Methods of improving daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome

Abstract

The present invention relates a method of treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome. More specifically, the present invention is directed to a method of administering a therapeutically effective amount of solriamfetol or a pharmaceutically acceptable salt thereof alone or in combination with other medications, for the treatment of daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome.

Description

ENCEPHALOMYELITIS / CHRONIC FATIGUE SYNDROMETECHNICAL FIELD

[0001] The present invention relates to a method of treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome. Myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) is a long-term illness with no treatment options that address the disease directly. Solriamfetol is a selective dual norepinephrine-dopamine reuptake inhibitor that promotes wakefulness in obstructive sleep apnea and narcolepsy.BACKGROUND OF THE INVENTION

[0002] Myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) is a debilitating illness of unknown etiology involving complex dysregulation of the central nervous, immune, and endocrine systems.11-31ME / CFS is characterized by the primary symptom of chronic fatigue. The rapid and sustained fatigability in response to low-level physical and mental exertion distinguishes ME / CFS from fatigue experienced from other conditions, particularly with the low threshold of onset and prolonged recovery unique to ME / CFS.1231The unexplained fatigue may be accompanied by impaired neurological, immune, gastrointestinal, urogenital, cardiovascular, and autonomic functioning.11 21ME / CFS is a long-term illness that ubiquitously affects all racial, ethnic, and socioeconomic groups.131Its prognosis is generally considered poor, with reported recovery rates of 0-8% and improvement rates ranging between 17% and 64%.141

[0003] ME / CFS is commonly found after infection, but there is no clearly defined pathophysiology.131Prevailing hypotheses suggest the involvement of neuroinflammation affecting the central nervous system and peripheral processes as underlying factors in disease onset.1351Several mechanisms leading to dysregulation have been implicated and supported by observational patient studies,16-91including an interplay between inflammatory pathways,191overactivated glial cells,1101altered serotonin transmission,111 121and neuroendocrine dysfunction.113141Without a definitive underlying mechanism,AXSOME 41 PCTthere are currently no medications specifically indicated for ME / CFS approved by the United States Food and Drug Administration (U.S. FDA) that address the disease directly. Instead, treatment plans include pharmacologic interventions that attempt to alleviate symptoms like depression, orthostatic intolerance, and pain, or to address perpetuating factors. These include mild pain relievers, COX-2 inhibitors, non-steroidal anti-inflammatory drugs, antidepressants, and immune modulators.115-171Non-pharmacologic treatments, like graded exercise and cognitive behavior therapy, may be beneficial for some patients, but evaluations yield inconsistent results.1171

[0004] The purported role of serotonin in the pathophysiology of ME / CFS has led to the investigation of selective serotonin reuptake inhibitors (SSRIs) to treat cognitive symptoms, fatigue, and secondary symptoms related to mood, activity, and sleep.115181Although some antidepressant trials, including those of venlafaxine and escitalopram, have demonstrated improvement in fatigue and depressive symptoms,119201there is insufficient evidence that serotonergic medications are a reliable treatment option for ME / CFS.121 221Initial investigations of drugs that modulate either dopamine or norepinephrine, such as modafinil or selegiline, have shown promise for alleviating secondary symptoms, but no consistent effect on fatigue has been found.123241Recent studies have more strongly supported the possibility that dual inhibitors of dopamine and norepinephrine may be more effective in treating fatigue.125261For example, bupropion, a norepinephrine and dopamine reuptake inhibitor (NDRI), improved fatigue and sleepiness symptoms in a large clinical population with major depressive disorder more effectively than a comparator SSRI and placebo.1271Similarly, CNS stimulants considered to be NDRIs, including methylphenidate, dextroamphetamine, and lisdexamfetamine, relieve fatigue and cognitive symptoms in some patients.128-311

[0005] Solriamfetol (formerly known as JZP-110 and ADX0N006) is a selective NDRI indicated to promote wakefulness in obstructive sleep apnea and narcolepsy.1321Solriamfetol has a lower binding affinity to dopamine and norepinephrine transporters than other stimulants and does not promote theAXSOME 41 PCTrelease of monoamines, as amphetamine stimulants do.133’341In previous trials for obstructive sleep apnea and excessive daytime sleepiness in adults, solriamfetol improved wakefulness, reduced sleepiness, and improved patient ratings on the Patient Global Impression of Change Scale compared to placebo. These effects extended to improvements in daily functioning, health-related quality of life, and work productivity over 12 weeks of treatment.134351Solriamfetol would be a preferable treatment option compared to many of the stimulants proposed to treat ME / CFS because of its milder side effect profile and lower risk of abuse and dependence.1361Due to its mechanism of action as a dual reuptake inhibitor of dopamine and norepinephrine and the symptom improvement documented in patients with excessive daytime sleepiness, the present study evaluates the efficacy of solriamfetol in treating fatigue symptoms in adults with ME / CFS.OBJECTS OF THE INVENTION

[0006] Accordingly, there is a need for the treatment of daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome.SUMMARY OF THE INVENTION

[0007] The present invention is directed to a method of treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome comprising the administration of a therapeutically effective amount of solriamfetol or pharmaceutically acceptable salts thereof, to a mammal in need of treatment.

