Formulations of t-type calcium channel modulators and methods of use thereof

Abstract

To provide dosage forms and compositions useful for preventing and / or treating a disease or condition relating to aberrant function of a T-type calcium channel, such as epilepsy and epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or a genetic epilepsy), tremor (e.g., essential tremor), and psychiatric disorder (e.g., mood disorders (e.g., major depressive disorder)).SOLUTION: Provided is an oral dosage form comprising: a compound of the following formula or a pharmaceutically acceptable salt thereof; and a modified-release polymer.SELECTED DRAWING: None

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application Nos. 62 / 873,022, filed July 11, 2019, 62 / 934,820, filed November 13, 2019, and 62 / 958,923, filed January 9, 2020, each of which is incorporated by reference in its entirety.

[0002] T-type calcium channels are low-voltage activated ion channels that mediate calcium influx into cells. Abnormal function of these ion channels is associated with several diseases or conditions, including psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremors (e.g., essential tremor), epilepsy, or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy). Therefore, compounds that selectively regulate T-type calcium channels in mammals can be useful in treating such diseases. Summary of the Invention [Means for solving the problem]

[0003] Described herein are compositions and dosage forms useful for preventing and / or treating diseases or conditions associated with abnormal function of T-type calcium channels, such as epilepsy and epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy) and mood disorders (e.g., major depressive disorder).The present invention further includes methods for regulating the function of T-type calcium channels.

[0004] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an excipient that functions to modify the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0005] In one aspect, the present invention provides an oral dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a modified release polymer (e.g., a sustained release polymer, a hydrophilic matrix polymer, e.g., an HPMC polymer as the hydrophilic matrix polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)). In some embodiments, the dosage form comprises about 0.9% to about 40% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In other embodiments, the dosage form comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0006] The dosage forms disclosed herein may comprise from about 10% to about 70% by weight of a modified release polymer. The dosage forms disclosed herein may also comprise a diluent (e.g., microcrystalline cellulose).

[0007] In another aspect, the present invention discloses an oral dosage form comprising about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of an HPMC polymer.

[0008] In another aspect, the present invention provides an oral dosage form comprising about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0009] Also provided herein is an oral dosage form comprising about 3 mg to 8 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)); and about 55 mg to 65 mg of an HPMC polymer.

[0010] In one aspect, provided herein is an oral dosage form comprising about 3% to about 8% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0011] The present invention provides, in part, a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)); and a modified release polymer (e.g., a sustained release polymer, a hydrophilic matrix polymer, e.g., HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)).

[0012] In some embodiments, the composition comprises about 0.9% to about 40% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II)). In certain embodiments, the composition comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II)).

[0013] Also provided herein is an oral (e.g., microparticle) composition comprising about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of HPMC.

[0014] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0015] Provided herein, in part, are oral (e.g., microparticle) compositions comprising about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of HPMC.

[0016] This invention discloses, in part, oral (e.g., microparticle, swellable core) compositions comprising about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0017] In one aspect, the present invention provides a crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II)), wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2.

[0018] In another aspect, the present invention provides a crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II)), wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, and 17.8±0.2.

[0019] The present invention provides, in part, a method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject an oral dosage, composition, or crystalline form disclosed herein. In some embodiments, the neurological disorder is epilepsy. In other embodiments, the epilepsy is juvenile epilepsy. In certain embodiments, the epilepsy is genetic epilepsy (e.g., CACNA1G-related genetic generalized epilepsy). In some embodiments, the neurological disorder is absence seizures. In other embodiments, the neurological disorder is absence epilepsy (e.g., CACNA1H-related absence epilepsy). In certain embodiments, the neurological disorder is CACNA1G, H, or I-related epilepsy. In some embodiments, the epilepsy is childhood absence epilepsy (CAE). In other embodiments, the epilepsy is juvenile absence epilepsy (JAE). In certain embodiments, the epilepsy is Lennox-Gastaut syndrome. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). In other embodiments, the neurological disorder is tremor (e.g., essential tremor, Parkinson's tremor, or cerebellar tremor, CACNA1G-associated tremor). In certain embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia, or spinocerebellar ataxia with CACNA1G mutations). In other embodiments, the neurological disorder is tinnitus. In some embodiments, the neurological disorder is a disturbance of arousal.

[0020] In another aspect, provided herein is a method for treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject an oral dosage, composition, or crystalline form disclosed herein. In some embodiments, the psychiatric disorder is a mood disorder. In other embodiments, the mood disorder is major depressive disorder.

[0021] In certain embodiments of the method described herein, the dosage form is administered to the subject once a day.The dosage form may be administered to the subject twice a day.The dosage form may be administered to the subject every other day.

[0022] In some embodiments of the methods described herein, about 15 mg to 25 mg (e.g., about 20 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) may be administered to a subject daily, or about 30 mg to 50 mg (e.g., about 40 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) is administered to a subject daily.

[0023] In certain embodiments of the methods described herein, the dosage form, upon administration to a subject, exhibits a reduced C relative to a reference oral dosage form (e.g., a dosage form having any intended release rate profile, e.g., a modified release rate profile, a dosage form not having a modified release rate profile, a dosage form not having a release-modifying polymer, e.g., an HPMC polymer). max In other embodiments of the methods disclosed herein, the dosage form, upon administration to a subject, may have a t that is greater than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a release modifying polymer, e.g., an HPMC polymer). max may have

[0024] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage form, composition, or crystalline form disclosed herein) that results in a reduction in the number of epileptic seizures.

[0025] Also provided herein, in one aspect, is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage form, composition, or crystalline form disclosed herein) that results in a reduction in epileptic seizure density as measured by electroencephalogram (EEG).

[0026] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising, in part, administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage form, composition, or crystalline form disclosed herein) that results in a reduction in mean epileptic seizure duration as measured by EEG.

[0027] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising, in part, administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage form, composition, or crystalline form disclosed herein) that results in a reduction in cumulative epileptic seizure duration as measured by EEG.

[0028] Provided herein, in part, are methods for treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage, composition, or crystal described herein) that results in a reduction in hyperventilation and total time with 2.5-4 Hz spike discharges following photic provocation, as measured by EEG.

[0029] In another aspect, provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage form, composition, or crystalline form) that results in a reduction in global severity as measured by Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score.

[0030] Also provided herein is a method for treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form, composition, or crystalline form disclosed herein) to reduce essential tremor as assessed by the Essential Tremor Rating Assessment Scale (TETRAS) score. In some embodiments, the reduction in essential tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) upper extremity score. In other embodiments, the reduction in essential tremor is assessed by the TETRAS-ADL (Activities of Daily Living). The reduction in essential tremor is assessed by the TETRAS activity subscale score or individual items of the TETRAS activity.

[0031] Also provided herein is a method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage, composition, or crystalline form disclosed herein) that results in a reduction in essential tremor as assessed by an accelerometer-based upper extremity score.

[0032] In another aspect, provided herein is a method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) (e.g., an oral dosage form, composition, or crystalline form disclosed herein) that results in a reduction of the sigma frequency band. In some embodiments, the essential tremor is upper limb tremor.

[0033] Other objects and advantages will become apparent to those skilled in the art upon consideration of the following brief description of the drawings, detailed description, examples, and claims. [Brief explanation of the drawings]

[0034] [Figure 1]FIG. 1 is a powder X-ray diffractogram of Form C of compound of formula (II). [Figure 2] FIG. 2 is a differential scanning calorimetry (DSC) thermogram of Form C of the compound of formula (II). [Figure 3] FIG. 3 is a thermogravimetric analysis (TGA) thermogram of Form C of the compound of formula (II). [Figure 4] FIG. 4 is a hot stage microscope (HSM) micrograph of Form C of compound of formula (II). [Figure 5] FIG. 5 is a graph depicting the mean concentration-time profiles of the compound of formula (I) following a single 20 mg oral dose of modified release tablets and immediate release capsules of the compound of formula (II). [Figure 6] FIG. 6 shows the reduction in tremor in the Archimedes spiral task by administration of a compound of formula (II). [Figure 7] FIG. 7 is a powder X-ray diffractogram of pattern B of compound of formula (II). [Figure 8] FIG. 8 is a differential scanning calorimetry (DSC) thermogram of Pattern B of the compound of formula (II). [Figure 9] FIG. 9 is a thermogravimetric analysis (TGA) thermogram of Pattern B of compound of formula (II). [Figure 10] FIG. 10 is a hot stage microscope (HSM) micrograph of pattern B of compound of formula (II). [Figure 11] FIG. 11 shows the mean (±SD) concentrations after a single oral dose of 5 mg tablet Formulation 4. [Figure 12] FIG. 12 shows phase I sleep EEG in a healthy volunteer (NREM sigma). DETAILED DESCRIPTION OF THE INVENTION

[0035] As generally described herein, the present invention provides compositions or dosage forms (e.g., comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof) useful for preventing and / or treating diseases or conditions associated with T-type calcium channel function, such as epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy). Methods useful for modulating T-type calcium channel function are also provided, as are methods for treating mood disorders (e.g., depression, major depressive disorder, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD)). Also provided are methods useful for modulating T-type calcium channel function. Also provided are methods for treating pain (e.g., acute pain, chronic pain, neurological disorders), and pain disorders (e.g., pain, muscular atrophy, muscular dystrophy, and muscular dystrophy). Also presented are methods for treating neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine. Also presented are methods for treating tremor (e.g., essential tremor, Parkinson's disease tremor, or cerebellar tremor). Also presented are methods for treating ataxia (e.g., spinocerebellar ataxia, cerebellar ataxia, or spinocerebellar ataxia with CACNA1G mutation). Also presented are methods for treating tinnitus. Also presented are methods for treating insomnia.

[0036] definition Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response. As will be understood by those skilled in the art, the effective amount of the compound of the invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health, and condition of the subject. The effective amount encompasses both therapeutic and prophylactic treatment.

[0037] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0038] As used herein, the term "refractory" refers to a disease, disorder, or condition that does not readily succumb to or respond to a therapy or treatment, or that is not controlled by a therapy or treatment. In some embodiments, the diseases, disorders, or conditions described herein are refractory (e.g., refractory epilepsy or refractory absence seizures) and do not respond to standard therapies or treatments.

[0039] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0040] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0041] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from the specified disease, disorder, or condition.

[0042] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. See, for example, Berge et al. al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, lanthanide ... Pharmaceutically acceptable salts include phosphate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and their stereoisomers (e.g., enantiomers, diastereomers), etc. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0043] The term "modified release polymer" refers to a polymer used in formulations (e.g., tablets and capsules) to modify the release rate of a drug upon administration to a subject. For example, modified release polymers are used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, modified release polymers are sustained-release polymers. For example, modified release polymers or sustained-release polymers are HPMC polymers. In some embodiments, modified release polymers may include hydrophilic matrix polymers (e.g., hypromellose, HPMC (hydroxyl-propylmethylcellulose)), hydrophobic matrix polymers (e.g., ethylcellulose, Ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS100).

[0044] As used herein, the term "diluent" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dibasic calcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0045] As used herein, the term "lubricant" refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, lubricants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0046] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping together and sticking to the tablet punch or capsule filling machine. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0047] As used herein, the term "coating agent" refers to an excipient that protects tablet ingredients from deterioration due to moisture in the air and makes large or unpleasant-tasting tablets easier to swallow. These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above exemplary list of substituents.

[0048] Dosage Forms and Compositions In one aspect, the invention features a dosage form or composition for T-type calcium channel modulation and a disease, disorder, or condition associated with its function (e.g., a mood disorder (e.g., major depressive disorder), epilepsy or an epileptic syndrome such as absence seizures, juvenile myoclonic epilepsy, status epilepticus, or genetic epilepsy).

