Treatment methods for essential tremor

Abstract

The present disclosure relates to a method of treating essential tremor, the method comprising administering to a subject in need thereof a compound of formula (I): JPEG2026507197000027.jpg2578 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject once daily at a dose of about 60 mg to about 100 mg, whereby the subject's Essential Tremor Rating Scale (TETRAS) performance score is reduced after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to the subject's TETRAS performance score before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. Provisional Patent Application No. 63 / 542053, filed October 2, 2023; U.S. Provisional Patent Application No. 63 / 531467, filed August 8, 2023; U.S. Provisional Patent Application No. 63 / 467471, filed May 18, 2023; U.S. Provisional Patent Application No. 63 / 449676, filed March 3, 2023; and U.S. Provisional Patent Application No. 63 / 449676, filed March 2, 2023. This application claims priority to application Ser. No. 09 / 449,528, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] T-type calcium channels are low-voltage activated ion channels that mediate calcium influx into cells. Abnormal function or activity of these ion channels has been 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).

[0003] In treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, a factor to be considered is the tolerability of potential drug therapy. In the investigation of new therapeutic agents, tolerability is a clinically defined term that relates to information from both the patient (or study participant) and the clinician (or investigator). Information from the patient includes willingness to continue taking the therapeutic agent, while information from the clinician includes an assessment of the severity and / or number of adverse effects associated with the therapeutic agent and a recommendation as to whether the patient should continue receiving the therapeutic agent. Either party may determine that the drug is intolerable, which may result in its discontinuation.

[0004] Assessment of tolerability may also be based on the relationship between adverse effects, which inform tolerability, and expected or perceived benefit. Thus, a therapeutic agent or therapeutic dose used to treat a life-threatening disease or condition may tolerate more severe or numerous adverse events than a therapeutic agent or therapeutic dose used to treat a less severe disease or condition, and subsequently designate the therapeutic agent or therapeutic dose as intolerable.

[0005] Essential tremor, a disorder characterized by abnormal function or activity of T-type calcium channels, can affect an individual's ability to perform daily activities, although it is often not life-threatening. However, essential tremor can significantly impact family life, work life, social life, or any combination thereof. For example, individuals with essential tremor may have difficulty performing daily activities, including certain tasks or jobs that require motor skills, or may feel embarrassed by their tremor. Essential tremor is one of the most common movement disorders and is characterized by postural and / or kinetic tremors, and in some cases, gait disturbances accompanied by other non-motor symptoms. Propranolol (a beta-blocker) and primidone (an anticonvulsant), currently used to treat essential tremor, have serious side effects and are ineffective in some patients. Therefore, new methods for treating essential tremor are needed. Summary of the Invention [Means for solving the problem]

[0006] Thus, in some aspects, the present disclosure provides a method of treating essential tremor, the method comprising administering to a subject in need thereof, e.g., a human subject with essential tremor, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject once daily at a dose of about 60 mg to about 100 mg, such that the subject's Essential Tremor Rating Scale (TETRAS) performance score is reduced after administration of the compound of formula (I), compared to the subject's TETRAS performance score before administration of the compound of formula (I).

[0007] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 60 mg.

[0008] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 100 mg.

[0009] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject after an initial titration period.

[0010] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 60 mg after an initial titration period comprising administering to the subject once daily the compound of Formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 5 mg during a first period, followed by a dose of about 10 mg during a second period, followed by a dose of about 20 mg during a third period, followed by a dose of about 40 mg during a fourth period.

[0011] In some embodiments, the first period, second period, third period, and fourth period are each 7 days in length.

[0012] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 100 mg after an initial titration period comprising administering to the subject once daily the compound of Formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 5 mg during a first period, followed by a dose of about 10 mg during a second period, followed by a dose of about 20 mg during a third period, followed by a dose of about 40 mg during a fourth period, followed by a dose of about 60 mg during a fifth period, followed by a dose of about 80 mg during a sixth period.

[0013] In some embodiments, the first period, second period, third period, fourth period, fifth period, and sixth period are each 7 days in length.

[0014] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 8 weeks.

[0015] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 12 weeks.

[0016] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 14 weeks.

[0017] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 52 weeks.

[0018] In some embodiments, the TETRAS performance score includes an ADL subscore, wherein the ADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of a compound of Formula (I) compared to the subject's ADL subscore before administration of the compound of Formula (I).

[0019] In some embodiments, the ADL subscore is reduced by at least about 2 points after at least 8 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the ADL subscore is reduced by at least about 3 points after at least 8 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the TETRAS performance score includes the mADL subscore, wherein the mADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of a compound of Formula (I) compared to the subject's ADL subscore before administration of the compound of Formula (I).

[0022] In some embodiments, the mADL subscore is reduced by at least about 2 points after at least 8 weeks of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the mADL subscore is reduced by at least about 3 points after at least 8 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the mADL subscore is reduced by at least about 4 points after at least 8 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the subscore for at least one item assessed as part of the mADL subscale is decreased, and the item is selected from the group consisting of item 3 (drinking from a glass), item 4 (hygiene), item 5 (dressing), item 6 (pouring), item 7 (carrying), item 8 (using a key), item 9 (writing), and item 11 (global impairment).

[0026] In some embodiments, the TETRAS performance score includes the mADL11 subscore, wherein the mADL11 subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, or at least about 10 points after administration of a compound of Formula (I) compared to the subject's ADL subscore before administration of a compound of Formula (I).

[0027] In some embodiments, the mADL11 subscore is reduced by at least about 2 points after at least 8 weeks of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the mADL11 subscore is reduced by at least about 2.5 points after at least 8 weeks of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the subject does not have an intention tremor.

[0030] In some embodiments, the subject is a human. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 is a schematic diagram illustrating the design of a Phase 2 study to evaluate the efficacy and safety / tolerability of Compound 1 at doses of 60 mg or 100 mg compared to placebo in participants with moderate to severe essential tremor (ET). [Figure 2] Figure 2 is a summary listing the items included in the TETRAS and TETRAS-modified total scores. [Figure 3] FIG. 3 is a schematic diagram showing the status of patients in the clinical trial described in Example 1. [Figure 4] FIG. 4 is a table showing patient demographics and baseline characteristics (mITT). [Figure 5] FIG. 5 is a table showing the TEAS performed by patients in the clinical trial described in Example 1. [Figure 6] Figure 6 is a table showing TEAEs and the dose at the time of the event. [Figure 7] FIG. 7 is a table showing Compound 1 discontinuation in the mITT patient population. [Figure 8] FIG. 8 is a bar graph showing the change in mADL and ADL scores for the mITT population treated with Compound 1 (ulixacaltamide) and placebo. [Figure 9] FIG. 9 is a bar graph showing the change in mADL score at day 56 for patients receiving ulixacultamide (Compound 1) or placebo. [Figure 10] FIG. 10 is a schematic diagram showing the changes compared to baseline observed in scores for individual items assessed as part of the mADL and ADL assessments. [Figure 11] FIG. 11 is a bar graph showing the fold change at day 56, adjusted for placebo change, for individual items assessed as part of the mADL assessment. [Figure 12] FIG. 12 shows a graph depicting the status of patients in the mITT population as measured using the PGI-C and CGI-S scales. [Figure 13] FIG. 13 is a schematic diagram showing the results of Pearson's correlation assessment for changes from baseline in ADL and PS scores and other measures. [Figure 14] Figure 14 is a bar graph showing the change in mADL score at day 56 for each patient receiving ulixacultamide or placebo when the PS items (spiral-left and right, and handwriting) are excluded from the assessment. The data from Figure 8 are also included in Figure 14 for comparison. [Figure 15] Figure 15 is a graph showing the change in mADL score and mADL score excluding PS (mADL11) at each scored time point. Figure 15 shows the improvement in both mADL score and mADL score excluding PS (mADL11) score comparing ulixacultamide with placebo after 14 days. [Figure 16] FIG. 16 is a graph and table showing the endpoint analysis of the mITT population. [Figure 17] FIG. 17 is a bar graph showing the results of a post-hoc responder analysis using the MCID distribution method in the mITT population. [Figure 18] FIG. 18 is a bar graph showing mADL scores and mADL scores excluding PS in the mITT population excluding patients with intention tremor. [Figure 19] FIG. 19 is a schematic diagram showing the change from baseline observed in scores for individual items assessed as part of the mADL assessment in patients without intention tremor. [Figure 20] FIG. 20 is a bar graph showing the change in placebo-adjusted PS-excluded mADL score in mITT patients without intention tremor for the two tested dosing regimens (60 mg and 100 mg). [Figure 21]FIG. 21 is a bar graph showing the change from baseline in mADL11 scores by study week from week 8 to week 14. [Figure 22] Figure 22 is a schematic diagram showing the design of a Phase 3 trial comparing the efficacy and safety of ulixacultamide (Compound 1) with placebo in participants aged 18-80 years with a diagnosis of ET. DETAILED DESCRIPTION OF THE INVENTION

[0032] Treatment methods for essential tremor In some aspects, the disclosure provides a method of treating essential tremor, the method comprising administering to a subject in need thereof a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject once daily at a dose of about 60 mg to about 100 mg, such that the subject's Essential Tremor Rating Scale (TETRAS) performance score is reduced after administration of the compound of formula (I), compared to the subject's TETRAS performance score before administration of the compound of formula (I).

[0033] As used herein, the "subject" to which administration is intended includes, but is not limited to, humans and non-human animals. The non-human animal may be a mammal, such as, for example, a primate (e.g., a cynomolgus monkey or a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent (e.g., a mouse or a rat), a cat, or a dog. In some embodiments, the subject is a non-human animal. In other embodiments, the subject is a human. In some embodiments, the subject is a male or female of any age group, such as, for example, a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly person). The terms "human" and "patient" may be used interchangeably herein.

[0034] In some embodiments, the subject is a human. In some embodiments, the subject has essential tremor. In some embodiments, the subject does not have intention tremor.

[0035] 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, e.g., essential tremor, and that reduce the severity of 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.

[0036] The method of the disclosure comprises administering to a subject in need thereof a compound of formula (I): [ka] or a pharmaceutically acceptable salt (e.g., a co-crystal) or solvate thereof.

[0037] 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 known in the art. For example, Berge et al. describe 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 formed by using other methods used in the art, such as ion exchange.Other pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, cyclamate, digluconate, dodecyl sulfate, edisylate, ethanesulfonate, esylate, formate, fumarate, gentisinate, glucoheptonate, glycerophosphate, gluconate, glucuronate, glutamate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydroiodide, 2-hydroxy-ethanesulfonate, and isethionate. , ketoglutarate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, napadisylate, napsylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, oroate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and stereoisomers (e.g., enantiomers, diastereomers) thereof. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0038] In certain embodiments, the compound of formula (I) is, for example, the hydrochloride salt, for example, a compound of formula (II) below: [ka]

[0039] The compound of formula (I) may also be referred to as N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide, while formula (II) may also be referred to as N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride.

[0040] In some embodiments, the compound of formula (I) or formula (II) may also be referred to herein as "urixacultamide" or "compound 1."

[0041] In some embodiments, the methods of the disclosure include administering to a subject in need thereof 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): 16.2±0.2, 17.4±0.2, and 26.6±0.2. 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 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, 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 some embodiments, the X-ray powder diffraction pattern was obtained using CuKα radiation. In some embodiments, the crystalline form has a melting onset determined by differential scanning calorimetry at about 226.6°C.

[0042] In some embodiments, the methods of the disclosure include administering to a subject in need thereof 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. 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 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, 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 some embodiments, the X-ray powder diffraction pattern was obtained using CuKα radiation. In certain embodiments, the crystalline form has a melting onset as determined by differential scanning calorimetry at about 97.9, 131.6, 223.7, 83.8, 128.9, 168.9, or 224.4°C.