[0008] In another embodiment, the present invention provides a method which further comprises administering a therapeutically effective amount of at least one other therapeutic agent for the treatment of daily fatigue improving symptoms.

[0009] In another embodiment, the present invention provides a methodAXSOME 41 PCTwherein solriamfetol or a pharmaceutically acceptable salt thereof and the at least one other therapeutic agent for the treatment of daily fatigue are administered in the same composition.

[0010] In another embodiment, the present invention provides a pharmaceutical composition for treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome, comprising solriamfetol ora pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE DRAWINGSFigure 1: Change from baseline of FSI: Severity, the primary outcome, in patients receiving solriamfetol or placebo. Patients assigned to solriamfetol had significantly decreased FSI severity compared to placebo at week 8.Figure 2: Change from baseline of BRIEF-A: GEC scores, a secondary outcome, in patients receiving solriamfetol or placebo. Patients assigned to solriamfetol had significantly decreased BRIEF-A: GEC scores compared to placebo at week 8.Figure 3: Change from baseline of BRIEF-A: Metacognition Index scores, a secondary outcome, in patients receiving solriamfetol or placebo.Patients assigned to solriamfetol had significantly decreased BRIEF-A: Ml scores compared to placebo at weeks 6 and 8.Figure 4: Change from baseline of PGI-S, an exploratory outcome, in patients receiving solriamfetol or placebo. Patients assigned to solriamfetol had significantly decreased FSI severity compared to placebo at weeks 6 and 8.AXSOME 41 PCTDETAILED DESCRIPTION OF THE INVENTION

[0011] These and other objects of the invention will be more fully understood from the following description of the invention, the referenced drawings attached hereto and the claims appended hereto.

[0012] The present invention is directed to a method of treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome comprising the administration of a therapeutically effective amount of solriamfetol or pharmaceutically acceptable salts thereof, to a mammal in need of treatment.Definitions

[0013] For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

[0014] It is to be understood that this invention is not limited to the particular methodology, protocols, animal species or genera, and reagents described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention that will be limited only by the appended claims.

[0015] As used herein the term "subject" refers to an animal, preferably a mammal, and most preferably a human both male and female, who has been the object of treatment, observation or experiment.

[0016] The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the signs or symptoms of the disease or disorder being treated.

[0017] The term "prophylactically effective amount" is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk ofAXSOME 41 PCToccurrence of the biological or medical event that is sought to be prevented of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0018] The term "pharmaceutically acceptable salts" shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base. Examples of such salts include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate.

[0019] Therefore, the term "a patient in need of treatment" as used herein will refer to any subject or patient who currently has or may develop any of the above syndromes or disorders, including any mood disorder which can be treated by antidepressant medication, or any other disorder in which the patient s present clinical condition or prognosis could benefit from the administration of one or more compounds of Formula (1) alone or in combination with another therapeutic intervention including but not limited to another medication.

[0020] The term "treating" or "treatment" as used herein, refers to any indicia of success in the prevention or amelioration of an injury, pathology or condition of ADHD and modification of symptoms of ADHD, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline or worsening of the illness; making the final point of worsening less debilitating; or improving a subject's physical or mental well-being. The treatment or amelioration of symptoms canAXSOME 41 PCTbe based on objective or subjective parameters; including the results of a physical examination, neurological examination, and / or psychiatric evaluations. Accordingly, the term "treating" or "treatment" includes the administration of the compounds or agents of the present invention for treatment of any form of ADHD in both males and females. In some instances, treatment with the compounds of the present invention will done in combination with other compounds to prevent, inhibit, or arrest the progression of the ADHD.

[0021] The term "therapeutic effect" as used herein, refers to the effective improvement in or reduction of symptoms of ADHD. The term "a therapeutically effective amount" as used herein means a sufficient amount of one or more of the compounds of the invention to produce a therapeutic effect, as defined above, in a subject or patient in need of such ADHD treatment.

[0022] The terms "subject" or "patient" are used herein interchangeably and as used herein mean any mammal including but not limited to human beings including a human patient or subject to which the compositions of the invention can be administered. The term mammals include human patients, both male and female and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals.

[0023] Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. For example the compound can be employed at a daily dose in the range of about 0.1 mg to 400 mg usually on a regimen of I to 2 times per day, for an average adult human. The effective amount, however, may be varied depending upon the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

[0024] The compound may be administered to a subject by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral. Depending onAXSOME 41 PCTthe route of administration, solriamfetol or pharmaceutically acceptable salts thereof can be constituted into any form. For example, forms suitable for oral administration include solid forms, such as pills, gelcaps, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders. Forms suitable for oral administration also include liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. In addition, forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

[0025] To prepare the pharmaceutical compositions of this invention, solriamfetol or pharmaceutically acceptable salts thereof as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers are necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorings, sweeteners, preservatives, dyes, and coatings. In preparing compositions in oral dosage form, any of the usual pharmaceutical carriers may be employed. For example, for liquid oral preparations, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. For parenteral use, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

[0026] Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Suppositories may be prepared, in which case cocoa butter could be used as the carrier. The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pills can comprise an inner dosage and an outer dosage component, the latter being inAXSOME 41 PCTthe form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0027] The active drug can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0028] Active drug may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drug may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamidephenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.

[0029] Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories, for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.

