Methods of using T-type calcium channel modulators

Abstract

Described herein, in part, are methods useful for the prevention and / or treatment of diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as psychiatric disorders (e.g., mood disorders (e.g., severe depressive disorders), pain, tremor (e.g., idiopathic tremor), epileptic seizures (e.g., epileptic seizures), and the like. ), epilepsy, or epilepsy syndrome (e.g., adolescent muscular spasmodic epilepsy). The invention further includes methods for modulating the function of T-type calcium channels and methods of administering titration doses of T-type calcium channel antagonists.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. application 63 / 339,686, filed on May 9, 2022, which is incorporated herein in its entirety. Background Art

[0003] T-type calcium channels are low-voltage activated ion channels that mediate calcium influx into cells. Abnormal function or activity of these ion channels is associated with several diseases or conditions, including psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), epilepsy or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy).

[0004] When treating a disease or condition related to the abnormal function or activity of a T-type calcium channel, the tolerance of a potential drug therapeutic agent is a factor to be considered. When studying a new therapeutic agent, tolerance is a clinically defined term, referring to the input of both the patient (or research participant) and the clinician (or researcher). The patient input is the willingness to continue to receive treatment, and the clinician input is based on its evaluation of the severity and / or quantity of adverse effects and whether the patient should continue to receive treatment administration.

[0005] Either party may decide that a drug is not tolerated and, therefore, discontinue administration. Tolerability assessments may also be based on the relationship between adverse effects that affect tolerability and expected or perceived benefits. Thus, for example, a more severe or increased number of adverse events may be tolerated for a life-threatening disease or condition before designating a particular therapeutic agent or therapeutic dose as intolerable, while less severe or fewer adverse events may serve as a basis for considering a therapeutic dose as intolerable for a less severe disease or condition.

[0006] A disease with potential abnormal T-type calcium channel function or activity, essential tremor, may affect the ability of individuals to function in daily life, but is usually not life-threatening. Therefore, it is expected that any adverse events experienced by the patient will not deteriorate the patient's function, or the drug may be considered as intolerable by the patient and / or clinician. Certain therapeutic agents can cause relatively small adverse events, such as sedation or fatigue, which can be considered to be tolerable for serious neurological diseases (e.g., amyotrophic lateral sclerosis) or for potentially fatal conditions (e.g., refractory epilepsy). However, these same adverse events can be considered as intolerable in other conditions, including, for example, some essential tremor cases.

[0007] The tolerance or intolerance of a therapeutic agent for a given disease or condition can be supported by standard of care clinical experience, market research, and / or clinical trials. For example, researchers report that tolerance to certain essential tremor therapeutics (such as primidone and topiramate) exceeds 30% during relatively short trials (i.e., less than 11 weeks on average). Ferreira, JJ et al., MDS Evidence-Based Review of Treatments for Essential Tremor, Movement Disorders 2019: 1-9; see also PCT Publication No. WO 2020 / 072773 at Example 25, Table 34, which reported a 23% discontinuation rate in a 28-day essential tremor study of CX-8998, of which 17% were due to intolerance of adverse events. Likewise, discontinuation rates for various essential tremor therapeutics, including, for example, gabapentin, propranolol, primidone, and topiramate, have been shown to increase steadily over time.

[0008] Furthermore, although clinical trials for two non-selective T-type calcium channel inhibitors, zonisamide and topiramate, have shown that these two compounds are effective in treating essential tremor, adverse effects leading to patient discontinuation have limited the development of these non-selective T-type calcium channel inhibitors for the treatment of essential tremor. Haubenberger et al., Essential Tremor, N Engl J Med., 2018, 378:1802-10; Handforth et al., Zonisamide for essential tremor: an evaluator blinded study, Mov. Disord., 2009, 24:437-40; Chang et al., Efficacy and safety of topiramate for essential tremor: a meta-analysis of randomized controlled trials, Medicine, 2015, 94:1-7.

[0009] Adverse events are thought to be related to the pharmacokinetic parameters of the drug substance, including, for example, the maximum plasma concentration of the drug after administration (C max ) and the area under the plasma concentration-time curve (AUC) from the time of administration. max and / or AUC increases, and reported adverse events increase. Malangu, N., Linkages between Pharmacokinetics and Adverse Effects of Drugs, Pharmacokinetics and Adverse Effects of Drugs–Mechanisms and Risk Factors 2018.

[0010] Thus, the pharmacokinetic parameters are adjusted and an effective therapeutic dose and / or an effective therapeutic dose schedule is developed, in particular allowing an increase in the therapeutically effective dose and / or pharmacokinetic parameters (such as C max and AUC 24 ) without increasing the number or severity of adverse events, may help improve patient compliance and thereby benefit patients suffering from diseases or conditions involving T-type calcium channels, including, for example, essential tremor. Summary of the invention

[0011] Described herein are methods for preventing and / or treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), epileptic seizures (e.g., absence seizures), epilepsy or epilepsy syndromes (e.g., juvenile myoclonic epilepsy). Also disclosed herein are methods for modulating the function of T-type calcium channels and methods for administering titrated doses of T-type calcium channel antagonists, such as compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0012] In one aspect, the method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof comprises: (a) administering to the subject a first dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first period of time, wherein after administering the first dose of the compound for the first period of time, the subject's maximum plasma drug concentration (C max ) ranges from about 30 ng / mL to about 130 ng / mL and / or the area under the plasma concentration-time curve (AUC 24) in the range of about 490 ng*hr / mL to about 2030 ng*hr / mL; (b) increasing the amount of the compound in the first dose and administering one or more increasing doses of the compound to the subject to reach a maximum titrated dose; and (c) administering the maximum titrated dose of the compound to the subject to maintain a C in the range of about 280 ng / mL to about 470 ng / mL in the subject. max and / or an AUC ranging from about 3480 ng*hr / ml to about 5800 ng*hr / ml 24 Typically, each dose is administered once daily; however, max and / or AUC 24 value, the frequency of administration can be varied, as discussed elsewhere in this application.

[0013] In certain aspects, step (b) comprises increasing the first dose to a second dose, and administering the second dose of the compound to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's C max The range is about 80 ng / mL to about 300 ng / mL and / or AUC 24 The range of C is about 1220 ng*hour / ml to about 4070 ng*hour / ml. In some aspects, step (b) comprises increasing the first dose to a second dose, and administering the second dose of the compound to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's C max The range is from about 80 ng / mL to about 220 ng / mL and / or AUC 24 The range of the compound is about 1220 ng*hour / ml to about 3330 ng*hour / ml; and increasing the second dose to a third dose, and administering the third dose of the compound to the subject for a third period of time, wherein after administering the third dose of the compound for the third period of time, the subject's C max The range is from about 180 ng / mL to about 380 ng / mL and / or AUC 24 The range is about 2440 ng*hr / ml to about 4700 ng*hr / ml.