[0049] In another aspect, the present invention provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt (e.g., co-crystal) or solvate thereof.

[0050] In another aspect, the present invention provides a dosage form comprising a compound of formula (II): [ka]

[0051] Modified-Release Dosage Forms and Compositions In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an excipient that functions to modify the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0052] In one aspect, the disclosure provides an oral dosage form comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)); and a modified release polymer (e.g., a sustained release polymer, a hydrophilic matrix polymer such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)).

[0053] In one aspect, the present invention provides a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) and a release-modifying polymer (e.g., a sustained-release polymer, a hydrophilic matrix polymer, e.g., an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)), e.g., in an amount sufficient to modify the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) upon administration to a subject.

[0054] In some embodiments, the dosage form comprises from about 0.9% to about 40% by weight (e.g., from about 0.9% to about 30% by weight, from about 1% to about 25% by weight, from about 2% to about 25% by weight, from about 3% to about 20% by weight, from about 4% to about 20% by weight, from about 5% to about 20% by weight, from about 5% to about 15% by weight, from about 5% to about 10% by weight, or from about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, or about 40% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form contains about 30% to about 40% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0055] In some embodiments, the dosage form comprises about 14% to about 25% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 19% to about 20% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 21% to about 22% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 4% to about 15% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 4% to about 10% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 4% to about 5% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 5% to about 6% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form comprises about 9% to about 10% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0056] In another aspect, the present invention provides a pharmaceutical composition comprising about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) and a modified release polymer (e.g., a sustained release polymer, a hydrophilic matrix polymer such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100), e.g., in an amount sufficient to modify the release rate of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) upon administration to a subject.

[0057] In other embodiments, the dosage form contains about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In certain embodiments, the dosage form contains about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the dosage form contains about 5 mg to about 15 mg (e.g., about 10 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In other embodiments, the dosage form contains about 25 mg to about 35 mg (e.g., about 30 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In certain embodiments, the dosage form contains about 35 mg to about 45 mg (e.g., about 40 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0058] In some embodiments, the dosage form comprises about 55 mg to 65 mg of a modified release polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 10% to about 70% by weight of a modified release polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 50% to about 60% by weight of a modified release polymer (e.g., an HPMC polymer).

[0059] In some embodiments, the dosage form further comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the dosage form comprises about 15 mg to 40 mg of microcrystalline cellulose (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg). In some embodiments, the dosage form comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 15% to about 35% by weight (e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, 30% to about 35% by weight).

[0060] In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises colloidal silicon dioxide. In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the dosage form further comprises a coating agent.

[0061] In some embodiments, about 80% of the compound of Formula (I) is released within 7 hours upon administration to a subject. In certain embodiments, about 80% of the compound of Formula (I) is released in 7 hours using USP Apparatus Type I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

[0062] In some embodiments, the dosage form, upon administration to a subject, exhibits a reduced C relative to a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a release-modifying polymer, e.g., an HPMC polymer). max In some embodiments, the dosage form, upon administration to a subject, has a t that is greater than that of a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a release-modifying polymer, e.g., an HPMC polymer). max It has.

[0063] In other embodiments, the dosage form is administered to a patient once a day. In certain embodiments, the dosage form is administered to a patient twice a day. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.

[0064] In another aspect, the present invention provides an oral dosage form comprising about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of an HPMC polymer.

[0065] In another aspect, the present invention provides an oral dosage form comprising about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0066] In another aspect, the present invention provides an oral dosage form comprising about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of an HPMC polymer.

[0067] In another aspect, the present invention provides an oral dosage form comprising about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0068] In another aspect, the present invention provides oral (e.g., microparticle) compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and a modified release polymer (e.g., a sustained release polymer, e.g., an HPMC polymer as the hydrophilic matrix polymer).

[0069] In some embodiments, the composition comprises about 0.9% to about 40% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 14% to about 25% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 19% to about 20% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 21% to about 22% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 4% to about 15% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 4% to about 10% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 4% to about 5% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 5% to about 6% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In some embodiments, the composition comprises about 9% to about 10% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0070] In some embodiments, the composition comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In certain embodiments, the composition comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In certain embodiments, the composition comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0071] In some embodiments, the composition comprises about 55 mg to 65 mg of modified release polymer. In some embodiments, the composition comprises about 10% to about 70% by weight of modified release polymer. In some embodiments, the composition comprises about 50% to about 60% by weight of modified release polymer.

[0072] In some embodiments, the composition includes a diluent. In some embodiments, the diluent includes microcrystalline cellulose. In other embodiments, the composition includes about 15 mg to 40 mg of microcrystalline cellulose (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 40 mg). In some embodiments, the composition includes about 15% to about 35% by weight of microcrystalline cellulose (e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, or 30% to about 35% by weight).

[0073] In some embodiments, the composition comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the composition comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises colloidal silicon dioxide. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the composition further comprises a coating agent. In some embodiments, the compound of Formula (I) or (II) is stable in the formulation for at least 24 months at about 25°C and 60% relative humidity. In some embodiments, the compound is stable for at least 36 months at about 25°C and 60% relative humidity. In some embodiments, the compound is stable for at least 48 months at about 25°C and 60% relative humidity. In other embodiments, the compound is stable for at least 60 months at about 25°C and 60% relative humidity. In some embodiments, the compound is stable for at least 6 months at about 40°C and 75% relative humidity.

[0074] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of HPMC.

[0075] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0076] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 55 mg to 65 mg of HPMC.

[0077] In another aspect, the present invention provides an oral (e.g., microparticle) composition comprising about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53% to about 64% by weight of an HPMC polymer.

[0078] In some embodiments of the oral dosage forms or compositions described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is in a crystalline form. In certain embodiments, the crystalline form is a crystalline form described herein.

[0079] Crystalline forms of the compound of formula (II) Also provided herein is a crystalline form of the compound of Formula (II), which exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2.

[0080] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, and 26.6±0.2. In other embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2. In certain embodiments, the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1. In some embodiments, the X-ray powder diffraction pattern was obtained using CuKα radiation. In certain embodiments, the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 226.6° C. In some embodiments, the crystalline form has a differential scanning calorimetry curve substantially the same as that shown in FIG.

[0081] In another aspect, provided herein is a crystalline form of the compound of Formula (II), wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, and 17.8±0.2.

[0082] In some embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, and 20.5±0.2. In other embodiments, the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2, and 21.2±0.2. In certain embodiments, the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7. In some embodiments, the X-ray powder diffraction pattern was obtained using CuKα radiation. In certain embodiments, the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 97.9, 131.6, 223.7, 83.8, 128.9, 168.9, or 224.4° C. In some embodiments, the crystalline form has a differential scanning calorimetry curve substantially the same as that shown in FIG.

[0083] Immediate-release formulations In another aspect, the present invention provides a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is released immediately upon administration to a subject.

[0084] Also provided herein is an oral capsule for immediate release comprising about 15 mg to about 20 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)); and about 75 mg to 85 mg of a diluent; about 2 mg to 10 mg of a binder; about 1% to about 5% disintegrant; and about 0.1 mg to 5 mg of a lubricant.

[0085] Administration In some embodiments, the dosage form is administered to a subject more than once per day (eg, twice per day, three times per day, or four times per day).

[0086] In some embodiments, the dosage form is administered to a subject once daily (e.g., one 20 mg tablet per day, two 20 mg tablets per day, three 20 mg tablets per day). In some embodiments, the dosage form is administered to a subject twice daily. In some embodiments, the dosage form is administered to a subject every other day. In certain embodiments, about 1 mg to 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) is administered to a subject daily. In other embodiments, about 15 mg to 25 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) is administered to a subject daily. In certain embodiments, about 30 mg to 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) is administered to a subject daily.

[0087] In some embodiments, the dosage form, upon administration to a subject, exhibits a reduced C relative to a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a release-modifying polymer, e.g., an HPMC polymer). max In some embodiments, the dosage form, upon administration to a subject, has a tmax that is greater than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a dosage form with a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a release-modifying polymer, e.g., an HPMC polymer).

[0088] Treatment method Described herein are compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)), and their use for treating diseases, disorders, or conditions associated with T-type calcium channel function.

[0089] In one aspect, provided herein is a method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject an oral dosage form or oral composition disclosed herein. In some embodiments, the subject has a mutation in one or both of the T-type calcium channel genes CACNA1H and CACNA1G. In some embodiments, the neurological disorder is epilepsy. In some embodiments, the epilepsy is juvenile epilepsy. In some embodiments, the epilepsy is genetic epilepsy. In some embodiments, the neurological disorder is absence seizures. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). In some embodiments, the neurological disorder is tremor (e.g., essential tremor, Parkinson's tremor, or cerebellar tremor). In other embodiments, the neurological disorder is characterized by tremor, but Parkinson's disease is not tremor itself. In some embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with CACNA1G mutation). In some embodiments, the neurological disorder is tinnitus. In certain embodiments, the neurological disorder is arousal disorder.

[0090] In some embodiments, the compositions provided by the present invention are effective in treating tremors (e.g., essential tremor). In some embodiments, the compositions provided by the present invention are useful in treating epilepsy or epilepsy syndromes, such as absence seizures, juvenile myoclonic epilepsy, status epilepticus, or genetic epilepsy. The compositions of the present invention can also regulate all T-type calcium channels, such as Cav3.1, Cav3.2, and / or Cav3.3. In some embodiments, the compositions provided by the present invention are effective in treating psychiatric disorders, such as mood disorders, for example, major depressive disorder.

[0091] In another aspect, provided herein is a method for treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject an oral dosage form disclosed herein. In some embodiments, the psychiatric disorder is a mood disorder. In some embodiments, the mood disorder is major depressive disorder.

[0092] Epilepsy and epilepsy syndromes Compositions described herein are useful for treating epilepsy and epilepsy syndrome.Epilepsy is a CNS disorder that causes the activity of nerve cells in the brain to be disrupted, resulting in epileptic seizures, which can manifest as abnormal movements, unusual behavior, sensations and sometimes periods of unconsciousness.The symptoms of epileptic seizures vary greatly, from a simple blank stare for a few seconds to repeated jerks of arms or legs during epileptic seizures.

[0093] Epilepsy can involve generalized epileptic seizures or partial or focal epileptic seizures. All areas of the brain are involved in generalized epileptic seizures. A person experiencing a generalized epileptic seizure may scream or make some noise, stiffen for a few seconds to a few minutes, and then have rhythmic movements of the arms and legs. The eyes are typically open, and the person may appear not to be breathing and may actually turn blue. Consciousness returns gradually, and the person may be confused for a few minutes to a few hours. The main types of generalized epileptic seizures are: tonic-clonic seizures, tonic-clonic seizures, myoclonic seizures, myoclonic tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures, and absence (typical, atypical, myoclonic, eyelid myoclonic) epileptic seizures, and epileptic spasms. In partial or focal epileptic seizures, only part of the brain is involved, and therefore only part of the body is affected. Symptoms can vary, depending on the part of the brain that has abnormal electrical activity.

[0094] Epilepsy as described herein includes generalized, partial, complex partial (e.g., epileptic seizures that involve only part of the brain but impair consciousness), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0095] The compositions described herein can also be useful in treating epilepsy syndrome.Severe syndromes with diffuse brain dysfunction caused at least in part by some aspects of epilepsy are also called epileptic encephalopathy.They are associated with frequent epileptic seizures that are resistant to treatment and severe cognitive impairment, such as West syndrome.

