WO2019136224A1 - Amphetamine-guanfacine combinations for treatment of neuropsychiatric disorders - Google Patents

Abstract

The invention relates to pharmaceutical compositions and dosage forms comprising at least one form of amphetamine and at least one form of guanfacine. The pharmaceutical composition may be present in a dosage form including immediate release, slow release, and combination dosage forms. The invention further relates to methods of treating neuropsychiatric disorders with the pharmaceutical compositions and pharmaceutical dosage forms comprising at least one form of amphetamine and at least one form of guanfacine.

Description

AMPHETAMINE-GUANFACINE COMBINATIONS FOR TREATMENT OF

NEUROPSYCHIATRIC DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/614,101, filed January 5, 2018 and U.S. Provisional Application No. 62/614,122, filed January 5, 2018, the disclosure of each of which is herein incorporated by reference in its entirety.

FIELD OF INVENTION

[0002] The present invention is related to pharmaceutical compositions and dosage forms comprising at least one form of amphetamine and at least one form of guanfacine. The invention further relates to methods of treating neuropsychiatric disorders with the pharmaceutical compositions and pharmaceutical dosage forms comprising at least one form of amphetamine and at least one form of guanfacine.

BACKGROUND OF THE INVENTION

[0003] Neuropsychiatric disorders are complex, heterogeneous conditions resulting from the interaction of factors including genetic, neurobiological, and cultural factors, and life experiences and may arise directly from cerebral dysfunction in and of itself, or secondarily from indirect effects of other disease processes. Neurodevelopmental disorders (NDDs) represent a diverse group of syndromes characterized by abnormal development of the central nervous system and whose symptomatology includes cognitive, emotional, sensory, and motor impairments. Neuroscience research is beginning to elucidate the biological underpinnings of many of these disorders. These advances have the potential to improve diagnosis, inform treatment selection, and facilitate development of new and better interventions.

[0004] Treatments for neuropsychiatric and neurodevelopmental conditions and disorders encompassing, for example, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), autism spectrum disorder (ASD), major depressive disorder (MDD), Angelman syndrome, Rett syndrome, multiple sclerosis, neurofibramatosis type 1, chronic fatigue syndrome, or fragile X syndrome, obesity, narcolepsy, appetite suppression, depression, anxiety and wakefulness, have been researched for many years.

[0005] Stimulants, including amphetamine and its derivatives, enhance the activity of the sympathetic nervous system and/or central nervous system (CNS). Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in children have been treated with stimulants for many years. However, more recently, the increase in number of prescriptions for ADHD therapy in adult population has, at times, outperformed the growth of the pediatric market. Although there are various drugs currently in use for the treatment of ADHD, such as methylphenidate (commercially available from, for example, Novartis International AG (located in Basel, Switzerland) under the trademark Ritalin®) and non-stimulant atomoxetine (commercially from Eli Lilly and Company (located in Indianapolis, Ind.) as Strattera®), amphetamine has been the forerunner in ADHD therapy.

[0006] ADDERALL® is an immediate release composition, which includes a mixture of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate This combination of amphetamines is indicated for the treatment of Attention Deficit Hyperactivity Disorder in children from 3-10 years of age.

[0007] One disadvantage of immediate release-only treatments for children is that two separate doses are administered, one in the morning and one approximately 4-6 hours later, commonly away from home under other than parental supervision. This requires a second treatment, which is time-consuming, inconvenient and may be problematic for those children having difficulties in swallowing tablet formulations. ADDERALL XR® met the need for a dosage form, which can be administered once, in place of the two oral doses which are needed using the conventional drug delivery formulations of the prior art. See U S. Pat. Nos. 6,322,819 and 6,605,300; copending Reissue Application Nos. 11/091,010 and 11/091,011. There are currently two medications (ADDERALL XR® and STRATTERA™) approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD in adults.

[0008] ADDERALL XR® is a mixed amphetamine salts medication. STRATTERA™ is an atomoxetine (a norepinephrine reuptake inhibitor) medication. Long acting stimulant preparations, such as ADDERALL XR® and CONCERTA® (methylphenidate), are designed to provide a duration of effect up to 12 hours. However, clinicians have noted that a proportion of patients treated with these formulations require additional treatment with a short-acting stimulant to extend the daily therapeutic effect. For patients taking long-acting stimulant formulations who require duration of clinical benefit beyond 10-12 hours, clinicians have augmented the morning long-acting formulation, typically at 8-10 hours post-dose, with a dose of the same immediate- release (IR) medication. Typically, the dose of the IR medication is smaller than the long-acting dose. This augmentation strategy is most relevant to the "longer day demands" of adult and adolescents, rather than school age, pediatric patients. In order to provide sufficient therapeutic benefit throughout the day, a large dose morning dose is commonly administered. Such large doses of stimulants are frequently associated with significant side effects, including insomnia, abdominal pain, loss of appetite, and anorexia. Children administered large doses of stimulants can also experience slowed or reduced growth resulting in diminished height. Children, who commonly suffer from ADHD, are particularly susceptible to disruption of sleep and/or eating habits and the additional downstream consequences thereof.

[0009] ADHD symptoms, aggression and irritability are prevalent in individuals with ASD and fragile X syndrome and present a significant source of functional impairment. Current approved treatments for this indication include risperidone and aripiprazole, and are associated with weight gain and neurologic sequelae.

[00010] Further concerns about stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines. Use of prescription stimulants to stay awake has become prevalent in young adults, as they seek to manage daily demands of academics, work and social pressure. Up to 50% of young adults ages 18-25 report misusing prescription stimulants to study or improve academic performance, with 41% reporting misusing prescription stimulants to stay awake.

[00011] Given these concerns, non-stimulant medications have been considered as an alternative option for treating neuropsychiatric disorders. Non-stimulants provide a treatment option to subjects who are nonresponsive to stimulants. Other benefits may include a lower incidence of specific side effects associated with stimulants and a lower potential for misuse. INTUNIV® is an extended-release formulation of non-stimulant guanfacine hydrochloride (HC1), N-amidino-2-(2,6dichlorophenyl) acetamide monohydrochloride, for oral administration for the treatment of ADHD as a monotherapy, as well as an adjunctive therapy to stimulant medications. At higher doses, INTUNIV® has been linked to side effects such as cardiovascular effects (e.g., hypertension) and somnolence. [00012] Drug side effects, including difficulty sleeping, loss of appetite, and abdominal pain, are a significant medical issue. Insomnia, difficulty falling asleep, or difficulty remaining asleep can result in problem sleepiness, which impairs the health, quality of life and safety of those affected. Appetite disorders, such as loss of appetite, can cause reduced energy, health, quality of life, and can cause additional downstream nutritional deficiencies. Abdominal pain can greatly reduce the quality of life for a patient, and greatly reduce compliance with a therapy regimen. Another ADHD drug-related side effect includes exacerbation of tics, particularly for children with underlying disorders that may cause tics. Also, children and adolescents using high doses of stimulant drugs may have slowed or stunted growth. Drug side effects often become more pronounced as drug dosages are increased to achieve longer lasting benefits.

[00013] Thus, there exists an unmet need, not solved by current medications, for a once- daily, long-acting oral composition that provides effective treatment of neuropsychiatric disorders including ADHD and ASD with reduced side effects, which balances the need for open access to stimulant medication and minimizes non-medical use in young adults.

SUMMARY OF THE INVENTION

[00014] Various non-limiting aspects and embodiments of the invention are described below.

[00015] In one aspect, a pharmaceutical composition is provided, comprising a form of amphetamine, a form of guanfacine, and a pharmaceutically acceptable carrier. In one embodiment, the form of amphetamine is a prodrug of amphetamine, or a pharmaceutically acceptable salt thereof. In one embodiment, the prodrug of amphetamine is a conjugate of homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof. In one embodiment, the form of amphetamine and the form of guanfacine are present in the composition as a fixed-dosage combination (FDC).

[00016] In one aspect, a pharmaceutical composition is provided, comprising a conjugate of homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof, and guanfacine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one embodiment, the conjugate of homoarginine and amphetamine is L-homoarginine- dextroamphetamine dihydrochloride.