[0030] Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.AXSOME 41 PCT

[0031] The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful, suppository and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. For example, the pharmaceutical compositions herein can contain, per unit dosage unit, from about 25 to about 400 mg of the active ingredient. Preferably, the range is from about 50 to about 200 mg of the active ingredient.

[0032] In some embodiments of the present invention solriamfetol or pharmaceutically acceptable salts thereof will be administered either singly or concomitantly with at least one or more other compounds or therapeutic agents. In these embodiments, the present invention provides methods to treat ADHD and modification of symptoms associated with ADHD in a patient. The method includes the step of; administering to a patient in need of treatment, an effective amount of solriamfetol or pharmaceutically acceptable salts thereof in combination with an effective amount of one or more other compounds or therapeutic agents.

[0033] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as the methods provided herein.

[0034] The present invention also includes the use of mixtures of enantiomers of solriamfetol or pharmaceutically acceptable salts thereof. In one aspect of the present invention, one enantiomer will predominate. An enantiomer that predominates in the mixture is one that is present in the mixture in an amount greater than any of the other enantiomers present in the mixture, e.g., in an amount greater than 50%. In one aspect, one enantiomer will predominate to the extent of 90% or to the extent of 91 %, 92%, 93%, 94%, 95%, 96%, 97% or 98% or greater.AXSOME 41 PCT

[0035] The present invention provides methods of using enantiomers and enantiomeric mixtures of solriamfetol or pharmaceutically acceptable salts thereof. Solriamfetol or pharmaceutically acceptable salts thereof contains a chiral center on the second aliphatic carbon adjacent to the phenyl ring. An enantiomer that is isolated is one that is substantially free of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that is separated via separation techniques or prepared free of the corresponding enantiomer. The term "substantially free", as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In preferred embodiments, the compound includes at least about 90% by weight of a preferred enantiomer. In other embodiments of the invention, the compound includes at least about 99% by weight of a preferred enantiomer. Preferred enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred enantiomers can be prepared by methods described herein.Solriamfetol as a Pharmaceutical:

[0036] In general, solriamfetol or pharmaceutically acceptable salts thereof can be administered as pharmaceutical compositions by any method known in the art for administering therapeutic drugs including oral, buccal, topical, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, subcutaneous, or intravenous injection.) Administration of the compounds directly to the nervous system can include, for example, administration to intracerebral, intraventricular, intacerebroventricular, intrathecal, intracisternal, intraspinal or peri-spinal routes of administration by delivery via intracranial or intravertebral needles or catheters with or without pump devices.

[0037] Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, emulsions, syrups, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention in combination with at leastAXSOME 41 PCTone pharmaceutically acceptable excipient. Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, can be found in such standard references as Alfonso AR: Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton PA, 1985, the disclosure of which is incorporated herein by reference in its entirety and for all purposes. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, and glycols.

[0038] Solriamfetol or pharmaceutically acceptable salts thereof can be provided as aqueous suspensions. Aqueous suspensions of the invention can contain solriamfetol in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can include, for example, a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), ora condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).

[0039] The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolarity.

[0040] Oil suspensions for use in the present methods can be formulated by suspending solriamfetol in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax,AXSOME 41 PCThard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a mixture of these.

[0041] Suitable emulsifying agents include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0042] The compound of choice, alone or in combination with other suitable components can be made into aerosol formulations (i.e., they can be "nebulized") to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.

[0043] Formulations of the present invention suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, can include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- orAXSOME 41 PCTdiglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter.

[0044] Where the compounds are sufficiently soluble they can be dissolved directly in normal saline with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol. Dispersions of the finely divided compounds can be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in suitable oil, such as arachis oil. These formulations can be sterilized by conventional, wellknown sterilization techniques. The formulations can contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.

[0045] The concentration of a compound in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluents or solvent, such as a solution of 1 ,3-butanediol. The formulations of commends can be presented in unitdose or multi-dose sealed containers, such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0046] Solriamfetol or pharmaceutically acceptable salts thereof can be and is preferably administered orally. The amount of a compound of the present invention in the composition can vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary skill in the art. In general, the final composition canAXSOME 41 PCTcomprise, for example, from 0.000001 percent by weight ( % w) to 50 % w solriamfetol, preferably 0.00001 % w to 25% w, with the remainder being the excipient or excipients.

[0047] Pharmaceutical formulations for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical formulations to be formulated in unit dosage forms as tablets, pills, powder, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc. suitable for ingestion by the patient.

[0048] Formulations suitable for oral administration can consist of (a) liquid solution, such as an effective amount of the pharmaceutical formulation suspended in a diluents, such as water, saline or polyethyleneglycol (PEG) 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions.

[0049] Pharmaceutical preparations for oral use can be obtained through combination of the compounds of the present invention with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable additional compounds, if desired, to obtain tablets or dragee cores. Suitable solid excipients are carbohydrate or protein fillers and include, but are not limited to sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose; and gums including arabicand tragacanth; as well as proteins such as gelatin and collagen.

[0050] If desired, disintegrating or solubilizing agents can be added, such as the crosslinked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents,AXSOME 41 PCTbuffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art.