[0096] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for genetic generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)). Am J Hum Genet. 2019 Aug 1;105(2):267-28. In some embodiments, the epilepsy syndrome is Doze syndrome or myoclonic astatic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spike-and-wave sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0097] Absence seizures Absence seizures are one of the most common types of epileptic seizures in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsia 2000). Absence seizures are relatively brief, nonconvulsive seizures characterized by the sudden onset of loss of consciousness and responsiveness, usually lasting 10–30 seconds, followed by a rapid return to normal consciousness without postictal confusion. Seizures are characterized by the sudden onset and disappearance of typical 1–6 Hz (e.g., 3 Hz) spike-wave discharges on accompanying EEG recordings. Absence seizures often occur multiple times per day, interfering with learning and psychosocial functioning and presenting a risk of injury due to the frequent episodes of loss of consciousness. Absence seizures typically begin in early childhood and resolve by the late teens. However, in a minority of patients, they persist into adulthood, often becoming drug-resistant, and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures are usually highly disabling, particularly because the period of time during which the affected individual is unable to obtain a driver's license or pursue work and hobbies, posing safety risks, and significant psychosocial impairment (Wirrell et al., 1997).

[0098] Although there is a common perception that absence seizures are relatively "easy" to treat, randomized controlled trials in patients with childhood absence epilepsy showed that even the most effective antiepileptic drugs, ethosuximide and valproate, completely controlled seizures in only 53% and 58% of patients, respectively, at 16 weeks and in 45% and 44% of patients, respectively, at 12 months, as assessed by video-EEG recordings (Glauser et al., 2010). Lamotrigine, another AED commonly used to treat absence seizures, controlled seizures in only 29% of patients at 16 weeks and 21% at 12 months. Furthermore, both ethosuximide and valproic acid are commonly associated with intolerable side effects (occurring in 24% of patients treated with either of these medications) (Glauser et al., 2010), and the latter is now generally considered contraindicated in girls and women of childbearing age. Other treatment options for absence seizures are limited; only benzodiazepines have established efficacy, and these are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat; patients are often treated with multiple medications, resulting in significant side effects, without achieving seizure control.

[0099] There is a large body of evidence that low-threshold (T-type) calcium channels play an important role in the generation and maintenance of absence seizures and are a key component of the oscillatory burst firing that occurs in thalamocortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the invention features a method of treating absence seizures using a composition described herein. In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0100] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizures are atypical absence seizures. In some embodiments, the absence seizures include adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0101] In some embodiments, the methods described herein further comprise identifying a subject with absence seizures.

[0102] In another aspect, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in the number of epileptic seizures.

[0103] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in the average or total duration of epileptic seizures.

[0104] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) to result in a reduction in epileptic seizure frequency, duration, or both, as measured by electroencephalogram (EEG).

[0105] Contemplated methods include a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the mean duration of epileptic seizures as measured by EEG.

[0106] Provided herein, in part, are methods of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in cumulative epileptic seizure duration as measured by EEG.

[0107] In one aspect, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in hyperventilation and total time with 2.5 to 4 Hz spike discharges following photic provocation, as measured by EEG.

[0108] Also provided herein is a method for treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) that results in a reduction in overall severity as measured by Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) scores. The CGI-S is a 7-point scale test that assesses the severity of a patient's illness at the time of evaluation, compared with the clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test that assesses the improvement of a patient's illness compared with baseline.

[0109] In another aspect, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in the number of epileptic seizures.

[0110] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in epileptic seizure density as measured by electroencephalogram (EEG).

[0111] Contemplated methods include a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the mean duration of epileptic seizures as measured by EEG.

[0112] Provided herein, in part, are methods of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in cumulative epileptic seizure duration as measured by EEG.

[0113] In one aspect, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in hyperventilation and total time with 2.5 to 4 Hz spike discharges following photic provocation, as measured by EEG.

[0114] Also provided herein is a method for treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) that results in a reduction in overall severity as measured by Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) scores. The CGI-S is a 7-point scale test that assesses the severity of a patient's illness at the time of evaluation, compared with the clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test that assesses the improvement of a patient's illness compared with baseline.

[0115] In another aspect, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in the number of epileptic seizures.

[0116] Also provided herein is a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) that results in a reduction in epileptic seizure density as measured by electroencephalogram (EEG).

[0117] Contemplated methods include a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in the mean duration of epileptic seizures as measured by EEG.

[0118] Provided herein, in part, are methods of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in cumulative epileptic seizure duration as measured by EEG.

[0119] In one aspect, the disclosure provides a method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) that results in a reduction in hyperventilation and total time with 2.5 to 4 Hz spike discharges following photic provocation, as measured by EEG.

[0120] Also provided herein is a method for treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) that results in a reduction in overall severity as measured by Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) scores. The CGI-S is a 7-point scale test used to assess the severity of a patient's illness at the time of evaluation, compared with the clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test used to assess the improvement of a patient's illness compared with baseline.

[0121] Hereditary epilepsy In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. These include 2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0122] In some embodiments, the methods described herein may involve administering to a patient suffering from epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant spasms, or genital dysplasia) prior to administration of a composition described herein. The method further includes identifying a subject having epileptic seizures, SCN2A epileptic encephalopathy, focal epilepsy with an SCN3A mutation, cryptogenic childhood partial epilepsy with an SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0123] In one aspect, the present invention provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial newborn ... The present invention features methods for treating neonatal-infant epileptic seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen's encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0124] The compositions of the invention may also be used to treat epileptic encephalopathy, in which the subject is afflicted with any of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT 1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX mutations.

[0125] In some embodiments, the methods described herein include administering to a subject an additional 20 or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF The method further includes identifying a subject having one or more mutations in one or more of: 2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0126] The compositions of the invention may also be used to treat epileptic encephalopathy, in which the subject is afflicted with ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM 1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GO SR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1 , KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SE RPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3 GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15,ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2 mutations.

[0127] One of the specific switch types that can be configured in a different way is ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, and ARHGEF 9. ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2. CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN 5. CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK 1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GA BRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRI N2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2 KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, L IAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY 1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNK P、PNPO、POLG、PPT1、PRICKLE1、PRIMA1、PRRT2、PURA、QARS、RELN、ROGDI、SA TB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SI K1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SL C6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX 1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1 SC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H.The method further comprises identifying a subject having one or more mutations in CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0128] The compositions of the invention may also be used to treat epileptic encephalopathy, in which a subject has ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1 A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNP U, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8 (CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3, NR2F1, NRXN1, PACS1, PCDH19, PIGA, PIGO, PIGV, PLCB1, PNK P, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC1 3A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2 mutations.

[0129] In some embodiments, the methods described herein include any of ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X , DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2 , GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ 2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NP RL3, NR2F1, NRXN1, PACS1, PCDH19, PIGA, PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB 2, further comprising identifying a subject having one or more mutations in SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1 (CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0130] The compositions of the invention may also be used to treat epileptic encephalopathy, in which the subject is afflicted with any of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KC NQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1 , PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5 , SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2 mutations.

[0131] In some embodiments, the methods described herein may comprise administering to a patient an effective amount of any of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCN T1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, PO LG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2 The method further includes identifying a subject having one or more mutations in one or more of: A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0132] Mood disorders Also provided herein are methods for treating psychiatric disorders such as mood disorders, for example, clinical depression, postpartum depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, treatment-refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior.In some embodiments, the methods described herein provide therapeutic benefits to subjects suffering from depression (e.g., moderate or severe depression).In some embodiments, the mood disorder is associated with the diseases or disorders described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0133] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience difficulty sleeping, weight loss, and generally feeling agitated and irritable. Clinical depression affects how individuals feel, think, and behave and can lead to a variety of emotional and physical problems. Individuals with clinical depression may struggle to perform everyday activities and feel that life is not worth living.

[0134] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, emotional withdrawal from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0135] Postpartum depression (PND), also known as postpartum depression (PPD), refers to the type of clinical depression that affects women after birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0136] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy.This depression is herein referred to as perinatal depression.In embodiments, the subject who experiences perinatal depression is at increased risk of experiencing PND.

[0137] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or drowsiness (hypersomnia), a feeling of heaviness in the legs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0138] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, depressed mood that is more prominent than sadness or loss, excessive weight loss, or excessive guilt.

[0139] Psychotic major depression (PMD) or psychotic depression refers specifically to a major depressive episode of a melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0140] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, immobile, or exhibit purposeless or bizarre movements.

[0141] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that fall in the fall or winter.

[0142] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. These tend to be less severe but last longer (e.g., at least two years).

[0143] Dual depression refers to a significant depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0144] Depressive personality disorder (DPD) refers to a personality disorder that has depressive traits.

[0145] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, each lasting no more than two weeks, typically less than two to three days.

[0146] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0147] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). Depending on the manic period, individuals may feel or function unusually happy, energetic, or irritable. They often make decisions with little consideration for the consequences. The need for sleep is usually reduced. During periods of depression, individuals may cry, make poor eye contact with others, and have a negative outlook on life. The risk of suicide in those with the disorder is high at over 6% over a 20-year period, while self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0148] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0149] Treatment-resistant depression refers to the state that individuals are treated for depression, but symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve their symptoms, but then return.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatment, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, and non-pharmacological treatments (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0150] Postoperative depression refers to feelings of depression after a surgical procedure (e.g., as a result of having to face death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in normally enjoyable hobbies and activities, or persistent feelings of worthlessness or despair.

[0151] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) that is associated with (eg, results from) a women's health condition or disorder (eg, as described herein).

[0152] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal obsession with suicide. The spectrum of suicidal ideation varies widely, from fleeting thoughts to extensive thinking, detailed plans, role-playing, and abortive attempts. Symptoms include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless in the situation, increased alcohol or drug use, doing risky or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0153] Symptoms of depression include persistent anxiety or sadness, helplessness, despair, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, challenging exercise, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thinking or planning, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide, and suicide attempts.The presence, severity, frequency, and duration of symptoms may vary in some cases.Depression symptoms and their alleviation can be confirmed by a doctor or psychologist (for example, by mental status examination).

[0154] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysthymic disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0155] In some embodiments, the method includes monitoring the subject using a known depression scale, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression-Improvement (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total scale exhibited by the subject. The therapeutic effect can be evaluated over a specific treatment period. For example, the therapeutic effect can be determined by a reduction from baseline in the HAM-D total scale after administration of a composition described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more after administration; or 1 day, 2 days, 14 days, 21 days, or 28 days after administration; or 1 week, 2 weeks, 3 weeks, or 4 weeks after administration; or 1 month, 2 months, 6 months, or 10 months after administration; or 1 year, 2 years, or lifetime).

[0156] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is 14 or greater and 18 or less. In some embodiments, the subject's baseline HAM-D total score is 19 or greater and 22 or less. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total scale after treatment with a composition described herein is about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the HAM-D total scale after treatment with a composition described herein is less than 10, 7, 5, or 3. In some embodiments, the reduction in the HAM-D total scale is from a baseline scale of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27), to a HAM-D total scale of about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8) after treatment with a composition described herein. In some embodiments, the reduction in the HAM-D total score from baseline after treatment with a composition described herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50. In some embodiments, the percentage reduction in the HAM-D total score from baseline after treatment with a composition described herein is at least 50% (e.g., 60%, 70%, 80%, or 90%).In some embodiments, the therapeutic effect is measured as a decrease in the HAM-D total score after treatment with a composition described herein compared to the baseline HAM-D total score.