[0014] In various other aspects disclosed herein, step (b) comprises: (i) increasing the first dose to a second dose, and administering the second dose of the compound to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's Cmax The range is from about 80 ng / mL to about 130 ng / mL and / or AUC 24 The range of the second dose is about 1220 ng*hour / ml to about 2030 ng*hour / ml; (ii) increasing the second dose to a third dose, and administering the third dose of the compound to the subject for a third period of time, wherein after administering the third dose of the compound for the third period of time, the subject's C max The range is about 130 ng / mL to about 220 ng / mL and / or AUC 24 (iii) increasing the third dose to a fourth dose, and administering the fourth dose of the compound to the subject for a fourth period of time, wherein after administering the fourth dose of the compound for the fourth period of time, the subject's C max The range is about 180 ng / mL to about 300 ng / mL and / or AUC 24 and (iv) increasing the fourth dose to a fifth dose and administering the fifth dose of the compound to the subject for a fifth period of time, wherein after administering the fifth dose of the compound for the fifth period of time, the subject's C max The range is about 230 ng / mL to about 380 ng / mL and / or AUC 24 The range is about 2820 ng*hr / ml to about 4700 ng*hr / ml.

[0015] Further 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 a first dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 5 mg to about 40 mg per day for a first period of time; (b) increasing the amount of the compound in the first dose and administering to the subject one or more increasing doses of the compound to reach a maximum titrated dose; and (c) administering to the subject the maximum titrated dose of the compound in an amount ranging from about 20 mg per day to about 120 mg per day.

[0016] In certain aspects disclosed herein, step (b) comprises increasing the first dose to a second dose and administering the second dose of the compound to the subject in an amount ranging from about 40 mg per day to about 80 mg per day for a second time period, and in various other aspects, step (b) comprises increasing the first dose to a second dose and administering the second dose of the compound to the subject in an amount ranging from about 40 mg per day to about 60 mg per day for a second time period; and increasing the second dose to a third dose and administering the third dose of the compound to the subject in an amount ranging from about 80 mg per day to about 100 mg per day for a third time period.

[0017] In one aspect of all methods, each of the first time period, the second time period, and the third time period ranges from about 3 days to about 9 days, such as from about 3 days to about 7 days, and in one aspect, each of the first time period, the second time period, and the third time period is 3 days. In other aspects disclosed herein, each of the first time period and the second time period is 3 days, and the third time period is 7 days.

[0018] In one aspect of the present disclosure, in the first time period, the compound is used in an amount ranging from about 20 mg to about 40 mg per day, such as about 20 mg per day or about 40 mg per day. In certain embodiments, in the second time period, the compound is used in an amount ranging from about 40 mg per day to about 80 mg per day, such as about 40 mg per day, about 60 mg per day or about 80 mg per day. In other embodiments, in the third time period, the compound is used in an amount ranging from about 60 mg per day to about 120 mg per day, such as about 60 mg per day, about 80 mg per day, about 100 mg per day or about 120 mg per day. In certain embodiments, the second dose increases no more than 40 mg per day and / or the third dose increases no more than 40 mg per day relative to the first dose.

[0019] In some aspects, the methods disclosed herein further include increasing the third dose to a fourth dose, and administering the fourth dose of the compound to the subject in an amount of about 120 mg per day for a fourth time period. In some aspects, the method includes increasing a first dose of about 20 mg administered daily for a first time period of about 3 days to a second dose, and administering the second dose of the compound to the subject in an amount of about 40 mg per day for a second time period.

[0020] In certain aspects, in the methods disclosed herein wherein the second period of time is 3 days and the compound is administered in an amount of about 40 mg per day, the method further comprises increasing the second dose to a third dose in step (b) and administering the third dose of the compound to the subject in an amount of about 60 mg per day for a third period of time; increasing the third dose to a fourth dose and administering the fourth dose of the compound to the subject in an amount of about 80 mg per day for a fourth period of time; and increasing the fourth dose to a fifth dose and administering the fifth dose of the compound to the subject in an amount of about 100 mg per day for a fifth period of time, wherein the maximum titrated dose of the compound is about 120 mg per day.

[0021] In certain aspects of the methods disclosed herein, the first time period is 3 days, and the compound is administered in an amount of about 20 mg per day, and the second time period is about 3 days, and the compound is administered in an amount of about 40 mg per day. In certain embodiments, the third time period is 3 days, and the compound is administered in an amount of about 80 mg per day, and the method further comprises administering about 120 mg of the compound to the subject every day for a fourth time period.

[0022] In certain aspects of the methods disclosed herein, the first time period is 3 days and the compound is administered in an amount of about 20 mg per day; the second time period is 3 days and the compound is administered in an amount of about 40 mg per day; the third time period is 7 days and the compound is administered in an amount of about 60 mg per day, and the method further comprises: (d) administering to the subject about 80 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a fourth time period ranging from about 3 days to about 9 days; (e) administering to the subject about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a fifth time period ranging from about 3 days to about 9 days; and (f) administering to the subject about 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a sixth time period.

[0023] In certain aspects disclosed herein, step (b) comprises increasing the first dose to a second dose and administering the second dose of the compound to the subject in an amount ranging from about 40 mg per day to about 80 mg per day for a second period of time, and in various other aspects, step (b) comprises increasing the first dose to a second dose and administering the second dose of the compound to the subject in an amount ranging from about 40 mg per day to about 60 mg per day for a second period of time.

[0024] In one aspect of all methods, each of the first time period, the second time period, the third time period, the fourth time period, the fifth time period, the sixth time period, or the seventh time period ranges from about 2 days to about 10 days, 3 days to about 9 days, such as about 3 days to about 7 days, about 4 days to about 6 days, and in one aspect, each of the first time period, the second time period, and the third time period is 3 days, 4 days, 5 days, 6 days, or 7 days. In other aspects disclosed herein, the first time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, the second time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, the third time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, the fourth time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, the fifth time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, and the sixth time period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

[0025] In another aspect of the method, the last time period, such as the fourth time period, the fifth time period, the sixth time period or the seventh time period can be 1 month, 3 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years or longer.

[0026] In another aspect disclosed herein, the scope of the sixth time period is about 3 days to about 16 days, and on the one hand, the sixth time period is 14 days. In other aspects disclosed herein, the seventh time period is 14 days or more. On the other hand, the scope of the seventh time period is about 1 year to about 100 years. In some aspects, the scope of the seventh time period is about 5 years to about 80 years. In other aspects, the scope of the seventh time period is about 10 years to about 75 years. In some aspects, the seventh time period is about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years and about 20 years. On the other hand, the seventh time period is lifelong.

