth in more detail in the description of the invention below.Brief Description of the Drawings

[0013] Some embodiments of the present invention are illustrated as an example and are not limited by the figures of the accompanying drawings, in which like references may indicate similar elements and in which:Figure 1. CONSORT FlowchartFigure 2a. Study DesignFigure 2b. Clinic Visit StructureFigure 3a. Overall Change From Baseline in DSST RBANS ScoreFigure 3b. Change From Baseline in DSST RBANS Score by Time PointFigure 4. Change From Baseline in Overall BC-CCI ScoreFigure 5. Overall Change from Baseline in PGI-S ScoreFigure 6. Overall Change from Baseline in ESS ScoreFigure 7. NNT for Categorical Improvement in PGIc and CGIc for SolriamfetolCompared With Placebo.Figure 8. NNT for Achieving >25% Decrease in ESS Score or ESS <10 for Solriamfetol Compared With PlaceboFigure 9. NNT for Achieving MWT of >20 Minutes for Solriamfetol Compared With Placebo in Participants With OSAFigure 10. The Most Common Starting Dose of Solriamfetol Was 37.5 mg / dayFigure 11. Mean Decrease in ESS Scores3With Solriamfetol Was >5 Points, Indicating Clinically Meaningful Improvement in EDSFigure 12. Patients and Physicians Perceived Improvements in Symptoms in Approximately 90% of PatientsFigure 13. Most Patients Reported That the Effects of Solriamfetol Lasted >8 HoursFigure 14. Study DesignDetailed Description of the Invention

[0014] The present invention can be embodied in different forms and 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 invention to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Abbreviations which may be used in this description include:BC-CCI, British Columbia Cognitive Complaints InventoryCl, confidence intervalC-SSRS, Columbia-Suicide Severity Rating ScaleDSST, Digit Symbol Substitution Test EDS, excessive daytime sleepiness ESS, Epworth Sleepiness Scale OSA, obstructive sleep apnea PAP, positive airway pressure PGI-S, Patient Global Impression of Severity RBANS, Repeatable Battery for the Assessment of Neuropsychological StatusSD, standard deviationSE, standard errorTAAR1 , trace amine-associated receptor 1 TEAE, treatment-emergent adverse events US, United StatesWAIS-IV, Wechsler Adult Intelligence Scale, 4th EditionWPA, wake-promoting agent

[0016] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described herein can be used in any combination.

[0017] Moreover, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.

[0018] 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.

[0019] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes.

[0020] As used herein, “a,” “an,” or “the” can mean one or more than one. For example, “a” cell can mean a single cell or a multiplicity of cells.

[0021] 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”).

[0022] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ± 10%, ± 5%, ± 1 %, ± 0.5%, or even ± 0.1 % of the specified amount.

[0023] The term “consists essentially of” (and grammatical variants), as applied to the compositions of this invention, means the composition can contain additional components as long as the additional components do not materially alter the composition. The term “materially altered,” as applied to a composition, refers to an increase or decrease in the therapeutic effectiveness of the composition of at least about 20% or more as compared to the effectiveness of a composition consisting of the recited components.

[0024] The term “therapeutically effective amount” or “effective amount,” as used herein, refers to that amount of a composition, compound, or agent of this invention that imparts a modulating effect, which, for example, can be a beneficial effect, to asubject 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 refer to 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 100%.

[0025] “Treat” or “treating” or “treatment” refers to any type of action 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, and / or change in clinical parameters, disease or illness, etc., as would be well known in the art.

[0026] “Pharmaceutically acceptable,” as used herein, means a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any 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-, 21sted. 2005).

[0027] “Concurrently” means 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 thecompounds in two different formulations, for example, at the same point in time but at different anatomic sites or using different routes of administration.

[0028] The present invention relates to a method of enhancing one or more cognitive function, said method comprising administering to a subject with OSA and EDS which has resulted in one or more cognitive impairment a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the one or more cognitive function is selected from executive function, memory, and learning. In some embodiments, the one or more cognitive function is selected from working memory, cognitive flexibility, and response inhibition.

[0030] Another aspect of the invention relates to a method of treating one or more cognitive impairment, said method comprising administering to a subject having said one or more cognitive impairment resulting from OSA and EDS a therapeutically effective amount of a compound of formula Ior a pharmaceutically acceptable salt thereof.

[0031] A further aspect of the inventio relates to a method of delaying or slowing an increase in one or more cognitive impairment, said method comprising administering to a subject with OSA and EDS having or at risk of having said one or more cognitive impairment a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof, thereby treating one or more cognitive impairment in the subject. The subject may be one that has been diagnosed with OSA and EDS resulting in one or more cognitive impairment and worsening of the impairments is delayed or slowed relative to a subject not treated with the method of the invention. The subject may be one with OSA and EDS that is at risk of developing one or more cognitive impairment and onset of the impairments is delayed relative to a subject not treated with the method of the invention.

[0032] In some embodiments, the subject with OSA and EDS is identified as having a neurological disorder associated with cognitive impairment, e.g., identified as having Alzheimer’s Disease, schizophrenia, autism, or obsessive-compulsive disorder.

[0033] In some embodiments, the cognitive impairment is selected from impaired executive function, impaired learning, and impaired memory. In some embodiments, the cognitive impairment is selected from impaired cognitive flexibility, impaired working memory, and impaired response inhibition.

[0034] In some embodiments of the methods of the invention, the compound is the compound of formula Ior a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the hydrochloride salt of the compound of formula II or I.

[0035] The methods of the present invention may be carried out using compounds, formulations and unit dosage forms provided herein. In some embodiments, the formulations and dosage forms can be utilized to achieve immediate release of APC,as well as pharmaceutically acceptable salts, hydrates, isomers, including tautomers, solvates and complexes of APC.

[0036] Suitable salts of APC include, without limitation, acetate, adipate, alginate, aspartate, benzoate, butyrate, citrate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, hydroxynapthoate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compound of the invention and their pharmaceutically acceptable acid addition salts. In certain embodiments, the salt is the hydrochloride salt.

[0037] APC compounds include those having quaternization of any basic nitrogencontaining group therein.

[0038] The discussion herein is, for simplicity, provided without reference to stereoisomerism or the addition of deuterium atoms. Those skilled in the art will appreciate that APC can contain one or more asymmetric centers and thus occur as racemates and racemic mixtures and single optical isomers. All such isomeric and deuterated forms of these compounds are expressly included in the present invention.

[0039] The discussion herein is also provided without reference to polymorphs, hydrates, clathrates, solvates, inclusion compounds, isomers, or other forms of the compound. All such forms of APC are expressly included in the present invention.

[0040] Further, the compounds of the invention include prodrugs of the compounds that are converted to the active compound in vivo. For example, the compound can be modified to enhance cellular permeability (e.g., by esterification of polar groups) and then converted by cellular enzymes to produce the active agent. Methods of masking charged or reactive moieties as a pro-drug are known by those skilled in the art (see, e.g., P. Korgsgaard-Larsen and H. Bundgaard, A Textbook of Drug Design and Development, Reading U.K., Harwood Academic Publishers, 1991).

[0041] The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood, see, e.g., T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of theA.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also U.S. Patent No. 6,680,299. Exemplary prodrugs include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of the compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an amide of an amine group or carboxylic acid group, if such groups are present in the compound; a urethane of an amine group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; a N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described, for example, in U.S. Patent No. 6,680,324 and U.S. Patent No. 6,680,322.

[0042] The term “pharmaceutically acceptable prodrug” (and like terms) as used herein refers to those prodrugs of APC which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk / benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compound of the invention.

[0043] APC or a pharmaceutically acceptable salt thereof may be obtained or synthesized by methods known in the art and as described herein. Details of reaction schemes for synthesizing APC have been described in U.S. Patent Nos. 5,705,640; 5,756,817; 5,955,499; 6,140,532; and 10,829,443, all incorporated herein by reference in their entirety.

[0044] Another aspect of the invention relates to a composition, e.g., a dosage form, comprising APC that is suitable for used in the methods of the invention. In some embodiments, the composition is a pharmaceutical composition comprising APC and a pharmaceutically acceptable carrier. In some embodiments, the dosage form is an oral dosage form, e.g., a tablet or a capsule, e.g., an immediate release dosage form.

[0045] In some embodiments, the dosage form is an immediate release tablet that releases at least 85%, e.g., at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%, of the APC contained therein within a period of less than 15 minutes after administration ofthe tablet to a subject, e.g., as described in U.S. Patent Nos. 10,195,151 ; 10,512,609; and 11 ,439,597.