[00017] In one embodiment, the prodrug of amphetamine (e g., a conjugate of homoarginine and amphetamine) is formulated as an extended release composition, a delayed release composition, a controlled release composition, or an immediate release composition. In one embodiment, the guanfacine is formulated as an extended release composition, a delayed release composition, a controlled release composition, or an immediate release composition. In one embodiment, the prodrug of amphetamine (e.g., a conjugate of homoarginine and amphetamine) is formulated as an immediate release composition, and the guanfacine is formulated as an extended release composition. In another embodiment, both the prodrug of amphetamine and the guanfacine are formulated as an extended release composition.

[00018] In another embodiment, pharmaceutical dosage forms comprising compositions of the invention are provided. In one embodiment, the compositions are provided in a solid oral dosage form or a liquid oral dosage form. In one embodiment, the composition is in the form of a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, an inhalable powder, an oral film, a thin strip, a sachet, a cachet, a solution, a suspension, an elixir, or a syrup. In one embodiment, the composition is in the chewable form, e.g., a chewable tablet, a chewable troche, or a chewable lozenge. In another embodiment, the composition is in the form of a capsule.

[00019] In one embodiment, the prodrug of amphetamine, or a pharmaceutically acceptable salt thereof, (e.g., a conjugate of homoarginine and amphetamine) is present in the composition in an amount of about 5 mg to about 100 mg. In one embodiment, the guanfacine, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount of about 0.01 to about 0.12 mg per kg of subject body weight. In one embodiment, the guanfacine, or a pharmaceutically acceptable salt thereof, is present in the composition in an amount of about 1 mg to about 7 mg.

[00020] In another aspect, a method of treating a neuropsychiatric disorder in a subject in need of such treatment is provided, the method comprising administering to the subject a pharmaceutical composition comprising a form of amphetamine, a form of guanfacine, and a pharmaceutically acceptable carrier. In one embodiment, the method of treating a neuropsychiatric disorder comprises administering the form of amphetamine and the form of guanfacine are present in the composition as a fixed-dosage combination (FDC).

[00021] In another aspect, a method of treating a neuropsychiatric disorder in a subject in need of such treatment is provided, the method comprising administering to the subject a pharmaceutical composition comprising a prodrug of amphetamine, or a pharmaceutically acceptable salt thereof, and guanfacine, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier.

[00022] In one embodiment, a method of treating a neuropsychiatric disorder in a subject in need of such treatment is provided, the method comprising administering to the subject a pharmaceutical composition comprising a conjugate of homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof, and guanfacine, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier.

[00023] In one embodiment, the neuropsychiatric disorder may be a neurodevelopmental disorder, e.g., autism spectrum disorder. In one embodiment, the neuropsychiatric disorder is attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), Angelman syndrome, Rett syndrome, multiple sclerosis, neurofibramatosis type 1, chronic fatigue syndrome, or fragile X syndrome.

[00024] In one embodiment, the subject in need of treatment is under 18 years of age, e.g., an adolescent 13-17 years of age, a child 6-12 years of age, or a child under 6 years of age. In another embodiment, the subject is an adult, e.g., an adult male or an adult female.

[00025] In one embodiment, the subject treated with the pharmaceutical compositions of the invention may exhibit a reduction in undesirable side effects as compared to a subject treated with a prodrug of amphetamine alone, or guanfacine alone. In one embodiment, the undesirable side effects comprise, but are not limited to, decreased appetite, weight loss, insomnia, somnolence, and combinations thereof. In one embodiment, insomnia is reduced by at least 20% as compared to a treatment consisting of a prodrug of amphetamine alone.

[00026] In one embodiment, the pharmaceutical composition is administered once daily. In one embodiment, the pharmaceutical composition is administered in the morning. In one embodiment, the pharmaceutical composition is administered in the evening.

[00027] These and other aspects of the present invention will become apparent to those skilled in the art after a reading of the following detailed description of the invention, including the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[00028] Figure 1 shows the ADHD-RS-IV Total Score mean change from baseline by psychostimulant group for each visit and at endpoint (FAS) for the SPD503-205 study. [00029] Figure 2 A shows the ADHD-RS-IV Hyperactivity/Impulsivity & Inattentive subscale scores as a function of time for the Intuniv AM & PM groups and the Stimulant Alone group. Figure 2B shows the CGI-I score overall distribution at endpoint for the Intuniv AM & PM groups and the Stimulant Alone group for the SPD503-313 study.

[00030] Figure 3 shows mean seated systolic blood pressure over time by psychostimulant group for the SPD503-205 study.

[00031] Figure 4 shows mean seated diastolic blood pressure over time by psychostimulant group for the SPD503-205 study.

DETAILED DESCRIPTION

[00032] Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely illustrative of the invention that may be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the invention is intended to be illustrative, and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

[00033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[00034] As used in this specification and the appended claims, the singular forms“a”, “an”, and“the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to“a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure.

[00035] The terms“treat” or“treatment” of a state, disorder or condition include: (1) preventing, delaying, or reducing the incidence and/or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[00036] A“subject” or“patient” or“individual” or“animal”, as used herein, refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models of diseases (e.g., mice, rats). In a preferred embodiment, the subject is a human.

[00037] As used herein the term“effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.

[00038] The phrase “pharmaceutically acceptable”, as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., a human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[00039] In some embodiments, the pharmaceutically acceptable salt thereof may be an acefyllinate, 4-acetamidobenzoate, acetate, aceturate, adipate, aminosalicylate, ammonium, ascorbate, 1 -aspartate, benzoate, besylate, bicarbonate, borate, butyrate, calcium, camphocarbonate, camphorate, d-camsylate, l-camsylate, camsylate, carbonate, cholate, citrate, cypionate, decanoate, dichloroacetate, edentate, edisylate, estolate, esylate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate (enanthate), hexanoate, hippurate, hybenzate, hydrobromide/bromide, hydrochloride/chloride, hydroxide, hydroxybenzoate, iodide, isethionate, d-lactate, l-lactate, d,l-lactate, lactobionate, laurate, lithium, magnesium, malate, d,l-malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methyl sulfate, myristate, napadisilate, 2-napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, palmitate, pamoate, phenylpropionate, phosphate, picrate, pivalate, potassium, propionate, pyrophosphate, salicylate, salicylsulfate, sodium, stearate, succinate, sulfate, sulfosalicylate, tannate, d-tartrate, kartrate, d, 1-tartrate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triflate, undecylenate, valerate, valproate, xinafoate, zinc, and mixtures thereof.

[00040] As used herein, the term "once daily" refers to a pharmaceutical that is formulated for administration to a subject one time per day. The pharmaceutical may provide the therapeutic result for a full 24 hours, or may provide treatment for only a desired/anticipated fraction thereof (e.g., 8 hours, 10 hours, 12, hours, 16 hours), depending upon the intended function of the pharmaceutical. In cases where a once daily dose provides less than 24 hours of therapeutic action, the duration of action achieved is the desired time span and re-administration in the same 24-hour period is not required. Due to the side effects of a pharmaceutical (e.g., insomnia), it may be desired/beneficial for the therapeutic action of a once daily dose to last less than 24 hours (e.g., 8 hours, 10 hours, 12, hours, 16 hours).

[00041] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, so such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants. (See e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975]).

[00042] Pharmaceutical Compositions and Dosage Forms

[00043] In one aspect, the present pharmaceutical compositions and dosage forms provide a combination, e.g., a fixed-dosage combination, of two compounds, comprising at least one form of amphetamine and at least one form of guanfacine. The pharmaceutical compositions and dosage forms of the invention may provide optimized release of each of the individual compounds (namely, a prodrug of amphetamine (e.g., a conjugate of homoarginine and amphetamine) and guanfacine), thus providing additive benefits not present when each compound is administered separately.

[00044] Amphetamine Forms [00045] In some embodiments, the at least one form of amphetamine may be a prodrug of amphetamine or a pharmaceutically acceptable salt thereof. The amphetamine prodrug may be derived from either a dextro- (d-) or levo (1-) form of amphetamine, or a racemic form, or may be a mixture thereof In some embodiments, the prodrugs of d-amphetamine can be used in combination with a prodrug of l-amphetamine or 1 -amphetamine itself.

[00046] In some embodiments, the prodrug of amphetamine may be a conjugate of a non standard amino acid and amphetamine or a pharmaceutically acceptable salt thereof. The non standard amino acid conjugated to amphetamine may be either a dextro- (d-) or levo (1-) form amino acid, racemic amino acid, or a mixture thereof. The non-standard amino acid may be conjugated to amphetamine directly (e.g., via amide bond formation) or through a linker (e.g., a C1-C6 hydrocarbon linker).