[0027] In some aspects, the methods disclosed herein further include increasing the third dose to a fourth dose, and administering the fourth dose of the compound to the subject in an amount of about 80 mg per day for a fourth time period. In some aspects, the method includes increasing a first dose of about 20 mg administered daily for a first time period of about 7 days to a second dose, and administering the second dose of the compound to the subject in an amount of about 40 mg per day for a second time period.

[0028] In certain aspects, in the methods disclosed herein wherein the second period of time is 4 days and the compound is administered in an amount of about 40 mg per day, the method further comprises increasing the second dose to a third dose in step (b) and administering the third dose of the compound to the subject in an amount of about 60 mg per day for a third period of time; increasing the third dose to a fourth dose and administering the fourth dose of the compound to the subject in an amount of about 80 mg per day for a fourth period of time; increasing the fourth dose to a fifth dose and administering the fifth dose of the compound to the subject in an amount of about 100 mg per day for a fifth period of time; increasing the fifth dose to a sixth dose and administering the sixth dose of the compound to the subject in an amount of about 120 mg per day for a sixth period of time; and continuing or reducing the sixth dose at an amount of about 120 mg, about 100 mg, about 80 mg, about 60 mg, about 40 mg, about 20 mg, or about 0 mg per day for a seventh period of time, wherein the maximum titrated dose of the compound is about 120 mg per day.

[0029] In certain aspects of the methods disclosed herein, the first time period is 3 days, and the compound is administered in an amount of about 20 mg per day, and the second time period is about 4 days, and the compound is administered in an amount of about 40 mg per day. In certain embodiments, the third time period is 7 days, and the compound is administered in an amount of about 60 mg per day, and the method further comprises administering about 80 mg of the compound to the subject every day for a fourth time period.

[0030] In certain aspects of the methods disclosed herein, the first time period is 3 days and the compound is administered in an amount of about 20 mg per day; the second time period is 4 days and the compound is administered in an amount of about 40 mg per day; the third time period is 7 days and the compound is administered in an amount of about 60 mg per day, and the method further comprises: (d) administering to the subject about 80 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a fourth time period ranging from about 3 days to about 9 days; (e) administering to the subject about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a fifth time period ranging from about 3 days to about 9 days; (f) administering to the subject about 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a sixth time period ranging from about 3 days to about 16 days.

[0031] In one aspect of all methods, each of the first time period, the second time period, the third time period, the fourth time period, and the fifth time period ranges from about 3 days to about 9 days, such as about 3 days to about 7 days; the sixth time period ranges from about 3 days to about 14 days. In other aspects disclosed herein, the first time period is 3 days, the second time period is 4 days, and the third time period is 7 days. In another aspect disclosed herein, the first time period is 3 days, the second time period is 4 days, the third time period is 7 days, the fourth time period is 7 days, the fifth time period is 7 days, and the sixth time period is 14 days. In certain aspects of all methods, the seventh time period ranges from about 5 years to about 80 years. In other aspects, the seventh time period ranges from about 10 years to about 75 years. In certain aspects, the seventh period of time is about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 11 years, about 12 years, about 13 years, about 14 years, about 15 years, about 16 years, about 17 years, about 18 years, about 19 years, and about 20 years. In another aspect, the seventh period of time is lifelong.

[0032] In various aspects of the present disclosure, the pharmaceutically acceptable salt is the hydrochloride salt of formula (II). In certain aspects, the subject is a human aged 18 to 55 years, and in certain aspects, the subject is a human aged 55 to 75 years.

[0033] In some aspects, the disease or condition associated with abnormal function or activity of T-type calcium channels is a psychiatric disorder, pain, tremor, epileptic seizure, epilepsy or epilepsy syndrome. In some aspects, the disorder is tremor, such as essential tremor. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a modified release dosage formulation comprising at least one modified release polymer, such as a modified release polymer selected from hydroxypropyl methylcellulose, ethyl cellulose and polyacrylate polymers. In some aspects of all embodiments disclosed herein, the pharmaceutically acceptable salt of formula (II) is Form C, and in some aspects, the pharmaceutically acceptable salt of formula (II) is Form B.

[0034] In certain aspects of the methods disclosed herein, the methods cause a decrease in the EEG sigma band during non-rapid eye movement (NREM) sleep of the subject and / or cause a decrease in the EEG γ band during a wake state under eyes open (EO) conditions or eyes closed (EC) conditions. In certain embodiments, the ratio of the NREM sigma band after administration to the NREM sigma band baseline is in the range of about 0.4 to about 0.7, such as a ratio of about 0.5 to about 0.6. In certain embodiments, when the subject is administered C max From about 5 ng / mL to about 470 ng / mL, such as C maxThe methods disclosed herein cause a decrease in NREMΣ frequency in a subject when a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 ng / mL to about 300 ng / mL. In certain embodiments, when a subject is administered a C ave From about 10 ng / mL to about 200 ng / mL, such as C ave The methods disclosed herein cause a decrease in the frequency of NREMΣ in a subject when the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 12 ng / mL to about 150 ng / mL. In certain embodiments, when the subject is administered a compound having a C max From about 30 ng / mL to about 470 ng / mL, such as C max When the compound of formula (I) or its pharmaceutically acceptable salt is about 280ng / mL to about 470ng / mL, the method disclosed herein causes the EO or ECγ band of the subject to decrease. In certain embodiments, when the subject is administered a compound of formula (I) or its pharmaceutically acceptable salt at a plasma concentration of about 75ng / ml to about 310ng / mL, such as a plasma concentration of about 90 to about 190ng / mL, the method disclosed herein causes the EO or ECγ band of the subject to decrease.

[0035] In certain aspects of the invention, the method of administering a compound of formula (I) reduces a subject's TETRAS performance score by at least 25% compared to the subject's TETRAS performance score prior to treatment with the compound of formula (I).

[0036] In another aspect of the invention, the method of administering a compound of formula (I) improves the subject's accelerometer performance score by at least 20% compared to the subject's accelerometer performance score prior to treatment with the compound of formula (I).

[0037] In another aspect of the invention, the method of administering a compound of formula (I) provides a subject with an improvement in an Archimedes Screw Task Test compared to the subject's Archimedes Screw Task Test prior to treatment with the compound of formula (I).

[0038] In a related aspect of the invention, the method of administering a compound of formula (I) comprises administering a compound of formula (I) for a period of at least 3 months.

[0039] In a related aspect of the invention, the method of administering a compound of formula (I) comprises administering a compound of formula (I) for a period of at least 6 months.

