Sorafenicol for treating cognitive impairment in subjects suffering from cognitive impairment associated with obstructive sleep apnea and daytime hypersomnosia

Abstract

The present invention relates to carbamoylphenylalaninol compounds and methods of using the same to enhance one or more cognitive functions in subjects suffering from cognitive impairment associated with obstructive sleep apnea and hypersomnia in daytime and methods of treating one or more cognitive impairment in such patients.

Description

Invention Field

[0001] This invention relates to carbamoylphenylalanine compounds and methods of using them to enhance one or more cognitive functions in subjects suffering from cognitive impairment associated with obstructive sleep apnea and excessive daytime sleepiness, as well as methods of using them to treat one or more cognitive impairments in such patients. Background of the Invention

[0003] (R)-2-amino-3-phenylpropylcarbamate (APC; solriamfetol; SUNOSI) ®) is a phenylalanine analogue. Somfetol is a dopamine and norepinephrine reuptake inhibitor approved for use in adults in selected countries in the United States, Canada, and Europe for the treatment of EDS associated with OSA (37.5–150 mg / day) and narcolepsy (75–150 mg / day). Somfetol 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 ExpTher. 2018;366(2):367–376. Previous studies have confirmed its short-term and long-term efficacy, including improvements in wakefulness, 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 suggests that solriamfetol is active against 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 that 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. The structure of the free base of 18P2 APC is shown in Formula I below.

[0004] I

[0005] Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA). OSA is characterized by recurrent upper airway obstruction during sleep, which causes fragmented sleep and episodes of intermittent hypoxia, leading 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.) Although positive airway pressure (PAP) can improve sleep quality and reduce hypoxic events, residual EDS persists in 10%–28% of patients treated with PAP. 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 apnea patients: the French multicentre study. Eur Respir J. 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 EDS may experience impairment in occupational and social functioning, increased risk of workplace injury and motor vehicle accidents, and decreased quality of life.Garbarino S, Guglielmi O, Sanna A, Mancardi GL, Magnavita N. Risk of occupational accidents in workers with obstructive sleepapnea: systematic review and meta-analysis. 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。 Cognitive deficits are troublesome in this population, with up to 68% of patients exhibiting 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, BertolucciPH, 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; despite PAP treatment, cognitive impairment may persist. (Gabryelska A, Białasiewicz 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.)

[0006] Currently, pharmacological agents used to treat EDS include stimulants and wakefulness agents (WPA). Abad VC, Guilleminault C. Solriamfetol for the treatment of daytime sleepiness inobstructive sleep apnea. Expert Rev Respir Med. 2018;12(12):1007-1019; Gandhi KD, Mansukhani MP, Silber MH, Kolla BP. Excessive daytime sleepiness: aclinical review. Mayo Clin Proc. 2021;96(5):1288-1301; Ronnebaum S, Bron M, Patel D et al. Indirect treatment comparison of solriamfetol, modafinil, andarmodafinil for excessive daytime sleepiness in obstructive sleep apnea. J Clin Sleep Med. 2021;17(12):2543-2555. Modafinil (WPA) is approved in the United States, Canada, and Australia for improving wakefulness in several sleep disorders, including OSA and EDS, and in select European countries for treating somnolence associated with narcolepsy. Modafinil [Product Characteristics Overview]. 2011. Available at: https: / / www.ema.europa.eu / en / documents / referral / modafinil-annex-iii-summary-product-characteristics-labeling-package-leaflet_en.pdf. Accessed: October 14, 2021; PrMar-modafinil [product monograph]. Ottawa, Ontario: Marcan Pharmaceuticals Inc.;2017. Modavigil. 2023. Available at: https: / / www.healthdirect.gov.au / medicines / brand / amt,3390011000036106 / modavigil. Accessed: July 10, 2023. Armodafinil (WPA) is approved in the United States and Australia for improving wakefulness in similar sleep disorders (e.g., OSA and EDS). Nuvigil [package insert]. North Wales, PA: Teva Pharmaceuticals; 2018. Armodafinil for sleep disorders. Aust Prescr. 2016;39:221-222. However, it is unclear whether modafinil or armodafinil improves cognitive function in this patient population. Avellar AB, Carvalho LB, Prado GF, PradoLB. 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)

[0007] Cognitive impairment is a broad term used to describe a degree of difficulty in cognitive function. Impairment can vary in intensity and may involve problems with memory, attention, language, sensorimotor skills, decision-making, and learning. Cognitive impairment is prevalent in our aging population, with approximately 16% of people over 70 years of age experiencing some type of mild cognitive impairment. Currently, there are no FDA-approved treatments for cognitive impairment.

[0008] This invention overcomes the limitations of the art by evaluating whether somfitor improves cognitive function in participants with cognitive impairment associated with OSA and EDS.

[0009] Invention Summary

[0010] This invention relates to a method for developing a way to enhance one or more cognitive functions in patients with cognitive impairment associated with obstructive sleep apnea and excessive daytime sleepiness.

[0011] Therefore, one aspect of the present invention relates to a method for enhancing one or more cognitive functions, the method comprising administering a therapeutically effective amount of a compound of formula II to a subject suffering from cognitive impairment associated with obstructive sleep apnea and excessive daytime sleepiness.

[0012] II

[0013] Or its pharmaceutically acceptable salt.

[0014] Another aspect of the invention relates to a method for treating one or more cognitive impairments, the method comprising administering a therapeutically effective amount of a compound of formula II to a subject suffering from obstructive sleep apnea and excessive daytime sleepiness that cause one or more cognitive impairments.

[0015] II

[0016] Or its pharmaceutically acceptable salt.

[0017] A further aspect of the invention relates to a method for delaying or mitigating an increase in one or more types of cognitive impairment, the method comprising administering a therapeutically effective amount of a compound of formula II to a subject suffering from or at risk of cognitive impairment caused by one or more types of obstructive sleep apnea and excessive daytime sleepiness.

[0018] II

[0019] Or its pharmaceutically acceptable salt, thereby treating one or more cognitive impairments in the subject.

[0020] In some embodiments, the compound is a compound of formula I.

[0021] I

[0022] Or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a hydrochloride salt of a compound of formula II or I.

[0023] These and other aspects of the invention are set forth in more detail in the following description of the invention. Brief description of the attached diagram

[0025] Some embodiments of the invention are shown by way of example and are not limited to the figures in the accompanying drawings, in which the same reference numerals may indicate similar elements, and wherein:

[0026] Figure 1 CONSORT Flowchart

[0027] Figure 2a Research Design

[0028] Figure 2b Clinical visit structure

[0029] Figure 3a Total change in DSST RBANS score from baseline

[0030] Figure 3b Changes in DSST RBANS scores from baseline at different time points

[0031] Figure 4 Overall BC-CCI score change from baseline

[0032] Figure 5 Total change in PGI-S score from baseline

[0033] Figure 6 Total change in ESS score from baseline

[0034] Figure 7 Compared with placebo, somifexo showed absolute improvement in categorical improvement in PGIc and CGIc in NNT.

[0035] Figure 8 Compared with placebo, somfitropin achieved a ≥25% reduction in ESS score or an ESS ≤10 NNT.

[0036] Figure 9 In participants with OSA, NNT achieved MWT ≥ 20 minutes compared to placebo.

[0037] Figure 10The most common starting dose of somfitropin is 37.5 mg / day.

[0038] Figure 11 Using Somfito's ESS score a An average reduction of ≥5 points indicates a clinically significant improvement in EDS.

[0039] Figure 12 Patients and doctors perceived an improvement in symptoms in approximately 90% of patients.

[0040] Figure 13 Most patients reported that the effect of somfitrop lasted ≥8 hours.

[0041] Figure 14 Research Design Invention Details

[0043] This invention may be embodied in various 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 shown with respect to one embodiment may be incorporated into other embodiments, and features shown with respect to a particular embodiment may be removed from that embodiment. Furthermore, many variations and additions to the embodiments presented herein will be apparent to those skilled in the art based on this disclosure, without departing from the invention.

[0044] 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 pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. Abbreviations that may be used in this specification include:

[0045] BC-CCI, British Columbia Cognitive Subjective Questionnaire

[0046] CI, confidence interval

[0047] C-SSRS, Columbia Suicide Severity Rating Scale

[0048] DSST, Numerical Symbol Substitution Test

[0049] EDS, excessive daytime sleepiness

[0050] ESS, Epworth Sleepiness Scale

[0051] OSA, obstructive sleep apnea

[0052] PAP, Positive Airway Pressure

[0053] PGI-S, Patient Overall Severity Impression

[0054] RBANS is a repeatable battery for assessing neuropsychological status.

[0055] SD, standard deviation

[0056] SE, standard error

[0057] TAAR1, Trace Amine-Associated Receptor 1

[0058] TEAE, adverse events occurring during treatment

[0059] US

[0060] WAIS-IV, Wechsler Adult Intelligence Scale, 4th Edition

[0061] WPA, a wake-up stimulant

[0062] Unless the context otherwise requires, it is specifically indicated that the various features of the invention described herein can be used in any combination.

[0063] Furthermore, the present invention also anticipates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0064] For clarity, if the specification states that the complex comprises components A, B, and C, it specifically indicates that any one of A, B, or C, or any combination thereof, may be omitted or discarded individually or in any combination.