[0046] Formulations of APC, including immediate release formulations, may be processed into unit dosage forms suitable for oral administration, such as for example, filled capsules, compressed tablets or caplets, or other dosage form suitable for oral administration using conventional techniques. Immediate release dosage forms prepared as described may be adapted for oral administration, so as to attain and maintain a therapeutic level of the compound over a preselected interval. In certain embodiments, an immediate release dosage form as described herein may comprise a solid oral dosage form of any desired shape and size including round, oval, oblong cylindrical, or polygonal. In one such embodiment, the surfaces of the immediate release dosage form may be flat, round, concave, or convex.

[0047] In particular, when the immediate release formulations are prepared as a tablet, the immediate release tablets contain a relatively large percentage and absolute amount of the compound and so are expected to improve patient compliance and convenience, by replacing the need to ingest large amounts of liquids or liquid / solid suspensions. One or more immediate release tablets as described herein can be administered, by oral ingestion, e.g., closely spaced, in order to provide a therapeutically effective dose of the compound to the subject in a relatively short period of time.

[0048] Where desired or necessary, the outer surface of an immediate release dosage form may be coated, e.g., with a color coat or with a moisture barrier layer using materials and methods known in the art.

[0049] In some embodiments, the composition is an immediate release compressed tablet, the tablet comprising:APC or a pharmaceutically acceptable salt thereof in an amount of about 90-98% by weight of the tablet; at least one binder in an amount of about 1-5% by weight of the tablet; and at least one lubricant in an amount of about 0.1-2% by weight of the tablet; wherein the tablet releases at least 85% of the APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 15 minutes after administration of the tablet to a subject.

[0050] In one embodiment, the tablet comprises:APC or a pharmaceutically acceptable salt thereof in an amount of about 91-95% by weight of the tablet; at least one binder in an amount of about 2-3% by weight of the tablet; at least one lubricant in an amount of about 0.1-1 % by weight of the tablet; and optionally, a cosmetic film coat in an amount of about 3-4% by weight of the tablet; wherein the tablet releases at least 85% of the APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 15 minutes after administration of the tablet to a subject.

[0051] In one embodiment, the tablet comprises:APC or a pharmaceutically acceptable salt thereof in an amount of about 93.22% by weight of the tablet; at least one binder (e.g., hydroxypropylcellulose) in an amount of about 2.87% by weight of the tablet; at least one lubricant (e.g., magnesium stearate) in an amount of about 0.52% by weight of the tablet; and optionally, a cosmetic film coat (e.g., Opadry® II yellow) in an amount of about 3-4% by weight of the tablet; wherein the tablet releases at least 85% of the APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 15 minutes after administration of the tablet to a subject.

[0052] In some embodiments, the composition is an immediate release oral dosage form of APC, the oral dosage form comprising:APC or a pharmaceutically acceptable salt thereof in an amount of about 90-98% by weight of the oral dosage form; at least one binder in an amount of about 1-5% by weight of the oral dosage form; and at least one lubricant in an amount of about 0.1-2% by weight of the oral dosage form; wherein the oral dosage form releases at least 85% of the APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 15 minutes after administration of the oral dosage form to a subject.

[0053] In certain embodiments, the tablet does not comprise a disintegrant. The term “disintegrant,” as used herein, refers to an agent added to a tablet to promote the breakup of the tablet in an aqueous environment. The tablets of the present invention are advantageous in that they dissolve rather than disintegrate. In the present invention the presence of disintegrant in the formulation may actually slow down release of APC.

[0054] In certain embodiments, APC or a pharmaceutically acceptable salt thereof is present in an amount of about 90%, 90.5%, 91 %, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, or 98% by weight of the tablet or any value or range therein. In certain embodiments, APC or a pharmaceutically acceptable salt thereof is present in an amount of about 90% to about 98%, about 92% to about 98%, about 94% to about 98%, about 96% to about 98%, about 90% to about 92%, about 90% to about 94%, about 90% to about 96%, about 92% to about 94%, about 92% to about 96%, or about 94% to about 96%.

[0055] In certain embodiments, the at least one binder is present in an amount of about 1 %, 1 .5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight of the tablet or any value or range therein. In certain embodiments, the at least one binder is present in an amount of about 1 % to about 5%, about 2% to about 5%, about 3% to about 5%, about 4% to about 5%, about 1 % to about 2%, about 1 % to about 3%, about 1 % to about 4%, about 2% to about 3%, about 2% to about 4%, or about 3% to about 4%. The tablet may comprise at least one binder, e.g., 1 , 2, 3, 4, 5, or more binders.

[0056] In certain embodiments, the at least one binder is selected from at least one of hydroxypropyl cellulose, ethylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxyethyl cellulose, povidone, copovidone, pregelatinized starch, dextrin, gelatin, maltodextrin, starch, zein, acacia, alginic acid, carbomers (cross-linked polyacrylates), polymethacrylates, sodium carboxymethylcellulose, guar gum, hydrogenated vegetable oil (type 1), methylcellulose, magnesium aluminum silicate, and sodium alginate or any combination thereof. In some embodiments, the at least one binder is hydroxypropyl cellulose.

[0057] In certain embodiments, the at least one lubricant is present in an amount of about 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1 %, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% by weight of the tablet or anyvalue or range therein. In certain embodiments, the at least one lubricant is present in an amount of about 0.1 % to about 2.0%, about 0.5% to about 2.0%, about 1 .0% to about 2.0%, about 1.5% to about 2.0%, about 0.1 % to about 0.5%, about 0.1 % to about 1.0%, about 0.1% to about 1.5%, about 0.5% to about 1.0%, about 0.5% to about 1.5%, or about 1.0% to about 1.5%. The tablet may comprise at least one lubricant, e.g., 1 , 2, 3, 4, 5, or more lubricants. Where the immediate release formulation is provided as a tableted dosage form, still lower lubricant levels may be achieved with use of a “puffer” system during tableting. Such systems are known in the art, commercially available and apply lubricant directly to the punch and die surfaces rather than throughout the formulation.

[0058] In certain embodiments, the at least one lubricant is selected from at least one of magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearyl fumarate, and zinc stearate or any combination thereof. In some embodiments, the at least one lubricant is magnesium stearate. In other embodiments, magnesium stearate may be used in combination with one or more other lubricants or a surfactant, such as sodium lauryl sulfate. In particular, if needed to overcome potential hydrophobic properties of magnesium stearate, sodium lauryl sulfate may also be included when using magnesium stearate (Remington: the Science and Practice of Pharmacy, 20thedition, Gennaro, Ed., Lippincott Williams & Wilkins (2000)).

[0059] In some embodiments, the at least one binder is hydroxypropyl cellulose. In some embodiments, the at least one lubricant is magnesium stearate. In some embodiments, the at least one binder is hydroxypropyl cellulose and the at least one lubricant is magnesium stearate.

[0060] In certain embodiments, the tablet is coated. The coating may be, without limitation, a color overcoat.

[0061] In some embodiments, the APC or a pharmaceutically acceptable salt thereof is APC hydrochloride.

[0062] The tablet may be any shape that is suitable for immediate release and allows the release of at least 85% of the APC or a pharmaceutically acceptable salt thereof contained therein within a period of less than 15 minutes after administration of thetablet to a subject. In some embodiments, the tablet maximizes surface area to volume ratio to promote rapid dissolution. In some embodiments, the tablet is oblong in shape.

[0063] The tablet may contain any amount of APC or a pharmaceutically acceptable salt thereof suitable for administration as a unit dosage form. In some embodiments, the tablet contains about 1 mg to about 1000 mg of the drug or any range or value therein, e.g., about 100 mg to about 500 mg, e.g., about 37.5 mg, about 75 mg, about 150 mg, or about 300 mg.

[0064] “Immediate release” as used herein, refers to a composition that releases APC or a pharmaceutically acceptable salt, hydrate, isomer, tautomer, solvate or complex thereof substantially completely into the gastrointestinal tract of the user within a period of less than about 15 minutes, usually between about 1 minute and about 15 minutes from ingestion. Such a delivery rate allows the drug to be absorbed by the gastrointestinal tract in a manner that is bioequivalent to an oral solution. Such rapid absorption will typically occur for an immediate release unit dosage form, such as a tablet, caplet or capsule, if the drug included in such dosage form dissolves in the upper portion the gastrointestinal tract.