[0040] In a related aspect of the invention, the method of administering a compound of formula (I) comprises administering the compound of formula (I) for a period of 9 months.

[0041] In a related aspect of the invention, the method of administering a compound of formula (I) comprises administering a compound of formula (I) for a period of at least 1 year.

[0042] In a related aspect of the invention, the method of administering a compound of formula (I) comprises administering a compound of formula (I) for a period of at least 5 years.

[0043] In a related aspect of the invention, the method of administering a compound of formula (I) comprises administering a compound of formula (I) for a period of at least 10 years.

[0044] Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing description of the drawings, detailed description, examples, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 is an X-ray powder diffraction (XRPD) pattern of Form C of the compound of Formula (II).

[0046] Figure 2 is a differential scanning calorimetry (DSC) thermogram of Form C of the compound of formula (II).

[0047] Figure 3 is a thermogravimetric analysis (TGA) thermogram of Form C of the compound of formula (II).

[0048] Figure 4 is a hot stage microscopy (HSM) photomicrograph of Form C of the compound of Formula (II).

[0049] Figure 5 is a graph showing the mean concentration-time profile of the compound of formula (II) following a single 20 mg oral dose of the modified release tablets (Formulation 1, Formulation 2, and Formulation 3) and immediate release (IR) capsules of the compound of formula (II).

[0050] Figure 6 A reduction in tremor in the Archimedean screw task was shown with administration of the compound of formula (II).

[0051] Figure 7 is the XRPD of Form B of the compound of Formula (II).

[0052] Fig. 8A is a DSC thermogram of Form B of the compound of Formula (II) at a heating rate of 10 degrees Celsius per minute.

[0053] Figure 8B is a DSC thermogram of Form B of the compound of Formula (II) at a heating rate of 2 degrees Celsius per minute.

[0054] Fig. 9is a TGA thermogram of Form B of the compound of formula (II).

[0055] Fig.10 is a HSM micrograph of Form B of the compound of formula (II).

[0056] Fig.11 Mean (± SD) concentrations following a single oral dose of 5 mg tablet Formulation 4 are shown.

[0057] Fig.12 Stage 1 sleep EEG (NREMΣ) in healthy volunteers is shown.

[0058] Fig.13 Shown are mean (± SD) concentrations following a single oral dose of 5 mg tablet Formulation 4 (Day 1), oral dose of 10 mg (2 x 5 mg tablet Formulation 4) (Day 5), and oral dose of 20 mg tablet Formulation 3 (Day 9) after repeated administration.

[0059] Fig.14 Shown are the mean (± SD) dose normalized concentrations following single oral dosing of 5 mg tablet Formulation 4 (Day 1), oral dosing of 10 mg (2 x 5 mg tablet Formulation 4) (Day 5), and oral dosing of 20 mg tablet Formulation 5 (Day 9) after repeated administration.

[0060] Fig.15 Preliminary site data from open-label studies of essential tremor (TETRAS UL and TETRASPS) are shown.

[0061] Fig.16 Exposure of plasma concentrations (ng / mL) of modified release formulation 3 based on the compound of formula (II) as described in Example 5 at single ascending doses (SAD) of 20 mg, 40 mg and 60 mg and multiple ascending doses (MAD) of 40 mg at day 8 is shown.

[0062] Fig.17 NREM Σ power ratios from baseline for increasing administered doses of the compound of formula (II) as described in Example 13 are shown.

[0063] Fig.18 The NREMΣ absolute power versus mean concentration (C) as described in Example 13 is shown. ave ), where the thick black line represents the nonparametric smoother and the shaded area represents the 95% confidence interval of the smoother. Individual traces are represented by solid thin lines in part A and dashed thin lines in part B.

[0064] Fig.19The concentration (C) of the eye opening (EO) gamma absolute power versus measurement time as described in Example 13 is shown. (t) ), where the thick black line represents the nonparametric smoother and the shaded area represents the 95% confidence interval of the smoother. Individual traces are represented by solid thin lines in part A and dashed thin lines in part B.

[0065] Fig. 20 The concentration (C) of the eye closure (EC) gamma absolute power versus the measurement time as described in Example 13 is shown. (t) ), where the thick black line represents the nonparametric smoother and the shaded area represents the 95% confidence interval of the smoother. Individual traces are represented by solid thin lines in part A and dashed thin lines in part B.

[0066] Fig.21 The mean change from baseline in modified ADL before and after cessation of dosing of Formula (I) as described in Example 16 is shown.

[0067] Fig. 22 The mean change in improved ADL from Day 42 to Day 57 following cessation of dosing of Formula (I) as described in Example 16 is shown.

[0068] Fig.23 Shown are mean changes from baseline in tremor obtained using tremor amplitude analysis before and after discontinuation of dosing of Formula (I) as described in Example 16.

[0069] Fig.24 Shown are mean changes in tremor obtained using tremor amplitude analysis from Day 42 to Day 56 following cessation of dosing of Formula (I) as described in Example 16.

[0070] Fig.25 The Archimedean screw tasks from patients before Formula (I) administration (Day 1 Baseline), during Formula (I) administration (Day 42), and during placebo administration (Day 56) are shown.

[0071] Fig.26 is a line graph of the least squares mean change from baseline in TETRAS upper extremity score in Part A of Example 16 over time.

[0072] Fig. 27 is a line graph of the least squares mean change from baseline in TETRAS upper extremity score during the open-label titration phase of Part B of Example 16 over time.

[0073] Fig.28 is a line graph of the least squares mean change in TETRAS upper extremity score from randomization baseline during the randomized withdrawal phase of Part B of Example 16 over time.

[0074] Fig.29 is a line graph of the least squares mean change from baseline in the accelerometer-based upper extremity score in Part A of Example 16 over time.

[0075] Fig.30 is a line graph of the least squares mean change from baseline in accelerometer-based upper extremity scores during the open-label titration phase of Part B of Example 16 over time.

[0076] Fig.31 is a line graph of the least squares mean change in accelerometer-based upper extremity scores relative to randomization over time during the double-blind randomized withdrawal phase of Part B of Example 16. DETAILED DESCRIPTION

[0077] The present application discloses methods for preventing and / or treating diseases or conditions associated with abnormal function or activity of T-type calcium channels, such as psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), seizures (e.g., absence seizures), epilepsy or epilepsy syndromes (e.g., juvenile myoclonic epilepsy).