[0065] All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety for all purposes.

[0066] As used herein, “an,” “a,” or “the” can mean one or more. For example, “an” cell can refer to a single cell or multiple cells.

[0067] As used herein, “and / or” refers to and includes any and all possible combinations of one or more of the related listed items, as well as combinations lacking when interpreted in the alternative (“or”) context.

[0068] Furthermore, as used herein, the term "about" refers to a variation of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of a specified amount when referring to measurable values ​​such as the amount, dosage, time, temperature, etc. of the compounds or reagents of the present invention.

[0069] When applied to the compositions of the present invention, the term "substantially composed of" (and grammatical variations) means that the composition may contain additional components, provided that the additional components do not substantially alter the composition. When applied to the composition, the term "substantially alter" means that the therapeutic efficacy of the composition is increased or decreased by at least about 20% or more compared to the efficacy of a composition composed of said components.

[0070] As used herein, the term "therapeutic effective amount" or "effective amount" refers to the amount by which the compositions, compounds, or reagents of the present invention impart a moderating effect to a subject suffering from a disorder, disease, or ailment. This moderating effect may be, for example, a beneficial effect, including improving the subject's condition (e.g., one or more symptoms), delaying or slowing the progression of the condition, preventing or delaying the onset of the condition, and / or altering clinical parameters, diseases, or ailments, as is well known in the art. For example, a therapeutic effective amount or effective amount may refer to the amount of a composition, compound, or reagent that improves the subject's condition by at least 5%, such as 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%.

[0071] "Treatment" refers to any type of moderating effect that imparts a moderating effect to a subject suffering from a disorder, disease, or ailment, such moderating effect being, for example, a beneficial effect including improving the subject's condition (e.g., one or more symptoms), delaying or slowing the progression of the condition, and / or altering clinical parameters, disease, or ailment, as is well known in the art.

[0072] As used herein, "pharmaceutically acceptable" means a substance that is not biologically or otherwise undesirable, i.e., a substance that can be administered to an individual in conjunction with the compositions of the present invention without causing substantially harmful biological effects or interacting in an adverse manner with any other component of the composition comprising it. As is well known to those skilled in the art, substances are naturally selected to minimize any degradation of the active ingredient and any adverse side effects in the subject (see, for example, Remington's Pharmaceutical Science; 21st edition, 2005).

[0073] "Concurrently" means that events are sufficiently close in time to produce a combined effect (i.e., simultaneous can be simultaneous, or it can be two or more events occurring within a short period of time before or after each other). In some embodiments, "simultaneous" administration of two or more compounds means that the two compounds are administered sufficiently close in time such that the presence of one alters the biological effect of the other. The two compounds can be administered in the same or different formulations or sequentially. Simultaneous administration can be achieved by mixing the compounds before administration or by administering compounds in two different formulations, for example, at the same time point but at different anatomical sites or using different routes of administration.

[0074] This invention relates to a method for enhancing one or more cognitive functions, the method comprising administering a therapeutically effective amount of a compound of formula II to a subject suffering from OSA and EDS that cause one or more cognitive impairments.

[0075] II

[0076] Or its pharmaceutically acceptable salt.

[0077] In some embodiments, the one or more cognitive functions are selected from executive functions, memory, and learning. In some embodiments, the one or more cognitive functions are selected from working memory, cognitive flexibility, and response inhibition.

[0078] Another aspect of the invention relates to a method for treating one or more types of cognitive impairment, the method comprising administering a therapeutically effective amount of a compound of formula I to a subject suffering from one or more types of cognitive impairment caused by OSA and EDS.

[0079] I

[0080] Or its pharmaceutically acceptable salt.

[0081] A further aspect of the invention relates to a method for delaying or mitigating the increase of one or more cognitive impairments, the method comprising administering a therapeutically effective amount of a compound of formula II to a subject suffering from said one or more cognitive impairments or at risk of suffering from OSA and EDS.

[0082] II

[0083] Or a pharmaceutically acceptable salt thereof, thereby treating a subject with one or more cognitive impairments. The subject may be a subject already diagnosed with OSA and EDS causing one or more cognitive impairments, and the progression of said impairment is delayed or slowed relative to a subject not treated with the method of the present invention. The subject may be a subject with OSA and EDS who is at risk of developing one or more cognitive impairments, and the onset of said impairment is delayed relative to a subject not treated with the method of the present invention.

[0084] In some implementations, subjects with OSA and EDS are identified as having a neurological disorder associated with cognitive impairment, such as being identified as having Alzheimer's disease, schizophrenia, autism, or obsessive-compulsive disorder.

[0085] In some implementations, cognitive impairment is selected from impaired executive function, impaired learning, and impaired memory. In some implementations, cognitive impairment is selected from impaired cognitive flexibility, impaired working memory, and impaired response inhibition.

[0086] In some embodiments of the method of the present invention, the compound is a compound of formula I.

[0087] I

[0088] Or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a hydrochloride salt of a compound of formula II or I.

[0089] The methods of this invention can be carried out using the compounds, formulations, and unit dosage forms provided herein. In some embodiments, the formulations and dosage forms can be used to achieve the immediate release of APC, as well as pharmaceutically acceptable salts, hydrates, isomers (including tautomers), solvates, and complexes of APC.

[0090] Suitable APC salts include, but are not limited to, acetates, adipates, alginates, aspartates, benzoates, butyrates, citrates, fumarates, glycolates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobroms, hydroiodates, 2-hydroxyethanesulfonates, lactates, maleates, malonates, methanesulfonates, nicotinates, nitrates, oxalates, palmitates, pectinates, persulfates, hydroxynaphthylcarbamates, neopentanoates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, and undecanoates. Other acids, such as oxalic acid, although not pharmaceutically acceptable on their own, can be used to prepare salts that can be used as intermediates to obtain the compounds of the present invention and their pharmaceutically acceptable acid addition salts. In some embodiments, the salt is a hydrochloride salt.

[0091] APC compounds include those compounds that are quaternized and have any basic nitrogen-containing group.

[0092] For simplicity, the discussion herein is provided without mention of stereoisomerism or the addition of deuterium atoms. Those skilled in the art will understand that APCs can contain one or more asymmetric centers and thus exist as racemic mixtures and single optical isomers. All such isomers and deuterated forms of these compounds are explicitly included in this invention.

[0093] The discussion herein also includes polymorphs, hydrates, cage compounds, solvates, inclusion compounds, isomers, or other forms of compounds not mentioned herein. All of these forms of APC are explicitly included in this invention.

[0094] Furthermore, the compounds of the present invention include prodrugs of compounds that are converted into active compounds in vivo. For example, compounds may be modified to enhance cell permeability (e.g., by esterification of polar groups) and then converted by cellular enzymes to produce the active agent. Methods for masking charged or reactive portions as prodrugs are known to those skilled in the art (see, for example, P. Korgsgaard-Larsen and H. Bundgaard, A Textbook of Drug Design and Development, Reading UK, Harwood Academic Publishers, 1991).

[0095] The term "prodrug" refers to a compound that is rapidly converted in the body to produce the parent compound of the above formula, for example, by hydrolysis in the bloodstream. See, for example, T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. See also U.S. Patent No. 6,680,299. Exemplary prodrugs include prodrugs that are metabolized in vivo by a subject to an active pharmaceutical ingredient having the activity of a compound 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 amino or carboxylic acid group if such a group is present in the compound; an amino carbamate if such a group is present in the compound; an alcohol acetal or ketal if such a group is present in the compound; an amino N-Mannich base or imine if such a group is present in the compound; or a carbonyl Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidinedione if such a group is present in the compound, such as those described in U.S. Patent Nos. 6,680,324 and 6,680,322.

[0096] As used herein, “pharmaceuticalally acceptable prodrug” (and similar terms) refers to those prodrugs of APC that are suitable for contact with tissues of humans and / or other animals without excessive toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical judgment, are commensurate with a reasonable risk / benefit ratio, and are effective for their intended use, as well as zwitterionic forms of the compounds of the present invention (if possible).

[0097] APC or a pharmaceutically acceptable salt thereof may be obtained or synthesized by means of methods known in the art and described herein. Details of the 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 of which are incorporated herein by reference in their entirety.

[0098] Another aspect of the invention relates to a composition, such as a dosage form, comprising an APC suitable for the methods of the invention. In some embodiments, the composition is a pharmaceutical composition comprising an APC and a pharmaceutically acceptable carrier. In some embodiments, the dosage form is an oral dosage form, such as a tablet or capsule, for example, an immediate-release dosage form.

[0099] In some embodiments, the dosage form is an immediate-release tablet that releases at least 85%, such as at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the APC contained therein, for example, as described in U.S. Patent Nos. 10,195,151; 10,512,609; and 11,439,597, within a time period of less than 15 minutes after administration of the tablet to a subject.

[0100] Formulations of APCs, including immediate-release formulations, can be processed using conventional techniques into unit dosage forms suitable for oral administration, such as filled capsules, compressed tablets, or capsules, or other dosage forms suitable for oral administration. Immediate-release dosage forms prepared as described are suitable for oral administration to achieve and maintain therapeutic levels of the compound within a pre-selected interval. In some embodiments, immediate-release dosage forms as described herein can comprise solid oral dosage forms of any desired shape and size, including circular, elliptical, rectangular, oblong cylindrical, or polygonal shapes. In one such embodiment, the surface of the immediate-release dosage form can be flat, circular, concave, or convex.