[0043] In some embodiments, the compound of Formula (I), the compound of Formula (II), or the crystalline form of the compound of Formula (II) is administered to a subject in need thereof according to the methods of the present disclosure as part of a pharmaceutical composition that also includes a release-modifying polymer. The term "release-modifying polymer," as used herein, refers to a polymer used in a composition (e.g., a tablet or capsule) to modify the release rate of a drug upon administration to a subject. For example, a release-modifying polymer is used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, the release-modifying polymer is a release-controlling polymer. For example, the release-controlling polymer or release-modifying polymer is an HPMC polymer. In some embodiments, the release-modifying polymer can include a hydrophilic matrix polymer (e.g., hypromellose, HPMC (hydroxyl-propylmethylcellulose)), a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100).

[0044] In some embodiments, pharmaceutical compositions comprising a compound of Formula (I), a compound of Formula (II), or a crystalline form of the compound of Formula (II) contain a diluent. As used herein, the term "diluent" refers to an excipient used to increase weight and improve the uniformity of the contents. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), and sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0045] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a crystalline form of the compound of Formula (II) comprises a glidant. As used herein, the term "glidant" refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0046] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a crystalline form of the compound of Formula (II) contains a lubricant. As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping together and sticking to a 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 material and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0047] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), or a crystalline form of the compound of Formula (II) comprises a coating. As used herein, the term "coating" refers to an excipient that protects tablet ingredients from degradation due to moisture in the air, for example, and makes large or unpleasant-tasting tablets easier to swallow.

[0048] The method of the present disclosure for treating essential tremor comprises administering a set dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such that the final dose or maintenance dose (i.e., final dose) exceeds the initial dose or exceeds the dose at which adverse events are likely to occur in the absence of dose adjustment (the maximum tolerated dose achieved in the absence of dose adjustment). As used herein, administering a set dose refers to a method of starting with a low dose and gradually increasing to one or more higher doses. The administration of a set dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is described, for example, in WO2021 / 222342A1. The entire content of this document is incorporated herein by reference.

[0049] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject in the context of the present disclosure at a final dose (e.g., 60 mg or 100 mg) after an initial titration period. When used in connection with administering a final dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for example, a dose of about 60 mg or about 100 mg, the term "initial titration period" refers to a period during which the subject is administered escalating doses lower than the final dose of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, until a final dose, such as a dose of about 60 mg or about 100 mg of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is reached.

[0050] For example, the initial titration period may include administering to the subject escalating doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof until a dose of about 60 mg is reached. In some embodiments, the initial titration period may include administering to the subject one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of about 5 mg, about 10 mg, about 20 mg, and about 40 mg. In some embodiments, the initial titration period may include administering to the subject a dose of about 5 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof during a first period, followed by a dose of about 10 mg during a second period, followed by a dose of about 20 mg during a third period, followed by a dose of about 40 mg during a fourth period. In some embodiments, the first period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days in length. In some embodiments, the second period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the third period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the fourth period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the first, second, third, and fourth periods are each 7 days long. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0051] In another example, the initial titration period may involve administering to the subject escalating doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof until a dose of about 80 mg is reached. In some embodiments, the initial titration period may involve administering to the subject one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of about 5 mg, about 10 mg, about 20 mg, about 40 mg, and about 60 mg. In some embodiments, the initial titration period may involve administering to the subject a dose of about 5 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof during a first period, followed by a dose of about 10 mg during a second period, followed by a dose of about 20 mg during a third period, followed by a dose of about 40 mg during a fourth period, followed by a dose of about 60 mg during a fifth period. In some embodiments, the first period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the second period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the third period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the fourth period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the fifth period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the first, second, third, fourth, and fifth periods are each 7 days long. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0052] In yet another example, the initial titration period may comprise administering to the subject escalating doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof until a dose of about 100 mg is reached. In some embodiments, the initial titration period may comprise administering to the subject one or more doses of the compound of Formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 60 mg, and about 80 mg. In some embodiments, the initial titration period may comprise administering to the subject a dose of about 5 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof during a first period, followed by a dose of about 10 mg during a second period, followed by a dose of about 20 mg during a third period, followed by a dose of about 40 mg during a fourth period, followed by a dose of about 60 mg during a fifth period, followed by a dose of about 80 mg during a sixth period. In some embodiments, the first period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the second period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the third period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the fourth period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the fifth period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the sixth period of time may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days long. In some embodiments, the first, second, third, fourth, fifth, and sixth periods are each 7 days in length. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0053] In certain aspects of all embodiments disclosed herein, the administration period, e.g., the first, second, third, fourth, fifth, or sixth period, may range from about 3 days to about 1 year. For example, the first, second, third, fourth, fifth, and / or sixth period may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, 98, 105, 112, 119, 126, 133, 140, 147, 154, 166, 170, 177, 180, 184, 186, 188, 189, 190, 200, 201, 202, 203, 204, 205, 206, 207, 208, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 2 The seventh period may be 1 year, 161 days, 168 days, 175 days, 182 days, 189 days, 196 days, 203 days, 210 days, 217 days, 224 days, 231 days, 238 days, 245 days, 252 days, 259 days, 266 days, 273 days, 280 days, 287 days, 294 days, 301 days, 308 days, 315 days, 322 days, 329 days, 336 days, 343 days, 350 days, 357 days, 364 days, or 1 year in length. In certain aspects of all embodiments disclosed herein, the administration period, such as the seventh period, may be in the range of about 3 to about 16 days, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 days. In other aspects of the embodiments disclosed herein, the period, such as the first, second, third, fourth, fifth, sixth, or seventh administration period, may be greater than 14 days.

[0054] In certain embodiments, the increase in dosage compared to the previous dose is 40 mg or less per day. For example, in certain embodiments, the second dose is increased by 40 mg or less per day compared to the first dose, and in certain embodiments, the third dose is increased by 40 mg or less per day compared to the second dose. In other embodiments, the increase in dosage compared to the previous dose is 20 mg or less per day. For example, in certain embodiments, the second dose is increased by 20 mg or less per day compared to the first dose, and in certain embodiments, the third dose is increased by 20 mg or less per day compared to the second dose. In some embodiments, the third dose is a maintenance dose or a final dose.

[0055] In the context of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject once, twice, or three times daily at a dose of up to about 120 mg (e.g., about 5 mg to about 120 mg, about 10 mg to about 120 mg, about 15 mg to about 120 mg, about 20 mg to about 120 mg, about 40 mg to about 120 mg, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 15 mg to about 100 mg). In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject once daily.

[0056] In some embodiments, in the context of the present disclosure, a method of treating essential tremor in a subject in need thereof comprises: (a) administering to a subject 5 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) once daily for a first period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days); (b) administering 10 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) to the subject once daily for a second period of time (e.g., 3, 4, 5, 6, 7, 8, or 9 days); and (c) administering 20 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) to the subject once daily for a third period (e.g., 3, 4, 5, 6, 7, 8, or 9 days). In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject once daily.

[0057] In some embodiments, in the context of the present disclosure, a method of treating essential tremor in a subject in need thereof comprises: (a) administering to a subject 20 to 40 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a first period of time (e.g., 3, 5, 6, 7, 8, or 9 days); (b) administering to the subject 20 to 60 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a second period of time (e.g., 3, 5, 6, 7, 8, or 9 days); and (c) administering to the subject 20 to 80 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) for a third period (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0058] In some embodiments, the method further includes (d) administering to the subject 20 to 100 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a fourth period (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0059] In other embodiments, the method further includes (e) administering to the subject 20 to 120 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a fifth period (e.g., 3, 4, 5, 6, 7, 8, or 9 days).

[0060] In certain embodiments, the method further includes (f) administering to the subject 20 to 120 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a sixth period of time (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 days).

[0061] In certain embodiments, the method further includes (g) administering to the subject, if necessary, 20 to 120 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) for a seventh period (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or more).

[0062] A physician may choose not to continue dose escalation of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, resulting in fewer than seven periods. For example, only one, two, three, four, five, or six periods of dose escalation may be required to achieve a desired therapeutic effect. In some embodiments, the disclosed method includes two, three, or four periods of dose escalation. In some embodiments, the disclosed method includes five periods of dose escalation. In some embodiments, the disclosed method includes seven periods of dose escalation.

[0063] In some embodiments, the methods of the present disclosure include: (a) administering to the subject about 5 mg to about 40 mg, e.g., 20 mg or 40 mg per day, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for a first period of time ranging from about 3 to about 9 days; (b) administering to the subject about 10 mg to about 100 mg, e.g., 40 mg, 60 mg, or 80 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for a second period of time ranging from about 3 to about 9 days; and (c) administering to the subject about 20 mg to about 120 mg, e.g., 60 mg, 80 mg, 100 mg, or 120 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for a third period of time ranging from about 3 to about 9 days.

[0064] In some embodiments, the methods of the disclosure include: (a) administering to the subject a first dose of about 20 mg to about 40 mg per day of a compound of Formula (I) or a pharmaceutically acceptable salt thereof once daily during a first time period; (b) increasing the amount of the first dose of the compound and administering one or more increased doses of the compound to the subject to reach a maximum set dose of about 80 mg to about 120 mg per day; and (c) optionally administering the maximum set dose to the subject once daily.

[0065] In related embodiments, the dosage of the compound of formula (I) may be adjusted upward or downward in increments of 1, 2, 3, 4, 5, 10, 15, 20 mg, as deemed necessary by the physician, depending on the subject's response to previous doses of the compound of formula (I).

[0066] In various embodiments of the present disclosure, the methods disclosed herein include (a) administering a first dose of 20 mg per day for a first period of 3 days, (b) administering a second dose of 40 mg per day for a second period of 3 days, (c) administering a third dose of 60 mg per day for a third period of 7 days, (d) administering a fourth dose of 80 mg per day for a fourth period of 7 days, (e) administering a fifth dose of 100 mg per day for a fifth period of 7 days, and (f) administering a sixth dose of 120 mg per day thereafter, if necessary. In various other embodiments, the methods disclosed herein include (a) administering a first dose of 20 mg per day for a first period of 3 days, (b) administering a second dose of 40 mg per day for a second period of 3 days, (c) administering a third dose of 80 mg per day for a third period of 3 days, and (d) administering a fourth dose of 120 mg per day as needed.

[0067] In certain embodiments, a method of treating a disease or condition associated with abnormal T-type calcium channel function or activity in a subject in need thereof is disclosed, the method comprising: (a) administering to the subject about 20 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of about 3 days; (b) administering to the subject about 40 mg of the compound per day for a second period of about 3 days; (c) administering to the subject about 60 mg of the compound per day for a third period of about 3 days; (d) administering to the subject about 80 mg of the compound per day for a fourth period of about 3 days; (e) administering to the subject about 100 mg of the compound per day for a fifth period of about 3 days; and (f) administering to the subject about 120 mg of the compound per day for a sixth period of about 3 days. Also, the doses may be administered every 4, 5, or 6 days instead of every 3 days.

[0068] Also disclosed herein is a method of treating essential tremor in a subject in need thereof, the method comprising: (a) administering to the subject about 20 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of 7 days; (b) administering to the subject about 40 mg of the compound per day for a second period of about 7 days; (c) administering to the subject about 60 mg of the compound per day for a third period of about 7 days; (d) administering to the subject about 80 mg of the compound per day for a fourth period of about 7 days; (e) administering to the subject about 100 mg of the compound per day for a fifth period of about 7 days; and (f) administering to the subject about 120 mg of the compound per day for a sixth period of time.

[0069] In some embodiments, the disclosed methods include (a) administering to the subject a first dose of about 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of about 3 days, (b) administering to the subject about 80 mg of the compound per day for a second period of about 3 days, and (c) administering to the subject about 120 mg of the compound per day for a third period of time. Also, doses may be administered every 4, 5, or 6 days instead of every 3 days.

[0070] Also disclosed herein are methods of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, the method comprising: (a) administering to the subject about 40 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of about 7 days; (b) administering to the subject about 80 mg of the compound per day for a second period of about 7 days; and (c) administering to the subject about 120 mg of the compound per day for a third period of time.