[0051] Solriamfetol or pharmaceutically acceptable salts thereof can also be administered in the form of suppositories for rectal administration of the drug. These formulations can be prepared by mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures but liquid at the rectal temperatures and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[0052] Solriamfetol or pharmaceutically acceptable salts thereof can also be administered by intranasal, intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111 , 1995).

[0053] Solriamfetol or pharmaceutically acceptable salts thereof can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0054] Encapsulating materials can also be employed with the compounds of the present invention and the term "composition" can include the active ingredient in combination with an encapsulating material as a formulation, with or without other carriers. For example, the compounds of the present invention can also be delivered as microspheres for slow release in the body. In one embodiment, microspheres can be administered via intradermal injection of drug (e.g., mifepristone)-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao, Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles,AXSOME 41 PCTJ. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months. Cachets can also be used in the delivery of the compounds of the present invention.

[0055] In another embodiment, Solriamfetol or pharmaceutically acceptable salts thereof can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compound into target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pham. 46:1576-1587, 1989).

[0056] The pharmaceutical formulations of the invention can be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. In other cases, the preferred preparation can be a lyophilized powder which can contain, for example, any or all of the following: I mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.

[0057] Pharmaceutically acceptable salts refer to salts that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that may be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N methylglucamine, and the like. Pharmaceutically acceptable salts can also include acid addition salts formed from the reaction of amine moieties in the parent compound with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acidsAXSOME 41 PCT(e.g. acetic acid, citric acid, maleic acid, and the alkane- and arenesulfonic acids such as methanesulfonic acid and benzenesulfonic acid). When there are two acidic groups present, a pharmaceutically acceptable salt may be a monoacid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.

[0058] Compounds named in this invention can be present in unsalified form, or in salified form, and the naming of such compounds is intended to include both the original (unsalified) compound and its pharmaceutically acceptable salts. The present invention includes pharmaceutically acceptable salt forms of solriamfetol. More than one crystal form of an enantiomer of solriamfetol can exist and as such are also included in the present invention.

[0059] A pharmaceutical composition of the invention can optionally contain, in addition to Solriamfetol or pharmaceutically acceptable salts thereof, at least one other therapeutic agent useful in the treatment of fatigue. For example, solriamfetol can be combined physically with other fatigue treatments in fixed dose combinations to simplify their administration.

[0060] Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets. Second Edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications.Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems. Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc, the disclosure of which are herein incorporated by reference in their entireties and for all purposes.

[0061] The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.AXSOME 41 PCTDosage Regimens

[0062] The present invention provides methods of providing anti-fatigue action in a mammal using Solriamfetol or pharmaceutically acceptable salts thereof. The amount of the solriamfetol compound necessary to reduce or treat fatigue is defined as a therapeutically ora pharmaceutically effective dose. The dosage schedule and amounts effective for this use, i.e., the dosing or dosage regimen will depend on a variety of factors including the stage of the disease, the patient's physical status, age and the like. In calculating the dosage regimen for a patient, the mode of administration is also taken into account.

[0063] A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of Solriamfetol or pharmaceutically acceptable salts thereof for practice of this invention (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The art, Science and Technology of Pharmaceutical Compounding; and Pickar, 1999, Dosage Calculations). A therapeutically effective dose is also one in which any toxic or detrimental side effects of the active agent that is outweighed in clinical terms by therapeutically beneficial effects. It is to be further noted that for each particular subject, specific dosage regimens should be evaluated and adjusted overtime according to the individual need and professional judgment of the person administering or supervising the administration of the compounds.

[0064] For treatment purposes, the compositions or compounds disclosed herein can be administered to the subject in a single bolus delivery, via continuous delivery over an extended time period, or in a repeated administration protocol (e.g., by an hourly, daily or weekly, repeated administration protocol). The pharmaceutical formulations of the present invention can be administered, for example, one or more times daily, 3 times per week, or weekly. In one embodiment of the present invention, the pharmaceutical formulations of the present invention are orally administered once or twice daily.AXSOME 41 PCT

[0065] In this context, a therapeutically effective dosage of Solriamfetol or pharmaceutically acceptable salts thereof can include repeated doses within a prolonged treatment regimen that will yield clinically significant results to treat fatigue. Determination of effective dosages in this context is typically based on animal model studies followed up by human clinical trials and is guided by determining effective dosages and administration protocols that significantly reduce the occurrence or severity of targeted exposure symptoms or conditions in the subject. Suitable models in this regard include, for example, murine, rat, porcine, feline, non-human primate, and other accepted animal model subjects known in the art. Alternatively, effective dosages can be determined using in vitro models (e.g., immunologic and histopathologic assays). Using such models, only ordinary calculations and adjustments are typically required to determine an appropriate concentration and dose to administer a therapeutically effective amount of the biologically active agent(s) (e.g., amounts that are intranasally effective, transdermally effective, intravenously effective, or intramuscularly effective to elicit a desired response).

[0066] In an exemplary embodiment of the present invention, unit dosage forms of Solriamfetol or pharmaceutically acceptable salts thereof are prepared for standard administration regimens. In this way, the composition can be subdivided readily into smaller doses at the physician's direction. For example, unit dosages can be made up in packeted powders, vials or ampoules and preferably in capsule or tablet form.