[0101] In particular, when immediate-release formulations are prepared as tablets, these tablets contain a relatively large percentage and absolute amount of the compound, and are therefore expected to improve patient compliance and convenience by replacing the need to ingest large amounts of liquid or liquid / solid suspensions. One or more immediate-release tablets as described herein can be administered orally (e.g., at close intervals) to provide subjects with a therapeutically effective dose of the compound over a relatively short period of time.

[0102] When needed or necessary, the outer surface of an immediate-release formulation may be coated with materials and methods known in the art, such as color coating or moisture-proof coating.

[0103] In some embodiments, the composition is an immediate-release compressed tablet, the tablet comprising:

[0104] APC or its pharmaceutically acceptable salt, in a concentration of approximately 90-98% of the tablet weight;

[0105] At least one binder, in a content of about 1-5% of the tablet weight; and

[0106] At least one lubricant, in a content of about 0.1-2% of the tablet weight;

[0107] Wherein, after administration of the tablet to a subject, within a time period of less than 15 minutes, the tablet releases at least 85% of the APC contained therein or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the tablet comprises:

[0109] APC or its pharmaceutically acceptable salt, in a concentration of approximately 91-95% of the tablet weight;

[0110] At least one binder, in a content of about 2-3% of the tablet weight;

[0111] At least one lubricant, in a content of about 0.1-1% of the tablet weight; and

[0112] Optional, cosmetic film coating, in a concentration of approximately 3-4% of the tablet weight;

[0113] Wherein, after administration of the tablet to a subject, within a time period of less than 15 minutes, the tablet releases at least 85% of the APC contained therein or a pharmaceutically acceptable salt thereof.

[0114] In one embodiment, the tablet comprises:

[0115] APC or its pharmaceutically acceptable salt, in a concentration of approximately 93.22% by weight of the tablet;

[0116] At least one binder (e.g., hydroxypropyl cellulose) is present in a content of about 2.87% of the tablet weight;

[0117] At least one lubricant (e.g., magnesium stearate) is present in a concentration of about 0.52% by weight of the tablet; and

[0118] Optional, cosmetic film coating (e.g., Opalry) ® II (yellow), with a content of approximately 3-4% of the tablet weight;

[0119] Wherein, after administration of the tablet to a subject, within a time period of less than 15 minutes, the tablet releases at least 85% of the APC contained therein or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the composition is an immediate-release oral dosage form of APC, the oral dosage form comprising:

[0121] APC or its pharmaceutically acceptable salt, in a concentration of approximately 90-98% of the oral dosage form by weight;

[0122] At least one binder, in a content of about 1-5% of the oral dosage form by weight; and

[0123] At least one lubricant, in a content of about 0.1-2% of the weight of the oral dosage form;

[0124] Following administration of the oral dosage form to a subject, within a time period of less than 15 minutes, the oral dosage form releases at least 85% of the APC contained therein or its pharmaceutically acceptable salt.

[0125] In some embodiments, the tablets do not contain a disintegrant. As used herein, the term "disintegrant" refers to an agent added to a tablet to facilitate its disintegration in an aqueous environment. The tablets of the present invention are advantageous because they dissolve rather than disintegrate. In the present invention, the presence of a disintegrant in the formulation effectively slows the release of APC.

[0126] In some embodiments, APC or a pharmaceutically acceptable salt thereof is present in amounts 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% of the tablet weight, or any value or range thereof. In some embodiments, APC or a pharmaceutically acceptable salt thereof is present in amounts 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%.

[0127] In some embodiments, 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% of the tablet weight, or any value or range thereof. In some embodiments, 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 contain at least one binder, such as 1, 2, 3, 4, 5, or more binders.

[0128] In some embodiments, at least one adhesive is selected from at least one or any combination thereof of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, povidone, copovidone, pregelatinized starch, dextrin, gelatin, maltodextrin, starch, corn gluten, gum arabic, alginate, carbomer (cross-linked polyacrylate), polymethyl methacrylate, sodium carboxymethyl cellulose, guar gum, hydrogenated vegetable oil (type I), methyl cellulose, magnesium aluminum silicate, and sodium alginate. In some embodiments, at least one adhesive is hydroxypropyl cellulose.

[0129] In some embodiments, 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 any value or range thereof. In some embodiments, 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 contain at least one lubricant, such as 1, 2, 3, 4, 5, or more lubricants. When the formulation is delivered immediately in a compressed tablet form, a still lower lubricant level can be achieved by using a "blowing" system during tableting. Such systems are known in the art, are commercially available, and apply the lubricant directly to the punch and die surfaces rather than the entire formulation.

[0130] In some embodiments, at least one lubricant is selected from at least one or any combination 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 stearoyl fumarate, and zinc stearate. In some embodiments, at least one lubricant is magnesium stearate. In other embodiments, magnesium stearate may be used in combination with one or more other lubricants or surfactants (e.g., sodium dodecyl sulfate). In particular, if it is necessary to overcome the potential hydrophobic properties of magnesium stearate, sodium dodecyl sulfate may also be included when using magnesium stearate (Remington: the Science and Practice of Pharmacy, 20th edition, Gennaro, ed., Lippincott Williams & Wilkins (2000)).

[0131] In some embodiments, at least one binder is hydroxypropyl cellulose. In some embodiments, at least one lubricant is magnesium stearate. In some embodiments, at least one binder is hydroxypropyl cellulose, and at least one lubricant is magnesium stearate.

[0132] In some implementations, the tablets are coated. The coating may be, but is not limited to, a colored coating.

[0133] In some implementations, APC or a pharmaceutically acceptable salt thereof is APC hydrochloride.

[0134] The tablets can be of any shape suitable for immediate release and allow for the release of at least 85% of the contained APC or its pharmaceutically acceptable salt within a time period of less than 15 minutes after administration to a subject. In some embodiments, the tablets maximize the surface area to volume ratio to facilitate rapid dissolution. In some embodiments, the tablets are rectangular in shape.

[0135] Tablets may contain any amount of APC or a pharmaceutically acceptable salt thereof suitable for administration as a unit dosage form. In some embodiments, tablets contain about 1 mg to about 1000 mg or any range or value thereof, such as about 100 mg to about 500 mg, for example about 37.5 mg, about 75 mg, about 150 mg or about 300 mg of the drug.

[0136] As used herein, "immediate release" refers to a composition that releases APC, or its pharmaceutically acceptable salts, hydrates, isomers, tautomers, solvates, or complexes substantially completely into the user's gastrointestinal tract within less than about 15 minutes after ingestion, typically within a timeframe between about 1 minute and about 15 minutes. Such a delivery rate allows the drug to be absorbed by the gastrointestinal tract in a manner bioequivalent to that of an oral solution. For immediate-release unit dosage forms, such as tablets, capsules, or pouches, this rapid absorption typically occurs if the drug contained in such dosage forms dissolves in the upper gastrointestinal tract.

[0137] The release rate can be measured using standard dissolution test methods. For example, standard conditions can be those described in FDA guidance (e.g., 50 rpm, 37°C, USP 2 paddle method, pH 1.2 and pH 6.8 media, 900 ml, 1 test article per container).

[0138] Immediate-release formulations suitable for oral administration may include unit dosage forms, such as tablets, capsules, or filled capsules, which deliver a therapeutically effective dose of APC when a patient ingests one or more of the aforementioned dosage forms, each dosage form providing, for example, a dose of about 1 to about 1000 mg of APC. Additionally, immediate-release dosage forms may be molded or scored to facilitate dose adjustment by tablet splitting.

[0139] The formulations and structures of immediate-release dosage forms disclosed herein can be adapted to provide immediate-release performance suitable for specific dosing needs. In particular, the formulations and structures of dosage forms described herein can be adapted to provide any combination of the immediate-release performance characteristics described herein. In specific embodiments, for example, the immediate-release dosage forms disclosed herein provide rapid onset of action, releasing more than about 85%, for example more than about 90% or 95%, of the drug contained therein within a time period selected from less than 15 minutes, less than 12 minutes, less than 10 minutes, and less than 5 minutes after administration.

[0140] Furthermore, the rate of drug release from immediate-release formulations as disclosed herein can be adjusted as needed to facilitate a desired dosing regimen or achieve targeted drug delivery. In one embodiment, the immediate-release formulation can be formulated to deliver up to 1,000 mg of APC. In a specific embodiment, the total amount of drug contained in the immediate-release formulation according to this specification can be from about 50 mg to about 500 mg. For example, in some such embodiments, the total amount of the 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 thereof. In some of these embodiments, the total amount of the 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.

[0141] The immediate-release formulations described herein typically include an APC and a level of lubricant to facilitate formulation into unit dosage forms. Therefore, in some embodiments, the formulations described herein comprise a combination of an APC and a lubricant as described herein, and in some such embodiments, the immediate-release formulations are substantially free of other excipients or adjuvants. In other embodiments, the immediate-release formulations described herein comprise a combination of an APC, a lubricant, and a binder as described herein, and in some such embodiments, the immediate-release formulations are substantially free of other excipients or adjuvants. Although the immediate-release formulations described herein can be formulated using a combination of a drug product with one or more of lubricants and binders, in some embodiments, the compositions described herein may contain one or more additional excipients selected from, for example, fillers, compression aids, diluents, disintegrants, colorants, flavorings, buffers, coatings, flow aids, or other suitable excipients.