[0071] In certain embodiments, a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof is disclosed, the method comprising: (a) administering to the subject about 20 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of 7 days; (b) administering to the subject about 40 mg of the compound per day for a second period of about 7 days; (c) administering to the subject about 60 mg of the compound per day for a third period of about 7 days; (d) administering to the subject about 80 mg of the compound per day for a fourth period of about 7 days; (e) administering to the subject about 100 mg of the compound per day for a fifth period of about 7 days; (f) administering to the subject about 120 mg of the compound per day for a sixth period of about 14 days; and (g) optionally thereafter administering to the subject about 1-120 mg of the compound per day.

[0072] The physician may choose to stop escalating the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof once the subject has demonstrated the desired therapeutic effect. At this point, the physician may choose to have the subject continue the dose they are taking to achieve the desired therapeutic effect, or may choose to have the subject decrease the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to maintain the desired therapeutic effect, reduce side effects, or both. Achievement of the desired therapeutic effect may be observed, for example, by an improvement in the subject's TETRAS performance score, accelerometer performance score, or Archimedes spiral task test, etc.

[0073] In some embodiments, the present disclosure provides a method for treating essential tremor, comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, such that the subject's performance score on the Essential Tremor Rating Scale (TETRAS) is reduced after administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to the subject's TETRAS performance score before administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. TETRAS was developed to quantify the severity of essential tremor and its impact on activities of daily living, and is described in Elble et al., J. Neurol Neuromedicine (2016), 1(4):34-38, the entire contents of which are incorporated herein by reference. In certain embodiments, a method for treating essential tremor in a subject in need thereof can result in a change in the subject's TETRAS performance score. The TETRAS performance score is assessed using the TETRAS scale. The TETRAS scale consists of two sections: the Performance subscale (TETRAS-PS) and the Activities of Daily Living (TETRAS-ADL). The TETRAS-PS section includes the following nine items: [Table 12]

[0074] The TETRAS-ADL, or ADL subscale, is a 12-item assessment of typical daily activities affected by tremor. As shown in Figure 2, activities on the TETRAS-ADL subscale are assessed in the following functional domains: [Table 13]

[0075] Each functional impact is rated on a 5-point Likert scale ranging from 0 to 4. All ADL subscale scores are calculated as the sum of all 12 items and range from 0 to 48.

[0076] The TETRAS-modified ADL subscore (mADL) is the composite sum of items 1–11 from the TETRAS-ADL subscale (omitting item 12, social impact) and items 6 and 7 from the TETRAS-PS subscale (spiral drawing and handwriting). For mADL scoring, response options 0 and 1 are combined into a single response of "0 = normal," and scores of 2, 3, and 4 are adjusted to be 1, 2, and 3, respectively. The total TETRAS-modified score is the sum of the adjusted TETRAS-ADL and TETRAS-PS items and can range from 0 to 42. Higher values ​​represent an increased direct impact of tremor on activities of daily living. Items included in the total TETRAS-modified score are shown in Figure 2.

[0077] The TETRAS-Modified ADL (mADL11) score omits the performance subscale and is the composite sum of items 1–11 of the TETRAS-ADL (omitting item 12, the social impact score, and items 6 and 7 of the TETRAS-PS subscale). Scoring for each item is converted to a 4-point scale ranging from 0–3, with a total score ranging from 0–33.

[0078] In some embodiments, a decrease in one or more of the TETRAS performance scores, such as ADL, mADL, or mADL11, indicates a desirable therapeutic effect. In some embodiments, a decrease in one or more of the TETRAS performance scores, such as ADL, mADL, or mADL11, indicates an improvement in essential tremor symptoms.

[0079] In some embodiments, the method of treating essential tremor in a subject in need thereof provided by the present disclosure can result in a decrease in the subject's TETRAS performance score.Thus, in some embodiments, the subject's TETRAS performance score is reduced after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject according to the method of the present disclosure, compared to the subject's TETRAS performance score before administering the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the TETRAS performance score includes an ADL subscore, wherein the subject's ADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks. In some embodiments, the ADL subscore is reduced by at least about 2 points after administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks. In some embodiments, the ADL subscore is reduced by at least about 3 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

[0081] In some embodiments, the TETRAS performance score includes the mADL subscore, wherein the subject's mADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks. In some embodiments, the mADL subscore is reduced by at least about 2 points after administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks. In some embodiments, the mADL subscore is reduced by at least about 3 points after administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks. In some embodiments, the mADL subscore is reduced by at least about 2 points after administering the compound of Formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

[0082] In some embodiments, in the context of the present disclosure, administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof to treat essential tremor results in a decrease in at least one subscore of an item assessed as part of the mADL subscale. In some embodiments, the item is selected from the group consisting of item 3 (drinking from a glass), item 4 (hygiene), item 5 (dressing), item 6 (pouring), item 7 (carrying), item 8 (using a key), item 9 (writing), and item 11 (global impairment).

[0083] In some embodiments, the TETRAS performance score includes the mADL11 subscore, wherein the subject's mADL11 subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, or at least about 10 points after administration of a compound of Formula (I) compared to the subject's mADL11 subscore before administration of a compound of Formula (I). In some embodiments, the mADL11 subscore is reduced by at least about 2 points after at least 8 weeks of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the mADL11 subscore is reduced by at least about 2.5 points after at least 8 weeks of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, a method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, such as essential tremor, in a subject in need thereof may result in a change, such as a decrease, in the subject's TETRAS performance score. In some embodiments, a method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, such as essential tremor, in a subject in need thereof may result in a change, such as a decrease, in the subject's ADL performance subscore score. In some embodiments, a method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, such as essential tremor, in a subject in need thereof may result in a change, such as a decrease, in the subject's TETRAS-mADL performance subscore. In some embodiments, methods of treating a disease or condition associated with abnormal T-type calcium channel function or activity, such as essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points in the TETRAS-mADL performance subscore. In some embodiments, methods of treating a disease or condition associated with abnormal T-type calcium channel function or activity, such as essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of 2 or more points in the subject's TETRAS-mADL performance subscore.In some embodiments, a method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, such as, for example, essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points in a score on the TETRAS-mADL performance subscore when administered once daily at a dose of about 60 mg after an initial titration period.

[0085] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the context of this disclosure, is administered to a subject in need thereof for at least 8 weeks, at least 12 weeks, at least 14 weeks, at least 52 weeks, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or at least 10 years.

[0086] In some embodiments, the method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, e.g., essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of 2 or more points in the subject's score on the TETRAS-mADL performance subscore when administered at a dose of about 60 mg once daily after an initial titration period.

[0087] In some embodiments, a method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, e.g., essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of 2 or more points in the subject's score on the mADL11 performance subscore when administered at a dose of about 60 mg once daily after an initial titration period.

[0088] In some embodiments, a method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, e.g., essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the subject's score on the TETRAS-mADL performance subscore when administered at a dose of about 100 mg once daily after an initial titration period.

[0089] In some embodiments, the method of treating a disease or condition associated with abnormal function or activity of T-type calcium channels, e.g., essential tremor, in a subject in need thereof may result in a change, e.g., a decrease, of 2 or more points in the subject's score on the TETRAS-mADL performance subscore when administered at a dose of about 100 mg once daily after an initial titration period.

[0090] In various aspects, the methods disclosed herein result in an EEG sigma band reduction in a subject, such as an NREM sigma band reduction of about 0.4 to 0.7, such as about 0.5 to about 0.6, or about 0.5, from baseline during NREM sleep. In certain embodiments, the methods disclosed herein result in an EEG gamma band reduction, such as a gamma band reduction of at least about 25%, such as about a 50% reduction, compared to the baseline gamma band during wakefulness in an EO or EC state in the subject.

[0091] In certain embodiments, the methods disclosed herein produce an EEG sigma frequency reduction during NREM sleep and / or an EEG gamma band reduction during EO or EC states in a subject when the subject is administered a dosage of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that produces a Cmax of about 30 ng / mL to about 470 ng / mL, such as a Cmax in the range of about 30 ng / mL to about 50 ng / mL, about 80 ng / mL to about 130 ng / mL, about 130 ng / mL to about 222 ng / mL, about 180 ng / mL to about 300 ng / mL, about 230 ng / mL to 380 ng / mL, or about 280 ng / mL to about 470 ng / mL. In certain embodiments, the methods disclosed herein produce an EEG sigma frequency reduction during NREM sleep and / or an EEG gamma band reduction during EO or EC states in a subject when the subject is administered a dosage of a compound of Formula (I) or a pharmaceutically acceptable salt thereof that produces an AUC24 in the range of about 490 ng*hr / mL to about 5800 ng*hr / mL, such as an AUC24 in the range of about 490-820 ng*hr / mL, about 1220-2030 ng*hr / mL, about 2000-3330 ng*hr / mL, about 2440-4070 ng*hr / mL, about 2820-4700 ng*hr / mL, or about 3480-5800 ng*hr / mL.

[0092] In certain embodiments, the methods disclosed herein produce NREM sigma frequency reduction in a subject when the subject is administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a dosage amount that results in a Cmax of about 5 ng / mL to about 470 ng / mL, such as a Cmax of about 180 to about 300 ng / mL. In certain embodiments, the methods disclosed herein produce NREM sigma frequency reduction in a subject when the subject is administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a dosage amount that results in an average plasma concentration (Cave) of about 10 ng / mL to about 200 ng / mL, such as a Cave of about 12 to about 150 ng / mL, during EEG recording (i.e., over a period of about 24 hours). In certain embodiments, the methods disclosed herein produce EO or EC gamma band reduction in a subject when the subject is administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof in a dosage amount that results in a Cmax of about 280 to about 470 ng / mL. In certain embodiments, the methods disclosed herein result in EO or EC gamma-band reduction in a subject when the subject is administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof at a dosage that results in a plasma concentration of about 75 ng / ml to about 310 ng / mL, such as a plasma concentration of about 90 to about 190 ng / mL.

[0093] In certain aspects of all embodiments of the titration administration schedules disclosed herein, the maximum set dose can be increased, including, for example, increasing the maximum set dose above 120 mg in one or more additional titration steps, provided that the subject can safely tolerate the higher dose.

[0094] In certain aspects of all of the embodiments of the titrated administration schedules disclosed herein, the maximum titrated dose achieved is greater than 20 mg, greater than 40 mg, for example, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, or about 220 mg. In certain aspects of the present disclosure, the maximum dose for a subject is, for example, 40 mg, 60 mg, or 80 mg, if the subject achieves the desired therapeutic outcome.

[0095] In certain aspects of all embodiments of the set dosing schedules disclosed herein, the maximum set dosage reaches 42 days or less, such as 31 days or less, 28 days or less, 18 days or less, 10 days or less, or 7 days or less. In certain embodiments, the maximum set dosage reaches about 10 to about 42 days, such as, for example, about 36-42 days, about 22-28 days, about 16-18 days, about 10-12 days, or about 7-10 days.

[0096] Dosage Forms and Compositions In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as a compound of formula (II), may be administered as part of a dosage form or in a pharmaceutical composition.

[0097] In some embodiments, the composition that can be used in the methods described herein can be 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 can be a swellable core technology formulation.

[0098] In certain embodiments, a dosage form that can be used in the methods described herein can be 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 release-modifying polymer (e.g., a controlled-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)).

[0099] In other embodiments, a dosage form that can be used in the methods described herein can be a dosage form or composition that includes 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 controlled 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.

[0100] In some embodiments, the dosage form comprises about 0.9% to about 40% by weight (e.g., about 0.9% to about 30% by weight, about 1% to about 25% by weight, about 2% to about 25% by weight, about 3% to about 20% by weight, about 4% to about 20% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, or about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% by weight, or about 10% by weight. %, 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 a 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 30% to about 40% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0101] 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)).