[00047] In accordance with some embodiments of the presently described technology, d- amphetamine (dextroamphetamine) and a non-standard amino acid may be used to make an amphetamine prodrug. In one embodiment, the amino acid conjugated to amphetamine may be homoarginine. In one embodiment, 1-homoarginine may be conjugated to d-amphetamine. In one embodiment, the prodrug of amphetamine is L-homoarginine-dextroamphetamine according to the following structure:

[00048]

[00049] or a pharmaceutically acceptable salt thereof. In one embodiment, the prodrug of amphetamine is L-homoarginine-dextroamphetamine dihydrochloride.

[00050] Amphetamine-homoarginine conjugates and salts of the conjugates, and methods for synthesizing the conjugates, are disclosed in U.S. Patent No. 7,776,917 and U S. Patent Publication No. 2014/017510. Metabolites and derivatives of amphetamine can also be modified. Examples of metabolites of amphetamine include N-hydroxyamphetamine, 4- hydroxyamphetamine, a-hydroxyamphetamine, norephedrine, 4-hydroxynorephedrine, phenylacetone oxime, phenylacetone and l-phenyl-2-propanol.

[00051] In some embodiments, amphetamine forms, e.g., conjugates of homoarginine and amphetamine, are formulated according to any embodiments described herein, for example immediate release, delayed release, controlled release, extended releases, sustained release, co- administration (e.g., with one or more additional amphetamine forms), and any suitable combinations thereof.

[00052] In certain aspects, the compositions of the invention provide the lowest effective amphetamine dose. The customized delivery and release mechanism of the present invention optimizes the release of individual compounds, e.g., the amphetamine form, to achieve benefits as described below.

[00053] In some embodiments, 0.0001 mg to about 750 mg, about 0.001 mg to about 500 mg, about 0.01 mg to about 300 mg, about 0.1 mg to about 200 mg, about 1 mg to about 100 mg, about 5 mg to about 80 mg, or about 20 mg to about 60 mg of an amphetamine form per dose is administered to an individual. In some embodiments, about 5 mg to about 100 mg, or about 5 to about 20 mg, or about 5 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg, or about 50 mg, or about 60 mg, or about 70 mg, or about 80 mg, or about 90 mg, or about 100 mg of an amphetamine form (e.g., a conjugate of homoarginine and amphetamine) per dose is administered to an individual.

[00054] Guanfacine Forms

[00055] Guanfacine is a selective a?A receptor agonist. In some embodiments, the at least one form of guanfacine may be a pharmaceutically acceptable salt of guanfacine In one embodiment, the at least one form of guanfacine may be guanfacine hydrochloride, currently marketed under the brands Estulic, Tenex, and, in extended release form, Intuniv.

[00056] In some embodiments, guanfacine forms are formulated according to any embodiments described herein, for example immediate release, delayed release, controlled release, extended releases, sustained release, co-administration (e.g., with one or more additional non-stimulant forms), and any suitable combinations thereof. In one embodiment, guanfacine is formulated as an extended release form.

[00057] In certain aspects, about 0.001 mg to about 200 mg, about 0.01 mg to about 100 mg, about 0.1 mg to about 50 mg, about 0.5 mg to about 20 mg, about 1 mg to about 7 mg, or about 2 mg to about 4 mg, per dose of guanfacine is administered to an individual. In some embodiments, about 1 to about 7 mg, or about 1 mg, or about 2 mg, or about 3 mg, or about 4 mg, or about 5 mg, or about 6 mg, or about 7 mg per dose of guanfacine is administered to an individual. In one embodiment, about 2 mg to about 4 mg of a guanfacine form is administered to an individual. [00058] In certain aspects, about 0.001 to about 1 mg per kilogram, about 0.005 to about 0.5 mg per kilogram, about 0.07 to about 0.2 mg per kilogram, or about 0.01 to about 0.12 mg per kilogram per dose of guanfacine is administered to an individual.

[00059] When administered in the form of pharmaceutical compositions, the combination of active compounds may be administered with a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes. Such pharmaceutical compositions can be administered systemically. The term“systemic” as used herein includes parenteral, topical, transdermal, oral, by inhalation/pulmonary, rectal, nasal, buccal, and sublingual administration. Preferably, the compounds are orally, or intranasally in therapeutically effective amounts.

[00060] Pharmaceutical compositions of the invention can be prepared in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, each active ingredient, alone or in combination, is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of soft and hard capsules, tablets, pills, powders, lozenges, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), suppositories, sterile injectable solutions, and sterile packaged powders.

[00061] In some embodiments, the pharmaceutical composition of the invention is in liquid form. Liquid forms include, by way of non-limiting example, emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids and the like. In some embodiments, a pharmaceutical composition described herein is in liquid, semi-solid or solid ( e.g ., powder) form. In specific embodiments, a pharmaceutical composition described herein is in semi-solid form, e.g., a gel, a gel matrix, a cream, a paste, or the like. In some embodiments, semi-solid forms comprise a liquid vehicle. In some embodiments, the pharmaceutical composition of the invention is a solid dosage form, such a tablet, a granule, a sachet, or a powder. Also provided are pharmaceutical compositions of the invention in the form of a dissolving tablet, a dissolving wafer, a chewable tablet, a chewable troche, a chewable lozenge, a capsule, or a gel capsule. In certain embodiments, solid dosage forms described herein comprise a solid vehicle (e.g, as used in a tablet), and/or a gaseous vehicle (e.g, as used in DPI).

[00062] In some embodiments, a composition is in a unit dose formulation for oral, intranasal, or other administration to a patient. The term“unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[00063] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compounds actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's condition, and the like.

[00064] In one aspect, a composition or unit dosage form according to the invention is formulated for sublingual administration, wherein the unit dosage form is a film including one or more disintegrants (e.g, materials that favor disintegration or fast dissolution by virtue of their solubility in water, such as hydrolyzed starches, sugars, and glycerin, which may play a dual role as a plasticizer and disintegrant) and a plasticizing agent, the film having a first portion including apomorphine hydrochloride, and a second portion including pH neutralizing agent, wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and the pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.0, preferably between 4.5 and 6.5, (e.g., a pH of between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0) when the unit dosage form is placed in unbuffered water at pH 7 (e.g., the pH observed within 5 minutes of placing the unit dosage form in 1, 5, or 10 mL of unbuffered water). The film can include from 1 to 50% (w/w) (e.g., l±0.75%, 2±1.5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, l8±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) of the one or more disintegrants. In certain embodiments, the unit dosage form further includes a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In other embodiments, the unit dosage form further includes a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. The pH neutralizing agent can be an organic base (e.g., pyridoxine, meglumine, or any organic base described herein) or an inorganic base (e g., magnesium hydroxide, sodium bicarbonate, or an inorganic base described herein). In particular embodiments, the unit dosage form includes 35±5% (w/w) disintegrant, from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and pyridoxine present in an amount sufficient to produce a solution having a pH of between 4.5 and 6.5 when the unit dosage form is placed in unbuffered water at pH 7. Suitable film for oral administration of the compositions according to the invention is disclosed in, e.g., U.S. Pat. No. 8,846,074.

[00065] In some embodiments, a composition or unit dosage form described herein is administered as an emulsion, a solution, a suspension, a syrup, a slurry, a dispersion, a colloid, a dissolving tablet, a dissolving wafer, a chewable tablet, a chewable troche, a chewable lozenge, a capsule, a gel capsule, a semi-solid, a solid forma gel, a gel matrix, a cream, a paste, a tablet, a granule, a sachet, a powder, or the like.

[00066] In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

[00067] To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is often intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a fixed dosage form. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, manifold, lactose, and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques. The use of these dosage forms may significantly enhance the bioavailability of the compounds in the patient. Thus, for liquid oral preparations such as suspensions, elixirs, and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used.

[00068] For preparing solid compositions such as tablets, the active ingredients are mixed, alone or in combination, with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the active ingredients. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 5 mg to about 100 mg of an amphetamine form, and about 1 mg to 7 mg of a guanfacine form, or about 5 mg to about 100 mg of homoarginine-amphetamine dihydrochloride, and about 1 mg to 7 mg of guanfacine hydrochloride. In one embodiment, a unit dosage form according to the invention may comprise about 5 mg to about 20 mg of homoarginine- amphetamine dihydrochloride, and about 2 mg to 4 mg of guanfacine hydrochloride.