[0157] In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as measured by a reduction in the Hamilton Depression Scale (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within the first or second day of treatment with a composition described herein. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 14 days from the start of treatment with a composition described herein. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 21 days from the start of treatment with a composition described herein. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 28 days from the start of treatment with a composition described herein. In some embodiments, the therapeutic benefit is a reduction from baseline in the HAM-D total score after treatment with a composition described herein. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is 14 or greater and 18 or less. In some embodiments, the reduction in the HAM-D total score after treatment of a subject with a composition described herein compared to the baseline HAM-D total score is at least 10. In some embodiments, the reduction in the HAM-D total score after treatment of a subject with a composition described herein compared to the baseline HAM-D total score is at least 15.In some embodiments, treatment of a subject with a composition described herein is associated with a HAM-D total score of no greater than a number in the range of 6 to 8. In some embodiments, treatment of a subject with a composition described herein is associated with a HAM-D total score of no greater than 7.

[0158] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Clinical Global Impression-Improvement scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit within the second day of the treatment period. In some embodiments, the therapeutic benefit is a reduction from baseline in the CGI scale at the end of the treatment period (e.g., 14 days after administration).

[0159] In some embodiments, the CNS disorder is a depressive disorder, for example, major depressive disorder. In some embodiments, the method for treating a depressive disorder, for example, major depressive disorder, produces a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in the MADRS scale at the end of the treatment period (e.g., 14 days after administration).

[0160] The effectiveness of treatment for major depressive disorder can be determined by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score shown by the subject. For example, the MADRS score can be reduced within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (related to apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0161] pain The dosage forms and compositions described herein may be useful in the treatment of pain. In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0162] In some embodiments, the methods described herein further include identifying a subject with pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine) prior to administration of a dosage form or composition described herein (e.g., a dosage form or composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II))).

[0163] Tremor The methods described herein can be used to treat tremors, for example, cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinsonism tremor, physiological tremor, or rubral tremor. Tremors include those caused by genetic, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases; peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (neuroleptic tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, early orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonism tremor, cerebellar tremor, Holmes tremor (i.e., Rubral tremor), velar tremor, neuropathic tremor, toxin- or drug-induced tremor, and psychogenic tremor. Tremor may be familial tremor.

[0164] Tremor is an involuntary, rhythmic muscle contraction and relaxation that may involve shaking or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0165] Cerebellar tremor or intention tremor is the slow, widespread tremor of limbs that occurs after purposeful movement.Cerebellar tremor is caused by the lesion or damage to the cerebellum, such as tumor, stroke or other localized lesion disease (such as multiple sclerosis) or neurodegenerative disease.

[0166] Dystonic tremor occurs in individuals with dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful, abnormal postures or positions.Dystonic tremor can affect any muscle in the body.Dystonic tremor occurs irregularly and can often be alleviated by complete rest or specific sensory manipulation.

[0167] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, beginning on one side of the body and progressing slowly, typically affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors can decrease with age, but the severity may increase. Increased emotion, stress, fever, physical exhaustion, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally progress over time and can be visible and persistent after onset.

[0168] Orthostatic tremor is characterized by rapid (greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Spasms can be felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one position. Orthostatic tremor can occur in patients with essential tremor.

[0169] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is typically seen as a "pill-making" movement of the hands that may also affect the jaw, lips, legs, and trunk. The onset of parkinsonian tremor typically begins after age 60. Movements may begin in one leg or one side of the body and progress to involve the other side.

[0170] Rubral tremor is characterized by a rough, slow tremor that can be present at rest, in position, and with intention. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0171] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor.

[0172] In another aspect, provided herein is a method for treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I), resulting in a reduction in essential tremor, as assessed by the Essential Tremor Rating Assessment Scale (TETRAS) score.As used herein, the term "Essential Tremor Rating Assessment Scale (TETRAS)" refers to a scale developed to quantify the severity of essential tremor and its impact on daily activities.It includes an Activities of Daily Living (ADL) section and an Activity section.The ADL section has 12 items that are rated from 0 to 4, and the Activity section has 9 items that are rated from 0 to 4.

[0173] In some embodiments, reduction in essential tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) Upper Extremity score.

[0174] In some embodiments, reduction in essential tremor is assessed by the TETRAS Activity subscale score or individual items of the TETRAS Activity.

[0175] In another aspect, provided herein is a method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) that results in a reduction in essential tremor as assessed by an accelerometer-based score, e.g., an accelerometer-based upper extremity score.

[0176] In some embodiments, the essential tremor is upper limb tremor.

[0177] In another aspect, provided herein is a method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of Formula (I) that results in a reduction in essential tremor as assessed by CGI score.

[0178] The effectiveness of the compounds or compositions described herein for treating essential tremor can be measured by the methods described in the following references: Ferreira, JJ et al., "MDS Evidence-Based Review of Treatments for Essential Tremor." Mov. Disord. 2019 July; 34(7): 950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor." Mov. Disord. 2013 November; 28(13): 1793-800; Deuschl G. et al. "Treatment of patients with essential tremor." Lancet Neurol. 2011; 10: 148-61; Reich SGet al. "Essential Tremor." Med. Clin. N. Am. 103(2019) 351-356. The disclosures of the references are incorporated herein in their entirety.

[0179] ataxia Ataxia, including both cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally accompanied by a loss or failure of coordination. Patients with ataxia may have difficulty regulating the force, range, direction, speed, and rhythm involved in posture, balance, and leg movements. Trunk ataxia may result, for example, in increased postural instability and an inability to maintain the center of gravity above the base of support. Ataxia and primary or secondary symptoms of ataxic gait and leg tremor may be accompanied by speech impairment, dysphagia, abnormal ventilation and speech, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, which may substantially interfere with activities of daily living.

[0180] As mentioned above, ataxia can result from a wide range of underlying diseases and conditions in a patient, including cerebellar and neurodegenerative disorders and diseases resulting from chronic or long-term exposure to toxins. Ataxic symptoms can result from a wide range of diseases, disorders, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol), among others; in one embodiment, for example, the ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or disease resulting from long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may result in ataxic symptoms that can be treated according to the methods described herein include, among others, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (pigment epithelial retinal degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar agenesis (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, dorsal column conditions, autonomic dysfunction, balance disorders, paresthesia, endocrine disorders, diseases caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptic drugs), fragile X / tremor syndrome, and disorders of the cerebral cortex. Warren's ataxia syndrome, Friedreich's ataxia, frontal lobe dysfunction, genetic disorders, granulomatous vasculitis of the central nervous system, Hallervorden-Spatz disease, hereditary motor and sensory neuropathies, hydrocephalus (e.g., low or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller-Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonic ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, parkinsonism (atypical), peroneal muscular atrophy, phenyloin toxicity, dorsal column ataxia with retinitis pigmentosa, post-polio syndrome, severe injury to the brain (e.g., head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins,(caused by viral infection or brain tumor), spastic incomplete hemiplegia, spastic paraplegia 23, spastic paraplegia, glaucoma, precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy-hearing loss), spinocerebellar ataxia (dysmorphism), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal recessive 1), spinocerebellar ataxia (autosomal recessive 3), spinocerebellar ataxia Examples of ataxia include, but are not limited to, spinocerebellar ataxia (autosomal recessive 4), spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive, with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph disease type II), spinocerebellar ataxia (X-linked 2), spinocerebellar ataxia (X-linked 3), spinocerebellar ataxia (X-linked 4), spinocerebellar degeneration (Book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and diseases caused by vitamin deficiency. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia, and fragile X / ataxia syndrome. In another specific embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X / ataxia syndrome.

[0181] Tinnitus Methods for treating tinnitus in a subject in need thereof using the disclosed dosage forms or compositions are provided. Tinnitus is a condition in which the sufferer perceives sound in one or both ears or head in the absence of external sound. Tinnitus, often referred to as a "ringing" in the ears, can occur intermittently or consistently with a perceived volume ranging from slight to severely painful. However, objective measurements of tinnitus volume in one patient may be perceived as painful, while in another, the same volume may be perceived as slight. The perceived volume of tinnitus can vary from patient to patient.

[0182] Sleep disorders The present invention provides a method for treating or preventing sleep disorders (e.g., narcolepsy) using the medication or composition disclosed herein. For example, the sleep disorder may be central nervous system disorders of hypersomnia, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia caused by medical disorders, hypersomnia caused by medication or substances, hypersomnia associated with psychiatric disorders, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0183] Combination therapy The dosage forms or compositions described herein (for example, for use in modulating T-type calcium ion channels) can be administered in combination with other agents or therapies.The subject to be administered the compounds disclosed herein can have a disease, disorder, or condition, or its symptoms, that will benefit from treatment with another agent or therapies.These diseases or conditions can be related to epilepsy or epilepsy syndromes (for example, absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy) or tremor (for example, essential tremor).

[0184] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0185] painkillers Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include sedatives and morphine-like drugs such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors.Considering that the compound of the present invention can treat pain through the inhibition of T-type calcium channel (for example, Cav3.1, Cav3.2 and Cav3.3), the combination with analgesics is particularly expected.

[0186] Tremor drug treatment Tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, Topamax, Neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide. [Example]

[0187] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as in any way limiting the scope thereof.

[0188] Example 1: Analysis of crystallinity of compound of formula (II) by X-ray power diffraction Polymorph screening of the compound of formula (II) was performed to identify a stable solid state form, designated Form C. The crystallinity of Form C was analyzed by X-ray powder diffraction (XRPD).

[0189] XRPD analysis was performed using a Bruker D8 ADVANCE and the following conditions: Bragg Brentano geometry. 2θ range: 3°~40°. Step size: 0.02°. Process time: 0.25 seconds. Slit:0.3. Rotate the sample on: 15 rpm. Copper K α irradiation. A zero background silicon-filled sample folder was used.

[0190] The powder X-ray diffractogram of Form C of compound of formula (II) is shown in Figure 1. The positions and relative intensities of the ten largest peaks in the XRPD pattern of Form C are shown in Table 1. The sample is highly crystalline and shows no evidence of any baseline loss of significant amorphous matter. [Table 1]

[0191] Preparation of Form C The free base solution of the compound of Formula (I) was cooled to 0-10°C over 1 hour. Ethyl acetate / HCl (10-12%, 53.5 L, prepared in-house from ethyl acetate and anhydrous HCl gas) was added slowly to the batch over 30 minutes, maintaining the temperature between 0-10°C. The batch was warmed to 25-30°C over 1.25 hours and held at this temperature for 4 hours. Vacuum (600-700 mmHg) was applied and the batch was distilled below 33°C for 6.25 hours, at which point the distillate volume was 115 L. The batch was cooled to 25-30°C and diisopropyl ether (53.5 L, 5 volumes) was added. The batch was maintained at 25-30°C with stirring for 2 hours, then passed through a Nutsche filter NF202 under a nitrogen atmosphere and pulled dry for 30 minutes. The cake was slurried / washed twice with diisopropyl ether (10.7 L, 1 volume) and suction dried for 30 minutes to 1 hour. This material was dried in a vacuum oven VD201 at 65°C to 70°C under vacuum (600-650 mmHg) for 12 hours until the moisture content of the cake was 2.0 wt% or less to yield Form C of compound of Formula (II) (10.01 kg, 90% yield, 0.45% water by KF).

[0192] Polymorph screening identified another stable solid state form, designated Pattern B. The crystallinity of Form B was analyzed by X-ray powder diffraction (XRPD).

[0193] XRPD analysis was performed using a Bruker D8 ADVANCE and the same conditions as above.