[0102] In other embodiments, a dosage form that can be used in the methods described herein comprises about 1 mg to about 120 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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg) of 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 controlled 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) 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.

[0103] In other embodiments, the dosage form contains 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)). In certain embodiments, the dosage form contains 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)). In some embodiments, the dosage form contains about 5 mg to about 15 mg (e.g., about 10 mg) 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 contains about 25 mg to about 35 mg (e.g., about 30 mg) of the 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 the 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 45 mg to about 55 mg (e.g., about 50 mg) 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 55 mg to about 65 mg (e.g., about 60 mg) 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 contains about 65 mg to about 75 mg (e.g., about 70 mg) of the 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 75 mg to about 85 mg (e.g., about 80 mg) of the 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 85 mg to about 95 mg (e.g., about 90 mg) 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 95 mg to about 105 mg (e.g., about 100 mg) 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 contains about 105 mg to about 115 mg (e.g., about 110 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).In certain embodiments, the dosage form comprises about 115 mg to about 125 mg (e.g., about 120 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0104] In some embodiments, the dosage form comprises about 55 mg to 65 mg of a release-modifying polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 10% to about 70% by weight of a release-modifying polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 50% to about 60% by weight of a release-modifying polymer (e.g., an HPMC polymer).

[0105] 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, about 25% to about 30% by weight, about 30% to about 35% by weight).

[0106] In some embodiments, the dosage form further comprises a glidant. In some embodiments, the glidant 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.

[0107] In some embodiments, about 80% of the compound of Formula (I) or pharmaceutically acceptable salt thereof is released within 7 hours upon administration to a subject. In certain embodiments, about 80% of the compound of Formula (I) or pharmaceutically acceptable salt thereof is released in 7 hours using USP Apparatus Type I, medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

[0108] In some embodiments, the dosage form, upon administration to a subject, has a lower Cmax value than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a modified release rate profile, a dosage form without a modified release rate profile, e.g., an HPMC polymer). In some embodiments, the dosage form, upon administration to a subject, has a higher tmax value 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, e.g., an HPMC polymer).

[0109] In some embodiments, the dosage form is administered to a patient once daily. In certain embodiments, the dosage form is administered to a patient twice daily. 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.

[0110] In some embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form (e.g., microparticles) 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.

[0111] In other embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form (e.g., microparticles) 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.

[0112] In certain embodiments, a dosage form that can be used in the methods described herein can be an oral dosage form (e.g., microparticles) 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.

[0113] In some embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form (e.g., microparticles) 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.

[0114] In other embodiments, a dosage form that can be used in the methods described herein can be 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 release-modifying polymer (e.g., a release-controlling polymer, e.g., an HPMC polymer as the hydrophilic matrix polymer).

[0115] 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 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 5% to about 6% 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 9% to about 10% by weight of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0116] In some embodiments, the composition comprises about 1 mg to 120 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, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 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 other embodiments, 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)). In certain embodiments, the composition comprises about 25 mg to about 35 mg (e.g., about 30 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In other embodiments, the composition comprises about 35 mg to about 45 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)). In certain embodiments, the composition comprises about 45 mg to about 55 mg (e.g., about 50 mg) 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 55 mg to about 65 mg (e.g., about 60 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In other embodiments, the composition comprises about 65 mg to about 75 mg (e.g., about 70 mg) 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 75 mg to about 85 mg (e.g., about 80 mg) 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 85 mg to about 95 mg (e.g., about 90 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II)).In some embodiments, the composition comprises about 95 mg to about 105 mg (e.g., about 100 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In other embodiments, the composition comprises about 105 mg to about 115 mg (e.g., about 110 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)). In certain embodiments, the composition comprises about 115 mg to about 125 mg (e.g., about 120 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)).

[0117] 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 about 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).

[0118] 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 glidant. In some embodiments, the glidant 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. In some embodiments, the compound of Formula (I) or (II), including, for example, compound Form C or Form B, is stable in the formulation at about 25°C and 60% relative humidity for at least 24 months. In some embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 36 months. In some embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 60 months. In some embodiments, the compounds are stable at about 40° C. and 75% relative humidity for at least 6 months.

[0119] In other embodiments of the oral dosage forms or oral 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, such as, for example, crystalline form C or crystalline form B. In other embodiments, the crystalline form is crystalline form D. In certain embodiments, the crystalline form is a crystalline form previously or contemporaneously described, such as, for example, crystalline pattern B, crystalline pattern C, or crystalline pattern D. Crystalline pattern B and crystalline pattern C are described, for example, in WO 2021 / 007487, which is incorporated herein by reference in its entirety. Crystalline pattern D is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group consisting of a peak at about 12.0°, a peak at about 15.6°, a peak at about 16.7°, a peak at about 19.8°, a peak at about 21.2°, a peak at about 24.1°, a peak at about 25.2°, a peak at about 27.3°, and a peak at about 30.2°.

[0120] Crystalline forms of the compound of formula (II) The crystalline form of the compound of formula (II) used in the methods described herein may exhibit an X-ray powder diffraction (XRPD) pattern comprising at least one peak selected from the peaks at the following diffraction angles (2θ): 26.6±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, 11.5±0.2, 23.9±0.2, 18.3±0.2, 19.2±0.2, 18.5±0.2, or 20.0±0.2. In certain embodiments, the crystalline form of the compound of formula (II) disclosed herein may exhibit an XRPD pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2, and 26.6±0.2.

[0121] In some embodiments, the crystalline form exhibits an XRPD 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 some embodiments, the crystalline form exhibits an XRPD 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 some embodiments, the XRPD pattern was obtained using Cu Kα radiation. In certain embodiments, the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 226.6°C.

[0122] The crystalline form of the compound of formula (II) used in the methods described herein may exhibit an XRPD pattern comprising at least one peak selected from the 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, or 21.2±0.2. In certain embodiments, the crystalline form of the compound of formula (II) disclosed herein may exhibit an XRPD pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, and 17.8±0.2.

[0123] In some embodiments, the crystalline form exhibits an XRPD 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 some embodiments, the crystalline form exhibits an XRPD 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 some embodiments, the powder XRPD was obtained using Cu Kα radiation. In certain embodiments, the crystalline form has an onset of melting as determined by differential scanning calorimetry at about 97.9°C, 131.6°C, 223.7°C, 83.8°C, 128.9°C, 168.9°C, or 224.4°C.

[0124] Immediate-release formulations In some embodiments, a dosage form or composition that can be used in the methods described herein can be a dosage form or composition that includes 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 after administration to a subject.

[0125] In other embodiments, a dosage form that can be used in the methods described herein may be 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)), about 75 mg to 85 mg of a diluent, about 2 mg to 10 mg of a binder, about 1% to about 5% of a disintegrant, and about 0.1 mg to 5 mg of a lubricant.

[0126] Administration In some embodiments, the dosage form is administered to a subject more than once a day (eg, twice a day, three times a day, or four times a day).

[0127] In some embodiments, the dosage form is administered to a subject once daily (e.g., one 20 mg tablet once daily, two 20 mg tablets (or one 40 mg tablet) once daily, or three 20 mg tablets (or one 60 mg tablet) once daily). In some embodiments, the dosage form is administered to a subject twice daily (e.g., one 10 mg tablet twice daily, one 20 mg tablet twice daily, two 20 mg tablets twice daily, or three 20 mg tablets twice daily). In some embodiments, the dosage form is administered to a subject every other day, twice weekly, or once weekly. In certain embodiments, a dose of about 1 mg to 60 mg, e.g., 20 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, a dose of about 15 mg to 25 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. In certain embodiments, a dose of about 30 mg to 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.

[0128] In some embodiments, the dosage form has a lower Cmax value when administered to a subject compared to a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a modified release rate profile, a dosage form without a modified release rate profile, e.g., an HPMC polymer). In some embodiments, the dosage form has a higher tmax value when administered to a subject compared to a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., a modified release rate profile, a dosage form without a modified release rate profile, e.g., an HPMC polymer).

[0129] 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, using the medications or compositions disclosed herein. Tremors include hereditary, degenerative, and idiopathic disorders such as Wilson's disease (hereditary), Parkinson's disease (degenerative), and essential tremor (idiopathic), metabolic diseases, peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes, and complex regional pain syndrome), toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene), drug-induced (tricyclic neuroleptics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine), and psychogenic disorders. Clinical tremor can be neuropathic tremor, and can be classified into physiological tremor, strong physiological tremor, essential tremor syndrome (including classic essential tremor), primary orthostatic tremor, task-specific and position-specific tremor, dystonic tremor, Parkinsonism tremor, cerebellar tremor, Holmes tremor (i.e., Rubral tremor), palatal tremor, tremor induced by toxins or drugs, and psychogenic tremor. Tremor can also be familial tremor.

[0130] Tremor is an involuntary, rhythmic vibration of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0131] 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 of the cerebellum or pathway, such as tumor, stroke or other focal lesion disease (such as multiple sclerosis), or neurodegenerative disease.

[0132] Dystonic tremor occurs in individuals with dystonia, and is 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 certain sensory manipulations.

[0133] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor may be mild and non-progressive in some cases, or it may progress slowly, beginning on one side of the body and often affecting both sides. Essential tremor may also be moderate or severe. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease with age, but the severity may increase. Emotions, stress, fever, other illnesses, physical exhaustion, or increased hypoglycemia may trigger tremors and / or increase their severity. Symptoms generally progress over time and may be visible and persistent after onset.

[0134] 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.

[0135] Parkinsonism tremor is caused by damage to structures in the brain that control movement. Parkinsonism 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 Parkinsonism tremor usually begins after the age of 60. The movement may begin in one leg or one side of the body and progress to involve the other side.

[0136] Rubral tremor is characterized by a coarse, 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.

[0137] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor. In certain embodiments, the tremor is essential tremor. In various embodiments, essential tremor is accompanied or not by intention tremor. In certain embodiments, essential tremor is not accompanied by intention tremor.

[0138] The effectiveness of the compounds or compositions described herein for treating essential tremor can be measured by methods known in the art, such as those described in the following references: Ferreira, JJ et al., "MDS Evidence-Based Review of Treatments for Essential Tremor," Mov. Disord. 2019 Jul; 34(7): 950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor," Mov. Disord. 2013 Nov; 28(13): 1793-800; Deuschl G. et al., "Treatment of patients with essential tremor," Lancet Neurol. 2011; 10: 148-61; and Reich SGet al., "Essential Tremor," Med. Clin. N. Am. 2019; 103: 351-356. The disclosures of the references are incorporated herein in their entireties.

[0139] In some embodiments, the methods described herein result in at least a 25% reduction in upper extremity tremor score, which may be converted to amplitude, compared to baseline. For example, in certain embodiments, the methods described herein result in an average reduction of about 40% in tremor amplitude as measured by the Essential Tremor Rating Scale (TETRAS) upper extremity score, e.g., as described in Elble, RJ, "The Essential Tremor Rating Assessment Scale," J. Neurol. Neuromed. 2016;1(4):34-38. In some embodiments, the methods described herein result in at least a 25% reduction in TETRAS performance score compared to baseline. In some embodiments, the methods described herein result in an average reduction of at least a 35% reduction in symptom severity, as measured by TETRAS performance score, compared to baseline.

[0140] Combination therapy In the context of the present disclosure, the compound of formula (I) or its pharmaceutically acceptable salt may be administered in combination with one or more other agents or treatments.For example, the compound of formula (I) or its pharmaceutically acceptable salt may be administered to a subject in combination with one or more tremor medications.In the context of the present disclosure, examples of tremor medications that can be administered in combination with the compound of formula (I) or its pharmaceutically acceptable salt 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. In one embodiment, the tremor medication is propranolol. In another embodiment, the tremor medication is primidone.

[0141] In some embodiments, 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]

[0142] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as in any way limiting the scope thereof.