[0078] Also disclosed is a method for improving the prevention and / or treatment of a disease or condition associated with abnormal function or activity of a T-type calcium channel using a titration dosage regimen of a compound of formula (I) or a pharmaceutically acceptable salt thereof. By using a titration dosage regimen, it was unexpectedly found that a titration dose significantly greater than the maximum tolerated dose achieved without titration can be safely administered to a subject in need. Similarly, by using a titration dosage regimen, pharmacokinetic parameters (such as C max and AUC 24 ) can be significantly increased over that obtained when lower doses are administered without titration. max and / or AUC 24 value.

[0079] For example, as shown in the Examples, a C of about 130 ng / mL was achieved after administration. max and / or AUC of approximately 1910 ng*hr / mL 24 The modified release dosage form (60 mg) was not tolerated in the subjects. See Example 4. However, by using a titrated dose regimen, the maximum dose tested (120 mg) unexpectedly achieved a C of at least about 390 ng / ml. max and an AUC of at least about 4650 24, and was safely tolerated in patients. See Example 11. In addition, no maximum tolerated dose was determined in the titration protocol, which indicates that the dose and pharmacokinetic parameters of Formula (I) or a pharmaceutically acceptable salt thereof can be even further increased.

[0080] This finding is particularly surprising for T-type calcium channel antagonists of formula (I) or a pharmaceutically acceptable salt thereof, because this particular T-type calcium antagonist exhibits state dependence while being much less state-dependent than other T-type calcium antagonists (such as CX-8998, NBI-827104 and ABT-639) and having a significantly wider pharmacodynamic range. See, for example, Tringham, E. et al., T-type Calcium Channel Blockers That Attenuate Thalamic Burst Firing and Suppress Absence Seizures, Sci. Transl. Med. 2012; 4(121): 1-19, p. 3, which shows that compounds of formula (I) "are 2.5 to 4 times lower in the unactivated state of the T-type channel than in the closed state.See also Siegrist, R. et al., Structure-Activity Relationship, Drug Metabolism and Pharmacokinetics Properties Optimization, and in Vivo Studies of New Brain Penetrant Triple T-Type Calcium Channel Blockers, J. Med. Chem. 2016; 59: 10661-10675; PCT Published Application No. WO No. 2020 / 072773, pp. 27-28 (noting that CX-8998 "may be approximately 29-fold to approximately 45-fold more selective for Cav3 under hyperpolarized conditions than under depolarized conditions"); Lee, MS and Papapetropoulos, S., CX-8998, a Potent, Selective T-type Calcium Channel Antagonist Dose-dependently Suppresses Seizures in the WAG / Rij Genetic Model of Absence Epilepsy, Am. Acad. Neurol. 2018; Session P5, Abstract 281;. O. et al., Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsy, J. Med. Chem. 2017; 60: 9769-9789; and Jarvis, MF et al., A peripherally acting, selective T-type calcium channel blocker, ABT-639, effectively reduces nociceptive and neuropathic pain in rats, Biochem. Pharmacol. 2014; 89(4): 536-44.

[0081] In addition, other highly state-dependent T-type calcium channel inhibitors (such as CX-8998) benefit little or nothing from titrated doses, achieving daily titrated doses of only 20 mg (see, for example, Papapetropoulos et al., Frontiers in Neurology, 2019 and Papapetropoulos et al., Movement Disorders 2021), which are not significantly greater than the highest non-titrated dose of the compound safely administered to patients (16 mg). See, for example, PCT Publication No. WO2020 / 072773, page 220 ("Single doses up to 16 mg are generally well tolerated. ... 20 mg and 24 mg doses are poorly tolerated because of inattention, headaches, mood changes, anxiety, irritability, and vivid dreams after evening dosing."). Therefore, the fact that the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be increased to at least twice the non-titrated maximum tolerated dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is particularly surprising, given that CX-8998 is substantially more state-dependent than the compound of Formula (I).

[0082] Therefore, in one aspect of the present disclosure, for a compound of formula (I) or a pharmaceutically acceptable salt thereof, the maximum tolerated C max Less than 130 ng / mL, such as between 30 ng / mL and 130 ng / mL, and / or maximum tolerated AUC without titration24 Less than 2000 ng*h / ml, such as between 490 ng*h / ml and 2000 ng*h / ml. Thus, in certain embodiments, by using the titrated dosage regimen disclosed herein, a C max Greater than 130 ng / mL, such as ranging from about 180 ng / mL to 300 ng / mL, about 230 ng / mL to 380 ng / mL, or about 280 ng / mL to 470 ng / mL and / or achieving an AUC of 24 Greater than 2000 ng*h / ml, such as about 2440 ng*h / ml to 4070 ng*h / ml, about 2820 ng*h / ml to 4700 ng*h / ml, or about 3480 ng*h / ml to 5800 ng*h / ml. In certain embodiments of the present disclosure, titration of the initial dose to the maximum tolerated C achieved without titration is provided. max and / or maximum tolerated AUC 24 at least about 1.5 times the maximum tolerated C as achieved without titration max and / or AUC 24 The method is at least about 2 times, at least about 2.5 times, or at least about 3 times greater.

[0083] In other aspects of the present disclosure, the maximum tolerated dose achieved without titration is less than 60 mg, such as about 55 mg, about 50 mg, about 45 mg or about 40 mg. Therefore, in certain embodiments, the maximum titration dose is at least about 60 mg, for example, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg or at least about 220 mg. Therefore, in certain embodiments of the present disclosure, a method is provided in which the initial dose is titrated to at least about 2 times (for example, about 2 times of 40 mg, or a maximum titration dose of about 80 mg) of the maximum tolerated dose achieved without titration. In certain embodiments of the present disclosure, methods are provided for titrating an initial dose to at least about 2.5 times the maximum tolerated dose achieved without titration (e.g., at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, or at least about 5.5 times the maximum tolerated dose achieved without titration).

[0084] Also provided are methods for treating tremor (eg, essential tremor, Parkinson's tremor, or cerebellar tremor) or epilepsy or an epilepsy syndrome (eg, absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy). Also provided are methods for treating mood disorders (e.g., depression, major depressive disorder, dysthymic disorder (e.g., minor depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), and / or obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)). Also provided are methods for modulating function and blocking T-type calcium channels. Also provided are methods for treating pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain; e.g., thalamic pain; or migraine). Also provided are methods for treating ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with a CACNA1G mutation). Also provided are methods for treating tinnitus. Also provided are methods for treating arousal disorders.

[0085] definition

[0086] In general, an "effective amount" of a compound means an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount includes both therapeutic and prophylactic treatments.

[0087] As used herein, and unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the efficacy of another therapeutic agent.

[0088] As used herein, the term "refractory" refers to a disease, disorder, or condition that does not readily yield or respond to therapy or treatment, or is not controlled by therapy or treatment. In certain embodiments, the diseases, disorders, or conditions described herein are refractory (e.g., refractory epilepsy or refractory absence seizures) and do not respond to standard therapy or treatment.