[00069] The capsules, tablets or pills containing the active compounds can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the capsule, tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the 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 permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[00070] The combination can include a "fixed dose combination" (FDC). These fixed dose combinations can be in the form of pill in pill, capsule in capsule, bilayer tablet or other formulation method with or without physical separation between a form of amphetamine and a form of guanfacine.

[00071] A dosage form according to the present invention may combine forms of release known to persons of ordinary skill in the art. These conventional release forms include immediate release, extended release, pulse release, variable release, controlled release, timed release, sustained release, delayed release, long acting, and combinations thereof. The ability to combine immediate release, extended release, pulsed release, controlled release, timed release, sustained release, delayed release, and combinations thereof is known in the art. Thus, for example, composition of the invention may be formulated for approximately 12 to 16 hours of coverage in a pediatric patient. An adult patient, who typically has longer awake hours, may receive the composition of the present invention that is formulated to provide approximately 16 hours of coverage. Furthermore, the composition of the invention may be formulated to provide one type of release of one active, e.g., an immediate release for an amphetamine form, in combination with the same or a different type of release of another active, e.g., an extended release for a guanfacine form, or, conversely, an extended release for an amphetamine form, in combination with an immediate release for a guanfacine form.

[00072] In certain embodiments, the compositions disclosed herein include, but are not limited to tablets, minitablets or beads contained in a soluble capsule. The minitablets or beads comprising an amphetamine form (e.g., a conjugate of homoarginine and amphetamine) and/or a guanfacine form can include a drug containing core or a drug coated inert bead core in which the drug core or dmg layer can also contain an optional disintegrant, osmagent or pore forming agent. In certain embodiments, the disintegrant can be a superdisintegrant. In certain embodiments, the drug layer or core is enclosed by a sustained release layer that can include a water insoluble and water permeable polymer layer that controls the rate of absorption of water and release of the drug. The outer, delayed release layer is coated on the sustained release layer. The delayed release layer may contain a plasticizer or solubility is pH dependent. The delayed release layer can thus be a pH dependent layer that is insoluble in aqueous solution at a pH below 5.0 and soluble at the higher pH in the ilium or colon, or it can be a pH independent layer. In certain embodiments, an outer, pH dependent layer dissolves in the higher pH of the ilium or colon. As the sustained release layer then loses integrity the sustained release layer ruptures and releases the remaining drug in the core.

[00073] Especially when formulated for pediatric patients, the capsule, tablet or pill is of suitable size and shape and may include an aromatizer, a flavoring, and/or a sweetener.

[00074] Combination treatment benefits

[00075] In some embodiments, pharmaceutical compositions and dosage forms of the invention comprising a form of amphetamine and a form of guanfacine may provide additive benefits. These benefits may include, but are not limited to, reduced undesirable side effects as compared to a treatment consisting of a prodrug of amphetamine alone, or guanfacine alone. These undesirable side effects may include, but are not limited to, decreased appetite, weight loss, insomnia, somnolence, increased blood pressure, increased heart rate, and combinations thereof.

[00076] In one non-limiting embodiment, a reduction in insomnia is achieved, as compared to a treatment consisting of a prodrug of amphetamine alone. In one embodiment, a reduction of insomnia by 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or greater than 50% as compared to a treatment consisting of a prodrug of amphetamine alone is achieved. In one embodiment, a reduction in appetite suppression by 10%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or over 80% as compared to a treatment consisting of a prodrug of amphetamine alone is achieved. In one embodiment, a reduction in increased blood pressure and heart rate as compared to a treatment consisting of a prodrug of amphetamine alone is achieved. In one embodiment, no weight reduction or gain is reported by patients receiving the compositions of the invention. In one embodiment, a reduction in somnolence by 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or greater than 50% as compared to a treatment consisting of guanfacine alone is achieved.

[00077] The benefits may further include, but are not limited to, higher efficacy, reduced dosages, quick onset of action (“on-board upon waking”), improvement in sleep wake cycle, including but not limited to fewer or less frequent awakenings, as well as convenience to patient, and higher patient compliance. [00078] Methods of Treatment

[00079] In one aspect, methods of treating a neuropsychiatric disorder in a subject in need of such treatment, comprising administering to the subject a pharmaceutical composition comprising a form of amphetamine (e.g., a conjugate of homoarginine and amphetamine) and a form of guanfacine are provided. In some embodiments, the neuropsychiatric disorder may be a neurodevelopmental disorder, such as ASD.

[00080] In some embodiments, the neuropsychiatric disorder may be attention deficit hyperactivity disorder (ADHD), including, but not limited to, uncomplicated ADHD, refractory ADHD, and comorbid ADHD, as well as ADHD-like symptoms and conditions; autism spectrum disorder (ASD), major depressive disorder (MDD), Angelman syndrome, Rett syndrome, multiple sclerosis, neurofibramatosis type 1, chronic fatigue syndrome, or fragile X syndrome, and combinations thereof.

[00081] Multiple Sclerosis according to the present invention includes relapsing-remitting, primary progressive, progressive-relapsing, and secondary progressive multiple sclerosis. Fatigue is a common, and often disabling, symptom of multiple sclerosis. Cognitive symptoms such as inattention also occur in patients with multiple sclerosis.

[00082] Chronic fatigue syndrome (CFS) is characterized by extreme fatigue that cannot be explained by an underlying medical condition. The fatigue may worsen with physical or mental activity, but does not improve with rest. Cognitive symptoms (cognitive impairments) in CFS may include difficulty with: memory (including visual memory and verbal memory), attention, information processing, reaction times, and concentration.

[00083] Major depressive disorder (MDD) according to the present invention may be diagnosed in a patient by a physician according to, for example, the criteria disclosed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). A patient suffering from MDD may have primary inattentive symptoms. A patient suffering from MDD may be of any age. In one embodiment, the patient suffering from MDD is elderly.

[00084] Rett syndrome (RTT), including classical form and atypical forms, such as congenital (Rolando) form, Zappella form, and Hanefeld form, is a brain disorder due to a genetic mutation of the MECP2 gene, which typically becomes apparent after six months of age in females. Symptoms include problems with language, coordination, and repetitive movements. Often there is slower growth, problems walking, and a smaller head size. Complications can include seizures, scoliosis, and sleeping problems.

[00085] Angelman syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, speech problems, balance and movement problems, seizures, and sleep problems. The symptoms generally become noticeable by one year of age. Angelman syndrome is typically due to a deletion or mutation of the UBE3A gene on chromosome 15. Angelman syndrome affects males and females equally.

[00086] Fragile X syndrome (FXS) is a genetic disorder typically due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome. Symptoms often include mild to moderate intellectual disability. About a third of people have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common and seizures occur in about 10%. Males are usually more affected than females. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding. Some individuals with fragile X syndrome also meet the diagnostic criteria for autism. Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS.

[00087] Neurofibromatosis type I (NF-l) is a complex multi-system human disorder caused by the mutation of a gene on chromosome 17 that is responsible for production of a protein called neurofibromin which is needed for normal function in many human cell types. NF- 1 causes tumors along the nervous system which can grow anywhere on the body. NF-l is one of the most common genetic disorders and is not limited to any person's race or sex. The most common complication in patients with NF-l is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 80% of children with NF-l and have significant effects on their schooling and everyday life. The most common cognitive problems are with perception, executive functioning and attention. ADHD has been shown to be present in approximately 38% of children with NF-l . Speech and language delays have also been identified in approximately 68% of preschool children with NF1. [00088] In some embodiments, patients with other conditions characterized by cognitive problems, e.g., inattention, fatigue, short-term memory problems, and problems with concentration and planning may be treated by the compositions of the invention comprising a form of amphetamine and a form of guanfacine. In some embodiments, these include post-cancer therapy patients, e.g., post-chemotherapy and post-radiation therapy cancer patients.

[00089] As used herein,“post-cancer therapy” and“post-cancer treatment” mean that a patient has undergone cancer therapy, which may include chemotherapy, radiation therapy (for example, cranial radiation therapy), surgery (for example, cranial surgery), and combinations thereof. Non-limiting examples of chemotherapy include glucocorticoids, methotrexate, 5- fluorouracil, doxorubicin, taxanes (e.g., docetaxel, paclitaxel), cisplatin, cyclophosphamide, capecitabine, and combinations thereof.