[0143] Example 1: Phase 2 study evaluating the efficacy of the compound of formula (I) in treating adults with essential tremor This is a Phase 2 study comparing Compound 1 with placebo to evaluate the efficacy and safety / tolerability of doses of 60 mg or 100 mg in participants with moderate-to-severe ET. ET severity was defined by the eligibility criteria of the TETRAS-ADL, CGI-S, and TETRAS-PS items 6 and 7. This dose-ranging study consists of three parts. Part 1 is randomized, double-blind (DB), and placebo-controlled. Part 2 is an optional extension consisting of an Extension DB Lead-in Period followed by an Extension Open-label (OL) Period. There is also a third part available to completers at the 99th visit. Part 3 consists of a 6-week re-randomization, blinded crossover period (referred to as the crossover period), after which all completers receive Formula (I) in an open-label setting. In the first part of the study, eligible participants were randomized to one of two dose levels of Compound 1 (60 mg or 100 mg) or placebo. The primary objective of the study was to evaluate the efficacy of Compound 1 administration compared to placebo in participants with ET and moderate to severe tremor after 56 days (end of the randomized, DB, and placebo-controlled portions) using a modified ADL. Secondary and exploratory objectives included further efficacy evaluation, safety and tolerability assessment, and determination of plasma concentrations of Formula (I) and its metabolites. The Phase 2 study design is shown in Figure 1. [Table 14-1] [Table 14-2]

[0144] Participants who continued to meet all clinical trial entry criteria on Day 1 were randomized to receive DB treatment with Compound 1 or placebo every morning (QAM) from Day 1 through Day 56. Participants were randomized in a 1:1:1 ratio to one of two fixed-dose regimens or placebo. No dose adjustments were allowed. [Table 1] [Table 2-1] [Table 2-2] [Table 3]

[0145] Throughout the intervention period (Days 1–56), participants who chose or were forced to discontinue treatment entered a safety follow-up period. All participants, except those who chose to enroll in the optional extension period of the study, were asked to return to the clinic for a safety follow-up visit 14 days after their last dose of study drug (see below).

[0146] On Day 1, participants received six tablets of study drug via QAM, and the TETRAS-PS, TETRAS-ADL, and CGI-S were administered pre-administration. Additional assessments, including pharmacokinetic (PK) sampling, were performed pre-administration.

[0147] Participants continued to take six tablets of study medication QAM throughout the DB period of the study.

[0148] Participants returned to the clinic for PK sampling, dosing, and efficacy and safety assessments on days 14, 28, 42, and 56. Primary efficacy assessments at these visits included the TETRAS-PS, TETRAS-ADL, CGI-S, CGI-I, and PGI C.

[0149] On days 7, 21, 35, and 54, participants received a telephone call from site staff inquiring about AEs and changes in concomitant medications.

[0150] After completing the DB period of the study, participants could choose to participate in the extension period. Participants who elected to participate in the extension period began receiving the OL study drug for up to 12 months, either at the beginning of the crossover period or after the 43-day extended DB lead-in period, whichever came first. During this extended DB lead-in period, participants who received placebo or 60 mg in the DB period of the study were dose-titrated up to 100 mg in a DB manner using the same titration regimen as in the DB period of the study. Participants who received 100 mg in the DB period of the study continued to receive 100 mg in a blinded manner until all participants had received Compound 1 100 mg QAM at Day 99. During the extended DB lead-in period, participants who were unable to tolerate the fixed dose escalation to 100 mg were asked to discontinue the study and participate in the safety follow-up / EOS-E visit. After the extended DB lead-in period, participants received Compound 1 (20–100 mg) QAM at the investigator's discretion during the extended OL period until the start of the crossover period. Participants who agreed to participate in the individual LTSS were able to terminate their participation in the study after completing the end-of-treatment visit and participate in the LTSS at any time during the extended OL period.

[0151] Participants who elected not to continue in the extension proceeded directly to the safety follow-up period from Day 57 to Day 70. The safety follow-up period lasted 14 days for participants in the DB period of the study and up to 14 days after the last dose of Compound 1 for participants in the extension period of the study. Participants in the extension period of the study who could not tolerate the set dose of the extended DB lead-in period were discontinued from the clinical trial to maintain the blinding of this extended DB lead-in period and completed the safety follow-up visit.

[0152] Compound 1 was provided as 5 mg and 20 mg modified-release tablets. A matching placebo was also provided. Compound 1 was provided to participants in prepackaged containers and administered orally QAM with or without food. During the blinded lead-in period of the DB and extension periods of the study, participants receiving Compound 1 received six tablets (a combination of Compound 1 and matching placebo tablets depending on their assigned dose level). Participants in the placebo group received six matching placebo tablets. At the Day 1 / Baseline study visit, study drug was dispensed via Interactive Response Technology (IRT), and in-clinic administration was administered from Kit A at the visit on Day 1. At subsequent study visits, in-clinic administration was the last dose drawn from Wallet Card B dispensed at the previous study visit.

[0153] Compound 1 (20 mg strength) was provided to participants in OL bottles at the Day 99 visit, so that open-label administration could begin the following day (Day 100), beginning the extension open-label period. Tablet volume varied depending on the dose level and formulation used.

[0154] At the re-randomization visit during the crossover period, and every 7 days during that period, treatment regimens were assigned by the IRT and dispensed by the site pharmacist for direct-to-patient (DTP) delivery. During the crossover period of the study, all participants were centrally assigned and randomized using the IRT to remain on their current regimen of Compound 1 or placebo. After 3 weeks, participants receiving placebo were switched to Compound 1 according to the regimens described in Table 3. The IRT assigned treatment regimens based on Tetras ADL response criteria after day 7.

[0155] During the DB period of the study, eligible participants were randomized to receive one of two Compound 1 dosing regimens (60 mg or 100 mg) or placebo, administered orally QAM. A fixed-dose regimen was used (Table 1). Participants were not allowed to adjust the number of tablets taken per day.

[0156] All participants who continue into the extension period of the study will participate in a 43-day extended DB lead-in period, during which they may be dose-titrated to the 100 mg dose in a blinded manner before receiving open-label Compound 1 (20–100 mg) flexibly for up to 12 months (days 100–459) during the extension OL period (Table 2).

[0157] Selected items from the TETRAS-ADL and TETRAS-PS (or TETRAS-CUL, as appropriate) were scored in a modified format and combined to generate a modified TETRAS total score. Items 1–11 of the TETRAS ADL subscale and items 6 and 7 of the TETRAS-PS were used to adjust the scores so that response choices of 0 and 1 were combined into a single response, with 0 = normal. Additionally, scores of 2, 3, and 4 were adjusted to 1, 2, and 3, respectively. The total TETRAS modified score is the sum of these adjusted TETRAS-ADL and TETRAS-PS items and can range from 0 to 42. Higher scores represent an increased direct impact of tremor on activities of daily living. Items included in the total TETRAS modified score are shown in Figure 2.

[0158] result Compound 1 was well tolerated in this study, with no new safety findings. The majority of TEAEs were mild to moderate in severity, consistent with previous findings. The proportion of subjects who discontinued in the Compound 1 group was high: 17% compared with 11% in the placebo group. Figure 3 is a schematic diagram of patient status in the clinical trial. Figure 4 is a table showing patient demographics and baseline characteristics (mITT). Figure 5 is a table showing TEAS experienced by patients in the clinical trial. Figure 6 is a table showing TEAEs and dose at the time of event occurrence. Figure 7 is a table showing discontinuation of Compound 1 in the mITT patient population.

[0159] The primary efficacy measure in this clinical trial was the change from baseline in mADL at day 56. The effect of ulixacultamide on individual mADL items was determined by calculating the placebo-adjusted fold change for each mADL item in mADL at day 56. Secondary efficacy measures included changes in Clinical Global Impression-Severity (CGI-S) score, Patient Global Impression-Change (PGI-C) score, TETRAS-ADL total score, TETRAS-UL score, TETRAS-CUL score, and TETRAS-PS score.

[0160] Figure 8 is a bar graph showing the change in mADL and ADL scores in the mITT population treated with Compound 1 (ulixacultamide) and placebo. As shown in Figure 8, Compound 1 demonstrated a numerical difference compared to placebo in mADL, with a mean difference in LS of 1.57 and p = 0.126. Participants treated with Compound 1 demonstrated a mean improvement from baseline in ADL scores, with a mean decrease of 3.6 points compared to baseline at day 56 (n = 78), and clinical and statistical differences from the placebo group (n = 38) (p -0.026). The modified ADL scores in participants treated with Compound 1 (mean decrease of 2.69 points, n = 78) also demonstrated improvement compared to placebo (mean decrease of 0.88 points, n = 38). The change in the secondary endpoint, TETRAS-ADL, achieved nominal statistical significance (mean difference in LS of 2.53 and p = 0.026).

[0161] Figure 9 is a bar graph showing the change in mADL score for patients taking ulixacultamide (Compound 1) or placebo at day 56. Figure 9 shows that more patients taking ulixacultamide showed improvement in mADL score compared to patients taking placebo.

[0162] Figure 10 is a schematic diagram showing the observed changes compared to baseline in scores for individual items assessed as part of the mADL and ADL assessments. Figure 11 is a bar graph showing the fold change at day 56, adjusted for placebo change, for individual items assessed as part of the mADL assessment. As shown in Figures 10 and 11, patients showed improvement in almost all components of the ADL assessment, but little or no improvement in the additional components added to the mADL assessment. Urixacultamide demonstrated consistent effects compared to placebo for 8 of the 11 scored ADL items. Patients treated with ulixacultamide showed less improvement than patients receiving placebo for the TETRAS PS items, dominant-hand handwriting, and left- and right-hand spirals.

[0163] Figure 12 shows a graph depicting the status of patients in the mITT population, as measured using the PGI-C and CGI-S scales. As shown in Figure 12, patients and investigators reported a greater overall improvement with Compound 1 compared to placebo, using the PGI-C scale (47% improvement) and the CGI-S scale (42% improvement). Nominal and statistically significant improvements were observed in the PGI-C and CGI-S.

[0164] To assess the correlation between different assessment items in this study, Pearson's correlations were calculated for the changes from baseline in ADL scores, PS scores, and other measures. The change from baseline in the total score for subjects in the placebo group was used to calculate r values ​​for the five assessments shown. Figure 13 is a schematic diagram showing the results of Pearson's correlation assessments for the changes from baseline in ADL and PS scores and other measures. The results shown in Figure 13 are consistent with the pattern of clinical discrepancy between ADL and PS assessments. ADL did not correlate with PS item 4 or total PS. Interestingly, ADL correlated more strongly with patient-reported status than PS. PS assessment correlated more strongly with clinician-reported status than ADL.

[0165] Figure 14 is a bar graph showing the change in mADL score at day 56 for each patient receiving ulixacultamide or placebo when the PS items (spiral-left and right, and handwriting) were excluded from the assessment. The data from Figure 8 are also included in Figure 14 for comparison. As shown in Figure 14, in a post-hoc analysis, when the PS items were excluded from the mADL, ulixacultamide demonstrated a nominally statistically significant improvement over placebo at day 56 (mITT) [LS mean difference 1.81 and p=0.042].

[0166] In a post-hoc responder analysis using the minimal clinically important difference distribution method, for the mITT population, patients taking ulixacultamide were determined to have a higher response rate for mADL and mADL excluding PS items compared with placebo patients. Considering a 0.5 SD threshold, more than 50% of participants treated with ulixacultamide had an improvement of at least 2 points in their total score. When a more stringent threshold of 1 SD was used, approximately 40% of subjects treated with ulixacultamide had an improvement of at least 4 points in their total score.

[0167] Figure 15 is a graph showing the change in mADL score and mADL score excluding PS (mADL11) at each scored time point. Figure 15 shows the improvement in both mADL score and mADL score excluding PS (mADL11) score comparing ulixacultamide with placebo after 14 days.

[0168] FIG. 16 is a graph and table showing the endpoint analysis of the mITT population.