[0089] As used herein, a "subject" contemplated for administration includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0090] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0091] As used herein, and unless otherwise indicated, the terms "treat" and "treatment" encompass actions that occur while a subject is suffering from a particular disease, disorder or condition, that reduce the severity of the disease, disorder or condition, or that delay or slow the progression of the disease, disorder or condition ("therapeutic treatment"), and also encompass actions that occur before a subject begins to suffer from a particular disease, disorder or condition ("prophylactic treatment").

[0092] The term "pharmaceutically acceptable salt" as used herein means a salt that is suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well 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 formed of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, lauryl sulfate, The pharmaceutically acceptable salts include, for example, hydroxyl groups ...

[0093] The term "modified release polymer" refers to a polymer that changes the release rate after the drug is administered to a subject in a formulation (e.g., tablets and capsules). For example, a modified release polymer is used to dissolve the drug over time so that it is released more slowly and more stably into the bloodstream. For example, a modified release polymer is a controlled release polymer. For example, a modified release polymer or a controlled release polymer is an HPMC polymer. In certain embodiments, a modified release polymer may include a hydrophilic matrix polymer (e.g., hydroxypropyl methylcellulose, HPMC (hydroxy-propyl methylcellulose)), a hydrophobic matrix polymer (e.g., ethylcellulose (ethylcellulose), ethylcellulose (ethocel)), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100).

[0094] The term "diluent" as used herein refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol and mannitol)).

[0095] As used herein, the term "glidant" refers to an excipient used to promote powder flow by reducing inter-particle friction and cohesion. For example, glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0096] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from agglomerating and sticking to a tablet punch or capsule filling machine. Lubricants are also used to ensure that tablet formation and discharge can occur under low friction between the solid and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, and fats (e.g., vegetable stearin).

[0097] As used herein, the term "coating agent" refers to an excipient that protects tablet ingredients from deterioration due to moisture in the air and makes large or bad-tasting tablets easier to swallow. These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present disclosure is not intended to be limited in any way by the above exemplary list of substituents.

[0098] Methods for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels

[0099] In one aspect, the present disclosure provides 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, the method comprising administering to the subject daily (e.g., once, twice, three times) a therapeutically effective amount of a compound of formula (I):

[0100] or a pharmaceutically acceptable salt (eg, co-crystal) or solvate thereof, for example, a compound of formula (II):

[0101]

[0102] Formula (I) can also be referred to as N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide, and the compound of formula (II) can be referred to as N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride.

[0103] Disclosed herein is a method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel, the method comprising administering a titration dose so that the end or maintenance dose exceeds the initial dose or the dose in which an adverse event may occur without titration (the maximum tolerated dose achieved without titration). As used herein, administering a titration dose refers to the practice of starting from a low dose and increasing to one or more higher doses. For example, in certain embodiments, disclosed herein is a method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need, the method comprising: (a) administering a first dose (e.g., a dose of about 20 mg or about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for a first time period, wherein after administering the first dose of the compound for the first time period, the subject's maximum plasma drug concentration (C max ) ranges from about 30 ng / mL to about 130 ng / mL and / or the area under the plasma concentration-time curve (AUC 24 ) in the range of about 490 ng*hr / mL to about 2030 ng*hr / mL; (b) increasing the amount of the compound in the first dose and administering one or more increasing doses of the compound to the subject to reach a maximum titrated dose; and (c) administering the maximum titrated dose of the compound to the subject to maintain a C in the range of about 280 ng / mL to about 470 ng / mL in the subject. max and / or an AUC ranging from about 3480 ng*hr / ml to about 5800 ng*hr / ml 24 Typically, each dose is administered daily, preferably once a day, however, as long as the desired C max and / or AUC 24 value, the frequency of administration can be varied, as discussed elsewhere in this application.

[0104] For example, in certain embodiments, step (b) comprises increasing the first dose to a second dose, e.g., a dose of about 40 mg to about 80 mg, and administering the second dose of the compound to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's C max The range of about 80 ng / mL to about 300 ng / mL, such as about 80 ng / mL to about 220 ng / mL, about 80 ng / mL to about 130 ng / mL, or about 130 ng / mL to about 300 ng / mL, and / or AUC 24 The range is from about 1220 ng*hr / mL to about 4070 ng*hr / mL, as shown in AUC 24 In some embodiments, step (b) may further include increasing the second dose to a third dose, such as a dose ranging from about 60 mg to about 100 mg, and administering the third dose of the compound to the subject for a third period of time, wherein after administering the third dose, the subject's C max The range of about 130 ng / mL to about 380 ng / mL, such as 130 ng / mL to about 220 ng / mL, about 180 ng / mL to about 300 ng / mL, or 230 ng / mL to about 380 ng / mL and / or AUC 24 The range is about 2000 ng*hr / ml to about 4700 ng*hr / ml, such as about 2000 ng*hr / ml to about 3330 ng*hr / ml, about 2440 ng*hr / ml to about 4070 ng*hr / ml or about 2820 ng*hr / ml to about 4700 ng*hr / ml.

[0105] Also disclosed herein are embodiments further comprising: increasing the third dose to a fourth dose, such as a dose of about 80 mg to about 100 mg, and administering the fourth dose of the compound to the subject for a fourth period of time, wherein after administering the fourth dose of the compound for the fourth period of time, the subject's C max The range is about 180 ng / mL to about 380 ng / mL, such as about 180 ng / mL to about 300 ng / mL or about 230 to about 380 ng / mL and / or AUC 24The range of is about 2440 ng*hr / ml to about 4700 ng*hr / ml, such as about 2440 ng*mL / mL to about 4070 ng*hr / ml or about 2820 ng*mL to about 4700 ng*hr / ml. In certain aspects, the methods disclosed herein may further include increasing the fourth dose to a fifth dose, such as a dose of about 100 mg, and administering the fifth dose of the compound to the subject for a fifth period of time, wherein after administering the fifth dose of the compound for the fifth period of time, the subject's C max The range is from about 230 ng / mL to about 380 ng / mL and the AUC 24 The range is about 2820 ng*hr / ml to about 4700 ng*hr / ml.