[0194] The powder X-ray diffractogram of Form B of compound of formula (II) is shown in Figure 7. The positions and relative intensities of the ten largest peaks in the XRPD pattern of Form C are shown in Table 2. The sample is highly crystalline and shows no evidence of any baseline loss of significant amorphous matter. [Table 2]

[0195] Preparation of Form B Preparation of material showing diffraction pattern B from ethyl acetate by controlled solvent evaporation. Approximately 200 mg of compound of formula (II) was placed in a 30-50 mL glass vial / beaker. 20 mL of ethyl acetate was added, and the sample was vortex-mixed / sonicated for approximately 1 minute until a clear solution was obtained. The solution was filtered through a syringe filter (Durapore PVDF 0.22 μm centrifugal filter from Millipore) to remove any potential seeds of input solid-state form. The solution was then opened to the environment and stirred at ambient conditions for 48 hours.

[0196] Example 2: Thermal properties of Form C and Form B of compound of formula (II) Form C of the compound of formula (II) was further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM). The compound has a high melting point and does not undergo physical or chemical changes below 180°C.

[0197] DSC DSC of Form C of compound of formula (II) was measured by Perkin Elmer Diamond Analysis was carried out using DSC and the following conditions: Aluminum pan under nitrogen purge gas. Sample size: 1-5 mg. Temperature range: 25℃~250℃. Heating rate: 2℃ / min, 5℃ / min, 10℃ / min.

[0198] The DSC thermogram of Form C of compound of formula (II) is shown in Figure 2. A summary of the obtained data is shown in Table 3. The obtained thermogram shows a single sharp endotherm with an onset temperature of 226.6°C, due to the melting of Form C. [Table 3]

[0199] TGA TGA analysis was performed using a perkin elmer Pyris 1 and the following conditions: Platinum pan under nitrogen purge gas. Sample size: 2-4 mg. Temperature range: ambient to 300°C. Heating rate: 10℃ / min

[0200] The TGA thermogram (Figure 3) shows a weight loss of approximately 0.8% w / w when heated from ambient temperature to 150°C, indicating that Form C of compound of formula (II) is neither a hydrate nor a solvate (theoretical weight loss for a monohydrate is 4.1% w / w). [Table 4-1]

[0201] HSM HSM of Form C of compound of Formula (II) was performed at ambient temperatures to 300°C (without sample equilibration) at heating rates of 10°C / min or 20°C / min. Figure 4 shows an HSM micrograph of Form C of compound of Formula (II). The experiment confirmed that the material remained unchanged up to approximately 180°C. The material began to melt at approximately 201°C, and melting of the final particles was complete at approximately 215°C. An endothermic event seen in the DSC thermogram with an onset temperature of 227°C corresponded to melting. Pattern B of compound of Formula (II) was further analyzed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy (HSM).

[0202] DSC thermograms for the Pattern B material at heating rates of 10°C / min and 2°C / min are shown in Figure 8. A summary of the data obtained is provided in Table 4. The DSC thermogram with a heating rate of 10°C / min showed three endothermic events. The first endotherm, with an onset temperature of approximately 98°C, can be assigned to the weight loss event seen in the TGA experiment (75°C to 125°C), likely due to water or solvent loss. A slower heating rate of 2°C / min was used to investigate the thermal events seen at higher temperatures. The resulting DSC thermogram recorded using a heating rate of 2°C / min showed four major events, three endothermic events and one exothermic event. The first endothermic event (onset temperature 84°C) is likely due to water or solvent loss. The second event (onset temperature 129°C) is due to dehydration of the compound or melting of a solvate form. An exothermic event (onset temperature 169°C) was observed after this melting, likely corresponding to the crystallization seen in the HSM (yielding Pattern C material). The final endothermic event (onset temperature 224°C) was shown to be a melt by HSM and corresponds to the melt of Pattern C material. [Table 4-2] [Table 4-3]

[0203] The TGA thermogram for the Pattern B material is shown in Figure 9. A summary of the data obtained is provided in Table 5. The TGA thermogram shows a gradual weight loss of approximately 4.0% w / w of hydrate over the temperature range of 75°C to 125°C. The theoretical weight of a monohydrate is 4.1%, indicating that Pattern B is a possible hydrate. Since it arises from a different solvent, it is likely not a solvent mixture; different solvates likely obtain the same diffraction pattern. This weight loss event corresponds to the first endotherm observed in the DSC thermogram. A significant weight loss of approximately 17% w / w was observed over the temperature range of 195°C to 300°C. Examination of the residue from the experiment revealed brown mass, indicating decomposition. Hot-stage microscopy confirmed melting at approximately 200°C, followed by decomposition. [Table 5]

[0204] HSM on the Pattern B material showed the appearance of a material that remained unchanged up to a maximum temperature of 128°C. The material began to melt at 128°C, with the final particle melting occurring at The reaction was completed at a temperature of approximately 135°C (see Figure 10). The phenomenon observed in DSC with an onset temperature of 227°C was confirmed to be due to the melt.

[0205] Recrystallization from the melt was observed between 161°C and 175°C, while The color change of the melt is the melting point of the recrystallized solid. The temperature was observed simultaneously at 189℃ to 195℃. Decomposition of compounds may occur differently in HSM when compared to DSC. HSM is performed under an air atmosphere and DSC is performed under an inert nitrogen atmosphere. Therefore, oxidation processes may occur in HSM but not in DSC.

[0206] Example 3: Modified-Release Tablet Formulation of Compound of Formula (II) formulation In a Phase 1 single ascending dose study of immediate-release ("IR") capsules, central nervous system (CNS)-related and psychiatric-related adverse events were the most commonly reported adverse events, typically occurring around the time of peak plasma concentration (Tmax). In a subsequent cohort in the same study, administration of 40 mg IR capsules as four 10 mg doses spaced 2 hours apart reduced the mean Cmax to approximately 50% of that observed after administration of a single oral 40 mg dose of the compound of formula (II), with mild headache and mild somnolence being the only adverse events reported after split dosing. Given these findings, a modified-release ("MR") tablet formulation of the compound of formula (II) was developed in an attempt to reduce the Cmax for a given dose while maintaining the overall AUC.

[0207] The composition of the immediate release capsules of the compound of formula (II) is provided in Table 6 below. [Table 6]

[0208] Starting tablet formulations of the compound of formula (II) (Form C) with different release rate profiles were prepared: Formulation 1 (releasing approximately 80% of the compound of formula (I) 2 hours after administration to a subject), Formulation 2 (80% release rate at 5 hours), and Formulation 3 (80% release rate at 7 hours). The compositions of the formulations are shown in Table 7. Each tablet contains 20 mg of the compound of formula (II). [Table 7]

[0209] Manufacturing Process The process for preparing modified-release tablets consists of six consecutive steps: 1) screening all ingredients (a compound of formula (I) or a pharmaceutically acceptable salt thereof, e.g., formula (II), and excipients), 2) mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof, e.g., a compound of formula (II), with excipients (containing granule lubrication therein), 3) roller compaction (including a milling step), 4) further granule lubrication, 5) tablet compression, and 6) tablet coating.

[0210] Example 4: Pharmacokinetic study of modified-release tablets Modified release tablets of the compound of formula (II) were developed in an attempt to mitigate some of the side effects observed with immediate release capsules of the compound of formula (II). C of three modified release tablet formulations of the compound of formula (II) compared to an immediate release capsule formulation of the compound of formula (II) max Reduction of t max The delay in serotonin levels was assessed under fasting conditions in healthy volunteers in a Phase 1 study.

[0211] The Phase 1 study was a randomized, open-label, four-way crossover study. Eligible subjects were randomized to one of four treatment sequences and received a single 20 mg dose of an immediate-release capsule formulation of the compound of Formula (II) (Compound of Formula (II)) and 20 mg doses of three modified-release tablet formulations of the compound of Formula (II) in the fasted state: Formulation 1 (80% release rate within 2 hours), Formulation 2 (80% release rate within 5 hours), and Formulation 3 (80% release rate within 7 hours). Study treatment was administered at four separate study visits, each separated by a minimum one-week washout period.

[0212] FIG. 5 shows the mean concentration-time profiles of the compound of formula (I) following a single 20 mg oral dose of modified release tablets and immediate release capsules of the compound of formula (II).

[0213] Following administration of 20 mg of the compound of formula (II) in the fasted state, plasma concentrations of the compound of formula (I) in the fasted state were quantifiable up to 0.75 hours after administration of each of the modified-release tablet formulations of the compound of formula (II) and the immediate-release capsule formulation (Figure 5). max After reaching C, the plasma concentration of the compound of formula (I) declined in a biphasic manner following administration of both the immediate-release capsule and Formulation 1 tablet in the fasted state. max After reaching a plateau, the compound of formula (I) decreased in a monophasic manner following administration of Formulation 2 and Formulation 3 tablets in the fasted state. The compound of formula (I) remained quantifiable for a duration that was the shortest sampling period of 36 hours following administration of the immediate release capsule and Formulation 1 tablets, and 48 hours following administration of Formulation 2 and Formulation 3 tablets.

[0214] The fasting formulation of 3 tablets is C max The compound of formula (I) remained quantifiable for the duration of the 48-hour sampling period after administration of Formulation 3 tablets in the fasted state (Figure 5).

[0215] Table 8 shows the median t for immediate release capsules, Formulation 1 tablets (2 hour release rate), Formulation 2 tablets (5 hour release rate), and Formulation 3 tablets (7 hour release rate). max , the observed geometric mean C max , the observed geometric mean AUC last , and AUC inf The longer the release rate of the modified release formulation, the lower the AUC last Delayed t compared to immediate release capsules while maintaining overall exposure as assessed by max and reduced C max The observed concentration 1 / 2 The absorption rate was similar for all formulations at approximately 8 to 10 hours. 1 / 2 There was no evidence to suggest that it affected AUC last The intersubject variability associated with serotonin was similar among the three modified-release tablet formulations. [Table 8]

[0216] Of the 18 subjects who received a single oral 20 mg dose of three modified release tablet formulations (Formulations 1 - 3) or IR capsules (see Example 4) in a fasting state, 17 subjects (94.4%) experienced at least one adverse event following administration of one of the formulations (Table 9). Adverse events associated with at least one agent were reported in 15 of the 18 subjects (83.3%). No serious or major adverse events were reported, and no subjects discontinued treatment with the study drug due to adverse events.

[0217] Consistent with the lower Cmax exposure experienced for the compounds of formula (I) for the MR tablets compared to the IR capsules, the percentage of subjects experiencing at least one adverse event and the percentage of subjects experiencing adverse events associated with at least one agent were lower following administration of each of the MR tablets compared to following administration of the IR capsules (Table 9). Among the MR tablets, the percentage of subjects experiencing any adverse event and the percentage of subjects experiencing adverse events associated with any agent were lowest for Formulation 3: · At least one adverse event was reported in 33.3% of subjects following administration of Formulation 3 tablets, 44.4% of subjects following administration of Formulation 2, 61.1% of subjects following administration of Formulation 1 tablets, and 72.2% of subjects following administration of the IR capsules. · Adverse events associated with at least one agent were reported in 16.7% of subjects following administration of Formulation 3, 44.4% of subjects following administration of Formulation 2, 44.4% of subjects following administration of Formulation 1, and 72.2% of subjects following administration of the IR capsules. The increase in the percentage of subjects experiencing any adverse event and adverse events associated with any agent was concentration - dependent and generally correlated with the order of Cmax (Formulation 3 < Formulation 2 < Formulation 1 < IR capsule).