[0067] Solriamfetol or pharmaceutically acceptable salts thereof in these unit dosage forms of the composition can be present in an amount of, for example, from about 10 mg to about one gram or more, for single or multiple daily administration, according to the particular need of the patient. By initiating the treatment regimen with a minimal daily dose of about one gram, the blood levels of solriamfetol can be used to determine whether a larger or smaller dose is indicated.AXSOME 41 PCT

[0068] Effective administration of Solriamfetol or pharmaceutically acceptable salts thereof can be administered, for example, at an oral or parenteral dose of from about 0.01 mg / kg / dose to about 150 mg / kg / dose.Preferably, administration will be from about 0. I mg / kg / dose to about 25 mg / kg / dose, more preferably from about 0.2 to about 18 mg / kg / dose. Therefore, the therapeutically effective amount of the active ingredient contained per dosage unit as described herein can be, for example, from about 1 mg / day to about 7000 mg / day for a subject having, for example, an average weight of 70 kg.

[0069] The methods of this invention also provide for kits for use in providing treatment of fatigue. After a pharmaceutical composition comprising Solriamfetol or pharmaceutically acceptable salts thereof, with the possible addition of one or more other compounds of therapeutic benefit, has been formulated in a suitable carrier, it can be placed in an appropriate container and labeled for providing fatigue treatment.

[0070] Additionally, another pharmaceutical comprising at least one other therapeutic agent useful in the fatigue treatment can be placed in the container as well and labeled for treatment of the indicated disease. Such labeling can include, for example, instructions concerning the amount, frequency and method of administration of each pharmaceutical.

[0071] Although the foregoing invention has been described in detail by way of example for purposes of clarity of understanding, it will be apparent to the artisan that certain changes and modifications are comprehended by the disclosure and may be practiced without undue experimentation within the scope of the appended claims, which are presented by way of illustration not limitation. The following examples are provided to illustrate specific aspects of the invention and are not meant to be limitations.AXSOME 41 PCT

[0072] A better understanding of the present invention may be obtained in light of the following examples that are set forth to illustrate, but are not to be construed to limit, the present invention.EXAMPLE

[0073] The following example illustrates the invention without limiting its scope.Example 1

[0074] This was a phase 4, double-blind, randomized, placebo-controlled trial of solriamfetol in adults with ME / CFS. Eligible participants were randomly assigned to receive 75mg (titrated to 150mg as needed) solriamfetol or placebo. Participants completed a battery of assessments at weekly visits. The primary outcome was Fatigue Symptom Inventory (FSI) scores, and the secondary outcome measure was Behavioral Rating Inventory of Executive Function for Adults (BRIEF-A), at weeks 6 and 8. T-tests assessed the differences in mean change from baseline between solriamfetol and placebo. Adverse events were monitored throughout the study.Study Design and Oversight

[0075] This phase 4, double-blind, randomized, placebo-controlled, single-center trial was reviewed and approved by the WCG Institutional Review Board and registered underClinicalTrials.gov identification number NCT04622293.Participants

[0076] Participants were adults aged 18-65 years at the time of consent who met the Institute of Medicine (IOM) 2015 diagnostic criteria for ME / CFS. Sexually active participants agreed to practice two different methods of contraception or remain abstinent during the trial and for 30 days after the end of the study. Women had to test negative for pregnancy, and all participants had to pass a drug screen for substances that are illegal for recreational use inAXSOME 41 PCTMichigan at the screening visit (visit 1). Participants must have had a minimum level of intellectual functioning as determined by the investigator, no history of intellectual impairment or a severe learning disability, be fluent in English, and score at least 4 on the Clinical Global Impression Scale-Severity (CGI-S)[371at visit 1.Treatment

[0077] All participants provided written informed consent before any study procedures began. Eligibility was assessed at visit 1 , where vital signs, urine pregnancy and drug screens, and psychometric assessments, including the Behavioral Rating Inventory of Executive Function for Adults (BRIEF-A),1381CGI-S,

[0037] CGI-Improvement (CGI-I),

[0037] Patient Global Impression-Severity (PGI-S),

[0039] Patient Global Impression-Improvement (PGI-I),

[0039] Fibromyalgia Impact Questionnaire (FIQ),

[0040] Fatigue Symptom Inventory (FSI),

[0041] Mini-International Neuropsychiatric Interview (MINI),1421and Columbia-Suicide Severity Rating Scale (C-SSRS)

[0043] were completed. At visit 2 (baseline), eligible patients were randomly assigned to solriamfetol or placebo. Jazz Pharmaceuticals, Inc. provided solriamfetol capsules and placebo tablets in matching capsules.Participants and researchers were blinded to treatment allocation throughout the study period. All participants started the study with 75mg solriamfetol (1 capsule) or matching placebo. They were instructed to take 1 whole capsule at the same time each morning upon waking, with or without food. Dose titration began on day 3 of the study, where solriamfetal could be titrated to 150mg as needed. The dose titration schedule is described in Supplementary Table 1. Solriamfetol could be safely discontinued without taper or titration at any time.