[0065] Release rates can be measured using standard dissolution test methods. For example, the standard conditions may be those described in FDA guidance (e.g., 50 rpm, 37°C, USP 2 paddles, pH 1 .2 and pH 6.8 media, 900 ml, 1 test article per vessel).

[0066] Immediate release formulations suitable for oral administration may comprise unit dosage forms, such as tablets, caplets or filled capsules, which can deliver a therapeutically effective dose of APC upon ingestion thereof by the patient of one or more of said dosage forms, each of which can provide a dosage of, for example, about 1 to about 1000 mg of APC. Additionally, the immediate release dosage forms can be shaped or scored to facilitate dose adjustment through tablet splitting.

[0067] The formulation and structure of an immediate release dosage form as disclosed herein can be adjusted to provide immediate release performance that suits a particular dosing need. In particular, the formulation and structure of the dosage forms as described herein can be adjusted to provide any combination of the immediate release performance characteristics described herein. In particular embodiments, for example, an immediate release dosage form as disclosed hereinprovides rapid onset of action, releasing more than about 85%, such as, for example, more than about 90% or 95%, of the drug contained therein within a period of time selected from less than 15 minutes, less than 12 minutes, less than 10 minutes, and less than 5 minutes after administration.

[0068] Moreover, the rate of drug release from an immediate release dosage form as disclosed herein may be adjusted as needed to facilitate a desired dosing regimen or achieve targeted dosing. In one embodiment, the immediate release dosage form may be formulated to deliver as much as 1 ,000 mg of APC. In particular embodiments, the total amount of drug contained within an immediate release dosage form according to the present description may be between about 50 mg and about 500 mg. For example, in certain such embodiments, the total amount of drug may be selected from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1000 mg or any range or value therein. In certain such embodiments, the total amount of drug may be about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 300 mg, about 30 mg to about 1000 mg, about 30 mg to about 500 mg, about 30 mg to about 300 mg, about 100 mg to about 1000 mg, about 10 mg to about 500 mg, about 100 mg to about 300 mg, about 150 mg to about 1000 mg, about 150 mg to about 500 mg, or about 150 mg to about 300 mg.

[0069] The immediate release formulations provided herein generally include APC and some level of lubricant to facilitate processing of the formulations into a unit dosage form. In some embodiments, therefore, the formulations described herein include a combination of APC and lubricant, as described herein, and in certain such embodiments, the immediate release formulations are substantially free of other excipients or adjuvants. In other embodiments, the immediate release formulations described herein include a combination of APC, lubricant, and binder, as described herein, and in certain such embodiments, the immediate release formulations are substantially free of other excipients or adjuvants. Though the immediate release formulations described herein may be formulated using a combination of drug and one or more of a lubricant and binder, in certain embodiments, the compositions described herein may include one or more additional excipients selected from, for example,fillers, compression aids, diluents, disintegrants, colorants, flavorants, buffering agents, coatings, glidants, or other suitable excipients.

[0070] The immediate release formulations described herein may be manufactured using standard techniques, such as wet granulation, roller compaction, fluid bed granulation, and dry powder blending. Suitable methods for the manufacture of the immediate release formulations and unit dosage forms described herein are provided, for example, in Remington, 20thedition, Chapter 45 (Oral Solid Dosage Forms). It has been found that, even without the aid of binders or non-lubricating excipients, such as compression aids, wet granulation techniques can afford flowable granules with compression characteristics suitable for forming unit dosage forms as described herein. Therefore, in certain embodiments, where a drug content greater than about 85%, 90% or 95% by weight is desired for the immediate release formulation, wet granulation techniques may be used to prepare immediate release formulations as described herein. In such embodiments, as illustrated in the Examples provided herein, conventional organic or aqueous solvents may be used in the wet granulation process. Suitable wet granulation processes can be performed as fluidized bed, high shear, or low shear (wet massing) granulation techniques, as are known in the art.

[0071] In addition to one or more of APC, lubricant, and binder, where desired, the immediate release formulations described herein may also include fillers or compression aids selected from at least one of lactose, calcium carbonate, calcium sulfate, compressible sugars, dextrates, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, and sucrose. Where a filler or compression aid is used, in certain embodiments, it may be included in the immediate release formulation in an amount ranging from about 1 %-15% by weight.

[0072] Immediate release formulations as described herein may be processed into unit dosage forms suitable for oral administration, such as for example, filled capsules, compressed tablets or caplets, or other dosage form suitable for oral administration using conventional techniques. Immediate release dosage forms prepared as described may be adapted for oral administration, so as to attain and maintain a therapeutic level of APC over a preselected interval. In certain embodiments, an immediate release dosage form as described herein may comprise a solid oral dosageform of any desired shape and size including round, oval, oblong, cylindrical, or polygonal. In one such embodiment, the surfaces of the immediate release dosage form may be flat, round, concave, or convex. In some embodiments, the shape may be selected to maximize surface area, e.g., to increase the rate of dissolution of the dosage form.

[0073] In particular, when the immediate release formulations are prepared as a tablet, the immediate release tablets contain a relatively large percentage and absolute amount of APC and so are expected to improve patient compliance and convenience, by replacing the need to ingest large amounts of liquids or liquid / solid suspensions. One or more immediate release tablets as described herein can be administered, by oral ingestion, e.g., closely spaced, in order to provide a therapeutically effective dose of APC to the subject in a relatively short period of time. For example, dissolution of a 10 mg-1000 mg tablet prepared according to the present description can provide about 80-100% of the APC to the subject in about 10-15 minutes.

[0074] Where desired or necessary, the outer surface of an immediate release dosage form as disclosed herein may be coated with a moisture barrier layer using materials and methods known in the art. For example, where the APC delivered by the unit dosage form is highly hygroscopic, providing a moisture barrier layer over the immediate release dosage form as disclosed herein may be desirable. For example, protection of an immediate release dosage form as disclosed herein from water during storage may be provided or enhanced by coating the tablet with a coating of a substantially water soluble or insoluble polymer. Useful water-insoluble or water- resistant coating polymers include ethyl cellulose and polyvinyl acetates. Further water-insoluble or water-resistant coating polymers include polyacrylates, polymethacrylates or the like. Suitable water-soluble polymers include polyvinyl alcohol and HPMC. Further suitable water-soluble polymers include PVP, HPC, HPEC, PEG, HEC and the like.

[0075] Where desired or necessary, the outer surface of an immediate release dosage form as disclosed herein may be coated with a color overcoat or other aesthetic or functional layer using materials and methods known in the art.

[0076] The dosage forms disclosed herein can also be provided as a kit comprising, separately packaged, a container comprising a plurality of immediate release tablets, which tablets can be individually packaged, as in foil envelopes or in a blister pack. The tablets can be packaged in many conformations with or without desiccants or other materials to prevent ingress of water. Instruction materials or means, such as printed labeling, can also be included for their administration, e.g. , sequentially over a preselected time period and / or at preselected intervals, to yield the desired levels of APC in vivo for preselected periods of time, to treat a preselected condition.

[0077] A daily dose of about 1 to about 2000 mg of APC or a pharmaceutically acceptable salt thereof may be administered to accomplish the therapeutic results disclosed herein. For example, a daily dosage of about 10-1000 mg, e.g., about 20- 500 mg, e.g., about 37.5, 75, 150, or 300 mg, in single or divided doses, is administered. In some embodiments, the daily dose may be about 0.01 to about 150 mg / kg body weight, e.g., about 0.2 to about 18 mg / kg body weight.

[0078] In one embodiment of the invention, APC is administered to the subject as needed to treat a disorder. The compound can be administered continuously or intermittently. In one embodiment, the compound is administered to the subject more than once a day, e.g., 2, 3, or 4 times per day, or once every 1 , 2, 3, 4, 5, 6, or 7 days. In another embodiment, the compound is administered to the subject no more than once a week, e.g., no more than once every two weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, or longer. In a further embodiment, the compound is administered using two or more different schedules, e.g., more frequently initially (for example to build up to a certain level, e.g., once a day or more) and then less frequently (e.g., once a week or less). In other embodiments, the compound can be administered by any discontinuous administration regimen. In one example, the compound can be administered not more than once every three days, every four days, every five days, every six days, every seven days, every eight days, every nine days, or every ten days, or longer. The administration can continue for one, two, three, or four weeks or one, two, or three months, or longer. Optionally, after a period of rest, the compound can be administered under the same or a different schedule. The period of rest can be one, two, three, or four weeks, or longer, according to thepharmacodynamic effects of the compound on the subject. In another embodiment the compound can be administered to build up to a certain level, then maintained at a constant level and then a tailing dosage.