[0106] In certain embodiments of the titrated dose regimens disclosed herein, the maximum titrated dose can be increased to maintain greater than 470 ng / mL and / or AUC 24 A Cmax greater than 5800 ng*hr / mL, provided that the subject can safely tolerate the higher dose. For example, in certain embodiments, the method comprises one or more additional titration steps to achieve a maximum titrated dose administered to the subject to maintain a Cmax of max The range is about 450 ng / mL to about 750 ng / mL, including, for example, about 450 ng / mL to about 650 ng / mL, about 450 ng / mL to about 550 ng / mL or about 450 ng / mL to about 500 ng / mL, and / or AUC 24 The range is about 5500 ng*hr / ml to about 9500 ng*hr / ml, including, for example, about 5500 ng*hr / ml to about 8500 ng*hr / ml, 5500 ng*hr / ml to about 7500 ng*hr / ml, or about 5500 ng*hr / ml to about 6500 ng*hr / ml.

[0107] Also disclosed herein is a method for treating a disease or condition related to abnormal function or activity of a subject in need of treatment of a T-type calcium channel, the method comprising: (a) applying about 5 mg to about 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for a first time period; (b) applying about 10 mg to about 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for a second time period; and (c) applying about 20 mg to about 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for a third time period. Typically, each of the first time period, the second time period, and the third time period ranges from about 3 days to about 9 days. However, depending on the subject, a shorter or longer time period may be used.

[0108] Also disclosed herein is a method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need of treatment, the method comprising: (a) administering to the subject about 5 mg per day to about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first period of time; (b) administering to the subject about 10 mg per day to about 100 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a second period of time; (c) administering to the subject about 20 mg per day to about 120 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a third period of time; (d) administering to the subject about 10 mg per day to about 120 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a third period of time; The subject applies about 20mg to about 120mg of the compound of formula (I) or its pharmaceutically acceptable salt every day for the fourth time period; (e) the subject applies about 20mg to about 120mg of the compound of formula (I) or its pharmaceutically acceptable salt every day for the fifth time period; (f) the subject applies about 20mg to about 120mg of the compound of formula (I) or its pharmaceutically acceptable salt every day for the sixth time period; and (g) the subject applies about 0mg to about 120mg of the compound of formula (I) or its pharmaceutically acceptable salt every day for the seventh time period. Typically, the first time period, the second time period, the third time period, the fourth time period and the fifth time period each range from about 3 days to about 9 days, the sixth time period ranges from about 3 days to about 16 days, and the seventh time period extends for more than 14 days. However, depending on the subject, a shorter or longer time period can be used for each time period.

[0109] In certain embodiments, the subject does not experience adverse events at any dose level in the titration dose regimen. In certain embodiments, in the absence of applying the first dose level, for a first dose period (e.g., about 5 mg to about 40 mg), the subject will experience adverse events at a second dose level (e.g., about 10 mg to about 100 mg, such as at least about 60 mg to about 100 mg) during the second dose period. In certain embodiments, in the absence of applying the first and second dose levels during the first and second dose periods, the subject will experience adverse events at a third dose level (e.g., about 20 mg to about 120 mg, such as at least about 60 mg to about 120 mg) applied during the third dose period.

[0110] In certain embodiments, where the subject would be likely to experience an adverse event at a second dose level administered during a second dose period in the absence of a first dose level administered during a first dose period, the dose can continue to be titrated to a dose level that is greater than the second dose level administered during the second dose period, such as a dose level that is at least about 25% greater, at least about 50% greater, at least about 75% greater, at least about 100% greater, at least about 125% greater, at least about 150% greater, at least about 175% greater, at least about 200% greater, at least about 250% greater, or at least about 300% greater than the dose level at which the adverse event would have occurred in the absence of titration.

[0111] In certain aspects of all embodiments disclosed herein, the range of the administration period, such as the first, second, third, fourth or fifth period, can be from about 3 days to about 9 days, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days or 9 days. In certain aspects of the embodiments disclosed herein, the range of the administration period (such as the sixth period) can be from about 3 days to about 16 days, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days or 16 days. In other aspects of the embodiments disclosed herein, the administration period, for example, the first period, the second period, the third period, the fourth period, the fifth period, the sixth period or the seventh period can be extended for more than 14 days.

[0112] In some aspects, the dosage increase relative to the previous dosage increase is no more than 40 mg per day. For example, in some embodiments, the second dosage is no more than 40 mg per day relative to the first dosage increase, and in some aspects, the third dosage is no more than 40 mg per day relative to the second dosage increase.

[0113] In another aspect, the present disclosure provides 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, the method comprising administering to the subject (e.g., once, twice, three times) 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 120 mg) per day. about 100 mg, about 20 mg to about 100 mg, about 40 mg to about 100 mg, about 5 mg to about 80 mg, about 10 mg to about 80 mg, about 15 mg to about 80 mg, about 20 mg to about 80 mg, about 40 mg to about 80 mg, about 5 mg to about 60 mg, about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, or about 40 mg to about 60 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0114] In another aspect, the present disclosure provides 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, the method comprising:

[0115] (a) administering 5 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 first period of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days);

[0116] (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

[0117] (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 of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days).

[0118] In another aspect, the present disclosure provides a method of treating a condition in a subject in need thereof, the method comprising:

[0119] (a) administering 20-40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) to the subject daily for a first period of time (e.g., 3 days, 5 days, 6 days, 7 days, 8 days, or 9 days);

[0120] (b) administering 20-60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) to the subject daily for a second period of time (e.g., 3, 5, 6, 7, 8, or 9 days); and

[0121] (c) administering 20-80 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) to the subject daily for a third period of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days).

[0122] In some embodiments, the method further includes (d) administering 20-100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) to the subject daily for a fourth period of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days).

[0123] In other embodiments, the method further comprises (e) administering to the subject 20-120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) per day for a fifth period of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, or 9 days).

[0124] In certain embodiments, the method further includes (f) administering 20-120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) to the subject daily for a sixth period of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, or 16 days).

[0125] In certain embodiments, the method further comprises (g) administering to the subject 20-120 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II)) daily as needed for a seventh period of time (e.g., 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days or more).

[0126] In certain aspects of these embodiments, the doctor may choose not to continue increasing the dosage of the compound of formula (I) or its pharmaceutically acceptable salt so that they can be less than the seven time periods described above. For example, only 1, 2, 3, 4, 5 or 6 dose increase time periods may be required to achieve the desired therapeutic effect.

[0127] For example, 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 5 mg per day to about 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 days to about 9 days, such as 20 mg or 40 mg per day; (b) administering to the subject about 10 mg per day to about 100 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 days to about 9 days, such as 40 mg, 60 mg or 80 mg per day; and (c) administering to the subject about 20 mg per day to about 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 days to about 9 days, such as 60 mg, 80 mg, 100 mg or 120 mg per day.

[0128] In certain aspects, disclosed herein is 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, the method comprising (a) administering to the subject a first dose of about 20 mg per day to about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof, once a day for a first period of time; (b) increasing the amount of the compound in the first dose and administering to the subject one or more increasing doses of the compound to reach a maximum titrated dose of about 80 mg per day to about 120 mg per day; and (c) administering to the subject the maximum titrated dose once a day as needed.