[0078] All participants completed baseline, week 3, and week 8 visits in person, while other weekly visits could be completed in person or with a primary investigator via a telehealth platform. Participants conducting telehealth visits were asked to take their own blood pressure and heart pulse rate, when possible, and completed study assessments with the investigator. Participants completed the eligibility screening, 8 weeks of double-blind treatment, and a post-treatment follow-up 1 week after the week 8 visit.AXSOME 41 PCTOutcome measures

[0079] The primary outcome was the FS I

[0041] score at weeks 6 and 8. The FSI is a 13-item fatigue self-report scale with excellent internal reliability and good convergent and construct validity.1441The four Severity subscale items ask respondents to rate their fatigue from 0 (“Not at all fatigued”) to 10 (“As fatigued as I could be”) on their most fatigued day during the past week, least fatigued day during the past week, average level of fatigue during the past week, and current fatigue. The seven Interference subscale items assess how much the fatigue interferes with the respondent’s activities of daily living, concentration, relationships, enjoyment of life, and mood from 0 (“No interference”) to 10 (“Extreme interference”). The last two questions assess the duration and frequency of the fatigue the respondent experiences.

[0080] The secondary outcome was the BRIEF-A1381at weeks 6 and 8.1381The BRIEF-A is a 75-item, 9-scale, self-report measure that assesses inhibition, self-monitoring, planning / organization, shifting, initiation, task monitoring, emotional control, working memory, and organization of materials. The BRIEF-A results in a Global Executive Composite (GEC) score composed of the Metacognition Index (Ml) (from the Initiation, Working Memory, Planning / Organization, Organization of Materials, and Task Monitoring subscales) and Behavior Regulation Index (BRI) (from the Inhibition, Shifting, and Emotional Control) subscales.1451

[0081] Exploratory outcome measures included the PGI-S, PGI-I ,

[0039] CGI-S, CGI-I,1371FIQ,1401and Sheehan Disability Scale (SDS).1461PGI-S and PGI-I are single item, six-point, self-rated scales to assess health severity and perceived change after receiving a particular therapy or treatment.139’47481The CGI-S rates illness severity on a 7-point scale from 1 (“normal”) to 7 (“extremely ill”), and the CGI-I rates improvement on a 7-point scale from 1 (“very much improved”) to 7 (“very much worse”) since the initiation of treatment.1371CGI-S and CGI-I have good validity and have proven useful in evaluating a variety of mental health conditions.149-521The FIQ is a 20-item assessment with questions pertaining toAXSOME 41 PCTseverity across three domains: physical function, overall impact, and symptoms. It has been one of the most frequently used assessment tools for fibromyalgia since its development in 1991 ,[401The SDS is a three-item tool to measure functional disability in work, family, and social life, originally designed for use in psychiatry. Each item assesses how much symptoms disrupt work, family, or social life from 0 (“not at all”) to 10 (“extremely”). The SDS has been shown to be sensitive to treatment effects, with strong internal consistency and construct validity for identifying patients with functional impairment.146531

[0082] Safety and tolerability were assessed from the time of consent through the follow-up visit taking place one week after the week 8 visit. A series of vitals, including blood pressure and pulse rate, were collected at every visit.Statistical Analysis

[0083] Before the trial, the sample size was determined with a power analysis using a two-sided variance test by effect size (Cohen’s d). Assuming a population effect size is 1.0, a minimum sample size of 34 total participants would be required to reject a null hypothesis of zero at a significance level of p < .05. Similar effect sizes are found for solriamfetol when compared to placebo for differences in wakefulness-promotion.

[0054] Outcomes were tested using t-tests to assess the difference between placebo and solriamfetol groups in the mean change from baseline for FSI and BRIEF-A subscales at week 8. Analyses utilized an intent to treat model and a significance level of p < .05.ResultsParticipant demographics and disposition

[0084] A total of 47 participants were screened. Nine participants did not meet screening requirements due to having a current comorbid uncontrolled psychiatric disorder (n = 4) and / or a serious chronic or acute unstable medical condition or illness (n = 7) and were excluded from the study. Three participants withdrew from the study after passing the screening visit, but before the baseline visit and before receiving treatment. The final sample consisted of 38 participants (demographic characteristics are summarized in Table 1). Of these,AXSOME 41 PCT18 received at least one dose of solriamfetol and 20 received placebo. Two participants in the placebo group and one in the solriamfetol group withdrew from the study due to on-label adverse events (AEs). One participant in the solriamfetol group withdrew due to travel requirements.AXSOME 41 PCTTable 1. Participant demographicsTreatmentSOL PLATotal enrolled, n 18 20 Age, y, mean (range) 41.30 (20 - 64) 39.11 (18 - 62) Gender, n (%)Male 5 (26.3%) 3 (15.0%) Female 13 (73.7%) 17 (85.0%) Nonbinary 0 (0%) 0 (0%) Race, n (%)White / Caucasian 17 18 Black / African American 1 1 Asian 0 0 Other 0 1Baseline characteristics

[0085] At the baseline visit, participants in the solriamfetol and placebo groups did not differ in any of the measured assessments (Table 2).Primary and secondary endpoints