[00090] In some embodiments, chronic inflammatory diseases may also be treated by the compositions of the invention comprising a form of amphetamine and a form of guanfacine.

[00091] In some embodiments, the present invention provides methods of administration to or treatment of pediatric subjects (e.g., 0-17 years), infant subjects (e.g., 0-2), children (e.g., 2- 12 years), adolescent subjects (e.g., 13-17 years), and/or adult subjects (e.g., 18+ years), including young adults (e.g., 18-25 years of age), and elderly adults (e g., 65+ years of age). In some embodiments, methods of administration to or treatment of children under 6 years of age, or 6 to 12 years of age are provided. In some embodiments, methods of administration to or treatment of adolescents 13 to 17 years of age are provided. In some embodiments, methods of administration to or treatment of adults are provided. In some embodiments, subjects are male. In some embodiments, subjects are female. In some embodiments, subjects are adult females.

[00092] In some embodiments, the compositions of the invention are administered once daily, or twice daily, or three times daily, or four times or more daily, or every other day, or once every three days, or once weekly. In one embodiment, the compositions of the invention are administered once daily. In one embodiment, the compositions of the invention are administered in the morning. In one embodiment, the compositions of the invention are administered in the evening.

[00093] EXAMPLES [00094] The following examples illustrate specific aspects of the instant description. The examples should not be construed as limiting, as the examples merely provide specific understanding and practice of the embodiments and their various aspects.

[00095] EXAMPLE 1 : SPD503-205 A Phase II, Open-Label Co-Admini strati on Study of SPD503 and Psychostimulants in Children and Adolescents Aged 6-17 with ADHD

[00096] The primary objective of this study was to assess the safety and tolerability of the co-administration of SPD503 (Guanfacine Hydrochloride), dosed to maximum tolerability (1, 2, 3, or 4mg/day) and psychostimulants (methylphenidate or amphetamine) for the treatment of ADHD in children and adolescents 6 to 17 years old who had suboptimal control on psychostimulants alone.

[00097] Secondary objectives of the study included:

[00098] · To assess the efficacy of the co-administration of SPD503 (1, 2, 3, or 4mg/day) and psychostimulants (methylphenidate or amphetamine) based on the Attention Deficit Hyperactivity Disorder - Rating Scale, Version IV (ADHD-RS-IV) total score;

[00099] · To assess the duration of effect, as determined via the Conners’ Parent Rating

Scale-Revised Short Form (CPRS-R);

[000100] · To assess the effect on global impressions of ADHD symptom severity and improvement from the perspective of the clinician based on the Clinical Global Impression (CGI) scores, and from the perspective of the parent/caregiver based on the Parent Global Assessment (PGA) scores, respectively; and

[000101] · To assess the effect on the Child Health Questionnaire-Parent Form (CHQ-

PF50) physical and psychosocial well-being summary scores.

[000102] Methodology:

[000103] Multi-center, open-label study of the safety and tolerability of the co administration of SPD503 (Guanfacine Hydrochloride) and psychostimulants (methylphenidate or amphetamine) for 9 weeks in children and adolescents with ADHD. To be eligible, subjects must have been on a stable dose of a psychostimulant approved for the treatment of ADHD for at least 1 month with suboptimal control in the opinion of the Investigator. The study was conducted in 17 centers in the United States. The study design was a dose escalation of SPD503 (to 4mg/day or the highest tolerated dose) while maintaining the subject’s current psychostimulant (same dose and frequency). [000104] Eligible subjects started SPD503 at lmg/day at Baseline (Visit 0) and increased in lmg weekly increments up to 4mg/day by Visit 3, or to the highest tolerated SPD503 dose. Subjects then maintained the SPD503 dose through Visit 6, unless they withdrew. Starting at Visit 6, the SPD503 dose was titrated downward in lmg weekly decrements until the End-of- study Visit (Visit 9). Eligible subjects visited the clinic on 12 different occasions over the course of approximately 3.5 months: Screening (Visit -1), Baseline (Visit 0), Treatment (Visits 1-9), and Follow-up (Visit 10). In addition, subjects received a planned follow-up phone contact 30±7 days following their last dose of SPD503 (Visit 11).

[000105] Main inclusion criteria:

[000106] · Aged 6 to 17 years, inclusive

[000107] · Functioning at age-appropriate levels intellectually, as deemed by the

Investigator

[000108] · Diagnostic and Statistical Manual of Mental Disorders, 4th edition - Text

Revision criteria for a primary diagnosis of ADHD (diagnostic codes 314.01 and 314.00) combined subtype, predominantly inattentive subtype or predominantly hyperactive-impulsive subtype based on a detailed psychiatric evaluation

[000109] · On a stable dose of a psychostimulant (methylphenidate or amphetamine) approved for the treatment of ADHD for at least 1 month, with suboptimal control in the Investigator’s opinion.

[000110] Main exclusion criteria:

[000111] · Current uncontrolled co-morbid psychiatric diagnosis (except oppositional defiant disorder and mild anxiety) with significant symptoms

[000112] · Morbid obesity (Body Mass Index >35)

[000113] · Orthostatic hypotension or diagnosis of hypertension

[000114] · Use of concomitant medications that affect blood pressure (BP) or heart rate

[000115] · Chronic use of other medications that have central nervous system effects or affect performance (i.e., sedating antihistamines and decongestant sympathomimetics) (bronchodilators were not exclusionary)

[000116] · Previously taken SPD503 for the treatment of ADHD

[000117] · Previously intolerant of guanfacine for any reason.

[000118] Summary Demographics [000119] Overall, the mean age was 11.4 years (ranging from 7 to 17 years). The age categories included 6 to 12 years (72.0%, 54 of 75 subjects) and 13 to 17 years (28.0%, 21 of 75 subjects).

[000120] The majority of subjects were male (73.3%, 55 of 75 subjects) and white (72.0%, 54 of 75 subjects). Weight varied widely in both psychostimulant groups and ranged from 61 to 197 pounds overall. Height ranged from 48.5 to 73.0 inches overall.

[000121] Overall, the majority of subjects were of the combined subtype (74.7%, 56 of 75 subjects). The years since ADHD diagnosis varied widely in both psychostimulant groups and ranged from 0 to 11 years overall with a mean of 3.7 years.

[000122] In general, the demographics of all enrolled subjects were similar between psychostimulant groups except for age category (78.6% of subjects in the methylphenidate group were in the 6 to l2-year group as compared to 63.6% of subjects in the amphetamine group) and ethnic origin (64.3% of subjects in the methylphenidate group were white as compared to 81.8% of subjects in the amphetamine group).

[000123] Table 1, shown below, summarizes the treatment efficacy as measured by ADHD- RS-IV Total Score for the psychostimulant patient group.

[000124] Overall, a significant change from baseline was observed for both the methylphenidate and the amphetamine groups.

[000125] As shown in Figure 1, beneficial effects were observed as early as during Visit 1, and were sustained over the course of treatment through the endpoint.

[000126] As Table 2 shows, below, SPD503 doses of 3-4 mg per day significantly reduced ADHD-RS Total Score at endpoint. SPD503 at 2 mg per day produced a similar reduction.

[000127] Table 3, below, summarizes weight-adjusted results of ADHD-RS-IV Total Score at endpoint.

[000128] The results indicate that SPD503 in the range of 0.05-0.12 mg per kilogram was most effective.

[000129] Efficacy Summary:

[000130] The subj ects’ mean age was 11.4 years and the mean years since ADHD diagnosis was 3.7 years. Baseline mean ADHD-RS-IV total scores were similar between psychostimulant groups: 29.1 and 26.3 in the methylphenidate and amphetamine groups, respectively. Baseline mean CGI-S scores were also similar between psychostimulant groups: 4.2 and 3.9 in the methylphenidate and amphetamine groups, respectively.

[000131] Mean changes from Baseline to Endpoint in ADEID-RS-IV total score statistically significant in both psychostimulant groups: -17.8 in the methylphenidate group (p<0.000l) and - 13.8 in the amphetamine group (p<0.000l). Subgroup analysis ADHD-RS-IV total score by age, statistically significant improvement in both age groups (6 to 12 years old and 13 to 17 years old) in both psychostimulant groups.