[0169] Figure 17 is a bar graph showing the results of a post-hoc responder analysis using the MCID distribution method in the mITT population. The results shown in Figure 17 show that patients taking ulixacultamide had a higher response rate compared to patients taking placebo, as assessed by mADL score and mADL score excluding PS items.

[0170] The patients who participated in the clinical trial included patients with intention tremor.The effect of ulixacultamide on the patient population without intention tremor was analyzed. Figure 18 is a bar graph showing the mADL score and the mADL score excluding PS in the mITT population excluding patients with intention tremor. Figure 19 is a schematic diagram showing the observed changes from baseline in the scores of individual items examined as part of mADL assessment in patients without intention tremor. Figures 18 and 19 show that ET patients without intention tremor show greater improvements from baseline in mADL scoring items.

[0171] Figure 20 is a bar graph showing the change in placebo-adjusted PS-excluded mADL score in mITT patients without intention tremor for the two tested dosing regimens (60 mg and 100 mg). Figure 20 shows that consistent effects were observed for both tested dosing regimens in mITT patients without intention tremor.

[0172] Ulixacultamide also showed benefit in patients on propranolol: Specifically, in this phase 2 study, 48% of patients on propranolol and ulixacultamide achieved an improvement of at least 3 points in mADL11, compared with 25% of patients on propranolol and placebo.

[0173] First, the modified TETRAS ADL items 1-11 (mADL11), which excludes the performance subscale (PS), were identified as a robust and clinically meaningful measure of treatment effectiveness in ET. For example, distribution and anchor-based analysis methods confirmed that a meaningful score difference (MSD) of approximately 2 points or more on the mADL11 is an indicator of effective treatment of ET for patients.

[0174] Example 2. Open-label extension of a Phase 2 study After completing the initial 8-week double-blind treatment phase of the Phase 2 study described in Example 1, eligible patients had the option to continue access to Compound 1 in an open-label extension (OLE) phase. Participants who continued into the open-label extension (OLE) phase remained blinded during a six-week lead-in phase.

[0175] In the extension period of the study, efficacy measures will include analysis of changes from baseline to days 70, 84, 99, 129, 159, 189, 279, 369, and 459 in the modified ADL, CGI-S, TETRAS ADL total score, TETRAS-PS total score, TETRAS UL score, TETRAS CUL score, and analysis of CGI-I and PGI-C scores at days 70, 84, 99, 129, 159, 189, 279, 369, and 459.

[0176] Overall safety outcomes remained unchanged through 14 weeks of treatment with Compound 1.

[0177] A total of 65 patients who completed the double-blind portion of the Phase 2 study described in Example 1 were eligible, participated in the OLE, and completed the Week 14 assessment. Figure 21 is a bar graph showing the change from baseline in mADL11 scores by study week from Week 8 through Week 14. Patients who were eligible and continued on Compound 1 (n=39) had a mean improvement of an additional 1.7 points in mADL11, from 3.09 points (95% CI: 0.98, 5.2) at Week 8 to 4.81 (95% CI: 2.38, 7.23) after 14 weeks of treatment. Patients (n=26) who switched from placebo to Compound 1 treatment during the 6-week lead-in had a mean improvement of 3.15 points in mADL11, from 1.21 (95% CI: -1.04, 3.46) at week 8 to 4.36 (95% CI: 1.68, 7.05).

[0178] Randomized withdrawal sub-study The open-label protocol was modified to further evaluate the criteria to be used in the upcoming Phase 3 randomized washout study (described in Example 3). In this substudy, patients were blinded and re-randomized to receive either placebo or continued treatment with Compound 1. Twenty-one patients who completed the 14-week evaluation of the open-label extension period were eligible to participate in the blinded substudy.

[0179] Patients were assessed weekly for a total of 6 weeks, with 11 patients assigned to Compound 1 and 10 patients assigned to placebo for the first 3 weeks and crossed over to either placebo or Compound 1 for the following 3 weeks. Blinded rescue was induced for placebo patients if the mADL11 decline exceeded 2 points at any time point.

[0180] Patients who switched from Compound 1 to placebo experienced a 47% mean decrease in effect per week in mADL11 (mean decrease in effect, -1.15 points / week), compared with a 6% improvement in overall mean change per week (mean improvement, 0.16 points / week) during the period receiving Compound 1. Additionally, 10 patients assigned to placebo met rescue criteria to restart Compound 1.

[0181] Eighty-five percent (17 of 20) of patients receiving Compound 1 and 52% of patients receiving placebo maintained mADL11 within 3 points compared to baseline, confirming the patient stability definition used in the Phase 3 program. No new safety signals emerged, and there was no change in the overall safety outcomes observed during the 8-week double-blind treatment phase.

[0182] Results from the substudy supported several proposed design elements for a future phase 3 randomized withdrawal study, including responder criteria and the feasibility of patient rescue with Compound 1.

[0183] Example 3. Phase 3 study evaluating the efficacy of the compound of formula (1) in treating adults with essential tremor overview This Phase 3 study is a three-part, randomized, double-blind, placebo-controlled, fixed-dose (post-titration) study comparing the efficacy and safety of Compound 1 with placebo in participants aged 18 to 80 years with a diagnosis of ET. The primary objective of the parallel design (PD) of Study 1 is to evaluate the change from baseline in mADL11 scores with Compound 1 compared with placebo after 12 weeks (84 days) of treatment. The primary objective of the randomized withdrawal (RW) of Study 2 is to evaluate maintenance of response by measuring the proportion of participants who maintain response after RW. Other efficacy assessments in Studies 1 and 2 include Clinical Global Impression-Severity (CGI-S), Patient Global Impression-Severity (PGI-S), Patient Global Impression-Change (PGI-C), and Archimedes spiral drawing. The primary objective of the long-term safety study (LTSS) of Study 3 is to evaluate the long-term safety of Compound 1 treatment for up to approximately 1 year. The safety and tolerability of Compound 1 will be evaluated across all three studies.

[0184] This is a decentralized Phase 3 clinical trial utilizing a combination of in-home and telehealth visits. It consists of three concurrent studies, including a randomized, DB, placebo-controlled PD study, a DB RW study, and an LTSS study. The research in this study is designed to evaluate the efficacy and / or safety of Compound 1 in participants aged 18-80 years who have been diagnosed with ET and have been symptomatic for at least three years. Participants in Study 1 PD and Study 2 RW will be informed about all three studies and, if deemed eligible, will be assigned to either Study 1 PD or Study 2 RW and must agree during informed consent to be transferred to Study 3 LTSS. For Phase 2 OLE participants, a specific informed consent form (ICF) will be used to transfer to Study 3 LTSS. In Study 1 PD, participants will receive either Compound 1 or a matching placebo in a DB fashion for 12 weeks (84 days). In Study 2 RW, participants will receive Compound 1 DB for 8 weeks (56 days), followed by a 4-week DB RW period. Responders will receive RW, while non-responders will continue Compound 1 treatment. Responder participants in the RW period who meet the defined relapse criteria will then be rolled over to Study 3 LTSS with blinded dose titration as described in Table 6. In Study 3 LTSS, participants will receive Compound 1 for up to approximately one year, including any prior study drug exposure.

[0185] Compound 1 will be titrated to 60 mg over 2 weeks (Table 8). After the baseline visit, participants will receive either Compound 1 or placebo at home every morning (QAM) before scheduled home or telehealth visits, as needed. Dose adjustments will not be permitted. Participants who completed Study 1 PD or Study 2 RW (completed all assessments through Day 84), met defined relapse criteria in Study 2 RW, or completed the Phase 2 EOT visit may be carried over into Study 3 LTSS, and their Day 84 assessment will also be carried over from their respective studies.

[0186] The duration of Study 1 PD and Study 2 RW, including the screening period (Table 4) and the treatment and safety follow-up (SFU) period (Tables 5 and 6), can be 18 weeks long. The duration of LTSS is approximately 1 year at most (Table 7).

[0187] FIG. 22 is a schematic showing the Phase 3 study design. [Table 4] [Table 5] [Table 6-1] [Table 6-2] [Table 7]

[0188] Eligible participants will be randomized to receive oral Compound 1 or placebo QAM. A fixed-titration regimen as described in Table 8 will be used.

[0189] No dose adjustments are permitted. [Table 8-1] [Table 8-2]

[0190] The objectives and endpoints of Study 1 PD are described below (Table 9). [Table 9-1] [Table 9-2]

[0191] The objectives and evaluation items of Study 2 RW are described below (Table 10). [Table 10-1] [Table 10-2]

[0192] The objectives and evaluation items of Study 3 LTSS are described below (Table 11). [Table 11]

[0193] Background and Clinical Trial Rationale Compound 1 is a novel small molecule being developed for the treatment of essential tremor (ET). It is a state-dependent, selective inhibitor of T-type calcium ion (Ca2+) channels with high affinity. T-type Ca2+ channels consist of three isoforms (CaV3.1, CaV3.2, and CaV3.3) and are widely expressed in the brain, particularly in the cerebellothalamocortical (CTC) circuit. In ET, abnormal bursts of CTC circuits occur with the same frequency as upper limb tremor.

[0194] ET is the most common adult movement disorder, affecting up to 2% of the United States (US) population, with an estimated true prevalence of 7 million people in the US. ET is characterized by a 6-12 Hz postural and kinetic tremor (i.e., tremor during voluntary movement) in the upper extremities. The most distinctive clinical feature is kinetic tremor in the arms and hands, but as the disease progresses, tremor may also occur in the head and voice, and less commonly, the face, feet, and trunk. Emerging evidence supports the understanding that ET is a heterogeneous syndrome, and diagnosis requires further differentiation based on clinical history and neurological examination.

[0195] ET significantly impacts the daily functioning of some patients, particularly writing and eating and drinking. Functional impairment is reported in over 70% of ET patients and is associated with comorbid anxiety and depression.

[0196] Despite being one of the most common movement disorders, ET is often incompletely treated or neglected, in part due to the limited number of available treatments. Propranolol and primidone are the medications most frequently used to treat ET. Propranolol is the only FDA-approved, orally administered treatment indicated for the treatment of ET. Originally developed and approved in 1967 for hypertension, propranolol was approved for the treatment of ET in 1986 based on a 2-week clinical trial that enrolled only nine patients and evaluated a limited dose range of 40 mg to 80 mg three times daily. As scientific understanding of ET matured and clinical experience with propranolol was gained, it proved to be an inappropriate and poorly tolerated treatment, leaving a significant unmet medical need in patients with ET. Propranolol has demonstrated limited efficacy in the treatment of ET and has side effects (e.g., bradycardia) that often lead to discontinuation. The American Academy of Neurology's 2011 ET treatment guidelines state that not all patients improve or tolerate primidone and propranolol. Our latest data show that for patients receiving drug therapy, more than 40% discontinue all drug treatment options after two years of treatment. Therefore, even though there is at least one approved treatment, the currently available medications for ET do not meet the needs of most patients.

[0197] Results from a phase 2 study with ulixacultamide (see Examples 1 and 2) support the efficacy and safety of ulixacultamide in patients with ET. The phase 2 study demonstrated a reduction in modified ADL (mADL) scores (i.e., a reduction in tremor symptoms) at daily doses ranging from 20 to 120 mg for up to 56 days. In the double-blind (DB) portion of the phase 2 study, after 56 days of treatment, rescored TETRAS-ADL items 1-11 (mADL11) scores were reduced in participants randomized to Compound 1 compared with placebo, with a least-squares mean (LSM standard error [SE]) score of 2.69 [0.81] compared with placebo (-0.87 [0.95]). The treatment difference in LSM (95% confidence interval [CI]) was -1.82 (95% CI: -3.565, -0.066, nominal p-value <0.05). During the phase 2 extension period, 20 participants completed a blinded 6-week crossover period. Participants were blinded and randomized to either Compound 1 60 mg for 3 weeks or placebo. Rescue treatment (Compound 1) was offered to participants if mADL11 worsened to a pre-specified threshold. During the crossover period, sustained response was observed in 17 of 20 participants receiving Compound 1, compared with 11 of 21 participants receiving placebo. When adjusted for propranolol use, family history, and intention tremor (IT), the chi-squared p-values ​​were 0.0249 and 0.0388. Zero participants treated with Compound 1 and 9 of 21 placebo-treated participants were eligible for and received rescue treatment within 3 weeks. No new safety signals were identified during this period of the study.