[0142] The immediate-release formulations described herein can be prepared using standard techniques, such as wet granulation, rolling, fluidized bed granulation, and dry powder mixing. Suitable methods for preparing the immediate-release formulations and unit dosage forms described herein are provided, for example, in Remington, 20th Edition, Chapter 45 (Oral Solid Dosage Forms). It has been found that wet granulation techniques can provide flowable particles with compression properties suitable for forming unit dosage forms as described herein, even without the aid of binders or non-lubricating excipients (e.g., compression aids). Therefore, in some embodiments, when the immediate-release formulation requires a drug content greater than about 85%, 90%, or 95% by weight, wet granulation techniques can be used to prepare the immediate-release formulations as described herein. In such embodiments, as shown in the examples provided herein, conventional organic or aqueous solvents can be used in the wet granulation method. Suitable wet granulation methods can be performed using fluidized bed, high-shear, or low-shear (wet massing) granulation techniques known in the art.

[0143] In addition to one or more of APC, lubricants, and binders, the immediate-release formulations described herein may, if desired, also include fillers or compression aids selected from at least one of lactose, calcium carbonate, calcium sulfate, compressible sugars, glucose binders, dextrin, dextrose, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, powdered cellulose, and sucrose. When fillers or compression aids are used, in some embodiments they may be included in the immediate-release formulation at an amount of about 1% to 15% by weight.

[0144] The immediate-release formulations described herein can be processed using conventional techniques into unit dosage forms suitable for oral administration, such as filled capsules, compressed tablets, or capsules, or other dosage forms suitable for oral administration. The immediate-release dosage forms prepared as described can be suitable for oral administration to achieve and maintain therapeutic levels of APC within a pre-selected interval. In some embodiments, the immediate-release dosage forms described herein can include solid oral dosage forms of any desired shape and size, including circular, elliptical, rectangular, cylindrical, or polygonal shapes. In one such embodiment, the surface of the immediate-release dosage form can be flat, circular, concave, or convex. In some embodiments, the shape can be selected to maximize surface area, for example, to increase the dissolution rate of the dosage form.

[0145] In particular, when immediate-release formulations are prepared as tablets, these tablets contain a relatively large percentage and absolute amount of APC, thus expected to improve patient compliance and convenience by replacing the need to ingest large amounts of liquid or liquid / solid suspensions. One or more immediate-release tablets as described herein can be administered orally (e.g., at close intervals) to provide a therapeutically effective dose of APC to the subject within a relatively short time period. For example, dissolution of 10 mg–1000 mg tablets prepared according to this specification can provide the subject with approximately 80–100% of the APC within approximately 10–15 minutes.

[0146] When needed or necessary, the outer surface of immediate-release dosage forms disclosed herein may be coated with a moisture-proof layer using materials and methods known in the art. For example, when APC delivered by unit dosage form is highly hygroscopic, providing a moisture-proof layer on immediate-release dosage forms disclosed herein may be desirable. For example, protection against water during storage of immediate-release dosage forms disclosed herein can be provided or enhanced by coating tablets with a substantially water-soluble or water-resistant polymer. Useful water-insoluble or water-resistant coating polymers include ethyl cellulose and polyvinyl acetate. Other water-insoluble or water-resistant coating polymers include polyacrylates, polymethacrylates, etc. Suitable water-soluble polymers include polyvinyl alcohol and HPMC. Further suitable water-soluble polymers include PVP, HPC, HPEC, PEG, HEC, etc.

[0147] When needed or necessary, the outer surface of immediate-release formulations, as disclosed herein, may be coated with a colored coating or other aesthetic or functional layer using materials and methods known in the art.

[0148] The dosage forms disclosed herein can also be provided as kits comprising separately packaged containers containing multiple immediately-release tablets, wherein the tablets may be individually packaged, such as in foil wrapping or blister packs. The tablets may be packaged in multiple configurations, with or without desiccants or other materials, to prevent water ingress. Instructions for application, such as printed labels, may also be included for their administration, e.g., sequential administration over a preselected time period and / or at preselected intervals, to produce a desired level of APC in vivo for the treatment of a preselected condition.

[0149] The therapeutic outcomes disclosed herein can be achieved by administering daily doses of about 1 to about 2000 mg of APC or a pharmaceutically acceptable salt thereof. For example, daily doses of about 10-1000 mg, such as about 20-500 mg, or about 37.5, 75, 150, or 300 mg, can be administered as a single dose or in divided doses. In some embodiments, the daily dose can be about 0.01 to about 150 mg / kg body weight, such as about 0.2 to about 18 mg / kg body weight.

[0150] In one embodiment of the invention, APC is administered to a subject as needed to treat the disorder. The compound may be administered continuously or intermittently. In one embodiment, the compound is administered to the subject more than once a day, for example, 2, 3, or 4 times a 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, for example, 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 more frequently. In a further embodiment, the compound is administered using two or more different schedules, for example, initially administered more frequently (e.g., to accumulate to a certain level, such as once a day or more), and then administered less frequently (e.g., once a week or less). In other embodiments, the compound may be administered by any discontinuous administration regimen. In one instance, the compound may be administered no more than once every three, four, five, six, seven, eight, nine, or ten days or more. Administration may continue for one week, two weeks, three weeks, or four weeks, or for one month, two months, or three months or more. Optionally, after a rest period, the compound may be administered at the same or different schedules. Depending on the pharmacodynamic effects of the compound on the subject, the rest period may be one week, two weeks, three weeks, four weeks, or longer. In another embodiment, the compound may be administered to accumulate to a certain level, then maintained at a constant level, followed by a tailing dosage.

[0151] In one aspect of the invention, APC is delivered to a subject simultaneously with an additional therapeutic agent. The additional therapeutic agent may be delivered in the same composition as the compound or in a separate composition. The additional therapeutic agent may be delivered to the subject at a different schedule or via a different route compared to the compound. The additional therapeutic agent may be any agent that provides benefit to the subject. Other agents include, but are not limited to, nootropic agents (e.g., cognitive enhancers), including but not limited to stimulants (e.g., caffeine, dimethylpentylamine, methylphenidate, amphetamine, nicotine, modafinil, armodafinil), lacracetams (e.g., piracetam, piracetam, phenylpiracetam, piracetam), tocapone, levodopa, atormoxetine, pramipexole, guanfasin, clonidine, and fexofenadine. Nootropics may also include herbs such as purslane (Bacopa monnieri), ginseng (Panax ginseng), ginkgo (Ginkgo biloba), and sage (Salvia officinalis), as well as dietary supplements such as omega-3 fatty acids, folic acid, vitamin B6, and vitamin B12. 12Vitamin E and L-theanine. One therapeutic agent that can be administered simultaneously is Xyrem, commercially sold by Jazz Pharmaceuticals. ® It is used to treat narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0152] This invention has applications in research, as well as in veterinary and medical fields. Suitable subjects are typically mammalian subjects. As used herein, the term "mammal" includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), etc. Human subjects include newborns, infants, adolescents, adults, and elderly subjects.

[0153] The subject can be a subject who "needs" the method of the present invention, for example, a subject who needs the therapeutic effect of the method of the present invention. For example, the subject can be a subject who is experiencing cognitive impairment, suspected of having cognitive impairment, and / or expects to experience cognitive impairment, and the methods and compositions of the present invention are used for therapeutic and / or preventive treatment.

[0154] The invention has been described and will be explained in more detail in the following embodiments, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0155] Example 1

[0156] A randomized, placebo-controlled, double-blind, repeated measures, crossover phase IV clinical trial investigating the effects of the wakefulness stimulant somfitor on cognitive function in obstructive sleep apnea accompanied by excessive daytime sleepiness and cognitive impairment.

[0157] Research Design and Methods

[0158] 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 evaluating the efficacy and safety of soriamfetol 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 (United States, 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. Recruitment ended after a change in sponsor in May 2022. Prior to database locking, the study protocol was revised in August 2022, changing the primary DSST-RBANS endpoint from the mean values ​​assessed at 2 and 4 hours post-dose to the mean values ​​assessed at 2, 4, 6, and 8 hours post-dose. The study protocol and revisions were approved by the ethics committee or institutional review committee of each institution. All participants provided written informed consent.

[0159] Participants

[0160] Participants were men and women aged 18–65 years diagnosed with OSA according to the International Classification of Sleep Disorders, third edition. Sateia MJ. International Classification of Sleep Disorders-third edition:highlights and modifications. Chest. 2014;146(5):1387–1394. Relevant EDS was defined as an Epworth Sleepiness Scale (ESS) score >10 at screening and baseline. Johns MW. A new method formeasuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540–545. Cognitive impairment was defined as an age-adjusted score ≤8 on the coding subtest (the Digit Symbol Substitution Test (DSST) version of the Wechsler Adult Intelligence Scale, fourth edition (DSST WAIS-IV)) and a score ≥9 on the British Columbia Cognitive Complaint Questionnaire (BC-CCI) at screening and baseline. Jaeger J. DigitSymbol Substitution Test: The case for sensitivity over specificity inneuropsychological 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.