[0086] The study met its primary endpoint of change from baseline in the severity subscale of the FSI at week 8, but not at week 6. At week 8, participants assigned solriamfetol exhibited a 2.02-point improvement compared to the 0.46-point improvement in the placebo group (p = .039) (Table 3, Figure 1). The secondary outcome of BRIEF-A change from baseline was analyzed by its three subscales, GEC, Ml, and BRI. For the GEC scale, patients assigned solriamfetol showed a greater improvement compared to placebo at week 8, and for the Ml scale, the solriamfetol group had greater improvements as early as week 6 (Table 3, Figures 2-3). There were no statistically significant differences between the solriamfetol- and placebo-assigned participants in the BRI subscale or the exploratory measures of CGI and FIQ change from baseline at weeks 6 or 8. There was an improvement with solriamfetol compared to placebo in the PGI-S scale at weeks 6 and 8. The Sheehan Disability Scale was not analyzable due to lack of subject responses from week 8.AXSOME 41 PCTTable 2. Baseline characteristicsSOL PLAAssessment n (mean ± SD) n (mean ± SD) FS I: Severity 18 6.57 (1.55) 20 7.14 (1.55) FSI: Interference 18 6.56 (1.78) 20 6.90 (1.72) BRIEF-A: GEC 16 16.20 (2.99) 20 16.79 (3.38) BRIEF-A: Ml 16 9.85 (2.10) 20 9.42 (1.74) BRIEF-A: BRI 16 6.95 (1.50) 20 6.78 (1.50) PGI-S 18 3.28 (0.67) 19 3.11 (0.94) CGI-S 18 4.56 (0.70) 17 5.06 (0.75) FIQ 18 69.83 (17.76) 20 69.50 (15.98)AXSOME 41 PCTTable 3. Test of FSI and BRIEF-A subscales and exploratory endpoints, PGI, CGI, and FIQ at weeks 6 and 8.BRI, Behavior Regulation Index; BRIEF-A; Behavioral Rating Inventory of Executive Function for Adults; CGI-S, Clinical Global Impression-Severity; FIQ, Fibromyalgia Impact Questionnaire; FSI, Fatigue Symptom Inventory; GEC, Global Executive Composite; Ml, Metacognition Index; PGI-S, Patient Global Impression-Severity; PLA, placebo; SOL, solriamfetol.Safety outcomes

[0087] In total, 14 (36.8%) patients randomized to receive solriamfetol or placebo reported at least one AE. Two participants in the placebo groupwithdrew due to AEs; both reported sleep loss and one also experiencedheadaches, dizziness, and anxiety. Remaining patients who receivedsolriamfetol and placebo reported a total of 13 and 16 AEs, respectively (Table4). The most common AE reported in patients who received solriamfetol wassleep loss (6 instances, 3 patients), whereas the AE experienced by the greatest number of patients in this group was anxiety (4 instances, 4 patients). Incontrast, the most common AE reported in patients who received placebo was headaches (8 instances, 4 patients), which was also the AE experienced by theAXSOME 41 PCTgreatest number of patients in this group. There were no new safety signals reported.Table 4. Participants who experienced AEs during the study.TreatmentSolriamfetol PlaceboParticipants with AEs, n (%) (n = 18) (n = 20)Dry mouth 1 (5.56)d0AE, adverse event.Matching superscript letters represent one participant who experiencedmultiple AEs.Discussion

[0088] Solriamfetol, titrated to an optimal dose of 75mg or 150mg depending on participants’ tolerance and response, led to significant improvements in fatigue symptoms and executive function over an 8-week treatment period. In this double-blind, placebo-controlled trial, participants demonstrated faster and more prominent improvements on the severity subscale of the FSI and the BRIEF-A (GEC and Ml) with solriamfetol compared with placebo. Solriamfetol has a unique mechanism of action that has shown benefit for patients with sleep disorders, and this trial demonstrates its potential to be an effective treatment for the fatigue and cognitive symptoms associated with ME / CFS.

[0089] The FSI, the primary outcome measure, has been validated in previous studies with heterogeneous patient populations across genders, age, and clinical diagnosis, including cancers.141 441The scale allows for the measurement of the intensity and duration of fatigue, with its questions pertaining to symptom severity and the degree to which the symptoms interfere with the patients’ lives. Interestingly, patients did not experience improvementsAXSOME 41 PCTin the interference subscale compared with placebo, although their symptom severity improved at week 8. In other studies, FSI severity and interference subscales demonstrate strong internal consistency reliability.

[0055] The discrepancy between the two measures could indicate delayed recovery as an effect of cumulative fatigue.1561If severity improves after 8 weeks of treatment, cumulative impacts of long-term fatigue may continue to disrupt daily activities. Longer follow-up would determine whether interference improves with more time on treatment.

[0090] At week 8, executive function improved with solriamfetol as measured by the BRIEF-A. Global improvement in executive function was driven by the Ml, which relates to planning, organization, and memory. In contrast, the BRI, relating to inhibition, shifting, and emotional control, was not affected by solriamfetol. Deficits in inhibition and behavioral shifting represent a low degree of cognitive flexibility, which can make higher order reasoning and planning more difficult.1571Differences in efficacy between BRIEF-A subscales can contribute to characterizing different types of fatigue and delineating the behaviors most impacted and most susceptible to treatment. For example, when compared with ADHD rating scales, Ml is more strongly correlated with inattention, and BRI is more strongly correlated with impulsivity and hyperactivity.1571Therefore, understanding that solriamfetol primarily enhances executive functioning related to metacognition may guide decisions regarding other interventions, particularly when impulsivity and hyperactivity are affecting daily functioning.