[0198] Across the clinical development program, Compound 1 was generally well tolerated following daily administration for up to 129 days at doses ranging from 5 to 120 mg, suggesting a favorable safety profile following the titration schedule. No deaths or serious adverse events (SAEs) deemed by the sponsor to be related to the study drug were reported following administration of Compound 1. Similarly, no suicide attempts or pregnancies were reported following administration of Compound 1.

[0199] This Phase 3 study is a three-part, randomized, placebo-controlled, fixed-dose (post-titration) study comparing the efficacy and safety of Compound 1 with placebo in participants aged 18 to 80 years with a diagnosis of ET. The primary objective of the parallel design (PD) of Study 1 is to evaluate the change from baseline in mADL11 scores with Compound 1 compared with placebo after 12 weeks (84 days) of treatment. The primary objective of the randomized withdrawal (RW) of Study 2 is to evaluate maintenance of response by measuring the proportion of participants who maintain response after RW. Other efficacy assessments in Studies 1 and 2 include Clinical Global Impression-Severity (CGI-S), Patient Global Impression-Severity (PGI-S), Patient Global Impression-Change (PGI-C), and Archimedes spiral drawing. The primary objective of the long-term safety study (LTSS) of Study 3 is to evaluate the long-term safety of Compound 1 treatment for up to approximately 1 year. The safety and tolerability of ulixacultamide will be evaluated across all three trials.

[0200] Overall Design This study is a decentralized, Phase 3, multi-study clinical trial evaluating the safety and efficacy of Compound 1 in ET. The study includes two separate, concurrent pivotal Phase 3 studies with all participants undergoing a single screening process. This concurrent study design promotes a more homogenous study population and ensures blinded study assignment and treatment group allocation across Study 1 PD and Study 2 RW, fulfilling objectives that would not be met if Study 2 RW were conducted alone.

[0201] The study consists of three concurrent, decentralized trials, including two pivotal DB placebo-controlled trials and LTSS in patients with ET: Study 1 PD: A 12-week PD, randomized, DB, placebo-controlled study to evaluate the change from baseline in mADL11 score with Compound 1 compared to placebo after 12 weeks (84 days) of treatment. Study 2 RW: A 12-week RW, DB, placebo-controlled study to evaluate efficacy and maintenance of response and durability of effect in participants who responded to Compound 1. Study 3 LTSS: An LTSS to evaluate the long-term safety of Compound 1 for up to approximately 1 year. The first 2 weeks of the LTSS include a 2-week blinded dose-finding period for participants who carry over from Study 1 PD and Study 2 RW to maintain the blinding of these studies. The remainder of the study will be open label. Participants enrolled in the Phase 2 open label extension (OLE) can carry over into Study 3 LTSS to begin a 2-week dose escalation to 60 mg or continue on the 60 mg dose.

[0202] Both pivotal studies will include a screening period, and all three studies will include an intervention period and a safety follow-up period. There will be two types of study visits: home health visits and telehealth visits. Home health visits will be staffed by trained study nurses who will travel to the participant's home. The investigator and / or study staff will participate in the home health visit remotely using audiovisual communication. Telehealth visits are remote audiovisual visits with the investigator and / or study staff. The investigator will oversee all visits. In addition to home health visits and telehealth visits, the study medication will be mailed directly to participants.

[0203] Screening and Baseline Period Key screening assessments included medical history, demographic characteristics, past and current medications, physical and neurological examination, drug / alcohol screening, pregnancy screening, clinical laboratory assessment, electrocardiogram (ECG), vital signs, the Columbia-Suicide Severity Rating Scale (C-SSRS), and assessment of ET severity using the Essential Tremor Rating Scale-Activities of Daily Living (TETRAS-ADL).

[0204] The screening period for participants who have not received Compound 1 will be 28 days. Once all screening assessments have been completed and participants are deemed eligible for the study, randomization will occur between Days -7 and -3 to allow time for the assigned study medication to be mailed to the participant's home.

[0205] Participants will complete the TETRAS-ADL assessment three times during the screening period (days -28, -14, and -7).

[0206] Phase 2 OLE participants are not required to complete this screening process, but investigators must review these participants' most recent safety assessments approximately one week before their first LTSS study visit. If a safety issue is identified, the investigator will review with the sponsor to determine whether the participant is eligible to continue Compound 1 in LTSS. Participants who elect to receive study drug throughout the intervention period in Study 1 PD, Study 2 RW, or Study 3 LTSS, or who must discontinue study drug, must schedule an early discontinuation (ED) visit as soon as possible. After completing Study 1 PD or Study 2 RW, if participants choose not to participate in Study 3 LTSS, they must enter a 14-day safety follow-up period. Participants who discontinue Study 1 PD or Study 2 RW earlier than normal are not eligible for LTSS participation.

[0207] Participants will self-administer either ulixacultamide or placebo at home every morning (QAM) before their scheduled home health visit or telehealth visit, as needed. Primary efficacy assessments will be conducted at select visits based on study assignment and will include the TETRAS-ADL, PGI-C, PGI-S, CGI-S, and Archimedes spiral drawing. Drug concentration samples (Days 56 and 70) will be collected according to the correct collection instructions, and clinical laboratory assessments will be performed simultaneously.

[0208] Test 1 PD All participants who continue to meet all clinical trial enrollment criteria on Day 1 and are assigned to Study 1 PD will receive DB treatment with Compound 1 or placebo using a fixed dosing regimen (after dose titration) from Day 1 through Day 84.

[0209] On the baseline day (Day 1), participants will receive one tablet of study medication during a home health visit, followed by self-administration via QAM from Days 2 through 84. CGI-S, PGI-S, and Archimedes spiral assessments will be performed in that order prior to administration.

[0210] For participants randomized to Compound 1, the titration period will consist of a 20 mg QAM dose during week 1 (days 1-7) and a 40 mg QAM dose during week 2 (days 8-14). On day 15, these participants will enter the maintenance period and receive a 60 mg QAM dose until the end of the intervention period (day 84). No dose adjustments will be allowed.

[0211] Participants who completed Study 1 PD could be carried forward into the ongoing Study 3 LTSS with an 84-day assessment from Study 1 PD.

[0212] Test 2 RW All participants who continue to meet all clinical trial enrollment criteria on Day 1 and are assigned to the Study 2 RW will enter the RW lead-in period.

[0213] RW lead-in period During the RW lead-in period, participants will receive Compound 1 during a home health visit on Day 1 and self-administer from Days 2 through 56. These participants will be blinded to whether they are participating in the main study or Study 1 PD, and will therefore receive Compound 1 in a DB format.

[0214] On Day 1 (baseline), participants will complete the CGI-S, PGI-S, and Archimedes Spiral assessments in that order, followed by administration.

[0215] All participants will undergo a titration period consisting of a 20 mg QAM dose during week 1 (days 1-7) and a 40 mg QAM dose during week 2 (days 8-14). On day 15, these participants will enter a maintenance period where they will receive a 60 mg QAM dose until the end of the intervention period (day 56). No dose adjustments will be allowed.

[0216] RW period Based on pre-specified inclusion criteria, a subset of participants who respond to Compound 1 will be randomized 1:1 in a DB fashion to either continue Compound 1 or receive placebo. No Compound 1 taper is required before initiating placebo. Participants who do not meet these criteria will continue Compound 1 at 60 mg throughout the remainder of the study. Study visits will be conducted weekly throughout the RW period as outlined in the SoA.

[0217] Participants who completed Study 2 RW, along with their 84-day assessment from Study 2 PD, could be carried forward into the ongoing Study 3 LTSS.

[0218] Participants who meet tremor worsening criteria (according to pre-specified relapse criteria) during RW will be carried forward to Study 3 LTSS. The final assessment conducted in Study 2 RW will be carried forward to Study 3 LTSS on Day 84.

[0219] Exam 3 LTSS Participants on placebo in Study 1 PD or 2 RW will undergo a DB titration period consisting of a 20 mg QAM dose during week 1 (days 84-90) and a 40 mg QAM dose during week 2 (days 91-97) (Table 9). Participants who received 60 mg of Compound 1 in the pivotal study when they rolled over to LTSS will maintain their 60 mg dose in a blinded manner throughout the titration period. On day 15, all participants will enter an open-label maintenance period and receive a 60 mg QAM dose throughout the remainder of the study. Participants in Phase 2 OLE (Example 2) will roll over to Study 3 LTSS at a 60 mg dose or will be titrated to 60 mg over two weeks based on their current dose, as needed. No dose adjustments will be allowed in Study 3 LTSS.

[0220] Scientific basis for clinical trial design This protocol includes two concurrent pivotal DB studies, designed to further evaluate the favorable efficacy and safety profile of Compound 1 demonstrated throughout the Phase 2 program. The multi-study protocol offers several advantages over traditional single-study protocols. Sharing study infrastructure allows for greater efficiency in enrollment, operations, data collection and management, and overall resource utilization across the three studies. Furthermore, concurrent study enrollment ensures more homogeneous patient populations across the two pivotal Phase 3 studies (Study 1 PD and Study 2 RW). By simultaneously initiating Study 1 PD and Study 2 RW under a single protocol, Compound 1 treatment administration during the RW lead-in period of Study 2 RW is blinded, resulting in more accurate determination of Compound 1 responders. Finally, all completers of Study 1 PD and Study 2 RW can enter LTSS directly. This allows for a seamless transition from the participant's perspective and ongoing safety data collection from the sponsor's perspective.

[0221] Study 1 PD and Study 2 RW will be conducted using two different study designs. Study 1 PD is similar to the Phase 2 study described in Example 1, but the total treatment period will be extended to 12 weeks, allowing for the evaluation of chronic treatment. The Study 2 RW design was selected for several reasons. First, it will further confirm the durability of effect in the RW group. The RW group is designed to evaluate a subpopulation defined as ulixacultamide responders. Because ET is known to be heterogeneous, the RW design is expected to be useful. Given this heterogeneity (i.e., patient characteristics, genotype / etiology, or phenotype specificity), it is likely that there is a subpopulation of ET participants that will respond more favorably to treatment than other subpopulations. The RW design will identify this subpopulation and its response to treatment, thereby providing a deeper understanding of the responder population. Additionally, during the RW period, participants will be evaluated weekly, and participants who meet pre-specified relapse criteria will be carried over to Study 3 LTSS. This limits the placebo period for participants who are true responders.

[0222] The intervention period for Studies 1 PD and 2 RW will be a maximum of 12 weeks, including a 2-week titration period. The 2-week titration period is deemed appropriate based on the tolerability observed in Phase 2. Furthermore, a 10-week maintenance treatment period at the 60 mg dose is considered sufficient to establish the durability of the effects of chronic administration. This is supported by evidence of treatment effects as early as 2 weeks in the Phase 2 study. In Phase 2, the change from baseline in LSM mADL11 scores compared to placebo showed a treatment effect of 1.44 at Day 28, with a sustained effect throughout the remainder of the study (Day 56). In participants without intention tremor (IT), a favorable treatment effect of 1.03 mADL11 points compared to placebo was observed as early as the first assessment point (Day 14).

[0223] In the Phase 2 OLE study (Example 2), rescue therapy was required in the placebo group within the 3-week crossover period, suggesting a rapid loss of drug effect and further supporting the 4-week RW duration selected for Study 2 RW.