[0161] Figure 1The CONSORT flowchart for this study is shown. Participants included those who: had consistent PAP usage hours for ≥5 nights per week for ≥1 month prior to baseline; had no current PAP treatment for ≥1 month prior to baseline but had a history of trying PAP for ≥1 month with ≥1 adjustment aimed at optimizing treatment; or had a history of surgical intervention aimed at treating OSA symptoms. Other criteria included: usual bedtime later than 1:00 AM; shift work; use of over-the-counter or prescription medications that may affect EDS; any contraindications to somfitropin; use of a PAP machine for which no downloadable adherence data was available; diagnosis of a sleep disorder other than OSA; positive urine drug screening during the study; anticipated excessive caffeine use (>600 mg / day) in the week prior to screening or during the study; and a history or current diagnosis of any clinically relevant medical, behavioral, or psychiatric disorder associated with cognitive impairment.

[0162] treat

[0163] At the baseline visit, participants were randomized 1:1 to receive oral somfitropin (75 mg / day for 3 days, then 150 mg / day) or a matched placebo for 2 weeks every morning. After a 1-week washout period, participants crossed over to receive the opposite treatment for 2 weeks.

[0164] Evaluate

[0165] Objective cognition was assessed using the coding subtest, a variant of the DSST (DSST RBANS) in a repeatable suite of tests for assessing neuropsychological states, which is an objective measure of cognitive function sensitive to pharmacological intervention. Based on DSST WAIS-IV, the DSST RBANS is a symbol-digit test that measures attention, processing speed, and executive function (e.g., working memory); participants are required to match symbols with digits based on a key. To avoid practice influence, the practice test was administered during screening and each assessment visit, followed by rotating versions of the DSST RBANS. The DSST RBANS score is the number of correct symbol-digit matches within 90 seconds.

[0166] Subjective cognition is assessed using the BC-CCI, a validated six-item questionnaire that assesses self-reported cognitive abilities in attention, memory, expressive thinking, word recognition, reasoning, and problem-solving. Each item has four answer options and is rated from 0 to 3, with higher scores indicating greater cognitive impairment. The BC-CCI score is the overall score across all items.

[0167] The perceived severity of problems with attention, memory, and thinking abilities was measured using the Patient Overall Severity Impression (PGI-S). Participants rated the severity of their problems over the past week as “none” (0) to “very severe” (4).

[0168] EDS is assessed using the ESS, a validated 8-item self-report questionnaire that measures the likelihood of falling asleep during various activities. Each item has four answer options and is rated from 0 to 3, with higher scores indicating more severe EDS. The ESS score is the total score across all items. Detailed clinical visit structure is provided in Figure 2b middle.

[0169] result

[0170] The primary efficacy endpoint was the change in mean DSST RBANS score from baseline to the end of each treatment period at 2, 4, 6, and 8 hours after administration. The key secondary endpoint was the change in BC-CCI score from baseline to the end of each treatment period. Other secondary endpoints included ESS and PGI-S, as well as time-specific changes in DSST RBANS score from baseline to the end of each treatment period.

[0171] Safety and tolerability were assessed based on treatment-examined adverse events (TEAEs) and vital signs. TEAEs were defined as any adverse event occurring during each treatment period from the start of treatment (placebo or somfitropium) until 7 days after the last dose of the study drug. Suicidal ideation was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS) at screening, baseline, and each study visit.

[0172] Statistical analysis and power calculation

[0173] Descriptive summaries of demographics, baseline clinical characteristics, and safety outcomes were provided, with analysis of the safety cohort (randomized participants who received ≥1 dose of the investigational drug). Efficacy outcomes were analyzed in the modified intention-to-treat cohort (participants who received ≥1 dose of the investigational drug and had DSST RBANS scores at baseline and from at least one treatment period).

[0174] As the primary endpoint, the mean post-dose DSST RBANS score was analyzed using repeated measures regression modeling, with baseline as a covariate to estimate treatment effect and controlling for treatment duration, treatment sequence, and subjects. Two-sided 95% confidence intervals (CIs) for treatment effect and treatment differences (suafilto-placebo) are presented. Cycle and sequence effects were assessed; carryover effect was not examined, taking into account the duration of the washout period. Secondary analyses were performed on DSST RBANS scores at each individual time point (2, 4, 6, and 8 hours post-dose).

[0175] For secondary endpoints, a fixed-grading test sequence was used to control for multiplicity, focusing primarily on changes in scores from baseline to the end of each treatment period in 1) BC-CCI, 2) PGI-S, and 3) ESS. Test sequences were stopped when the two-sided P-value was no longer significant (i.e., P > 0.05). Results are expressed as the least squares (LS) mean change from baseline and its standard error (SE). The effect size (Cohen's d) of the changes in DSST RBANS, BC-CCI, PGI-S, and ESS scores from baseline to the end of each treatment period was determined.

[0176] Exploratory analyses included Pearson correlations between changes in ESS and DSST RBANS scores, ESS and BC-CCI scores, and ESS and PGI-S scores from baseline to the end of treatment, stratified by treatment condition and controlled for treatment sequence.

[0177] The original sample size was determined based on the mean difference of ≥3.0 points and SD ≤9.0 points between somifexor and placebo in the change of DSST RBANS scores from baseline to the end of each double-blind treatment period at 2 and 4 hours after administration. This was known from previous randomized, parallel, placebo-controlled trials of vortioxetine. 36,37 Further details regarding the original primary results prior to the study revision are presented in the supplemental materials. Because the primary efficacy outcome of this study was the mean DSST RBANS scores at 2, 4, 6, and 8 hours post-dose (i.e., twice the time points), the overall SD was assumed to be 6.9. Using a two-group t-test with the crossover design used in this study and assuming a correlation of 0.5 between treatment periods, the sample size required 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 in total.

[0178] result

[0179] Participant Group

[0180] Of the 173 participants screened for this study, 59 were recruited and randomly assigned to one of two treatment sequences. The safety cohort consisted of 59 participants (sofivir / placebo, n=30; placebo / sofivir, n=29). Two participants (one in each treatment sequence) did not complete the study; one completed the first efficacy visit, resulting in 58 participants in the modified intention-to-treat population whose data were available for efficacy outcome analysis. Figure 1Baseline demographic and clinical characteristics were similar across treatment groups, including PAP use (Table 1). Overall, 42 (71.2%) participants used PAP, the majority 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). The mean ± standard deviation (SD) of baseline PAP use per night across all users was 6.3 ± 2.5 hours.

[0181] Table 1. Baseline demographic and clinical characteristics

[0182]

[0183]

[0184] a Age-corrected scale scores were used to determine eligibility during screening.

[0185] b Assess cognitive function issues, including attention, memory, and thinking abilities.

[0186] c Compliance is defined as the use of PAP for ≥4 hours per night for ≥70% of the nights within any given time frame.

[0187] BC-CCI, British Columbia Cognitive Complaint Questionnaire; BMI, Body Mass Index; DSST, Digit Symbol Substitution Test; DSST RBANS, Coding Subtest, a repeatable suite of tests used to assess neuropsychological state; ESS, Epworth Sleepiness Scale; PAP, Positive Airway Pressure; PGI-S, Patient Overall Severity Impression; SD, Standard Deviation; WAIS-IV, Wechsler Adult Intelligence Scale, 4th Edition.

[0188] Efficacy and safety

[0189] The primary endpoint, the change in mean DSST RBANS score from baseline to the end of treatment, showed a statistically significant difference between somfitropin and placebo. Figure 3a The mean change (SE) relative to baseline after somfitol treatment was significantly greater (i.e., improvement) compared to placebo (4.74 [0.65]) (6.49 [0.65]); the mean difference (somfitol vs placebo) was 1.75 (95% CI: 0.46, 3.04; P = 0.009; effect size: d = 0.37). Post-hoc analysis of the mean change in 2-hour and 4-hour DSST RBANS (the original primary endpoint before study revision) was consistent with the current primary endpoint.

[0190] When evaluated at each 2-hour time point, at 2, 6, and 8 hours post-dose, somifexo significantly improved DSST RBANS scores compared to placebo. Figure 3b The mean differences at 2, 4, 6, and 8 hours were 1.91 (95% CI: 0.16, 3.65; P=0.033), 1.38 (95% CI: −0.22, 2.97; P=0.089), 2.33 (95% CI: 0.78, 3.88; P=0.004), and 1.58 (95% CI: 0.23, 2.93; P=0.022), respectively. Period (P=0.274) or sequence (P=0.915) had no significant effect.

[0191] On the BC-CCI, the mean change (SE) from baseline to the end of each treatment period showed a significantly greater reduction (i.e., improvement) of -4.7 (0.48) after somfitropide treatment compared to -3.1 (0.48) after placebo treatment. Figure 4 The mean difference was -1.58 (95% CI: -2.53, -0.63; P=0.002); effect size: d=0.45.

[0192] The mean change from baseline on the PGI-S showed a significantly greater reduction (i.e., improvement) of -0.90 (0.10) after somfitropium treatment compared to -0.61 (0.10) after placebo treatment. Figure 5 The mean difference was -0.29 (95% CI: -0.57, -0.02; P=0.034; effect size: d=0.29).