[000132] The CPRS-R was completed at Visit 6 at 6:00 am (24 hours after the previous day’s dose), 6:00 pm (12 hours after the Visit 6 morning dose) and 8:00 pm (14 hours after the Visit 6 morning dose). Mean day total scores were obtained by averaging the scores over the three administrations. The CPRS-R total score showed statistically significant improvement at all time points and for the mean day total score in both psychostimulant groups

[000133] The proportions of subjects showing improvement for the dichotomized CGI-I at Endpoint were similar between the psychostimulant groups: 77.8% and 66.7% in the methylphenidate and amphetamine groups, respectively. The proportions of subjects showing improvement for the dichotomized PGA at Endpoint were similar in the methylphenidate group and the amphetamine group: 88.9% and 77.8%, respectively. A statistically significant improvement in parent-assessed quality of life, as measured by the CHQ-PF50, was demonstrated in the psychosocial summary score for both psychostimulant groups.

[000134] Table 4, below, summarizes treatment-emergent adverse effects by SPD503 weight-adjusted actual dose.

[000135] As Table 4 demonstrates, rates of anorexia and insomnia were not dose-dependent for SPD503 up to 0.12 mg/kg. Somnolence and sedation rates were highest at doses greater than 0.12 mg/kg.

[000136] Decreases in the Pediatric Daytime Sleepiness Score (PDSS) scores in both the methylphenidate and amphetamine groups suggested no increased sleepiness associated with the co-administration of SPD503 and either psychostimulant.

[000137] As evaluated using the PSERS, for both the methylphenidate group and amphetamine group, there was an increase in the numbers of subjects reporting clinically significant dull, tired, listless and decreases in the numbers of subjects reporting clinically significant loss of appetite and clinically significant trouble sleeping.

[000138] Overall, 42 of 75 (56.0%) of subjects experienced treatment-emergent (TE) somnolence, sedation, or fatigue (SSF) One of 72 (1.4%) of subjects at the 2mg SPD503 actual dose discontinued due to somnolence. The majority of events were mild or moderate; one of 40 (2.5%) of subjects at the 4mg SPD503 actual dose experienced severe fatigue. No sedative events were serious.

[000139] Most sedative events considered possibly related or related to SPD503. All TE events of sedation and somnolence, and most events of fatigue resolved during the study. The median onset for sedation, somnolence and fatigue occurred during Weeks 2 to 3. Median duration for somnolence, sedation, and fatigue was 1 to 2 weeks. TE sedation, somnolence and fatigue reported overall by 18.7%, 8.0%, and 34.7% of subjects, respectively, with no meaningful differences in the incidences of events between psychostimulant groups. The median duration of sedation was longer in the amphetamine group (23.0 days) as compared to the methylphenidate group (6.0 days). Mean all on treatment change in body weight from baseline (Screening) to Visit 9 was 0.29 pounds suggesting that the co-administration of SPD503 and psychostimulants was not associated with a clinically meaningful weight gain or loss.

[000140] As shown in Figures 3 and 4, vital sign changes appeared to primarily reflect effects of SPD503. Mean systolic and diastolic blood pressure and pulse tended to decrease as compared to Baseline during the upward dose titration period (Visits 1 through 4), began to increase (toward Baseline) during the downward dose titration period (Visits 7 and 8), and returned to slightly above titration/baseline levels at End-of-study/early termination (Visit 9) [000141] In summary: combining SPD503 with a psychostimulant is safe & well tolerated in children & adolescents with ADHD.

[000142] SPD503 + psychostimulant combination is efficacious. Improvements in ADHD- RS-IV total score and scores for the two subscales of hyperactivity/impulsivity and inattentiveness were similar and statistically significant in both psychostimulant groups. The majority of subjects in both psychostimulant groups showed improvement on the dichotomized CGI-I at endpoint and on the dichotomized PGA at endpoint.

[000143] Safety profile (adverse effects (AE), vital signs (VS)) profile of the combination appears weighted toward Guanfacine Hydrochloride, with higher rates of fatigue and somnolence, lack of appetite suppression, & decreases in VS measures.

[000144] EXAMPLE 2: A phase 3, double-blind, randomized, placebo-controlled, multicenter, dose optimization study evaluating the efficacy and safety of SPD503 (Guanfacine Hydrochloride) in combination with Psychostimulants in children and adolescents aged 6-17 yrs. with ADHD [000145] The primary objective was to assess the efficacy of optimized SPD503 (1, 2, 3, and 4mg/day), dosed either in the morning or evening, compared to placebo, when co administered with psychostimulants, in the treatment of children (6-12 years) and adolescents (13-17 years) with a diagnosis of ADHD, with a suboptimal, partial response to stimulants, as measured by the Attention-deficit Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) change from Baseline score at Endpoint.

[000146] The secondary objectives assessed efficacy utilizing the Conners’ Global Index - Parent (CGI-P) at morning and evening timepoints; Clinical Global Impressions - Severity of Illness Scale (CGI-S); Clinical Global Impressions - Improvement Scale (CGI-I); Parent Global Assessment (PGA); Before-school Functioning Questionnaire - Wil-Hammer (BSFQ); and the oppositional subscale of the Conners’ Parent Rating Scale - Revised Long Form (CPRS-R:L).

[000147] Additional secondary objectives assessed sleep parameters (measured by a Post- Sleep Questionnaire [PSQ]) and safety and tolerability (based on treatment-emergent adverse effects (TEAEs), clinical laboratory tests, physical examinations, vital signs, and ECGs).

[000148] Study Design

[000149] Double-blind, randomized, placebo-controlled, dose-optimization study of 461 subjects conducted in 59 centers in the US;

[000150] Children and adolescents (ages 6-17 y/o) with ADHD and suboptimal response to stimulants;

[000151] Suboptimal response defined as treatment (per patient/caregiver report) with a stable dose of psychostimulant for at least 4 wks with improvement but with residual ADHD symptoms; ADHD-RS-IV>24 and CGI-S>3;

[000152] Designed to evaluate Guanfacine Hydrochloride (1, 2, 3, and 4 mg/day) compared with placebo, when co-administered with a long-acting oral stimulant selected from Table 5, below. Eligible subjects were required to be receiving a stable dose of stimulant treatment for at least one month, with sub-optimal response to stimulants as determined by an ADHD-RS-IV Total score > 24 and Clinical Global Impressions - Severity of Illness (CGI-S) score > 3

Table 5: Long-acting oral stimulants taken by subjects in the study

[000153] The groups were 1 :1 : 1 randomized as follows:

[000154] Intuniv AM group: stimulant and Guanfacine Hydrochloride dosed upon awakening; placebo at bedtime

[000155] Intuniv PM group: stimulant and placebo dosed upon awakening; Guanfacine Hydrochloride at bedtime

[000156] Stimulant Alone group: stimulant and placebo dosed upon awakening; placebo at bedtime

[000157] Subjects were instructed to take one tablet (Intuniv (Guanfacine Hydrochloride) or placebo) every morning (upon awakening) and one tablet every evening (at bedtime) dose consistently with respect to the time of eating and type of food; if eaten with a meal, high-fat meals were to be avoided, while maintaining their current dose of stimulant treatment (dosed each morning).

[000158] The compliance rates for concomitant stimulant ranged from 95.3 to 97.4% across the study visits. Compliance with the stimulant may have been high because it was emphasized with subjects and their parents and assessed at each visit.

[000159] Subjects continued to take their current stable dose of stimulant each morning (dose of stimulant was fixed throughout the study). Subjects were not randomized to receive MPH or AMPH.

[000160] Treatment Period was 9 weeks long. Intuniv was initiated at a dose of 1 mg/day.

[000161] During the dose-optimization phase (Days 1 - 35), subjects were titrated to their optimal dose of Intuniv or placebo (defined as clinically significant reduction in ADHD symptoms with minimal side effects) based on tolerability and response. The dose could be increased at 1 mg weekly intervals up to a maximum of 4 mg/day.

[000162] During the dose-maintenance phase (Days 36 - 56), optimal doses of Intuniv were maintained. A 1 mg Intuniv dose reduction was allowed at any time during the study and only one dosage decrease was allowed for each patient during the study. Starting at Week 8, subjects entered the dose-tapering phase (Days 57 - 65).