[0079] In one aspect of the invention, APC is delivered to a subject concurrently with an additional therapeutic agent. The additional therapeutic agent can be delivered in the same composition as the compound or in a separate composition. The additional therapeutic agent can be delivered to the subject on a different schedule or by a different route as compared to the compound. The additional therapeutic agent can be any agent that provides a benefit to the subject. Further agents include, without limitation, nootropic agents (e.g., cognitive enhancers), including without limitation, stimulants (e.g., caffeine, dimethylamylamine, methylphenidate, amphetamine, nicotine, modafinil, armodafinil), racetams (e.g., piracetam, oxiracetam, phenylpiracetam, aniracetam), tolcapone, levodopa, atomoxetine, pramipexole, guanfacine, clonidine, and fexofenadine. Nootropic agents may also include herbs, such as Bacopa monnieri, Panax ginseng, Ginkgo biloba, and Salvia officinalis, and dietary supplements, such as omega-3 fatty acids, folate, vitamin Be, vitamin B12, vitamin E, and L-theanine. One therapeutic agent that can be administered during the same period is Xyrem®, sold commercially by Jazz Pharmaceuticals, which is used to treat narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0080] The present invention finds use in research as well as veterinary and medical applications. Suitable subjects are generally mammalian subjects. The term “mammal” as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), etc. Human subjects include neonates, infants, juveniles, adults and geriatric subjects.

[0081] The subject can be a subject “in need of” the methods of the present invention, e.g., in need of the therapeutic effects of the inventive methods. For example, the subject can be a subject that is experiencing cognitive impairment, is suspected of having cognitive impairment, and / or is anticipated to experience cognitive impairment, and the methods and compositions of the invention are used for therapeutic and / or prophylactic treatment.

[0082] Having described the present invention, the same will be explained in greater detail in the following examples, which are included herein for illustration purposes only, and which are not intended to be limiting to the invention.EXAMPLE 1A Randomized, Placebo-Controlled, Double-Blind, Repeated-Measures, Crossover, Phase IV Clinical Trial of the Effect of the Wake-Promoting Agent Solriamfetol on Cognitive Function in Obstructive Sleep Apnea With Excessive Daytime Sleepiness and Cognitive ImpairmentSTUDY DESIGN AND METHODS

[0083] SHARP (Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a Randomized Placebo-controlled Study) was a phase IV randomized, double-blind, placebo-controlled, crossover trial that evaluated the efficacy and safety of solriamfetol in participants with cognitive impairment associated with EDS and OSA (NCT04789174; EudraCT: 2020-004243-92). The study was conducted from May 2021 to September 2022 at 28 sites in North America (US, Canada) and Europe (United Kingdom, Netherlands, Spain, Italy) (e-Appendix 1 ) and in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines. Study enrollment ended following a change in sponsor in May 2022. Prior to database lock, the study protocol was amended August 2022, changing the primary DSST-RBANS endpoint from the average of the 2- and 4-hour post-dose assessments to the average of the 2-, 4-, 6-, and 8-hour post-dose assessments. Research protocols and amendments were approved by each institution’s ethics committee or institutional review board. All participants provided written informed consent.Participants

[0084] Participants were 18- to 65-year-old males and females diagnosed with OSA per the International Classification of Sleep Disorders 3rd Edition criteria. Sateia MJ. International Classification of Sleep Disorders-third edition: highlights and modifications. Chest. 2014; 146(5): 1387-1394. Associated EDS was defined as an Epworth Sleepiness Scale (ESS) score >10 at screening and baseline. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991 ;14(6):540-545. Impaired cognitive function was defined as an age- corrected scaled score <8 on the Coding subtest, a version of the Digit Symbol Substitution Test (DSST) in the Wechsler Adult Intelligence Scale, 4th Edition (DSST WAIS-IV) at screening and a score >9 on the British Columbia Cognitive Complaints Inventory (BC-CCI) at screening and baseline. Jaeger J. Digit Symbol Substitution Test: The case for sensitivity over specificity in neuropsychological testing. J Clin Psychopharmacol. 2018;38(5):513-519; Iverson GL, Lam RW. Rapid screening for perceived cognitive impairment in major depressive disorder. Ann Clin Psychiatry. 2013;25(2):135-140.

[0085] Figure 1 shows the CONSORT flowchart for the study. Participants were included if they were consistent in the number of hours of PAP use on >5 nights / week for >1 month prior to baseline; had no current PAP therapy for >1 month prior to baseline but a history of attempted PAP use for >1 month with >1 adjustments intended to optimize therapy; or a history of surgical intervention intended to treat OSA symptoms. Usual bedtime later than 1 :00 AM; shift work; use of over-the-counter or prescription medications that could affect EDS; any contraindication for solriamfetol; use of PAP machine without downloadable adherence data; diagnosis of a sleep disorder other than OSA; positive urine drug screen during the study; excessive caffeine use (>600 mg / day) 1 week prior to screening or anticipated during the study; and history or current diagnosis of any clinically relevant medical, behavioral, or psychiatric disorder associated with impaired cognitive function were exclusionary.Treatment

[0086] At the baseline visit, participants were randomized 1 :1 to treatment with oral solriamfetol (75 mg / day for 3 days, then 150 mg / day) or matching placebo each morning for 2 weeks. After a 1-week washout period, participants crossed over to receive the opposite treatment for 2 weeks.Assessments

[0087] Objective cognition was assessed with the Coding subtest, a variation of the DSST in the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS), an objective measure of cognitive function sensitive to pharmacologic intervention. Based on the DSST WAIS-IV, the DSST RBANS is a symbol-digit test that measures attention, processing speed, and executive functions (eg, working memory); participants were asked to match symbols to numbers in accordance with a key. To avoid practice effects, a practice test followed by rotating versions of the DSST RBANS were administered during screening and each assessment visit. The DSST RBANS score was the number of correct symbol-digit pairings within 90 seconds.

[0088] Subjective cognition was assessed with the BC-CCI, a validated 6-item questionnaire that assessed self-reported problems with concentration, memory, expressing thoughts, word finding, thinking, and solving problems. Each item had four response options and was scored from 0 to 3, with higher scores indicating greater cognitive impairment. The BC-CCI score was the total score across items.

[0089] Perceived severity of problems with concentration, memory, and thinking skills was measured with the Patient Global Impression of Severity (PGI-S). Participants rated severity of problem over the last week from “none” (0) to “very severe” (4).

[0090] EDS was assessed with the ESS, a validated 8-item, self-report questionnaire that measures the likelihood of falling asleep in various activities. Each item had four response options and was scored 0-3, with higher scores indicating greater EDS.The ESS score was the total score across items. A detailed clinical visit structure is provided in Figure 2b.Outcomes

[0091] The primary efficacy endpoint was change from baseline to the end of each treatment period in the DSST RBANS scores averaged over the 2-, 4-, 6-, and 8- hour post-dose timepoints. A key secondary endpoint was the change from baseline to the end of each treatment period in BC-CCI scores. Other secondary endpoints included change from baseline to the end of each treatment period for the ESS and PGI-S and for the timepoint-specific DSST RBANS scores.

[0092] Safety and tolerability were assessed based on treatment-emergent adverse events (TEAEs) and vital signs. TEAEs were defined as any adverse event that started between treatment initiation (placebo or solriamfetol) up to 7 days after the last dose of study drug in each treatment period. Suicidal ideation was evaluated at screening, baseline, and each study visit using the Columbia-Suicide Severity Rating Scale (C-SSRS).Statistical Analysis and Power Calculation

[0093] Demographics, baseline clinical characteristics, and safety outcomes were summarized descriptively and were analyzed for the safety population (randomized participants who received >1 dose of the study drug). Efficacy outcomes were analyzed for the modified intent-to-treat population, (participants who received >1 dose of the study drug and had DSST RBANS scores at baseline and from at least 1 treatment period).

[0094] As the primary endpoint, average post-dose DSST RBANS scores were analyzed with a repeated-measures regression model estimating treatment effects with baseline as a covariate and controlling for treatment period, treatment sequence, and subject. The treatment effect and the two-sided 95% confidence interval (Cl) of the treatment difference (solriamfetol - placebo) are presented.Period and sequence effects were evaluated; carryover effect was not examined, considering the duration of the washout period. A secondary analysis was conducted on the DSST RBANS scores of each individual time point (2, 4, 6, and 8 hours postdose).