[0091] The PGI-S was significantly improved with solriamfetol at weeks 6 and 8, but CGI-S was not affected by treatment. Although the CGI is widely used in psychiatry, clinician ratings in certain settings may not fully capture the patient’s perspective on their impairment.1581In a study of patients being treated for multiple sclerosis, patients less frequently rated themselves as unchanged compared to their physicians, who were less likely to report improvement.1591In the case of ME / CFS, physicians may be less likely to change their severity rating if distress and impairment are still present, even when patients experienceAXSOME 41 PCTreduced fatigue. Discordance between patient- and clinician-reported severity can be a barrier to effective treatment, so patient and clinician alignment is paramount in order to ensure treatment plans are meeting the patient’s needs.1601

[0092] FIQ scores were not impacted by solriamfetol at any time point. The scale was included as an exploratory measure because there is broad overlap between ME / CFS symptoms and fibromyalgia symptoms.121 611However, the FIQ includes questions related to physical functioning, work difficulties, pain, fatigue, morning tiredness, stiffness, anxiety, and depression. The wakefulnesspromoting properties of solriamfetol may have the potential to subsequently benefit pain and physical impairments measured by the FIQ. However, fibromyalgia and ME / CFS are distinct disorders, and the FIQ may not be the most effective scale to measure the cognitive fatigue experienced in ME / CFS.1211Future research could explore more targeted assessments of cognitive fatigue and its relationship to treatments like solriamfetol in ME / CFS patients to better understand its potential impact.

[0093] The current study is limited by the small, homogenous sample. As a single-center study with limited geographical reach and racial and gender diversity, these findings provide a foundation on which a larger clinical trial should be conducted to corroborate the results. Additionally, there was a large degree of variability in the baseline scores, although these were controlled for by analyzing changes from baseline. Overall, future studies with larger, more diverse populations will be crucial to further validate the current findings and improve generalizability.

[0094] In this study, solriamfetol compared to placebo improved fatigue and cognitive symptoms after 6 and 8 weeks of treatment in adult patients with ME / CFS. Specifically, solriamfetol improved overall fatigue as measured by the FSI severity subscale and metacognitive symptoms related to planning, organization, and memory components of executive function measured by the BRIEF-A Ml. Patients reported improvement in disease severity, and treatmentAXSOME 41 PCTwas well-tolerated. These findings support solriamfetol, with its wakefulnesspromoting characteristics, as a promising treatment for ME / CFS, a disease with no currently-approved treatments.Supplementary Table 1. Dose titration schedule.Visit 1 2 3 4 5 6 7 8 WeekSolriamfetol N / A 75 mg 75 mg or 75 mg or 75 mg or 75 mg or 75 mg or 75 mg or dose 150 mg 150 mg 150 mg 150 mg 150 mg 150 mgAbbreviations

[0095] AE, adverse event

[0096] BRIEF-A, Behavioral Rating Inventory of Executive Function for Adults

[0097] BRI, behavioral regulation index

[0098] CFS, chronic fatigue syndrome

[0099] CGI, Clinical Global Impression[000100] FIQ, Fibromyalgia Impact Questionnaire[000101] FSI, Fatigue Symptom Inventory[000102] GEC, global executive composite[000103] ME, myalgic encephalitis[000104] Ml, metacognition index[000105] PGI, patient global impression[000106] The present invention is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the invention. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatus within the scope of the invention, in addition to those enumerated herein will be apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications and variations are intended to fall within the scope of the appended claims. The present inventionAXSOME 41 PCTis to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled.References cited[000107] All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.[000108] The discussion of references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinence of the cited references.[000109] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.1. 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T., Arcos-Burgos, M., & Lidbury, B. A. (2019). Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics, 9(3), 91.AXSOME 41 PCThttps: / / doi.org / 10.3390 / diagnostics9030091li, A., Lacout, C., Fortrat, J.-O., Depres, K., Ghali, M., & Lavigne, C.(2022). Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. Diagnostics, 72(10), 2540. https: / / doi.org / 10.3390 / diagnostics12102540sford, J. A. G. (2017). The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS). Frontiers in Physiology, 8. https: / / doi.org / 10.3389 / fphys.2017.00088atomi, Y., Mizuno, K., Ishii, A., Wada, Y., Tanaka, M., Tazawa, S., Onoe, K., Fukuda, S., Kawabe, J., Takahashi, K., Kataoka, Y., Shiomi, S., Yamaguti, K., Inaba, M., Kuratsune, H., & Watanabe, Y. (2014).Neuroinflammation in Patients with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. 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Claims

1. CLAIMS1. A method of treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome, comprising administering a therapeutically effective amount of solriamfetol or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the method further comprises administering a therapeutically effective amount of at least one other therapeutic agent for the treatment of daily fatigue.

3. The method of claim 1 , wherein solriamfetol or a pharmaceutically acceptable salt thereof and the at least one other therapeutic agent for the treatment of daily fatigue are administered in the same composition.

4. A pharmaceutical composition for treating daily fatigue in patients with myalgic encephalomyelitis / chronic fatigue syndrome, comprising solriamfetol or a pharmaceutically acceptable salt thereof.

5. A method or pharmaceutical composition substantially as shown and described in the preceding claims.AXSOME 41 PCT

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