[0193] As measured by the ESS score, somifexo significantly improved EDS. The mean change in SE from baseline to the end of somifexo treatment was -4.41 (0.57) compared with -2.31 (0.56) for placebo. Figure 6 The mean difference was -2.10 (95% CI: -3.51, -0.68; P = 0.004; effect size: d = 0.40).

[0194] Controlling the treatment sequence, changes in ESS scores from baseline to the end of each treatment period were statistically significantly correlated with daily mean DSST RBANS scores (sofipheral, r=-0.28, P=0.036; placebo, r=-0.30, P=0.023), BC-CCI scores (sofipheral, r=0.54, P<0.001; placebo, r=0.60, P<0.001), and PGI-S scores (sofipheral, r=0.56, P<0.001; placebo, r=0.46, P<0.001). In all cases, greater decreases in ESS corresponded to better improvements in cognitive outcomes.

[0195] There were no deaths, serious TEAEs, or TEAEs leading to study discontinuation. Overall, 16 of the 59 patients in the safety cohort (27.1%) experienced any TEAE throughout the study; all were mild or moderate in severity. The incidence of any TEAE with somifexo (19.0%) was higher than that with placebo (10.3%; Table 2). The most common TEAEs with somifexo were nausea (7%) and anxiety (3%). No participants had suicidal thoughts or behaviors as identified by the C-SSRS.

[0196] Table 2. Adverse events occurring during treatment

[0197]

[0198] TEAE refers to adverse events that occur during treatment.

[0199] *In the safety cohort of 59 participants, 57 received both somifexo and placebo. Of the two participants lost to follow-up, one received somifexo only and the other received placebo only. Therefore, 58 participants received somifexo during the study period, and 58 participants received placebo.

[0200] Compared with placebo (0.5 [0.6] mmHg, SD: 4.6 mmHg, P=0.033), the change in diastolic blood pressure from baseline was greater with somfitor (LS mean [SE]: 2.0 [0.6] mmHg, SD: 4.7 mmHg). There were no significant differences from baseline in terms of systolic blood pressure (sofiodine: 1.0 [0.8] mmHg, SD: 6.3 mmHg; placebo: -0.4 [0.8] mmHg, P=0.146, SD: 6.3 mmHg), pulse rate (sofiodine: 0.1 [1.0] bpm, SD: 7.1 bpm; placebo: -0.6 [1.0] bpm, SD: 7.1 bpm, P=0.396) or weight (sofiodine: 0.03 [0.19] kg, SD: 1.40 kg; placebo: 0.27 [0.19] kg, SD: 1.38 kg, P=0.252) between somfitine and placebo.

[0201] discuss

[0202] Somifexo significantly improved cognitive function in patients with cognitive impairment associated with OSA and EDS. Overall improvement in objective cognition on the DSST RBANS score over a 2-week treatment period confirmed the efficacy of somifexo relative to placebo. Analysis of the original primary endpoint yielded similar results. This effect was generally consistent over time (2 to 8 hours post-dose), indicating that the therapeutic effect of somifexo was maintained throughout the 8-hour daytime. Participants reported overall subjective improvement in cognitive function with somifexo in the BC-CCI. In conclusion, these results demonstrate that somifexo is superior to placebo in both objective and subjective measures of cognitive function.

[0203] As expected, somifexo improved EDS relative to placebo. This is consistent with findings from the pivotal somifexo trial, in which somifexo improved ESS scores within 1 week of treatment initiation at the same dose as in this study (75 mg / day escalated to 150 mg / day after 3 days). 25 A long-term open-label extended study confirmed that the awakening effect of somfitropin lasted for up to 52 weeks of treatment.

[0204] Studies of OSA patients who received or did not receive PAP treatment have shown that dissociations between subjective somnolence and objective measures of cognitive impairment are common in this population. 38-40Although somnofibrate improved subjective somnolence and objective performance outcomes compared to placebo, these effects may be dissimilar. This possibility is supported by the relatively strong correlation observed between subjective outcomes and a more moderate correlation between subjective outcomes and objective DSST RBANS performance. Preclinical evidence suggests that somnofibrate may be a TAAR1 agonist. 29 It has the expected beneficial effects on cognitive function. 30 This is also consistent with the view that somfitor, in addition to its arousal effect, can alleviate cognitive impairment in OSA accompanied by EDS.

[0205] The tolerability of somfitol in this study is consistent with its known safety profile. 26 No serious treatment-associated adverse events (TEAEs) occurred, and no participants withdrew from the study due to TEAEs related to the study drug. The most common TEAEs were nausea and anxiety. Although this study involved short-duration somfitrop exposure, the long-term safety and tolerability of somfitrop in patients with end-stage renal syndrome (EDS) associated with OSA have been demonstrated. In a 52-week open-label study (n=417 OSA patients), 26 Common TEAEs include headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, loss of appetite, and upper respiratory tract infection; most TEAEs are mild to moderate in severity. Furthermore, there is no evidence of tolerance, rebound drowsiness, or withdrawal after abrupt discontinuation of long-term somnol. 26

[0206] In murine models of cognitive impairment associated with OSA and EDS, significant improvements in cognitive function (i.e., explicit memory) and / or anxiety-like behavior were observed with somfitor (200 mg / kg) instead of modafinil (200 mg / kg). 41,42 Human studies of WPA, which is not Somfitropin, have shown mixed results in cognitive measurements (including the cognitive drug study suite) in patients with OSA and EDS. 19,43-48 Here, somfitropin 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 to placebo in major depressive disorder. 36 When combined with clinical applications of DSST results related to effect size in similar populations, 33 This study demonstrates that somfitor meaningfully improves cognition in areas related to memory, processing speed, and attention in patients with cognitive impairment associated with OSA and EDS.

[0207] The exact mechanism of action of somfithospermia's arousal properties remains unclear. 21Somfitropin is a dopamine and norepinephrine reuptake inhibitor. 21,24 Increased noradrenergic and dopaminergic activity can mediate certain pro-cognitive effects. Preclinical evidence shows that somfitor is an agonist of TAAR1 and serotonin 1A receptors, which is unique to somfitor compared to modafinil and bupropion. 29 TAAR1 has been identified as a potential therapeutic target for several psychiatric disorders, and preclinical studies have shown that it may affect cognitive function. 29,30 More research is needed to better understand the role of these mechanisms in the cognitive function of patients with OSA and EDS.

[0208] One limitation of this study is its 5-week duration, which precludes conclusions about sustained effects on cognitive function over longer periods. The moderate sample size, drawn from a predominantly older (mean age 52.2%), male (64.4%), and Caucasian (72.9%) population, limits the generalizability of the results. Furthermore, the study design did not include direct comparisons with other WPAs. Further research is needed to assess the cognitive improvement of somfitor compared to other WPAs. One advantage of this study is its randomization, placebo-controlled, double-blind, repeated measures, and crossover design, where participants act as their own controls. This design reduces confounding factors and is statistically effective. Additionally, the study includes both objective and subjective measures of cognitive function. Follow-up studies should evaluate additional cognitive endpoints.

[0209] Interpretation

[0210] This study found that somifexo improved cognitive function in participants with cognitive impairment associated with OSA and EDS compared to placebo. Results from DSST RBANS indicated that somifexo objectively improved cognition. Participants perceived improvements in cognitive function and EDS, as shown in the BC-CCI and ESS results. Somifexo was well-tolerated in this study. These results support previous findings that somifexo improves EDS in patients with OSA with a favorable safety profile. 25-28 It also has the potential to improve cognitive function in patients with cognitive impairment associated with OSA and EDS.

[0211] Example 2

[0212] Somfitor and cognitive function in obstructive sleep apnea with excessive daytime sleepiness and cognitive impairment through primary airway therapy adherence: SHARP

[0213] Research Design and Methods

[0214] In SHARP, participants received somfitropin (75 mg / day for 3 days, then 150 mg / day) and placebo for 2 weeks, with a 1-week washout period. Participants were stratified according to PAP adherence (PAP use ≥4 hours / night on ≥70% of nights) and non-adherence (no reported PAP use or failure to meet adherence criteria). Results included changes from baseline in objective cognition as measured by the Number Symbol Replacement Test Coding Subtest of the Repeatable Suite Tests for Assessing Neuropsychological State (DSST RBANS), subjective cognition as measured by the British Columbia Cognitive Complaint Questionnaire (BC-CCI), and EDS as measured by the Epworth Sleepiness Scale (ESS). Results were presented for the modified intention-to-treat (mITT) group (participants who received ≥1 dose of the study drug and had DSST RBANS scores at baseline and from ≥1 treatment period).

[0215] result

[0216] SHARP recruited 59 participants (mean ± SD age 52.2 ± 10.7 years; 36% female). In the mITT group (N=58), 34 participants (59%) were PAP-compliant and 24 (41%) were non-compliant. On the DSST RBAN, the least squares mean ± SE difference between the somifexo group and placebo was comparable in the PAP-compliant group (1.7 ± 0.8) and non-compliant group (1.8 ± 1.1); the effect sizes (Cohen's d) were 0.38 and 0.33 for compliant and non-compliant participants, respectively. On the BC-CCI, the difference between the somifexo group and placebo was comparable regardless of PAP compliance (compliant: -1.7 ± 0.5; non-compliant: -1.4 ± 0.9); the effect sizes were 0.56 and 0.34 for compliant and non-compliant participants, respectively. Similar results were observed on ESS (compliance: -1.9 ± 0.8, d = 0.41; noncompliance: -2.4 ± 1.3, d = 0.38).