[0095] A fixed hierarchical testing sequence controlling for multiplicity was employed for the secondary endpoints, focusing on change in score from baseline to the end of each treatment period in 1) BC-CCI, 2) PGI-S, and 3) ESS. The testing sequence was stopped when the two-sided P value was no longer significant (ie, P>0.05). Results are presented as least squares (LS) mean change from baseline and its standard error (SE). Effect sizes (Cohen’s d) were determined for the change from baseline to the end of each treatment period in DSST RBANS, BC-CCI, PGI-S, and ESS scores.

[0096] Exploratory analyses included Pearson correlation between change from baseline to end of treatment period, stratified by treatment condition and controlling for treatment sequence, in ESS and DSST RBANS scores, ESS and BC-CCI scores, and ESS and PGI-S scores.

[0097] The original sample size determination was based on a >3.0 point mean difference between solriamfetol and placebo in the change from baseline to the end of each double-blind treatment period in DSST RBANS scores at 2 and 4 hours postdose, with a SD <9.0 points. This was informed by previous randomized, parallel, placebo-controlled trials of vortioxetine36 37; additional details on the original primary outcome prior to study amendment are presented in Supplemental Material.Because the primary efficacy outcome for the present study was the average of DSST RBANS scores at 2, 4, 6, and 8 hours post-dose (ie, twice as many time points), an overall SD of 6.9 points was assumed. Using a two-group t-test for the crossover design of the present study and assuming a correlation of 0.5 between treatment periods, the sample size needed to detect an equivalent effect size with at least 90% power at a two-sided type I error rate of 0.05 would be 29 participants per treatment sequence, or 58 participants overall.RESULTSParticipant Population

[0098] Of the 173 participants screened for this study, 59 were enrolled and randomly assigned to one of the two treatment sequences. The safety population included 59 (solriamfetol / placebo, n=30; placebo / solriamfetol, n=29) participants. Two participants (one in each treatment sequence) did not complete the study; one completed the first period efficacy visit, resulting in 58 participants in the modified intent-to-treat population with data available for analysis of efficacy outcomes (Figure 1). Baseline demographic and clinical characteristics were similar between treatment groups, including PAP use (Table 1). Overall, PAP was used by 42 (71.2%) participants, most of whom (n=34) were adherent users (defined as >4 hours of PAP use per night for >70% of nights in any given time frame). Mean ± standard deviation (SD) baseline PAP use per night among all users was 6.3 ± 2.5 hours.Table 1. Baseline Demographic and Clinical CharacteristicsaAge-corrected scaled score at screening to determine eligibility.bAssessed problems with cognitive function, including concentration, memory, and thinking skills.cAdherence defined as >4 hours of PAP use per night for >70% of nights in any given time frame.BC-CCI, British Columbia Cognitive Complaints Inventory; BMI, body mass index; DSST, Digit Symbol Substitution Test; DSST RBANS, the Coding subtest, a variation of the DSST in the Repeatable Battery for the Assessment of Neuropsychological Status; ESS, Epworth Sleepiness Scale; PAP, positive airway pressure; PGI-S, Patient Global Impression of Severity; SD, standard deviation; WAIS-IV, Wechsler Adult Intelligence Scale, 4th Edition.Efficacy and Safety

[0099] The primary endpoint of change from baseline to the end of treatment in average DSST RBANS scores showed a statistically significant difference between solriamfetol and placebo (Figure 3a). Mean (SE) change from baseline after solriamfetol treatment (6.49 [0.65]) was significantly greater (ie, improved) compared with placebo (4.74 [0.65]); the mean difference (solriamfetol vs placebo) was 1.75 (95% Cl: 0.46, 3.04; P=0.009; effect size: d=0.37). Post hoc analysis of the change in average of the 2- and 4-hour DSST RBANS (original primary endpoint prior to study amendment) was consistent with the current primary endpoint.

[0100] When evaluated at each 2-hour time point, DSST RBANS scores significantly improved with solriamfetol relative to placebo at 2, 6, and 8 hours after dosing (Figure 3b). Mean differences at 2, 4, 6, and 8 hours were 1.91 (95% Cl: 0.16, 3.65; P=0.033), 1.38 (95% Cl: -0.22, 2.97; P=0.089), 2.33 (95% Cl: 0.78, 3.88; P=0.004), and 1.58 (95% Cl: 0.23, 2.93; P=0.022), respectively. There was no significant effect of period (P=0.274) or sequence (P=0.915).

[0101] The mean (SE) change from baseline to end of each treatment period on the BC-CCI showed a significantly greater decrease (ie, improvement) of -4.7 (0.48) after solriamfetol treatment compared with -3.1 (0.48) after placebo (Figure 4), with a mean difference of -1 .58 (95% Cl: -2.53, -0.63; P=0.002); effect size: d=0.45.

[0102] The mean change from baseline on the PGI-S showed a significantly greater decrease (ie, improvement) of -0.90 (0.10) after solriamfetol treatment compared with -0.61 (0.10) after placebo (Figure 5), with a mean difference of -0.29 (95% Cl: -0.57, -0.02; P=0.034; effect size: d=0.29).

[0103] Solriamfetol significantly improved EDS as measured by ESS scores. The mean (SE) change from baseline to end of solriamfetol treatment was -4.41 (0.57), compared with -2.31 (0.56) for placebo (Figure 6); the mean difference was -2.10 (95% Cl: -3.51 , -0.68; P=0.004; effect size: d=0.40).

[0104] The change from baseline to the end of each treatment period in ESS scores had statistically significant correlations, controlling for treatment sequence, with day- average DSST RBANS scores (solriamfetol, r=-0.28, P=0.036; placebo, r=-0.30, P=0.023), BC-CCI scores (solriamfetol, r=0.54, P<0.001 ; placebo, r=0.60, P<0.001 ), and PGI-S scores (solriamfetol, r=0.56, P<0.001 ; placebo, r=0.46, P<0.001). In all cases, a greater drop in ESS corresponded with a greater improvement in cognitive outcomes.

[0105] There were no deaths, serious TEAEs, or TEAEs that led to discontinuation of the study. Overall, 16 of 59 patients (27.1 %) in the safety population experienced any TEAE throughout the study; all were mild or moderate in severity. The incidence of any TEAE with solriamfetol (19.0%) was higher than with placebo (10.3%; Table 2). The most common TEAEs with solriamfetol were nausea (7%) and anxiety (3%). No participants had suicidal thoughts or behaviors as determined by the C-SSRS.Table 2. Treatment-Emergent Adverse EventsTEAE, treatment-emergent adverse event.*0f the safety population of 59 participants, 57 received both solriamfetol and placebo treatments. Of the 2 participants lost to follow up, 1 received solriamfetol only and 1 received placebo only. Thus, 58 participants received solriamfetol during the study, and 58 received placebo.

[0106] The change from baseline in diastolic blood pressure was greater with solriamfetol (LS mean [SE]: 2.0 [0.6] mmHg, SD: 4.7 mmHg) than with placebo (0.5 [0.6] mmHg, SD: 4.6 mmHg, P=0.033). There were no significant differences between solriamfetol and placebo in change from baseline in systolic blood pressure (solriamfetol: 1.0 [0.8] mmHg, SD: 6.3 mmHg; placebo: -0.4 [0.8] mmHg, P=0.146, SD: 6.3 mmHg), pulse rate (solriamfetol: 0.1 [1.0] bpm, SD: 7.1 bpm; placebo: -0.6[1.0 bpm], SD: 7.1 bpm, P=0.396), or weight (solriamfetol: 0.03 [0.19] kg, SD: 1.40 kg; placebo: 0.27 [0.19] kg, SD: 1.38 kg, P=0.252).DISCUSSION

[0107] Solriamfetol significantly improved cognitive function in patients with cognitive impairment associated with OSA and EDS. The overall improvement in objective cognition on the DSST RBANS scores demonstrated efficacy of solriamfetol over placebo over a 2-week treatment period. Results from the analysis of the original primary endpoint were similar. This effect was generally consistent over time (2 to 8 hours after dosing), indicating the therapeutic effects of solriamfetol were maintained throughout an 8-hour day. Participants reported an overall improvement in subjective cognitive function with solriamfetol on the BC-CCI. Taken together, these results indicate solriamfetol’s efficacy over placebo in both objective and subjective measures of cognitive function.

[0108] As expected, solriamfetol improved EDS relative to placebo. This is consistent with findings from the solriamfetol pivotal trial, in which solriamfetol improved ESS scores within 1 week of treatment initiation at the same dose as this study (75 mg / day titrated to 150 mg / day after 3 days).25A long-term open-label extension study demonstrated that the wake-promoting effects of solriamfetol were maintained for up to 52 weeks of treatment.