[000163] As shown in Figure 2 A, ADHD-RS-IV Hyperactivity/Impulsivity & Inattentive subscale scores showed greater reductions from baseline in the Intuniv AM & PM groups than in the Stimulant Alone group. Further, as shown in Figure 2B, the CGI-I score overall distribution at endpoint showed a higher percentage of the very much improved scores for the Intuniv AM & PM groups (45.0% and 48.6%, respectively) as compared to the Stimulant Alone group (26.3%).

[000164] Safety Evaluation

[000165] No new safety signals emerged following the administration of Intuniv in combination with a stimulant compared with those reported with Intuniv or stimulant monotherapy. Mean Intuniv optimal dose at endpoint was 3.2 mg/day or 0.088 mg/kg/day (safety population). Majority of TEAEs were mild or moderate in severity.

[000166] TEAEs occurred in 76.8% of subjects receiving Intuniv plus a stimulant compared with 63.4% of subjects receiving placebo plus a stimulant. TEAEs (>5%) in subjects receiving Intuniv plus a stimulant were: somnolence (12.9%), headache (9.9%), fatigue (8.9%), dizziness (7.3%), insomnia (6.3%), and decreased appetite (5.6%).

[000167] Severe TEAEs were reported by 4.3% and 0.7% of subjects receiving Intuniv plus a stimulant and placebo plus a stimulant, respectively. Fatigue was the only severe TEAE reported by more than 1 subject (both events were reported by subjects in the Intuniv PM group). TEAEs leading to discontinuation were reported in 3.3% of subjects receiving Intuniv plus a stimulant compared with 0.7% of subjects receiving placebo plus a stimulant. Aggression was the only TEAE leading to discontinuation that occurred in more than 1 subject (1 in placebo, 1 in Intuniv AM, and 1 in Intuniv PM).

[000168] Table 6, below, summarizes TEAEs occurring in >5% of subjects. Percentages are based on the number of subjects in the safety population in each group.

[000169] Sedative events, including somnolence, sedation, and hypersomnia, were reported in 18.2% (55/302) of subjects receiving Intuniv plus a stimulant compared with 6.5% (10/153) of subjects receiving placebo plus a stimulant: 18.0% (27/150) in the Intuniv AM group and 18.4% (28/152) in the Intuniv PM group.

[000170] The majority of sedative events were mild to moderate in severity. No severe sedative events occurred during the study. Dose reduction due to a sedative event occurred in 25.8% and 15.2% of subjects in the Intuniv AM and Intuniv PM groups, respectively. The majority of sedative events occurred during dose titration and resolved prior to dose tapering.

[000171] Table 7, below, summarizes the mean change in vital signs from baseline to endpoint for the safety population

[000172] ECG Results

[000173] 3 subjects had ECG interpretations at endpoint that were considered abnormal and clinically significant per the Investigator: 1 subject in the Intuniv PM plus a stimulant group and 2 subjects in the placebo plus a stimulant group.

[000174] There were no differences for QTcF between subjects receiving Intuniv plus a stimulant and subjects receiving placebo plus a stimulant. No subject in any of the treatment groups had an uncorrected QT interval > 480msec, a QTcF > 480msec, or a QTcB interval > 500msec. There were no clinically meaningful differences between the Intuniv AM and PM groups regarding ECG outlier values.

[000175] Additional Safety Assessments

[000176] Clinical Laboratory Analysis There were no clinically notable differences between the treatment groups for hematology, chemistry, and urinalysis results both at baseline and in the mean changes from baseline at endpoint.

[000177] Height No meaningful differences between subjects receiving Intuniv plus a stimulant and subjects receiving placebo plus a stimulant.

[000178] Weight At endpoint, mean weights were slightly higher for subjects receiving Intuniv plus a stimulant compared with subjects receiving placebo plus a stimulant.

[000179] Summary Demographics

[000180] Four hundred sixty -one subjects were randomized into the study; 6 subjects did not receive study drug.

[000181] Three hundred eighty-six (83.7%) subjects completed the study through Visit 10 (end of maintenance phase), and 378 (82.0%) subjects completed the study through Visit 12 (final follow-up visit). The most frequent reason for early termination overall was refused further study participation (5.6%).

[000182] The mean age was 10.8 years, 79.3% of subjects were male, and 67.7% were white.

[000183] The study enrolled 79.3% children (6-12 years) and 20.7% adolescents (13-17 years). The largest proportion of subjects received CONCERTA (45.3%) as their concomitant psychostimulant followed by VYVANSE (29.5%) and ADDERALL XR (17.8%). There were no clinically important differences across the treatment groups for Baseline demographic characteristics.

[000184] The majority of subjects had the combined subtype of ADHD (80.9%). The mean time since diagnosis of ADHD was approximately 4 years and the mean ADHD-RS score at Baseline was approximately 37.

[000185] Twenty percent of subjects had a current diagnosis of ODD based on the K- SADS-PL at screening; however, 60.2% of subjects had significant oppositional symptoms based on a score of >14 for boys and >12 for girls on the oppositional subscale of the CPRS-RU.

[000186] Summary Efficacy

[000187] At Endpoint, subjects receiving SPD503 plus psychostimulant showed significantly greater improvement on the ADHD-RS-IV Total score compared with subjects receiving placebo plus psychostimulant. This was shown for both morning and evening administration of SPD503.

[000188] Significant improvements on the ADHD-RS-IV Total score were consistently evident in the SPD503 PM group from Visit 4 (2 weeks on treatment) and in the SPD503 AM group from Visit 7 (5 weeks on treatment).

[000189] At Endpoint, both children (6-12 years) and adolescents (13-17 years) in both the SPD503 AM and PM groups showed significant improvement from Baseline in ADHD-RS-IV Total score compared with placebo. Both SPD503 treatment groups had significantly greater improvement on the Hyperactivity/Impulsivity and Inattentive subscales of the ADHD-RS-IV compared with the placebo group. This was shown for both morning and evening administration of SPD503

[000190] At Endpoint, subjects receiving SPD503 plus psychostimulant showed significantly greater improvement on the CGI-I and were less severely ill as assessed by CGI-S compared with subjects receiving placebo plus psychostimulant. This was shown for both morning and evening administration of SPD503.

[000191] Parent ratings of behaviors in the morning and also behaviors in the evening via the CGI-P showed subjects receiving SPD503 plus psychostimulant had significantly greater improvement than subjects receiving placebo plus psychostimulant. This was shown for both morning and evening administration of SPD503.

[000192] In addition, parent ratings of morning behavior (before school) as measured by the BSFQ also showed significantly greater improvement in subjects receiving SPD503 plus psychostimulant compared with subjects receiving placebo plus psychostimulant. This was shown for both morning and evening administration of SPD503.

[000193] Significantly more subjects in the SPD503 plus psychostimulant groups were much improved or very much improved on the PGA compared with placebo plus psychostimulant. This was shown for both morning and evening administration of SPD503.

[000194] Subjects receiving SPD503 plus psychostimulant had significantly greater improvement in oppositional symptoms as measured by the oppositional subscale of the CPRS- R:L compared with subjects receiving placebo plus psychostimulant. This was shown for both morning and evening administration of SPD503.

[000195] In general, at the on-taper assessment (last dose on taper), the SPD503 AM and PM groups were similar to the placebo group. It is notable that improvement measured by the primary and secondary variables during the active phase of the study seems to disappear after tapering of SPD503.

[000196] For subjects with ADHD who were suboptimal responders to a long-acting, oral stimulant, significantly greater improvements were shown for Intuniv plus a stimulant compared with a stimulant alone (i.e., placebo) on: (1) ADHD-RS-IV Total Score (improvements observed for both AM and PM administration, both age groups (6-12 years and 13-17 years), and both subscales of the ADHD-RS-IV); (2) AM and PM timepoint assessments (CGI-P AM and PM, BSFQ parent, and improvements observed for both AM and PM administration), and (3) oppositional symptoms (oppositional subscale of CPRS-R:L) as well as global measures (CGI-I, CGI-S, and PGA) (improvements observed for both AM and PM administration).