Table 9

[0218] Example 5: Pharmacokinetic studies on modified-release tablets This was a two-part, Phase 1, double-blind, placebo-controlled study to evaluate the safety, tolerability, PK, and PD (including KSS, KDT, SQSQ, and 24-hour EEG recordings) of single-ascending (Part A: 20, 40, and 60 mg) and multiple-ascending (Part B: 20 ​​and 40 mg, 8 days) doses of the 20 mg tablet (Formulation 3) in healthy participants. Based on the results of this study, after a single oral dose of the 20 mg tablet formulation (Formulation 3), exposure to the compound of Formula (I) increased with dose over the dose range of 20 mg to 60 mg. Variability in Cmax and AUC increased with increasing dose after a single oral dose of the 20 mg tablet formulation (Formulation 3).

[0219] In this study, single and multiple (daily for 8 days) doses of 20 and 40 mg were well tolerated. A single 60 mg dose administered to six healthy volunteers was not tolerated. Five of the six participants experienced nausea, and three of the six participants vomited. [Table 10]

[0220] The pharmacokinetic properties of multiple 20 and 40 mg doses of the 20 mg tablet (Formulation 3) were determined on days 1 and 8 of dosing (Table 11). Based on the results of this study, after 8 days of once-daily dosing of the 20 mg tablet formulation, exposure to the compound of Formula (II) increased with dose over the dose range of 20 mg to 40 mg. Variability in Cmax and AUC increased modestly within the dose range studied. Steady state was achieved by day 5 of repeated daily dosing over the dose range of 20 to 40 mg. An approximately 2-fold increase in Cmax was observed over the 8 days of dosing. [Table 11]

[0221] T-type calcium channels expressed in the thalamus are critically involved in the generation and regulation of sleep spindles, a prominent thalamocortical oscillation during NREM sleep. Sleep spindles are detected in the EEG as the sigma frequency band (11-15 Hz) (FIG. 12). Thus, a decrease in power in the sigma frequency band in this study indicates compound of formula (I)-mediated blockade of T-type calcium channels in the thalamocortical circuit.

[0222] Example 6: Modified-Release Tablet Formulations of Compounds 4 and 5 of Formula (I) Formulations 4 and 5, provided as coated matrix modified-release (MR) tablets, are designed to release approximately 80% of the drug substance within 7 hours. The compositions for the clinical batches of product (Formulations 4 and 5) are shown in Table 12. Each active tablet contains the drug substance equivalent to 5 or 20 mg of the compound of formula (I), corresponding to approximately 5.475 mg or 21.90 mg of the compound of formula (II), respectively. [Table 12]

[0223] The dissolution method used to assess release is a chromatographic detection method using USP Apparatus Type I. The dissolution parameters and high performance liquid chromatography (HPLC) conditions for assessing release are shown below. [Table 13] [Table 14] [Table 15]

[0224] Manufacturing Process MR tablets are manufactured by selecting and blending excipients with lubricants. The blend is granulated by roller compaction and ribbon compaction milling. The granules are lubricated and then compressed into tablets. The tablets are then film coated.

[0225] A number of quality attributes are monitored in-process, during release testing and for stability, including hardness, friability, appearance, assay, related substances, content uniformity, water content and dissolution. Further formulations (Formulations 6-9) are provided in Table 16. [Table 16]

[0226] After administration of a single 5 mg dose of the compound of formula (II) (Formulation 4) to healthy volunteers, plasma concentrations of the free base of the compound of formula (I) (i.e., the compound of formula (II)) were quantifiable up to 0.50 hours after administration of the modified-release tablet formulation of the compound of formula (II). After reaching Cmax, the plasma concentration plateaued and then declined 24 hours after administration of Formulation 4. The compound of formula (I) as the free base (i.e., the compound of formula (II)) remained quantifiable for the duration of the 24-hour sampling period after administration of the 5 mg dose of Formulation 4. Figure 11 shows the mean (±SD) concentrations after a single oral administration of 5 mg tablet Formulation 4. [Table 17]

[0227] Example 7: Long-term stability of compound of formula (II) in formulations The drug product was chemically and physically stable for up to 48 months at 25°C / 60% RH (Table 11) or up to 6 months under accelerated conditions (40°C / 75% RH) (Table 19). Based on currently available stability data, a shelf life of 60 months was assigned for the drug product (Formulation 3) 20 mg packaged in a 40 cc high-density polyethylene (HDPE) bottle when stored at 20°C-25°C according to the United States Pharmacopeia (USP) definition of controlled room temperature. Based on the excellent stability of the essentially identical compositions of the drug product 20 mg and drug product 5 mg for at least 48 months, a shelf life of 24 months was assigned for the drug product (Formulation 4) 5 mg packaged in a 40 cc high-density polyethylene (HDPE) bottle when stored at 20°C-25°C.

[0228] A stability study of MR tablets containing the compound of Formula II was conducted at 25°C / 60% RH. The batch size was 10,000 tablets. Each film-coated tablet contained 20 mg of the compound of Formula II. The tablets were packaged in 40 cc HDPE bottles containing 30 tablets with CRC caps (Table 19). [Table 19]

[0229] Stability testing of MR tablets containing the compound of Formula II was performed at 40°C / 75%RH. The batch size was 10,000 tablets. Each film-coated tablet contained 20 mg of the compound of Formula II. The tablets were packaged in 40 cc HDPE bottles containing 30 tablets with CRC caps (Table 20). [Table 20]

[0230] A stability study of tablets of Formulation 4 containing the compound of formula (II) was conducted at 25°C / 60% RH. The batch size was 30,000 tablets. The tablets were packaged in 40 cc HDPE bottles containing 30 tablets with CRC caps (Table 21). [Table 21]

[0231] Example 8: Evaluation of the safety, tolerability, pharmacokinetics, and efficacy of ascending multiple oral doses in adults with generalized epilepsy syndromes with absence epileptic seizures This open-label, multi-agent drug study will primarily evaluate the safety and tolerability of 20 mg tablets (Formulation 3) at 20 mg daily and 20 mg twice daily doses as an adjunct to standard of care. Secondary objectives include characterizing the effects of tablets (Formulation 3) on PK, PD (sigma frequency output during NREM sleep), and seizure frequency.

[0232] subject Subjects for this study were male or female, aged 18-60 years. Subjects had a clinical diagnosis of an epilepsy syndrome with absence seizures consistent with the International League for Epilepsy-Revised Classification of Epilepsy (2017) (including, but not limited to, childhood absence seizures, juvenile absence seizures, juvenile myoclonic epilepsy, or Jeavons syndrome), persistent absence seizures despite documented trials with at least one standard antiepileptic treatment, and a history and electrographic evidence of absence epilepsy.

[0233] Methodology: Each participant completes three study periods: screening, treatment period (up to two dose levels followed by tapering), and safety follow-up.

[0234] All participants will undergo two weeks of dosing with a compound of formula (II), followed by a tapering: Dose Level 1: 20 mg twice daily for 7 days, up to a maximum of 14 days if not tolerated (Formulation 3). Dose level 2: 20 mg (formulation 3), twice daily for 7 days. Tapering: If the participant tolerates 20 mg twice daily for the full 7 days, tapering will be 20 mg daily for 2 days (days 15 and 16), followed by 20 mg every other day for 5 days (days 17, 19, and 21). If participants tolerated only 20 mg daily, the taper was 20 mg every other day for 7 days (Days 15-21).

[0235] Safety and Tolerability Safety variables include clinical laboratory assessments, physical examination, vital signs, 12-lead ECG, C-SSRS, and AE assessments including event type, frequency, seriousness, severity, timing, and relationship to IP.

[0236] Pharmacokinetics Pharmacokinetic parameters include the maximum observed concentration (Cmax), as well as steady-state (Cmax,SS), time to Cmax (Tmax) and Cmax,SS (Tmax,SS), area under the concentration-time curve throughout the dosing interval (AUCtau or AUCss), and total clearance at steady state (CLSS). If feasible, additional parameters such as half-life, accumulation, and volume of distribution at steady state (VSS) are calculated.

[0237] Effectiveness Efficacy will be assessed by a) the number of epileptic seizures reported by participant in an epileptic seizure diary, including absence seizures, generalized tonic-clonic seizures, and myoclonic seizures; b) EEG measures of seizure activity and pharmacodynamic effects of compounds of formula (I), including seizure density (the number of bilateral synchronous symmetric spike discharges of approximately 2.5-5 Hz >3 seconds in a period of approximately 24 hours encompassing seizures induced with photic stimulation and hyperventilation), mean seizure duration (the mean duration of 2.5-5 Hz discharges longer than 3 seconds in duration in a 24 hour period), cumulative seizure duration (the product of seizure density and median seizure duration), total time with 2.5-4 Hz spike discharges after hyperventilation and photic stimulation induction; and c) global severity, as measured by CGI-S and CGI-I scores.

[0238] Example 9: Evaluation of the efficacy, safety, tolerability and pharmacokinetics of the compound of formula (I) or a pharmaceutically acceptable salt thereof in essential tremor A randomized, controlled trial will be conducted to study the efficacy, safety, and tolerability of the compound of Formula (I) in essential tremor. Each patient will complete three study periods: screening, a treatment period (21 or 28 days), and safety follow-up.

[0239] Patients were men and women aged 18-75 years, diagnosed with essential tremor for at least three years. Patients received a stable dose of a single tremor medication throughout the clinical trial. Patients were excluded from the study if they had clinical evidence of psychogenic tremor, a history of other medical, neurological, or psychiatric conditions that could explain or cause tremor, prior magnetic resonance-guided focused ultrasound, or surgical intervention for essential tremor, or had a botulinum toxin injection for essential tremor in the six months prior to screening.

[0240] Patients receive 20 mg of the compound of formula (I) (Formulation 3) orally once daily for 14 days and twice daily for 7 days (Part A), or 20 mg of the compound of formula (I) (Formulation 3) or placebo orally once daily for 14 days and twice daily for 14 days (Part B).

[0241] The efficacy of compounds of formula (I) on upper limb tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb score at baseline, day 21 (Part A) and day 28 (Part B).

[0242] The efficacy of the compound of formula (I) on other measures of tremor severity is assessed by the TETRAS Activity subscale score and individual items of TETRAS Activity at baseline, Day 21 (Part A), and Day 28 (Part B).

[0243] The safety and tolerability of the compound of formula (I) will be assessed through a pooled analysis of the following endpoints at baseline, Day 1, Day 7, Day 14, Day 21, and Day 28 (Part B only): patient- and clinician-reported adverse events, vital signs, clinical laboratory results, electrocardiogram (ECG), and Columbia-Suicide Severity Rating Scale (C-SSRS).

[0244] Example 10: Evaluation of the efficacy, safety, tolerability and pharmacokinetics of compounds of formula (I) in essential tremor A clinical study was conducted to examine the efficacy, safety, and tolerability of compound of Formula (I) in essential tremor. Patients diagnosed with essential tremor completed three study periods: screening, a treatment period (14 days), and a safety follow-up. Patients received a stable dose of a single tremor medication throughout the clinical trial. Patients received 20 mg of compound of Formula (I) (one tablet of Formulation 5) orally once daily for 7 days and 40 mg of compound of Formula (I) (two tablets of 20 mg Formulation 5) orally once daily for 7 days (continuously for a total of 14 days).

[0245] The efficacy of compounds of formula (I) on upper limb tremor was assessed by the Essential Tremor Rating Assessment Scale (TETRAS) upper limb scores at baseline, day 7 and day 14.

[0246] The efficacy of compounds of formula (I) on other measures of tremor severity is assessed by the TETRAS Activity subscale scores and individual items of TETRAS Activity at baseline, day 7, and day 14.

[0247] The safety and tolerability of the compound of formula (I) was assessed through a pooled analysis of the following endpoints at baseline, Day 1, Day 7, Day 14, and Day 21: patient- and clinician-reported adverse events (e.g., dizziness or headache), vital signs, clinical laboratory results, electrocardiogram (ECG), and Columbia-Suicide Severity Rating Scale (C-SSRS).