[0109] Research in patients with OSA, with and without PAP treatment, has revealed that dissociations between subjective sleepiness and objective measures of cognitive impairment are common in this population.38-40While solriamfetol improved both subjective sleepiness and objective performance outcomes compared with placebo, these effects may be distinct. This possibility is supported by the relatively strong correlations observed between the subjective outcomes and more modest correlations for subjective outcomes versus objective DSST RBANS performance. Preclinical evidence showing that solriamfetol may be a TAAR1 agonist,29with anticipated beneficial effects on cognitive function,30is also consistent with the ideathat solriamfetol may mitigate cognitive impairment in OSA with EDS beyond its wake-promoting effect.

[0110] The tolerability of solriamfetol in this study was consistent with its known safety profile.26There were no serious TEAEs, and no participants withdrew from the study due to TEAEs related to the study drug. The most common TEAEs were nausea and anxiety. While this study had a short duration of solriamfetol exposure, the long-term safety and tolerability of solriamfetol in patients with EDS associated with OSA has been demonstrated. In a 52-week open-label study (n=417 patients with OSA),26common TEAEs were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory infection; most TEAEs were mild or moderate in severity. In addition, there was no evidence of tolerance, rebound hypersomnia, or withdrawal after sudden discontinuation of long-term solriamfetol use.26

[0111] In murine models of cognitive impairment associated with OSA and EDS, significant improvements in cognitive function (ie, explicit memory) and / or anxietylike behavior were observed with solriamfetol (200 mg / kg) but not modafinil (200 mg / kg).41 42Human studies of WPAs other than solriamfetol have shown mixed results on cognitive measures, including the Cognitive Drug Research battery, in patients with OSA and EDS.19’43-48Here, solriamfetol improved DSST RBANS scores with an effect size of 0.37. For comparison, an effect size of 0.25 led to the conclusion that vortioxetine significantly improved DSST performance compared with placebo in major depressive disorder.36When combined with the clinical utility of DSST outcomes related to effect sizes in similar populations,33the present study suggests that solriamfetol meaningfully improves cognition in domains related to memory, processing speed, and attention in patients with cognitive impairment associated with OSA and EDS.

[0112] The precise mechanism of action of solriamfetol’s wake-promoting properties is not clear.21Solriamfetol is a dopamine and norepinephrine reuptake inhibitor,21 24and increasing noradrenergic and dopaminergic activity may mediate some pro-cognitive effects. Preclinical evidence shows solriamfetol is an agonist of TAAR1 and serotonin 1A receptors, which is unique to solriamfetol compared with modafinil and bupropion.29TAAR1 has been identified as a potential therapeutic target for several psychiatric disorders, and preclinical studies suggest it may impact cognitive function.29 30More research is needed to better understand the role of these mechanisms on cognitive function in patients with OSA and EDS.

[0113] One limitation of this study was the 5-week study duration, which precludes conclusions on sustained effects on cognitive function over longer durations. The moderate sample size drawn from a predominantly older (mean age 52.2), male (64.4%), and Caucasian (72.9%) population limits generalizability of the results. In addition, the study design did not include direct comparisons with other WPAs. Research is needed to evaluate cognitive improvements from solriamfetol compared with other WPAs. A strength of this study was the randomized, placebo-controlled, double-blind, repeated-measures, crossover design, in which participants served as their own controls. This design reduced confounders and was efficient in terms of statistical power. Furthermore, the study included both objective and subjective measure of cognitive function. Follow-up studies should evaluate additional cognitive endpoints.INTERPRETATION

[0114] This study found that solriamfetol, compared with placebo, improved cognitive function in participants with cognitive impairment associated with OSA and EDS. The results of the DSST RBANS showed that solriamfetol improved cognition objectively. Participants perceived an improvement in cognitive function and EDS, as indicated by the results of the BC-CCI and ESS. Solriamfetol was well tolerated in this study. These results support previous findings that solriamfetol improves EDS in patients with OSA, has a favorable safety profile,25-28and has the potential to improve cognitive function in patients with cognitive impairment associated with OSA and EDS.EXAMPLE 2Solriamfetol and Cognitive Function in Obstructive Sleep Apnea With Excessive Daytime Sleepiness and Impaired Cognition Stratified by Primary Airway Therapy Adherence: SHARPSTUDY DESIGN AND METHODS

[0115] In SHARP, participants received solriamfetol (75 mg / day for 3 days, then 150 mg / day) and placebo for 2 weeks, with crossover separated by a 1-week washout. Here, participants are stratified by PAP adherence (PAP use >4 hours / night on >70% of nights) and nonadherence (no reported PAP use or failure to meet adherence criterion). Outcomes included change from baseline in objective cognition measured with the Digit Symbol Substitution Test coding subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (DSST RBANS), subjective cognition measured with the British Columbia-Cognitive Complaints Inventory (BC- CCI), and EDS measured with the Epworth Sleepiness Scale (ESS). Results for the modified intent-to-treat (mITT) population (participants who received >1 dose of study drug and had DSST RBANS scores at baseline and from >1 treatment period) are presented.RESULTS

[0116] SHARP enrolled 59 participants (mean±SD age 52.2±10.7y; 36% female). In the mITT population (N=58), 34 participants (59%) were PAP-adherent and 24 (41 %) were nonadherent. On the DSST RBANS, least-squares mean±SE differences from placebo in the solriamfetol group were comparable in participants who were PAP- adherent (1 ,7±0.8) and those who were nonadherent (1 ,8±1 .1); effect sizes (Cohen’s d) of 0.38 and 0.33 were found in adherent and nonadherent participants, respectively. On the BC-CCI, differences from placebo in the solriamfetol group were also comparable regardless of PAP adherence (adherent: -1.7±0.5; nonadherent:-1 ,4±0.9); effect sizes for adherent and nonadherent participants were 0.56 and 0.34,respectively. Similar results were observed on the ESS (adherent: -1 ,9±0.8, d=0.41 ; nonadherent: -2.4±1.3, d=0.38).CONCLUSIONS

[0117] Solriamfetol improved EDS and objective and subjective cognitive functioning in participants with impaired cognition associated with OSA and EDS regardless of adherence to PAP therapy. These results show that nonadherence to PAP therapy, which is common for persons with OSA, did not lead to clinically meaningful differences in the therapeutic effects of solriamfetol with regard to cognition and daytime sleepiness.EXAMPLE 3Solriamfetol for Excessive Sleepiness in Narcolepsy and Obstructive Sleep Apnea: Effect Sizes and Numbers Needed to Treat or HarmSTUDY DESIGN AND METHODS

[0118] Excessive daytime sleepiness (EDS) is common in patients with narcolepsy and obstructive sleep apnea (OSA) and can lead to impaired cognitive functioning, poor work productivity, and reduced quality of life. Solriamfetol (Sunosi®), a dopamine and norepinephrine reuptake inhibitor, is approved for use in adults in the United States and European Union for the treatment of EDS associated with narcolepsy (75-150 mg / day) or OSA (37.5-150 mg / day). Preclinical data indicate that solriamfetol activates trace amine-associated receptor 1 (TAAR1), a potential target for improving cognitive function. The efficacy and safety of solriamfetol have been established in two phase 3 studies, Treatment of Obstructive Sleep Apnea and Narcolepsy Excessive Sleepiness (TONES) 2 and TONES 3; efficacy was demonstrated based on (ESS) scores, Maintenance of Wakefulness Test (MWT) mean sleep latency, and Patient and Clinical Global Impression of Change (PGIcand CGIc). Effect size, number needed to treat (NNT), and number needed to harm (NNH) are statistical representations of efficacy and tolerability, and as such may be helpful in guiding clinicians’ treatment decisions.[0119JTONES 2 (NCT02348593), TONES 3 (NCT02348606). Participants were adult males and females 18-75 years of age and diagnosed with narcolepsy or OSA. Key inclusion criteria were EDS (ESS score >10), baseline 40-minute MWT mean sleep latency <25 minutes (narcolepsy) or <30 minutes (OSA), and total nightly sleep >6 hours; for patients with OSA, primary OSA therapy (current or prior use of PAP, mandibular advancement device, or surgical intervention). Key exclusion criteria were usual bedtime later than 1 :00 AM, nighttime employment or variable shift work, or diagnosis of any disorder (other than narcolepsy or OSA) associated with EDS. Note: n values indicate safety population. Participants assigned to the 150- and 300-mg doses received 75 and 150 mg, respectively, for the first 3 days and the full dose thereafter.