[000197] The majority of subjects reached optimal doses in the 0.05-0.08 mg/kg or 0.09- 0.12 mg/kg range. [000198] Safety Summary

[000199] No new safety signals emerged following co-administration of Intuniv with a stimulant (MPH or AMPH) compared to those reported with Intuniv or a stimulant administered alone. The majority of TEAEs were mild or moderate. Most common TEAEs with Intuniv plus a stimulant were somnolence, headache, fatigue, dizziness, insomnia, and decreased appetite. The majority of sedative events occurred during dose titration and resolved during the dose maintenance phase. Cardiovascular effects included small mean decreases in pulse, SBP, and DBP with Intuniv plus a stimulant. No differences for QTcF between subjects receiving Intuniv plus a stimulant and subjects receiving placebo plus a stimulant.

[000200] EXAMPLE 3: Comparison of Safety of SPD489 (Lisdexamfetamine Dimesylate) to the Combination of SPD503 (Guanfacine Hydrochloride) and a Stimulant

[000201] Table 8, below, summarizes the incidence of adverse effects for the indicated population groups.

[000202] As shown above, relative to monotherapy with SPD489, the adverse events were reduced for the Stimulant + SPD503: appetite suppression reduced by over 80%, insomnia reduced by over 50%, and no weight reduction or gain was reported. Additionally, somnolence was reduced by over 50% as compared to SPD503 alone.

[000203] Tables 9 and 10, below, summarize the comparison of changes from baseline in vital signs for SPD489 at Week 4 vs Stimulant + SPD503 at Week 8 of Treatment.

[000204] Table 9: changes in systolic and diastolic blood pressure and pulse for SPD489 at Week 4 vs Stimulant + SPD503 at Week 8 of Treatment

[000205] Table 10: changes in heart rate, PR interval, QRS, and QTcB for SPD489 at Week 4 vs Stimulant + SPD503 at Week 8 of Treatment

[000206] The studies described above confirm that combining SPD503 with a psychostimulant appears to be safe & well tolerated in children & adolescents with ADHD. No new safety signals were reported.

[000207] SPD503 + psychostimulant combination provided additional improvement in

ADHD symptoms beyond stimulant monotherapy. Most outcomes similar for AM and PM administration of SPD503.

[000208] Safety profile (AE, VS) profile of the combination was weighted toward Intuniv, with higher rates of fatigue and somnolence, lack of appetite suppression, & decreases in insomnia and VS measures.

[000209] References:

[000210] Wilens TE, Youcha S, Lyne A, Grannis K, Childress A, Findling R. A multisite placebo controlled trial of morning or evening dose extended-release guanfacine in combination with psychostimulants in children and adolescents with ADHD. Poster presented at the Society of Biological Psychiatry; 20-22 May 2010; New Orleans, LA.

[000211] Data on File, A Phase 3, Double-blind, Randomized, Placebo-controlled, Multicenter, Dose-optimization Study Evaluating the Efficacy and Safety of SPD503 in Combination with Psychostimulants in Children and Adolescents Aged 6-17 Years with a Diagnosis of Attention Deficit Hyperactivity Disorders (ADHD): Shire Pharmaceutical

Development; Final clinical study report SPD503-313 (25-26; 113). 30 March 2010.

* * *

[000212] As various changes can be made in the above-described subject matter without departing from the scope and spirit of the present invention, it is intended that all subject matter contained in the above description, or defined in the appended claims, be interpreted as descriptive and illustrative of the present invention. Many modifications and variations of the present invention are possible in light of the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variances which fall within the scope of the appended claims.

[000213] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising a conjugate of homoarginine and

amphetamine, or a pharmaceutically acceptable salt thereof, guanfacine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. The pharmaceutical combination of claim 1, wherein the conjugate of homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof, is L-homoarginine- dextroamphetamine dihydrochloride.

3. The pharmaceutical combination of claims 1 or 2, wherein the guanfacine, or a

pharmaceutically acceptable salt thereof, is guanfacine hydrochloride.

4. The pharmaceutical composition of any of claims 1-3, wherein the conjugate of

homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof, is formulated as an extended release composition, a delayed release composition, a controlled release composition, or an immediate release composition.

5. The pharmaceutical composition of any of claims 1-4, wherein the guanfacine, or a pharmaceutically acceptable salt thereof, is formulated as an extended release composition, a delayed release composition, a controlled release composition, or an immediate release composition.

6. The pharmaceutical composition of any of claims 1-5, wherein the conjugate of

homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof, is formulated as an immediate release composition, and the guanfacine is formulated as an extended release composition.

7. The pharmaceutical composition of any of claims 1-6, wherein the composition is in the form of a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, an inhalable powder, an oral film, a thin strip, a sachet, a cachet, a solution, a suspension, an elixir, or a syrup.

8. The pharmaceutical composition of claim 7, wherein the composition is in the form of a tablet, a troche, a lozenge, or a capsule.

9. The pharmaceutical composition of any of claims 1-8, wherein the conjugate of

homoarginine and amphetamine, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg to about 100 mg.

10. The pharmaceutical composition of any of claims 1-9, wherein the guanfacine, or a pharmaceutically acceptable salt thereof, is present in an amount of about 0.01 to about 0.12 mg per kg of subject body weight.

11. The pharmaceutical composition of any of claims 1-9, wherein the guanfacine, or a

pharmaceutically acceptable salt thereof, is present in an amount of about 1 mg to about 7 mg.

12. A method of treating a neuropsychiatric disorder in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition of any of claims 1-11.

13. The method of claim 12, wherein the neuropsychiatric disorder is attention deficit

hyperactivity disorder (ADHD), autism spectrum disorder (ASD), major depressive disorder (MDD), Angelman syndrome, Rett syndrome, multiple sclerosis,

neurofibramatosis type 1, chronic fatigue syndrome, or fragile X syndrome.

14. The method of claims 12 or 13, wherein the subject is under 18 years of age.

15. The method of any of claims 12-14, wherein the subject is an adolescent 13-17 years of age.

16. The method of any of claims 12-14, wherein the subject is a child 6-12 years of age.

17. The method of any of claims 12-14, wherein the subject is a child under 6 years of age.

18. The method of claims 12 or 13, wherein the disorder is ADHD or ASD and the subject is an adult.

19. The method of claim 18, wherein the subject is an adult female.

20. The method of any of claims 12-19, wherein the subject exhibits a reduction in

undesirable side effects as compared to a treatment consisting of a conjugate of homoarginine and amphetamine alone, or guanfacine alone.

21. The method of claim 20, wherein the undesirable side effects comprise decreased

appetite, weight loss, insomnia, somnolence, increased blood pressure, increased heart rate, and combinations thereof.

22. The method of claim 21, wherein insomnia is reduced by at least 20% as compared to a treatment consisting of a prodrug of amphetamine alone.

23. The method of any of claims 12-22, wherein the pharmaceutical composition is

administered once daily.

24. The method of claim 23, wherein the pharmaceutical composition is administered in the morning.

25. The method of claim 23, wherein the pharmaceutical composition is administered in the evening.

26. The method of any of claims 12-25, wherein the neuropsychiatric disorder is a

neurodevelopmental disorder.

27. A method of treating attention deficit hyperactivity disorder (ADHD) in a subject in need of such treatment, the method comprising administering to the subject a pharmaceutical composition of any of claims 1-11.

28. The method of claim 27, wherein the subject is under 18 years of age.

29. The method of claims 27 or 28, wherein the subject is an adolescent 13-17 years of age.

30. The method of claims 27 or 28, wherein the subject is a child 6-12 years of age.

31. The method of claims 27 or 28, wherein the subject is a child under 6 years of age.

32. The method of claim 27, wherein the subject is an adult.

33. The method of claim 27 or 32, wherein the subject is an adult female.

34. The method of any of claims 27-33, wherein the subject exhibits a reduction in

undesirable side effects as compared to a treatment consisting of a conjugate of homoarginine and amphetamine alone, or guanfacine alone.

35. The method of claim 34, wherein the undesirable side effects comprise decreased

appetite, weight loss, insomnia, somnolence, increased blood pressure, increased heart rate, and combinations thereof.

36. The method of claim 35, wherein insomnia is reduced by at least 20% as compared to a treatment consisting of a prodrug of amphetamine alone.

37. The method of any of claims 27-36, wherein the pharmaceutical composition is

administered once daily.

38. The method of claim 37, wherein the pharmaceutical composition is administered in the morning.

39. The method of claim 37, wherein the pharmaceutical composition is administered in the evening.