[0217] in conclusion

[0218] Regardless of adherence to PAP therapy, somfitol improved EDS and both objective and subjective cognitive function in participants with cognitive impairment associated with OSA and EDS. These results suggest that non-adherence to PAP therapy, which is common in people with OSA, does not lead to clinically meaningful differences in the therapeutic effects of somfitol on cognition and daytime sleepiness.

[0219] Example 3

[0220] Somfitropin for excessive sleepiness in narcolepsy and obstructive sleep apnea: effect size and number of effects requiring treatment or causing harm

[0221] Research Design and Methods

[0222] Excessive daytime sleepiness (EDS) is common in patients with narcolepsy and obstructive sleep apnea (OSA) and can lead to impaired cognitive function, poor work productivity, and reduced quality of life. Sunosi®, a dopamine and norepinephrine reuptake inhibitor, is approved in the US and EU for the treatment of EDS associated with narcolepsy (75-150 mg / day) or EDS associated with OSA (37.5-150 mg / day). Preclinical data suggest that Sunosi® activates trace amine-associated receptor 1 (TAAR1), a potential target for improving cognitive function. The efficacy and safety of Sunosi® have been established in two Phase 3 studies for the treatment of excessive sleepiness (TONES) in obstructive sleep apnea and narcolepsy (TONES)2 and TONES3; efficacy was confirmed based on ESS (Easy Sleep Status) scores, mean sleep latency on wakefulness maintenance tests (MWT), and changes in patient and clinical overall impression (PGIc and CGIc). Effect size, number of treatments required (NNT), and number of harms required (NNH) are statistical representations of efficacy and tolerability, and therefore may help guide clinicians in making treatment decisions.

[0223] TONES 2 (NCT02348593) and TONES 3 (NCT02348606). Participants were adult men and women aged 18–75 years diagnosed with narcolepsy or OSA. Key inclusion criteria were EDS (ESS score ≥10), baseline 40-minute mean sleep latency <25 minutes (narcolepsy) or <30 minutes (OSA), and total nighttime sleep ≥6 hours; for patients with OSA, primary OSA therapy (current or previous use of PAP, mandibula advancement device, or surgical intervention). Key exclusion criteria were a usual bedtime later than 1:00 AM, night work or variable shift work, or a diagnosis of any disorder associated with EDS (other than narcolepsy or OSA). Note: n-value represents the safety population. Participants assigned to 150 mg and 300 mg doses received 75 mg and 150 mg, respectively, for the first 3 days, followed by the full dose.

[0224] Based on changes from baseline to week 12, effect sizes for ESS score and mean sleep latency in MWT were determined compared to placebo (Cohen's d). Cohen's d effect sizes: small (d=0.2), moderate (d=0.5), and large (d=0.8)17. NNT (<10 was favorable) was determined for the percentage of participants whose score / score change at week 12 met the clinically meaningful response threshold.16 For ESS: ESS ≤10 and a reduction of ≥25% from baseline. For MWT (TONES 3 only): Achieved mean sleep latency ≥20 minutes. For PGIc and CGIc: Improvement, defined as a “minimum,” “more,” or “very much” improvement. NNH (≥10 was favorable) was determined for treatment-emergent adverse events (TEAEs) reported in ≥5% of participants treated with somfitropium and occurring more frequently than with placebo during the treatment period.

[0225] result

[0226] Compared to placebo, treatment with somfitropin 150 mg / day required treating three participants with narcolepsy or OSA to obtain one more participant who responded to PGIc or CGIc. See also Figure 7 Compared to placebo, treatment with somfitropin 150 mg / day required: 6 participants with narcolepsy and 3 participants with OSA to obtain 1 more participant with a ≥25% reduction in ESS score; and 5 participants with narcolepsy and 4 participants with OSA to obtain 1 more participant with a normal ESS score. See also Figure 8 Compared to placebo, treatment with somfitropin 150 mg / day required treating 3 participants with OSA to obtain 1 more participant with MWT ≥ 20 minutes. See also Figure 9 .

[0227] Table 3. Overview of the effect size and NNT of somfitor in TONES 2 and TONES 3

[0228]

[0229] a Based on the average change from the baseline. b Patients who achieved an average sleep latency of ≥20 minutes in the MWT. c This is not the approved dosage.

[0230] ESS, Epworth Sleepiness Scale; MWT, Wakefulness Maintenance Test; N / A, Not Applicable / Data Unavailable; NNT, Number of Treatments Required; OSA, Obstructive Sleep Apnea; TONES, Treatment for Obstructive Sleep Apnea and Excessive Sleepiness in Narcolepsy.

[0231] in conclusion

[0232] In TONES 2 and TONES 3, a large effect size of improved ESS and MWT was observed with higher doses of soamfiltox. In all outcomes, the NNT with soamfiltox at a dose of 150 mg / day ranged from 3 to 6 in patients with narcolepsy (TONES 2) and from 3 to 4 in patients with OSA (TONES 3). For common TEAEs, the concomitant NNH was >10 at all doses and at the approved dose of soamfiltox, except for headache in TONES 2. This post-hoc analysis confirms the beneficial effect size of soamfiltox in the treatment of EDS associated with narcolepsy and OSA, as well as the NNT and NNH values.

[0233] Example 4

[0234] The SURWEY Study of Somfitropin: Initiation, Dose Elevation, Safety, Efficacy, and Follow-up Experiences in German Patients with OSA

[0235] Research Design and Methods

[0236] Excessive daytime sleepiness (EDS) is a common symptom of obstructive sleep apnea (OSA) that persists in patients despite positive airway pressure (PAP) therapy and can pose a challenge to clinical symptom control. Somfitropin has been shown to activate trace amine-associated receptor 1 (TAAR1), a potential target for improving cognitive function. Real-world evidence regarding how physicians should initiate somfitropin in patients with OSA and associated EDS and subsequent treatment outcomes is limited; such data could help clinicians optimize patient care.

[0237] This real-world study characterizes the dosing and dose escalation strategies of European physicians who initiated somifexo, and the treatment outcomes after initiation in patients with EDS and OSA. The SUnosi Real World ExperienceStudY (SURWEY) is a retrospective graphical review of German physicians who have prescribed somifexo to patients with EDS associated with narcolepsy or OSA. This analysis focuses on data from 83 OSA patients from Germany. Eligible patients were ≥18 years of age, had reached a stable maintenance dose of somifexo due to a diagnosis of EDS with OSA, and had completed ≥6 weeks of treatment; patients receiving somifexo during clinical trials or early access programs were excluded. Somifexo initiation strategies: switching (from an existing EDS medication), add-on (added to a current EDS medication), and new treatment (no current / previous EDS medication). Descriptive summaries were provided of data related to somfitrop administration / dose escalation, comorbidities, Epworth Sleepiness Scale (ESS) scores, patient and physician-reported improvements in EDS, duration of somfitrop action, and adverse events.

[0238] result

[0239] Table 4. Baseline Demographic and Clinical Characteristics

[0240]

[0241]

[0242] ADHD, Attention Deficit Hyperactivity Disorder; BMI, Body Mass Index; ESS, Epworth Sleepiness Scale; SD, Standard Deviation.

[0243] New treatment was the most common initiation strategy (75%), followed by adjunctive therapy (14%) and conversion (11%). Obesity (58%) was the most common comorbidity. Overall, 73 (88%) patients used PAP therapy; 60 (72%) patients used PAP ≥4 hours / night, and 66 (80%) patients used PAP ≥4 nights / week. The most commonly used concomitant medication for EDS was telolide (pitolisant).

[0244] All nine (100%) patients in the switching group switched to somfitropin due to ineffectiveness of other EDS drugs. Dose escalation of somfitropin was performed in 53 (64%) patients, with the majority (57%) completing the escalation within 2 weeks. See also Figure 10 The mean improvement in ESS in the conversion group, the supplementary group, and the new treatment group was significantly greater than the minimum clinically important difference of 2–3 points. See also Figure 11Overall, 75 (91%) patients reported no change in nighttime sleep quality after treatment with somfitropium. See also Figure 12 and 13 The adverse events were consistent with those previously reported in clinical trials of somfitropin in participants with OSA.

[0245] Table 5. Adverse events occurring during the treatment period a

[0246]

[0247] TEAE refers to adverse events that occur during treatment.

[0248] a It has been reported in ≥2 patients.

[0249] in conclusion

[0250] In the SURWEY study of somfitrop in OSA patients, somfitrop was typically started at 37.5 mg / day, and most patients were new to treatment; dose escalation was common. Overall, the mean ESS score improved by 5.4 points, and the mean improvement across all groups was significantly greater than the minimum clinically important difference of 2–3 points. This is consistent with the improvement in somnolence reported in clinical trials of somfitrop. Regardless of the starting strategy, patients and physicians perceived improvement in EDS in the vast majority of patients. Most patients reported the effects of somfitrop lasting at least 8 hours. Common adverse events were consistent with previously reported adverse events associated with somfitrop.