[0120] Effect sizes compared with placebo (Cohen’s d) were determined for ESS scores and MWT mean sleep latency, based on changes from baseline to week 12. Cohen’s d effect sizes: small (d=0.2), medium (d=0.5), and large (d=0.8)17. NNT (<10 is favorablel 6) was determined for the percentage of participants with scores / changes in scores that met clinically meaningful response thresholds at week 12. For ESS: ESS <10 and >25% decrease from baseline. For MWT (TONES 3 only): achieving a mean sleep latency >20 minutes. For PGIc and CGIc: improvement, defined as responses of “minimally,” “much,” or “very much” improved. NNH (>10 is favorablel 6) was determined for treatment-emergent adverse events (TEAEs) that were reported in >5% of solriamfetol-treated participants and greater than placebo.RESULTS

[0121] Compared with placebo, with solriamfetol 150 mg / day, 3 participants with narcolepsy or OSA would need to be treated for 1 additional participant to achievePGIc or CGIc response. See Figure 7. Compared with placebo, with solriamfetol 150 mg / day: 6 participants with narcolepsy and 3 participants with OSA would need to be treated for 1 additional participant to achieve >25% decrease in ESS score; 5 participants with narcolepsy and 4 participants with OSA would need to be treated for 1 additional participant to achieve ESS scores in the normal range. See Figure 8. Compared with placebo, with solriamfetol 150 mg / day, 3 participants with OSA would need to be treated for 1 additional participant to achieve MWT >20 minutes. See Figure 9.Table 3. Summary of Effect Sizes and NNT With Solriamfetol in TONES 2 andTONES 3aBased on mean change from baseline.bPatients who achieved MWT mean sleep latency >20 minutes.cNot an approved dose.ESS, Epworth Sleepiness Scale; MWT, Maintenance of Wakefulness Test; N / A, not applicable / data not available; NNT, number needed to treat; OSA, obstructive sleep apnea; TONES, Treatment of Obstructive Sleep Apnea and Narcolepsy Excessive Sleepiness.CONCLUSIONS

[0122] In TONES 2 and TONES 3, large effect sizes were observed for improvement in ESS and MWT with higher solriamfetol doses. Across all outcomes, NNT with the 150 mg / day dose of solriamfetol ranged from 3 to 6 in patients with narcolepsy (TONES 2) and from 3 to 4 in patients with OSA (TONES 3). NNH pooled across all doses and across approved doses of solriamfetol for common TEAEs were >10, except for headache in TONES 2. This post hoc analysis demonstrates favorable effect sizes and NNT and NNH values for solriamfetol in the treatment of EDS associated with narcolepsy and OSA.EXAMPLE 4SURWEY Study of Solriamfetol: Initiation, Titration, Safety, Efficacy, and Follow-Up Experience for Patients With OSA in GermanySTUDY DESIGN AND METHODS

[0123] Excessive daytime Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA) that can persist in patients despite positive airway pressure (PAP) therapy, and may pose challenges to clinical management of symptoms. Solriamfetol has been shown to activate trace amine- associated receptor 1 (TAAR1 ), a potential target to improve cognitive functions. There is limited real-world evidence on how physicians initiate solriamfetol and subsequent treatment outcomes in patients with OSA and associated EDS9; such data may help clinicians optimize patient care.

[0124] This real-world study characterizes dosing and titration strategies among European physicians initiating solriamfetol, as well as treatment outcomes following initiation in patients with EDS and OSA. SUnosi Real World Experience StudY (SURWEY) was a retrospective chart review among physicians in Germany who have prescribed solriamfetol to patients with EDS associated with narcolepsy orOSA. The present analysis focuses on data from 83 patients with OSA from Germany. Eligible patients were >18 years of age, had a diagnosis of EDS due to OSA, had reached a stable maintenance dose of solriamfetol, and completed >6 weeks of treatment; patients who received solriamfetol during a clinical trial or early access program were excluded. Solriamfetol initiation strategies: changeover (switched / switching from existing EDS medication[s]), add-on (added / adding to current EDS medication[s]), and new-to-therapy (no current / previous EDS medication). Data related to solriamfetol dosing / titration, comorbidities, Epworth Sleepiness Scale (ESS) scores, patient- and physician-reported improvement in EDS, duration of solriamfetol effects, and adverse events were summarized descriptively.ResultsTable 4. Baseline Demographics and Clinical CharacteristicsADHD, attention deficit hyperactivity disorder; BMI, body mass index; ESS, Epworth Sleepiness Scale; SD, standard deviation.

[0125] New-to-therapy was the most common initiation strategy (75%), followed by add-on (14%) and changeover (11 %). Obesity (58%) was the most common comorbidity. Overall, 73 (88%) patients used PAP therapy; 60 (72%) patients used PAP for >4 hours / night and 66 (80%) patients used PAP on >4 nights / week. The most commonly used concomitant medication for EDS was pitolisant.

[0126] All 9 (100%) patients in the changeover group switched to solriamfetol due to lack of efficacy of other EDS medications. Solriamfetol was titrated in 53 (64%) patients, most of whom (57%) completed titration within 2 weeks. See Figure 10. Mean improvements in ESS in changeover, add-on, and new-to-therapy groups were substantially greater than the minimum clinically important difference of 2-3 points. See Figure 11. Overall, 75 (91 %) patients reported no change in nighttime sleep quality with solriamfetol. See Figures 12 and 13. Adverse events were consistent with those previously reported in clinical trials of solriamfetol in participants with OSA.TEAE, treatment-emergent adverse event. aReported in >2 patients.CONCLUSIONS

[0127] In the SURWEY study of solriamfetol in patients with OSA, solriamfetol was typically initiated at 37.5 mg / day and most patients were new-to-therapy; titration was common. Overall, mean ESS scores improved by 5.4 points, and mean improvement in all groups was substantially greater than the minimum clinicallyimportant difference of 2-3 points. This is consistent with improvements in sleepiness reported in clinical trials for solriamfetol. Both patients and physicians perceived improvement in EDS for the vast majority of patients, regardless of initiation strategies. The majority of patients reported the effects of solriamfetol lasted at least 8 hours. Common adverse events were consistent with those previously reported for solriamfetol.EXAMPLE 5Healthcare Utilization by Patients With Obstructive Sleep Apnea and Excessive Daytime Sleepiness After Airway Therapy in the United KingdomSTUDY DESIGN AND METHODS

[0128] Excessive Obstructive sleep apnea (OSA) is characterized by repeated interruptions in breathing during sleep. Continuous positive airway pressure (CPAP) therapy, the standard of care for OSA, reduces hypoxic events and mitigates sleep disruption; however, excessive daytime sleepiness (EDS) can persist in 10%-28% of patients despite CPAP use. Patients with OSA have increased healthcare resource utilization (HCRU), including medical costs, medication use, emergency department visits, and hospitalizations, compared with patients without OSA. There is limited real-world evidence on HCRU burden for patients with OSA treated with CPAP experiencing EDS.

[0129] The objective of this study was to characterize the patient demographics, comorbidities, medications, and HCRU in a population of patients after CPAP initiation both with and without claims supporting EDS.

[0130] This retrospective, observational, cohort study of the OSA patient population treated with CPAP was based on secondary use of electronic healthcare records from primary and secondary care databases. The study utilized a primary caredatabase, the Clinical Practice Research Datalink (CPRD) Aurum, linked to the Hospital Episode Statistics (HES) database, a secondary care database covering patient-level data. The observation period of the study was January 1 , 2008, to March 31 , 2020 (Figure 14). The index date was defined as the date of first recorded CPAP treatment during the eligibility period and after a diagnosis of OSA. The baseline period was defined as the 12-month period prior to the index date. The follow-up period was defined as the observation period from the index date until the earliest of the following: 24 months from the index date; end of the observation period on March 31 , 2020; or deregistration from the database (eg, due to relocation or death).

[0131] Key inclusion criteria: Patients >18 years of age at the time of OSA diagnosis whose records were permanently registered as “acceptable” in the CPRD Aurum database and whose first record for CPAP treatment occurred after a diagnosis of OSA and was between January 1 , 2009, and March 31 , 2018. Patient information was obtained using Read or Systematized Nomenclature of Medicine-Clinical Terms codes in CPRD. HCRU was described for 0-12 months and 12-24 months post- CPAP initiation. Primary care contacts were obtained from CPRD and included all general practice consultations (telephone or face to face) and referrals to secondary care. Secondary care contacts were obtained from the HES database and included: Elective and nonelective inpatient admissions (including day cases) overall and in a specialty department and associated length of stay; Outpatient visits overall and in a specialist department; Accident and emergency visits (A&E); Road traffic incidents.