[0224] The presence of IT is of particular interest because it is a distinct type of action tremor observed in some individuals with ET and may be associated with other specific neurological conditions. In contrast to the action or postural tremor observed in ET, IT is characterized by a large-amplitude, low-frequency coarse tremor that worsens with target-directed movement. The frequency and amplitude of tremor in ET are more consistent throughout the movement trajectory. Because IT can be associated with diagnoses other than ET, patients with IT are evaluated during screening to determine whether they may have a cerebellar etiology distinct from ET. Only participants determined by the central Eligibility Review Committee (ERC) reviewer to have IT associated with ET (ET with IT) and no other etiology for IT will be enrolled in this study. Functional, physiological, and anatomical data suggest that ET with IT may present a unique clinical manifestation that could potentially confound clinical trial outcome measures based on functional activity. Therefore, this subpopulation may confound the measurement and interpretation of the primary outcome measure, ADL performance. Based on this, participants with IT will be enrolled only if it is determined that the IT is associated with ET and not an alternative etiology. Participants assigned to Study 1 PD or Study 2 RW will be stratified for the presence of ET with IT. Participants determined to have ET with IT will be included in the sensitivity analyses for Study 1 PD and Study 2 RW.

[0225] The primary endpoint of Study 1PD and Study 2RW was based on mADL11 (TETRAS-ADL items 1-11, converted to a score of 0-3). In the Phase 2 study described in Example 1, the primary endpoint was mADL (TETRAS-ADL items 1-11 + Performance Subscale [PS] items 6 and 7, converted to a score of 0-3). Although mADL scores declined in the Phase 2 study, careful analysis of the data from the Phase 2 study described in Example 1 revealed that the PS items (Archimedes spiral and cursive handwriting) and ADL item 12 (social impact) did not have sufficient sensitivity, reliability, specificity, and / or clinical significance for assessing ET severity. Therefore, in line with feedback from the FDA, the mADL11 score was selected as the primary efficacy endpoint for Study 1PD and as a secondary endpoint for Study 2RW. The Archimedes spiral of the dominant hand will be analyzed as a secondary endpoint.

[0226] This is a decentralized clinical trial. The reduced burden of a decentralized trial enhances the engagement of participants without access to a research clinic, older participants with limited mobility (and other issues, such as mobility), and younger participants who may still be working and require a more convenient clinical trial schedule. This not only enhances the engagement, recruitment, enrollment, and retention of trial participants from a meaningfully diverse clinical population, but also increases investigator diversity, which is crucial for clinical trials in the United States. Furthermore, efficacy assessments are best collected at home, as they focus on functionally relevant ADLs, focusing on participants' daily experiences and disabilities related to ET. A phase 2 crossover trial demonstrated that decentralized trials can be effectively and safely conducted in participants with moderate to severe ET, and that the TETRAS-ADL can be consistently assessed via telehealth, with mADLs observed at multiple consecutive time points. Given this, these assessments are feasible, and collection by distributed investigators in rural areas can reduce bias. Finally, decentralized testing is appropriate given the good tolerability and well-characterized safety profile of Compound 1 documented in the Phase 2 study described in Example 1. Compound 1 is stable, allowing for direct delivery to patients, simple drug administration, and simple safety monitoring, making it suitable for decentralized testing.

[0227] Definition of clinical trial completion Participants are considered to have completed Studies 1 PD and 2 RW when they either roll over to Study 3 LTSS or complete an SFU or ED visit. The end of Study 3 LTSS will occur when the participant completes their last scheduled assessment, as indicated in the SoA. The study may be discontinued by the sponsor at any time.

[0228] Dosage justification When administered as a modified-release (MR) formulation, ulixacultamide demonstrated a favorable safety profile in healthy participants and patients with ET throughout the phase 2 development program in a dose-finding setting for up to 129 days at doses ranging from 5 to 120 mg.

[0229] In the Phase 2 study described in Example 1, participants were randomized to placebo or 60 or 100 mg of Compound 1. When evaluating the change from baseline in the mADL11 endpoint compared with placebo, the magnitude of benefit was similar between participants in the 60 mg or 100 mg Compound 1 groups. No additional benefit was observed when the dose was increased to 100 mg, and there was no significant difference in the safety profile between the 60 mg and 100 mg groups. Therefore, the benefit:risk ratio for the 60 mg dose was ideal, and evaluation of additional maintenance doses below 60 mg is not necessary.

[0230] The effect of a high-fat, high-calorie meal on the pharmacokinetics of Compound 1 was evaluated in healthy participants previously administered Compound 1 under fasting conditions in a Phase 1 study. After establishing a dose at which steady-state exposure was achieved in healthy adult participants, the effect of a high-fat, high-calorie meal on the PK of Compound 1 was evaluated at the 120 mg dose level. After administration of the 120 mg dose in the fed or fasted state, maximum plasma drug concentrations (Cmax) and AUCτ values ​​were similar. Based on this analysis, Compound 1 can be administered without regard to food.

[0231] Administration of the study drug Compound 1 will be supplied as 20 mg, 40 mg, and 60 mg modified-release tablets. A matching placebo will also be provided. The study drug will be administered orally QAM with or without food and will be provided to participants in prepackaged bottles. Participants receiving ulixacultamide will receive one tablet of study drug per day. Participants in the placebo group will receive one matching placebo tablet per day. For each home / telehealth visit, the dose must be drawn from a previously dispensed bottle. The interactive response technology (IRT) system can dispense replacement bottles as needed.

[0232] Eligible participants will be randomized to receive oral Compound 1 or placebo daily. A fixed-dose regimen will be used for the three studies, starting at 20 mg for 7 days, followed by 40 mg for 7 days, followed by a maintenance dose of 60 mg. (Note that participants who received placebo in Study 1 PD and Study 2 RW will require blinded dose titration upon rollover to Study 3 LTSS.) Dose adjustments will not be permitted.

[0233] Efficacy evaluation All TETRAS-ADL assessments throughout the study will be performed by trained and qualified investigators. Baseline CGI-S, PGI-S, and Archimedes spiral assessments on Day 1 (Baseline) must be performed prior to dosing.

[0234] Essential Tremor Rating Scale The TETRAS was developed by the Tremor Research Group (TRG; www.tremorresearchgroup.org) to quantify ET severity and its impact on ADL. The full scale has two subscales: performance and ADL. This study will collect only the TETRAS-ADL.

[0235] TETRAS Activities of Daily Living The TETRAS-ADL subscale is a 12-item assessment of typical daily activities affected by tremor. Activities are assessed in the following functional domains: speech, eating, drinking, personal hygiene, dressing, pouring, carrying, using keys, writing, working, overall disability, and social activities. The impact on each function is rated on a 5-point Likert scale ranging from 0 to 4. The total ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48.

[0236] TETRAS Modified Activities of Daily Living 11 The mADL11 score is a composite sum of items 1-11 of the TETRAS-ADL subscale (omitting item 12, the social impact score). Scoring for each item is converted to a 4-point scale ranging from 0 to 3, with a total score ranging from 0 to 33. TETRAS ADL is collected, and the mADL11 is used for data analysis purposes.

[0237] Clinical general impression The Clinical Global Impression (CGI) scale is a measure of symptom severity and response commonly used in clinical trials (Guy 1976). The CGI-S scale will be used in this clinical trial.

[0238] Clinical Global Impression - Severity The CGI-S assesses the clinician's impression of the participant's current illness status. Using their own overall clinical experience with this patient population, clinicians should rate the participant's current severity of ET on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (most severely ill patient).

[0239] Patient general impression Patient general impression - change The PGI-C assesses participants' improvement (or worsening). Participants are asked to rate their condition compared to baseline (before dosing on Day 1) on a 7-point scale from 1 (much improved) to 7 (much worsened). In all cases, the assessment must be made regardless of whether the participant believes the improvement / worsening is drug-related or not.

[0240] Patient Global Impression - Severity The PGI-S assesses participants' impressions of their current illness status. Participants are asked to rate their condition on a 7-point scale ranging from 1 (not present) to 7 (extremely severe).

[0241] Archimedes spiral Participants draw an Archimedean spiral using their dominant hand on a fixed, unlined, standard-sized piece of paper (letter) containing a preformed spiral diagram. A specific pen (to standardize across all drawings) is distributed and used. Participants are instructed to use their dominant hand to draw a spiral without crossing lines in the preformed spiral template, without practicing and without leaning toward their dominant forearm, wrist, or hand. Descriptive analysis is used to summarize findings.

[0242] 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 specification 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.

[0243] Furthermore, the present 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.

[0244] 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. In addition, any particular embodiment of the present invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be deemed known to those of ordinary skill in the art and therefore may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0245] 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.

Claims

1. 1. A method of treating essential tremor, comprising administering to a subject in need thereof a compound of formula (I): 【Transformation 5】 or a pharmaceutically acceptable salt thereof, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject once daily at a dose of about 60 mg to about 100 mg; whereby the subject's Essential Tremor Rating Scale (TETRAS) performance score is reduced after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to the subject's TETRAS performance score before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 60 mg.

3. 10. The method of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 100 mg.

4. The method of any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject after an initial titration period.

5. the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 60 mg after an initial titration period; 5. The method of claim 4, wherein the initial titration period comprises administering to the subject once daily the compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 5 mg for a first period, followed by a dose of about 10 mg for a second period, followed by a dose of about 20 mg for a third period, followed by a dose of about 40 mg for a fourth period.

6. 6. The method of claim 5, wherein the first period of time, the second period of time, the third period of time, and the fourth period of time are each seven days in length.

7. the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 100 mg after an initial titration period; 5. The method of claim 4, wherein the initial titration period comprises administering to the subject once daily the compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of about 5 mg during a first period, followed by a dose of about 10 mg during a second period, followed by a dose of about 20 mg during a third period, followed by a dose of about 40 mg during a fourth period, followed by a dose of about 60 mg during a fifth period, followed by a dose of about 80 mg during a sixth period.

8. 8. The method of claim 7, wherein the first period of time, the second period of time, the third period of time, the fourth period of time, the fifth period of time, and the sixth period of time are each seven days in length.

9. The method of any one of claims 1 to 8, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 8 weeks.

10. The method of any one of claims 1 to 8, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 12 weeks.

11. The method of any one of claims 1 to 8, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 14 weeks.

12. The method of any one of claims 1 to 8, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject for at least 52 weeks.

13. 13. The method of any one of claims 1-12, wherein the TETRAS performance score comprises an ADL subscore, and wherein the ADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of the compound of formula (I) compared to the subject's ADL subscore before administration of the compound of formula (I).

14. 14. The method of claim 13, wherein the ADL subscore is reduced by at least about 2 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

15. 14. The method of claim 13, wherein the ADL subscore is reduced by at least about 3 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

16. 13. The method of any one of claims 1-12, wherein the TETRAS performance score comprises an mADL subscore, and the mADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of the compound of formula (I) compared to the subject's ADL subscore before administration of the compound of formula (I).

17. 17. The method of claim 16, wherein the mADL subscore is reduced by at least about 2 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

18. 18. The method of claim 17, wherein the mADL subscore is reduced by at least about 3 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

19. 17. The method of claim 16, wherein the mADL subscore is reduced by at least about 4 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

20. 20. The method of any one of claims 16-19, wherein the subscore for at least one item assessed as part of the mADL subscale is reduced, said item being selected from the group consisting of item 3 (drinking from a glass), item 4 (hygiene), item 5 (dressing), item 6 (pouring), item 7 (carrying), item 8 (using a key), item 9 (writing), and item 11 (global impairment).

21. 13. The method of any one of claims 1 to 12, wherein the TETRAS performance score comprises a mADL11 subscore, and the mADL11 subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, or at least about 10 points after administration of the compound of formula (I) compared to the subject's ADL subscore before administration of the compound of formula (I).

22. 20. The method of claim 19, wherein the mADL11 subscore is reduced by at least about 2 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

23. 20. The method of claim 19, wherein the mADL11 subscore is reduced by at least about 2.5 points after administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for at least 8 weeks.

24. 24. The method of any one of claims 1-23, wherein the subject does not have an intention tremor.

25. The method of any one of claims 1 to 24, wherein the subject is a human.

Images