[0248] The upper limb tremor score on TETRAS was reduced compared to baseline after administration of 20 mg (Formulation 5) for 7 days (Day 7), and a further reduction was observed after administration of 40 mg (two tablets of 20 mg Formulation 5) for another 7 days (Day 14). On Day 14, the upper limb tremor score was reduced by at least 25% compared to baseline. Notably, after a 7-day washout, the upper limb score increased compared to that on Day 14, suggesting a gradual return to baseline dysfunction.

[0249] The TETRAS activity score was reduced compared to baseline after 7 days (day 7) of administration of 20 mg (formulation 5), and a further reduction was observed after another 7 days (day 14) of administration of 40 mg (two tablets of 20 mg formulation 5). On day 14, the TETRAS activity score was reduced by at least 25% compared to baseline. Notably, after 7 days of washout, the activity score increased compared to that on day 14, suggesting a gradual return to baseline impairment.

[0250] FIG. 6 shows the reduction in tremor in the Archimedes spiral task by administration of a compound of formula (I) (Formulation 5).

[0251] Kinesia ONE, accelerometer, and gyroscope assessments of upper limb tremor were reduced compared to baseline after 7 days (day 7) of 20 mg administration, and further reductions were observed after another 7 days (day 14) of 40 mg administration. On day 14, tremor amplitude measured by accelerometer was reduced by at least 25% compared to baseline. Notably, after 7 days of washout, tremor amplitude measured by accelerometer increased compared to that on day 14, suggesting a gradual return to baseline dysfunction.

[0252] The emerging data suggest that the compound of Formula (I) is well tolerated, reduces upper extremity tremor amplitude, and may improve ADLs, such as writing skills. Physician-rated scales, accelerometer-based tremor assessment tools, and patient symptom assessment scales all consistently demonstrated reductions in symptoms with administration of the compound of Formula (I) (Formulation 5). In addition, participant accounts suggest that once-lost abilities, such as carrying a tray with food or beverages, may be restored after taking the compound of Formula (I) (Formulation 5).

[0253] A non-randomized, uncontrolled trial will be conducted to study the efficacy, safety, and tolerability of compound of Formula (I) in essential tremor. Each patient will complete three study periods: screening, a 14-day treatment period, and a safety follow-up. A video of the TETRAS performance subscale will be completed during screening.

[0254] Patients will be men and women between the ages of 18 and 75 years old, diagnosed with essential tremor. Patients will receive a single stable dose of tremor medication throughout the clinical trial. Patients will be excluded from the study if they have clinical evidence of psychogenic tremor, a history of other medical, neurological, or psychiatric conditions that could explain or cause tremor prior to magnetic resonance-guided focused ultrasound or surgical intervention for essential tremor, or have had a botulinum toxin injection for essential tremor in the 6 months prior to screening.

[0255] The patient received 20 mg of the compound of formula (I) (Formulation 5) orally once daily for 7 days and 40 mg of the compound of formula (I) (two tablets of 20 mg Formulation 5) orally once daily for 7 days (total of 14 consecutive days).

[0256] The efficacy of compounds of formula (I) on upper limb tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) Upper Limb scores at baseline, 7 days and 14 days. The efficacy of compounds of formula (I) on other measures of tremor severity is assessed by TETRAS Activity subscale scores, individual items of TETRAS Activity, and accelerometer at baseline, day 7, and day 14.

[0257] The efficacy of the compounds of formula (I) may also be assessed by Clinical Global Impression (CGI), Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression Change (PGI-C).

[0258] The efficacy of the compounds of formula (I) may also be assessed by any of the methods described herein.

[0259] The safety and tolerability of the compound of formula (I) will be assessed through a pooled analysis of the following endpoints at baseline, Day 1, Day 7, Day 14, and Day 21: patient- and clinician-reported adverse events (e.g., dizziness or headache), vital signs, clinical laboratory results, electrocardiogram (ECG), and Columbia-Suicide Severity Rating Scale (C-SSRS).

[0260] Equality and scope In the claims, articles such as "a," "an," and "the" can mean one or more, unless otherwise indicated to the contrary or clear from the context. A claim or description including "or" between one or more elements of a group is considered to be satisfied if one, more than one, or all of the group elements are present in, employed in, or relevant to a given product or process, unless otherwise indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one element of a group is present in, employed in, or relevant to a given product or process. The invention includes embodiments in which two or more, or all, group elements are present in, employed in, or relevant to a given product or process.