[0251] Example 5

[0252] Medical use of airway therapy in patients with obstructive sleep apnea and excessive daytime sleepiness in the UK

[0253] Research Design and Methods

[0254] Excessive obstructive sleep apnea (OSA) is characterized by recurrent interruptions of breathing during sleep. Continuous positive airway pressure (CPAP) therapy is the standard of care for OSA, reducing hypoxic events and alleviating sleep interruptions; however, despite CPAP use, 10%–28% of patients still experience persistent excessive daytime sleepiness (EDS). Patients with OSA have increased healthcare resource utilization (HCRU) compared to those without OSA, including healthcare costs, medication use, emergency department visits, and hospitalizations. Real-world evidence regarding the burden of HCRU is limited for OSA patients treated with CPAP who experience EDS.

[0255] The aim of this study was to characterize patient demographics, comorbidities, medications, and HCRU in patient populations with and without supporting EDS statements after CPAP initiation.

[0256] A retrospective, observational, cohort study of OSA patients treated with CPAP was based on secondary use of electronic medical records from primary and secondary care databases. This study utilized the primary care database, the Clinical Practice Research Data Link (CPRD) Aurum, which links to the Hospital Event Statistics (HES) database, a secondary care database encompassing patient-level data. The observation period was from January 1, 2008 to March 31, 2020. Figure 14 The index date is defined as the date on which CPAP treatment was first recorded during the eligibility period and after an OSA diagnosis. The baseline period is defined as the 12-month period preceding the index date. The follow-up period is defined as the period from the index date to the earliest of the following: 24 months from the index date; the end of the observation period on March 31, 2020; or deregistration from the database (e.g., due to migration or death).

[0257] Key inclusion criteria: Patients aged ≥18 years at OSA diagnosis, whose records were permanently registered as “acceptable” in the CPRD Aurum database, and whose first CPAP treatment record occurred after OSA diagnosis and between January 1, 2009 and March 31, 2018. Patient information was obtained using Read codes in the CPRD or Systematized Nomenclature of Medicine – Clinical Terms codes. HCRU was described at 0–12 months and 12–24 months after CPAP initiation. Primary care contacts were obtained from the CPRD and included all general practitioner consultations (telephone or in person) and referrals to secondary care. Secondary care contacts were obtained from the HES database and included: elective and non-elective inpatient care in general and specialty settings (including daytime cases) and corresponding length of stay; outpatient visits in general and specialty settings; accidents and emergency (A&E); and road traffic accidents.

[0258] Based on data availability, patients with EDS were identified using the Epworth Sleepiness Scale (ESS) score. ESS scores were defined using codes from the CPRD and summarized over three time periods: during the patient's baseline period, the first 6 months after CPAP initiation, and ≥6 months after CPAP initiation until the end of follow-up. Patients with EDS were identified by the presence of definite EDS symptoms (defined as having an ESS ≥11 or a daytime fatigue code), while patients without EDS were identified by having an ESS <11 (if recorded) and no daytime fatigue code. HCRUs were summarized, as appropriate, using the mean and standard deviation (SD) of the number of events or days of hospitalization per patient per year during the follow-up period. Sensitivity analyses were performed where HCRUs were further described in the first 0–6 months and 6–12 months after CPAP initiation to illustrate the definition of EDS (fatigue records ≥6 months after CPAP initiation).

[0259] result

[0260] Table 6. Patient Demographic and Clinical Characteristics

[0261]

[0262] EDS, Excessive Daytime Sleepiness; SD, Standard Deviation.

[0263] The mean age of patients with EDS was 56.99 years; the majority were male (60.2%). Patients with EDS were more likely to have a history of psychiatric, gastrointestinal, and neurodegenerative disorders compared to those without EDS. See Table 6.

[0264] Table 7. Drug treatment at baseline for 12 months

[0265]

[0266] EDS, excessive daytime sleepiness.

[0267] *No cases were reported due to the small number of patients.

[0268] Compared to patients without EDS, a significantly larger proportion of patients with EDS were prescribed: psychiatric medications (antidepressants and hypnotics / anxiety medications); medications for acid-related stomach problems, proton pump inhibitors, nonsteroidal anti-inflammatory drugs, and corticosteroids.

[0269] The use of wakefulness stimulants such as modafinil is very low in both EDS and non-EDS patient populations.

[0270] Table 8. HCRU per patient at 0-12 months and 12-24 months after CPAP initiation

[0271]

[0272]

[0273]

[0274] This includes patients with ≥1 primary care contact record.

[0275] *N shows the total number of days in bed rest during this period; the average represents the number of days for each patient throughout the period.

[0276] A&E, Accidents and Emergencies; CPAP, Continuous Positive Airway Pressure; EDS, Excessive Daytime Sleepiness; HCRU, Medical Resource Utilization; N, Total Activity.

[0277] In the first year after CPAP initiation, patients with EDS had a significantly higher mean number of primary care contacts compared to those without EDS; in the second year, the number of contacts decreased slightly between the two groups, but remained significantly different. Patients with EDS had more outpatient visits in both the first and second years after CPAP initiation compared to those without EDS.

[0278] Table 9. Sensitivity analysis: HCRU per patient at 0-6 months and 6-12 months after CPAP initiation

[0279]

[0280]

[0281] This includes patients with ≥1 outpatient visit; patients with ≥1 elective hospitalization; and patients with ≥1 A&E visit.

[0282] *N shows the total number of days in bed rest during this period; the average represents the number of days for each patient throughout the period.

[0283] A&E, Accidents and Emergencies; CPAP, Continuous Positive Airway Pressure; EDS, Excessive Daytime Sleepiness; HCRU, Medical Resource Utilization; N, Total Activity; SD, Standard Deviation.

[0284] Sensitivity analysis showed that HCRU levels were similar during the 0-6 month and 6-12 month periods after CPAP initiation.

[0285] Whether the documentation of EDS and EDS severity is complete, and whether claims similar to EDS are used as alternative measures to appropriately identify patients with EDS, is unknown. Patients with more severe EDS may already be overrepresented. There is no data on adherence to primary airway therapy.

[0286] in conclusion

[0287] Patients with EDS had higher levels of primary and most secondary HCRU compared to those without EDS. In this cohort of patients with OSA treated with CPAP, the use of arousal-promoting drugs was low in both patients with and without EDS. In patients with EDS, the comorbidity burden and the use of medications (especially psychiatric medications) were both high.

[0288] This study found that somifexo improved cognitive function in participants with cognitive impairment associated with OSA and EDS compared to placebo. Results from DSST RBANS indicated that somifexo objectively improved cognition. Participants perceived improvements in cognitive function and EDS, as shown in the BC-CCI and ESS results. Somifexo was well-tolerated in this study. These results support previous findings that somifexo improves EDS in patients with OSA with a favorable safety profile. 25-28 It also has the potential to improve cognitive function in patients with cognitive impairment associated with OSA and EDS. This has been demonstrated.

[0289] * * * * *

[0290] The scope of this invention is not limited to the specific embodiments described herein. In fact, various modifications to the invention beyond those described herein will become apparent to those skilled in the art based on the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0291] All patents, applications, publications, test methods, documents and other materials cited in this article are incorporated herein by reference.

Claims

1. A method for enhancing one or more cognitive functions, the method comprising administering a therapeutically effective amount of a compound of formula II to a subject suffering from cognitive impairment associated with obstructive sleep apnea and excessive daytime sleepiness. II Or its pharmaceutically acceptable salt, thereby enhancing one or more cognitive functions of the subject.

2. The method of claim 1, wherein the compound is a compound of formula I. I Or its pharmaceutically acceptable salt.

3. The method of claim 1, wherein the compound is a 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 functions are selected from executive functions, memory, and learning.

6. The method of claim 1, wherein the cognitive function is an 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 functions are 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 a subject who requires it.

12. A method for treating one or more cognitive impairments in a subject suffering from cognitive impairment associated with obstructive sleep apnea and excessive daytime sleepiness, the method comprising administering to the subject suffering from said one or more cognitive impairments a therapeutically effective amount of a compound of formula II. II Or a pharmaceutically acceptable salt thereof, thereby treating one or more cognitive impairments in the subject.

13. The method of claim 12, wherein the compound is a compound of formula I. I Or its pharmaceutically acceptable salt.

14. The method of claim 12, wherein the compound is a 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 claim 12, wherein the cognitive impairment is selected from executive function impairment, learning impairment, and memory impairment.

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

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

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

20. The method of claim 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 an impairment of cognitive flexibility.

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

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 a subject suffering from one or more of the aforementioned cognitive impairments.

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

27. The method of claim 26, wherein the compound is a compound of formula I. I Or its pharmaceutically acceptable salt.

28. The method of claim 26, wherein the compound is a 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 executive function impairment, learning impairment, and memory impairment.

31. The method of claim 30, wherein the cognitive impairment is executive function impairment.

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

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

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 an impairment of cognitive flexibility.

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

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

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

39. The method of claim 26, further comprising administering a nootropic agent to a subject suffering from one or more of the aforementioned cognitive impairments.

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