[0132] Patients with EDS were identified using Epworth Sleepiness Scale (ESS) scores based on the availability of data. ESS scores were defined using a code in CPRD and summarized in 3 time periods: during the patient’s baseline period, the first 6 months post-CPAP initiation, and >6 months post-CPAP initiation until the end of follow-up. Patients with EDS were identified by the presence of clear signs of EDS, defined as having ESS >11 or presence of daytime fatigue code while patients without EDS were identified as having ESS <11 (if recorded) and the absence of daytime fatigue code. HCRU was summarized using mean, standard deviation (SD),of the number of events or hospitalization days per patient-year during the follow-up period as appropriate. Sensitivity analyses were conducted where HCRU was further described in the first 0-6 months and 6-12 months post-CPAP initiation to account for the definition of EDS as a record of tiredness >6 months after initiation of CPAP treatment.RESULTSTable 6. Patient Demographics and Clinical CharacteristicsEDS, excessive daytime sleepiness; SD, standard deviation.AXSOME 18 PCTSUBSTITUTE SHEET (RULE 26)

[0133] Mean age of patients with EDS was 56.99 years; most were male (60.2%). Compared with patients without EDS, those with EDS were more likely to have a history of psychiatric, gastrointestinal, and neurodegenerative disorders. See Table 6.Table 7. Medications in 12-month Baseline PeriodEDS, excessive daytime sleepiness.*Not reported due to small number of patients.

[0135] Compared with patients without EDS, a significantly greater proportion of patients with EDS were prescribed: psychiatric medications (antidepressants and hypnotics / anti-anxiety medications); medications for acid-related gastric disorders, proton pump inhibitors, nonsteroidal anti-inflammatory drugs, and corticosteroids.49 AXSOME 18 PCTSUBSTITUTE SHEET (RULE 26)

[0136] The use of wakefulness-promoting agents like modafinil was very low in both the EDS and no EDS patient populations.Table 8. HCRU Per Patient 0-12 and 12-24 Months Post-CPAP InitiationPatients with >1 primary care contact record(s) were included.*N shows total number of bed days in the time period; mean indicates days per patient across the period.A&E, accident and emergency; CPAP, continuous positive airway pressure; EDS, excessive daytime sleepiness; HCRU; healthcare resource utilization; N, total number of activities.50 AXSOME 18 PCTSUBSTITUTE SHEET (RULE 26)

[0137] In the first year after CPAP initiation, patients with EDS had a significantly higher mean number of primary care contacts compared with patients without EDS; in the second year, the number of contacts decreased slightly for both groups but remained significantly different. Compared with patients without EDS, patients with EDS had more outpatient visits in both the first and second year post-CPAP initiationTable 9. Sensitivity Analysis: HCRU Per Patient 0-6 and 6-12 Months Post-CPAP InitiationPatients with >1 outpatient visit were included; patients with >1 elective inpatient admission were included; patients with >1 A&E visit included.*N shows total number of bed days in the time period; mean indicates days per patient across the period.A&E, accident and emergency; CPAP, continuous positive airway pressure; EDS, excessive daytime sleepiness; HCRU; healthcare resource utilization; N, total number of activities; SD, standard deviation.

[0138] Sensitivity analyses showed similar levels of HCRU during the 0-6 months and 6-12 months after CPAP initiation.51 AXSOME 18 PCTSUBSTITUTE SHEET (RULE 26)

[0139] It was unknown whether the recording of EDS and EDS severity were complete, and whether utilizing EDS-like claims as a surrogate measure appropriately identifies patients with EDS. Patients with more severe EDS may have been overrepresented. Data were not available on adherence to primary airway therapyConclusions

[0135] Primary and most secondary HCRU levels were higher in patients with EDS compared with patients without EDS. Use of wake-promoting drugs was low among both patients with EDS and patients without EDS in this population of CPAP-treated patients with OSA. Comorbidity burden and use of medications, especially psychiatric medications, was high among patients with EDS.

[0136] This study found that solriamfetol, compared with placebo, improved cognitive function in participants with cognitive impairment associated with OSA and EDS. The results of the DSST RBANS showed that solriamfetol improved cognition objectively. Participants perceived an improvement in cognitive function and EDS, as indicated by the results of the BC-CCI and ESS. Solriamfetol was well tolerated in this study. These results support previous findings that solriamfetol improves EDS in patients with OSA, has a favorable safety profile,25'28and has the potential to improve cognitive function in patients with cognitive impairment associated with OSA and EDS. presented.

[0137] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0138] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

What is Claimed is:1 . A method of enhancing one or more cognitive function, said method comprising administering to a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof, thereby enhancing one or more cognitive function in the subject.

2. The method of claim 1 , wherein the compound is the compound of formula Ior a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is the hydrochloride salt of the compound.

4. The method of claim 1 , wherein the compound is administered orally.

5. The method of claim 1 , wherein the one or more cognitive function is selected from executive function, memory, and learning.

6. The method of claim 1 , wherein the cognitive function is executive function.

7. The method of claim 1 , wherein the cognitive function is memory.

8. The method of claim 1 , wherein the cognitive function is learning.

9. The method of claim 1 , wherein the one or more cognitive function is selected from working memory, cognitive flexibility, and response inhibition.

10. The method of claim 1 , wherein the compound is in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier.11 . The method of claim 1 , further comprising administering a nootropic agent to the subject in need thereof.

12. A method of treating one or more cognitive impairment in a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness, said method comprising administering to a subject having said one or more cognitive impairment a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof, thereby treating one or more cognitive impairment in the subject.

13. The method of claim 12, wherein the compound is the compound of formula Ior a pharmaceutically acceptable salt thereof.

14. The method of claim 12, wherein the compound is the hydrochloride salt of the compound.

15. The method of claim 12, wherein the subject is identified as having Alzheimer’s Disease, schizophrenia, autism, or obsessive-compulsive disorder.

16. The method of claims 12, wherein the cognitive impairment is selected from impaired executive function, impaired learning, and impaired memory.

17. The method of claim 16, wherein the cognitive impairment is impaired executive function.

18. The method of claim 16, wherein the cognitive impairment is impaired learning.

19. The method of claim 16, wherein the cognitive impairment is impaired memory.

20. The method of claims 12, wherein the cognitive impairment is selected from impaired cognitive flexibility, impaired working memory, and impaired response inhibition.21 . The method of claim 20, wherein the cognitive impairment is impaired cognitive flexibility.

22. The method of claim 20, wherein the cognitive impairment is impaired working memory.

23. The method of claim 20, wherein the cognitive impairment is impaired response inhibition.

24. The method of claim 12, wherein the compound is in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier.

25. The method of claim 12, further comprising administering a nootropic agent to the subject having said one or more cognitive impairment.

26. A method of delaying or slowing an increase in one or more cognitive impairment in a subject with impaired cognition associated with obstructive sleep apnea and excessive daytime sleepiness, said method comprising administering to a subject having or at risk of having said one or more cognitive impairment a therapeutically effective amount of a compound of formula IIor a pharmaceutically acceptable salt thereof, thereby treating one or more cognitive impairment in the subject.

27. The method of claim 26, wherein the compound is the compound of formula Ior a pharmaceutically acceptable salt thereof.

28. The method of claim 26, wherein the compound is the hydrochloride salt of the compound.

29. The method of claim 26, wherein the subject is identified as having Alzheimer’s Disease, schizophrenia, autism, or obsessive-compulsive disorder.

30. The method of claim 26, wherein the cognitive impairment is selected from impaired executive function, impaired learning, and impaired memory.31 . The method of claim 30, wherein the cognitive impairment is impaired executive function.

32. The method of claim 30, wherein the cognitive impairment is impaired learning.

33. The method of claim 30, wherein the cognitive impairment is impaired memory.

34. The method of claim 26, wherein the cognitive impairment is selected from impaired cognitive flexibility, impaired working memory, and impaired response inhibition.

35. The method of claim 34, wherein the cognitive impairment is impaired cognitive flexibility.

36. The method of claim 34, wherein the cognitive impairment is impaired working memory.

37. The method of claim 34, wherein the cognitive impairment is impaired response inhibition.

38. The method of claims 26, wherein the compound is in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier.

39. The method of claims 26, further comprising administering a nootropic agent to the subject having said one or more cognitive impairment.

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