[0261] Furthermore, the invention encompasses all variations, combinations, and permutations, including the introduction into another claim of one or more limitations, elements, clauses, and recited terms from one or more of the enumerated claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. Generally, when an invention, or an aspect of an invention, is described as including certain elements and / or features, it should be understood that a particular embodiment of the invention or aspect of the invention consists of, or consists essentially of, such elements and / or features. For purposes of brevity, those embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can be considered to be any specific value or subrange within the stated ranges of different embodiments of the invention, to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0262] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Additionally, any particular embodiment of the invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed to be known to those of ordinary skill in the art. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0263] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above detailed description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the present invention, as defined in the following claims. In certain embodiments, for example, the following items are provided: (Item 1) 1. An oral dosage form comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof; and An oral dosage form comprising a release-modifying polymer (e.g., a sustained-release polymer, a hydrophilic matrix polymer such as HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)). (Item 2) 2. The dosage form of item 1, wherein the dosage form comprises about 0.9% to about 40% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 3) 3. The dosage form of item 1 or 2, wherein the dosage form comprises about 14% to about 25% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 4) 4. The dosage form of any one of items 1 to 3, wherein the dosage form comprises about 19% to about 20% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 5) 4. The dosage form of any one of items 1 to 3, wherein the dosage form comprises about 21% to about 22% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 6) 3. The dosage form of item 1 or 2, wherein the dosage form comprises about 4% to about 15% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 7) 7. The dosage form of any one of items 1, 2, or 6, wherein the dosage form comprises about 4% to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 8) 8. The dosage form of any one of items 1, 2, 6, or 7, wherein the dosage form comprises about 4% to about 5% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 9) 8. The dosage form of any one of items 1, 2, 6, or 7, wherein the dosage form comprises about 5% to about 6% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 10) 8. The dosage form of any one of items 1, 2, 6, or 7, wherein the dosage form comprises about 9% to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 11) 11. The dosage form of any one of items 1 to 10, wherein the dosage form comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 12) 12. The dosage form of any one of items 1 to 11, wherein the dosage form comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 13) 12. The dosage form of any one of items 1 to 11, wherein the dosage form comprises about 15 mg to about 25 mg (e.g., about 20 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 14) 14. The dosage form of any one of items 1 to 13, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is crystalline. (Item 15) 15. The dosage form of item 14, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2. (Item 16) 16. The dosage form of item 14 or 15, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, and 26.6±0.2. (Item 17) 17. The dosage form of any one of items 14 to 16, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2. (Item 18) 18. The dosage form of any one of items 14 to 17, wherein the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in Figure 1. (Item 19) 19. The dosage form according to any one of items 14 to 18, wherein the X-ray powder diffraction pattern was obtained using CuKα radiation. (Item 20) 20. The dosage form of any one of items 14 to 19, wherein the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 226.6°C. (Item 21) 21. The dosage form of any one of the preceding items, wherein the dosage form comprises about 55 mg to 65 mg of the release modifying polymer. (Item 22) 22. The dosage form of any one of the preceding items, wherein the dosage form comprises from about 10% to about 70% by weight of the release-modifying polymer. (Item 23) 23. The dosage form of any one of the preceding items, wherein the dosage form comprises about 50% to about 60% by weight of the release-modifying polymer. (Item 24) 24. The dosage form according to any one of items 1 to 23, wherein the dosage form further comprises a diluent. (Item 25) 25. The dosage form of item 24, wherein the diluent comprises microcrystalline cellulose. (Item 26) 26. The dosage form according to item 25, wherein the dosage form comprises about 15 mg to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg) of microcrystalline cellulose. (Item 27) 26. The dosage form according to item 25, wherein the dosage form comprises about 15% to about 35% by weight (e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, 30% to about 35% by weight) of microcrystalline cellulose. (Item 28) 28. The dosage form according to any one of items 1 to 27, wherein the dosage form further comprises a lubricant. (Item 29) 29. The dosage form of item 28, wherein the lubricant comprises colloidal silicon dioxide. (Item 30) 30. The dosage form according to any one of items 1 to 29, wherein the dosage form further comprises a lubricant. (Item 31) 31. The dosage form of item 30, wherein the lubricant comprises magnesium stearate. (Item 32) 32. The dosage form according to any one of items 1 to 31, wherein the dosage form further comprises a coating agent. (Item 33) 33. The dosage form of any one of items 1 to 32, wherein about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is released within 7 hours upon administration to a subject. (Item 34) 34. The dosage form according to item 33, wherein about 80% of the compound of formula (I) is released in 7 hours using USP Apparatus Type I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm. (Item 35) The dosage form, upon administration to a subject, exhibits a reduced C relative to a reference oral dosage form (e.g., a dosage form having any intended release rate profile, e.g., a modified release rate profile, a dosage form not having a modified release rate profile, a dosage form not having a release-modifying polymer, e.g., an HPMC polymer). max 35. The dosage form according to any one of items 1 to 34, having a value. (Item 36) The dosage form, upon administration to a subject, exhibits a t that is greater than that of a reference oral dosage form (e.g., a dosage form having any intended release rate profile, e.g., a modified release rate profile, a dosage form not having a modified release rate profile, a dosage form not having a release-modifying polymer, e.g., an HPMC polymer). max 36. The dosage form according to any one of items 1 to 35, having a value. (Item 37) 37. The dosage form of any one of items 1 to 36, wherein the dosage form is administered to a patient once daily. (Item 38) 37. The dosage form of any one of items 1 to 36, wherein the dosage form is administered to a patient twice daily. (Item 39) 1. An oral dosage form comprising: about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and An oral dosage form comprising about 55 mg to 65 mg of HPMC polymer. (Item 40) 1. An oral dosage form comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and 1. An oral dosage form comprising about 53% to about 64% by weight of an HPMC polymer. (Item 41) 1. An oral dosage form comprising: about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and An oral dosage form comprising about 55 mg to 65 mg of HPMC polymer. (Item 42) 1. An oral dosage form comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and 1. An oral dosage form comprising about 53% to about 64% by weight of an HPMC polymer. (Item 43) 43. The dosage form according to any one of items 1 to 42, wherein the dosage form is a tablet. (Item 44) 43. The dosage form according to any one of items 1 to 42, wherein the dosage form is a capsule. (Item 45) 43. The dosage form according to any one of items 1 to 42, wherein the dosage form is a suspension. (Item 46) An oral (e.g., particulate) composition comprising: A compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and A composition comprising a modified release polymer (e.g., a sustained release polymer, a hydrophilic matrix polymer such as an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)). (Item 47) 47. The composition of claim 46, wherein the composition comprises about 0.9% to about 40% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 48) 48. The composition according to item 46 or 47, wherein the composition comprises about 14% to about 25% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 49) 49. The composition of any one of items 46 to 48, wherein the composition comprises about 19% to about 20% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 50) 49. The composition of any one of items 46 to 48, wherein the composition comprises about 21% to about 22% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 51) 48. The composition according to item 46 or 47, wherein the composition comprises about 4% to about 15% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 52) 52. The composition of any one of items 46, 47, or 51, wherein the composition comprises about 4% to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 53) 53. The composition of any one of items 46, 47, 51, or 52, wherein the composition comprises about 4% to about 5% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 54) 53. The composition of any one of items 46, 47, 51, or 52, wherein the composition comprises about 5% to about 6% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 55) 53. The composition of any one of items 46, 47, 51, or 52, wherein the composition comprises about 9% to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 56) 56. The composition of any one of items 46 to 55, wherein the composition comprises about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 57) 56. The composition of any one of items 46 to 55, wherein the composition comprises about 4 mg to about 6 mg (e.g., about 5 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 58) 56. The composition of any one of items 46 to 55, wherein the composition comprises about 15 mg to about 25 mg (e.g., about 20 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). (Item 59) 56. The composition of any one of items 46 to 55, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is in a crystalline form. (Item 60) 60. The composition of claim 59, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2. (Item 61) 61. The composition of claim 59 or 60, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, and 26.6±0.2. (Item 62) 62. The composition of any one of items 59-61, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2. (Item 63) 63. The composition of any one of items 59 to 62, wherein the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in Figure 1. (Item 64) 64. The composition according to any one of items 59 to 63, wherein the X-ray powder diffraction pattern was obtained using CuKα radiation. (Item 65) 65. The composition of any one of items 59 to 64, wherein the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 226.6°C. (Item 66) 66. The composition of any one of items 59 to 65, wherein the crystalline form has a differential scanning calorimetry curve substantially the same as that shown in Figure 2. (Item 67) 67. The composition of any one of items 46 to 66, wherein the composition comprises about 55 mg to 65 mg of the release-modifying polymer. (Item 68) 63. The composition of any one of items 42 to 62, wherein the composition comprises from about 10% to about 70% by weight of the release-modifying polymer. (Item 69) 64. The composition of any one of items 42 to 63, wherein the composition comprises about 50% to about 60% by weight of the release-modifying polymer. (Item 70) 65. The composition according to any one of items 42 to 64, wherein the dosage form comprises a diluent. (Item 71) 66. The composition of claim 65, wherein the diluent comprises microcrystalline cellulose. (Item 72) Item 67. The composition according to item 66, wherein the composition comprises about 15 mg to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg) of microcrystalline cellulose. (Item 73) Item 67. The composition according to item 66, wherein the composition comprises about 15% to about 35% by weight (e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, 30% to about 35% by weight) of microcrystalline cellulose. (Item 74) 69. The composition according to any one of items 42 to 68, wherein the composition further comprises a lubricant. (Item 75) 70. The composition of claim 69, wherein the lubricant comprises colloidal silicon dioxide. (Item 76) The composition according to any one of Items 42 to 70, further comprising a lubricant. (Item 77) 72. The composition of claim 71, wherein the lubricant comprises magnesium stearate. (Item 78) 73. The composition according to any one of items 42 to 72, wherein the composition further comprises a coating agent. (Item 79) 74. The composition of any one of items 42 to 73, wherein the compound is stable at about 25° C. and 60% relative humidity for at least 24 months. (Item 80) 75. The composition of any one of items 42 to 74, wherein the compound is stable at about 25° C. and 60% relative humidity for at least 36 months. (Item 81) 76. The composition of any one of items 42 to 75, wherein the compound is stable at about 25° C. and 60% relative humidity for at least 48 months. (Item 82) 77. The composition of any one of items 42 to 76, wherein the compound is stable at about 25° C. and 60% relative humidity for at least 60 months. (Item 83) 78. The composition of any one of items 42 to 77, wherein the compound is stable at about 40° C. and 75% relative humidity for at least 6 months. (Item 84) An oral (e.g., particulate) composition comprising: about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and A composition comprising about 55 mg to 65 mg of HPMC. (Item 85) An oral (e.g., particulate) composition comprising: about 14% to about 25% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and A composition comprising about 53% to about 64% by weight of an HPMC polymer. (Item 86) An oral (e.g., particulate) composition comprising: about 3 mg to 8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and A composition comprising about 55 mg to 65 mg of HPMC. (Item 87) 1. An oral (e.g., microparticle, swellable core) composition comprising: about 3% to about 8% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and A composition comprising about 53% to about 64% by weight of an HPMC polymer. (Item 88) A crystalline form of the compound of formula (II), wherein said crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2. (Item 89) 89. The crystalline form of item 88, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, and 26.6±0.2. (Item 90) 90. The crystalline form of item 88 or 89, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2, and 26.6±0.2. (Item 91) 91. The crystalline form of any one of items 88 to 90, wherein the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in Figure 1. (Item 92) 92. The crystalline form according to any one of items 88 to 91, wherein the X-ray powder diffraction pattern was obtained using CuKα radiation. (Item 93) 93. The crystalline form of any one of items 88 to 92, wherein the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 226.6°C. (Item 94) A crystalline form of the compound of formula (II), wherein said crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, and 17.8±0.2. (Item 95) 95. The crystalline form of item 94, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, and 20.5±0.2. (Item 96) 96. The crystalline form of item 94 or 95, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2, and 21.2±0.2. (Item 97) 97. The crystalline form of any one of items 94 to 96, wherein the crystalline form has an X-ray powder diffraction pattern substantially the same as that shown in Figure 7. (Item 98) 98. The crystalline form according to any one of items 94 to 97, wherein the X-ray powder diffraction pattern was obtained using CuKα radiation. (Item 99) 99. The crystalline form of any one of items 94 to 98, wherein the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 97.9, 131.6, 223.7, 83.8, 128.9, 168.9, or 224.4 °C. (Item 100) Item 101. A method for treating a neurological disorder in a subject in need thereof, comprising administering to the subject an oral dosage form according to any one of Items 1 to 45, a composition according to any one of Items 46 to 87, or a crystalline form according to any one of Items 88 to 99. 101. The method of claim 100, wherein the neurological disorder is epilepsy. (Item 102) Item 102. The method of item 101, wherein the epilepsy is juvenile epilepsy. (Item 103) 102. The method of claim 101, wherein the epilepsy is a genetic epilepsy (e.g., CACNA1G-associated genetic generalized epilepsy). (Item 104) 101. The method of claim 100, wherein the neurological disorder is absence seizures. (Item 105) Item 101. The method of item 100, wherein the neurological disorder is absence epilepsy (e.g., CACNA1H-associated absence epilepsy). (Item 106) 101. The method of claim 100, wherein the neurological disorder is epilepsy associated with CACNA1G, H, or I. (Item 107) Item 102. The method of item 101, wherein the epilepsy is childhood absence epilepsy (CAE). (Item 108) 102. The method of claim 101, wherein the epilepsy is juvenile absence epilepsy (JAE). (Item 109) 102. The method of claim 101, wherein the epilepsy is Lennox-Gastaut syndrome. (Item 110) 101. The method of claim 100, wherein the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). (Item 111) Item 101. The method of item 100, wherein the neurological disorder is tremor (e.g., essential tremor, Parkinson's tremor, or cerebellar tremor, CACNA1G-associated tremor). (Item 112) 101. The method of claim 100, wherein the neurological disorder is ataxia (e.g., spinocerebellar ataxia, or spinocerebellar ataxia with a CACNA1G mutation). (Item 113) 101. The method of claim 100, wherein the neurological disorder is tinnitus. (Item 114) Item 101. The method of item 100, wherein the neurological disorder is a disorder of arousal. (Item 115) Item 116. A method for treating a psychiatric disorder in a subject in need thereof, comprising administering to the subject an oral dosage form according to any one of items 1 to 45, a composition according to any one of items 46 to 87, or a crystalline form according to any one of items 88 to 99. Item 116. The method of item 115, wherein the psychiatric disorder is a mood disorder. (Item 117) Item 117. The method of item 116, wherein the mood disorder is major depressive disorder. (Item 118) 118. The method of any one of items 115 to 117, wherein the dosage form is administered to the subject once daily. (Item 119) 119. The method of any one of items 115 to 118, wherein the dosage form is administered to the subject twice daily. (Item 120) 120. The method of any one of items 115 to 119, wherein the dosage form is administered to the subject every other day. (Item 121) 121. The method of any one of items 100 to 120, wherein about 15 mg to 25 mg (e.g., about 20 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject daily. (Item 122) 121. The method of any one of items 100 to 120, wherein about 30 mg to 50 mg (e.g., about 40 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject daily. (Item 123) The dosage form, upon administration to the subject, exhibits a reduced C relative to a reference oral dosage form (e.g., a dosage form having any intended release rate profile, e.g., a modified release rate profile, a dosage form not having a modified release rate profile, a dosage form not having a release-modifying polymer, e.g., an HPMC polymer). max 123. The method according to any one of items 100 to 122, having a value (Item 124) The dosage form, upon administration to the subject, has a t that is greater than that of a reference oral dosage form (e.g., a dosage form having any intended release rate profile, e.g., a modified release rate profile, a dosage form not having a modified release rate profile, a dosage form not having a release-modifying polymer, e.g., an HPMC polymer). max 124. The method according to any one of items 100 to 123, wherein the value (Item 125) 1. A method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1 to 45, a composition described in any one of items 46 to 87, or a crystalline form described in any one of items 88 to 99) that results in a reduction in the number of epileptic seizures. (Item 126) 1. A method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1 to 45, a composition described in any one of items 46 to 87, or a crystalline form described in any one of items 88 to 99) that results in a reduction in epileptic seizure density as measured by electroencephalography (EEG). (Item 127) 1. A method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1 to 45, a composition described in any one of items 46 to 87, or a crystalline form described in any one of items 88 to 99) that results in a reduction in the mean duration of epileptic seizures as measured by EEG. (Item 128) 1. A method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II) (e.g., an oral dosage form described in any one of items 1-45, a composition described in any one of items 46-87, or a crystalline form described in any one of items 88-99) that results in a reduction in cumulative epileptic seizure duration as measured by EEG. (Item 129) 1. A method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1 to 45, a composition described in any one of items 46 to 87, or a crystalline form described in any one of items 88 to 99) that results in a reduction in hyperventilation and total time with 2.5 to 4 Hz spike discharges following photic provocation as measured by EEG. (Item 130) 1. A method of treating generalized epilepsy syndrome with absence seizures in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1 to 45, a composition described in any one of items 46 to 87, or a crystalline form described in any one of items 88 to 99) to result in a reduction in global severity as measured by Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score. (Item 131) 1. A method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1-45, a composition described in any one of items 46-87, or a crystalline form described in any one of items 88-99) to result in a reduction of the essential tremor as measured by an Essential Tremor Rating Assessment Scale (TETRAS) score. (Item 132) Item 132. The method of item 131, wherein the reduction in essential tremor is assessed by the Essential Tremor Rating Assessment Scale (TETRAS) Upper Extremity score. (Item 133) Item 132. The method of item 131, wherein the reduction in essential tremor is assessed by TETRAS-ADL (Activities of Daily Living). (Item 134) 133. The method of claim 131 or 132, wherein the reduction in essential tremor is assessed by the TETRAS Activity subscale score or an individual item of the TETRAS Activity. (Item 135) 10. A method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1-45, a composition described in any one of items 46-87, or a crystalline form described in any one of items 88-99), resulting in a reduction of the essential tremor as assessed by an accelerometer-based upper extremity score. (Item 136) 1. A method of treating essential tremor in a patient in need thereof, comprising administering to the patient a sufficient amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) (e.g., an oral dosage form described in any one of items 1-45, a composition described in any one of items 46-87, or a crystalline form described in any one of items 88-99) that results in a reduction in the sigma frequency band. (Item 137) 137. The method of any one of items 131 to 136, wherein the essential tremor is upper limb tremor.

Claims

[Claim 1] The invention described in this specification.

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