[0129] In a related embodiment, the physician may adjust the dose of the compound of Formula (I) upward or downward, as necessary, in increments of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, depending on the subject's response to the previous dose of the compound of Formula (I).

[0130] In various embodiments of the present disclosure, the methods disclosed herein include: (a) applying a first dose of 20 mg per day for a first period of 3 days; (b) applying a second dose of 40 mg per day for a second period of 3 days; (c) applying a third dose of 60 mg per day for a third period of 7 days; (d) applying a fourth dose of 80 mg per day for a fourth period of 7 days; (e) applying a fifth dose of 100 mg per day for a fifth period of 7 days; and (f) subsequently applying a sixth dose of 120 mg per day as needed. In various other embodiments, the methods disclosed herein include: (a) applying a first dose of 20 mg per day for a first period of 3 days; (b) applying a second dose of 40 mg per day for a second period of 3 days; (c) applying a third dose of 80 mg per day for a third period of 3 days; and (d) applying a fourth dose of 120 mg per day as needed.

[0131] In certain embodiments, a method for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need 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 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 time. The dose may also be administered every 4, 5, or 6 days instead of every 3 days.

[0132] Also disclosed herein is a method for 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 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; and (f) administering to the subject about 120 mg of the compound per day for a sixth period of time.

[0133] In certain embodiments, a method for 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 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof per day for a first period of 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. The dose may also be administered every 4, 5, or 6 days instead of every 3 days.

[0134] Also disclosed herein is a method for 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 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.

[0135] 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) subsequently administering to the subject about 1-120 mg of the compound per day as needed.

[0136] In certain embodiments of the method for treating a subject in need with the abnormal function of T-type calcium channel or the disease related to activity or symptom, once the subject shows the desired therapeutic effect, the doctor can choose to stop increasing the dosage of formula (I) compound or its pharmaceutically acceptable salt.At this point, the doctor can choose to continue to give the dosage that the subject has received, to achieve the desired therapeutic effect, or can choose to reduce the dosage of formula (I) compound or its pharmaceutically acceptable salt to the subject, to maintain the desired therapeutic effect.Realizing the desired therapeutic effect can be due to the improvement of, for example, the TETRAS performance score of the subject, the accelerometer performance score or the Archimedes spiral task test.

[0137] In some embodiments, the subject is a human from birth age to 100 years old, such as 10 to 90 years old, 20 to 70 years old, 18 to 55 years old, or 55-75 years old.

[0138] In various aspects, the methods disclosed herein cause a reduction in the EEG sigma band during NREM sleep in a subject, such as a reduction in the NREM sigma band from baseline of about 0.4 to 0.7, such as about 0.5 to about 0.6, or about 0.5. In certain embodiments, the methods disclosed herein cause a reduction in the EEG gamma band during wakefulness of a subject under EO conditions or under EC conditions, such as a reduction of at least about 25% compared to the baseline gamma band, for example, a reduction of about 50%.

[0139] In certain embodiments, when administering C max From about 30 ng / mL to about 470 ng / mL, such as C max When the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose ranging from 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 to about 470 ng / mL, the methods disclosed herein cause a decrease in EEG Σ frequency during NREM sleep of the subject and / or a decrease in EEG γ band during EO or EC state. In certain embodiments, when the subject is administered AUC 24 The range is from about 490 ng*h / mL to about 5800 ng*h / mL, as shown in AUC 24When the dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof ranges from about 490 ng*hr / ml to 820 ng*hr / ml, about 1220 ng*hr / ml to 2030 ng*hr / ml, about 2000 ng*hr / ml to 3330 ng*hr / ml, about 2440 ng*hr / ml to 4070 ng*hr / ml, about 2820 ng*hr / ml to 4700 ng*hr / ml or about 3480 ng*hr / ml to 5800 ng*hr / ml, the methods disclosed herein cause a decrease in EEG Σ frequency during NREM sleep of the subject and / or a decrease in EEG γ band during EO or EC state.

[0140] In certain embodiments, when administering C max From about 5 ng / mL to about 470 ng / mL, such as C max When the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 180 ng / mL to about 300 ng / mL, the methods disclosed herein cause a decrease in NREMΣ frequency in the subject. In certain embodiments, in certain embodiments, when the average plasma concentration (C ave ) is about 10 ng / mL to about 200 ng / mL, such as C ave The methods disclosed herein cause a decrease in the frequency of NREMΣ in a subject when the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of about 12 ng / mL to about 150 ng / mL. In certain embodiments, when the subject is administered a compound having a C max For about, such as C max When the compound of formula (I) or its pharmaceutically acceptable salt is about 280ng / mL to about 470ng / mL, the method disclosed herein causes the EO or ECγ band of the subject to decrease. In certain embodiments, when the subject is administered a compound of formula (I) or its pharmaceutically acceptable salt at a plasma concentration of about 75ng / ml to about 310ng / mL, such as a plasma concentration of about 90 to about 190ng / mL, the method disclosed herein causes the EO or ECγ band of the subject to decrease.

[0141] In other embodiments, the disease or condition associated with abnormal function or activity of a T-type calcium channel is selected from the group consisting of a psychiatric disorder (e.g., a mood disorder (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), seizure (e.g., absence seizure), and epilepsy or an epilepsy syndrome (e.g., juvenile myoclonic epilepsy).

[0142] In certain aspects of all embodiments of the titrated dose regimens disclosed herein, the maximum titrated dose can be increased, including, for example, increasing the maximum titrated dose to above 120 mg in one or more additional titration steps, provided that the subject can safely tolerate the higher dose.

[0143] In certain aspects of all embodiments of the titration dosage regimen disclosed herein, the maximum titration dosage achieved is greater than 20 mg, greater than 40 mg, greater than 60 mg, such as 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 invention, if the subject has achieved the desired therapeutic outcome, the maximum dosage achieved by the subject is, for example, 40, 60 or 80 mg.

[0144] In certain aspects of all embodiments of the titrated dose regimen disclosed herein, the maximum titrated dose is reached within 42 days or less (e.g., 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 titrated dose is reached within about 10 days to about 42 days, e.g., about 36-42 days, about 22-28 days, about 16-18 days, or about 10-12 days.

[0145] Dosage forms and compositions

[0146] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as a compound of formula (II), may be in a dosage form or in a pharmaceutical composition.

[0147] In some embodiments, the composition useful in the methods described herein may be a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an excipient for modifying the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0148] In certain embodiments, the 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 modified release polymer (e.g., a controlled release polymer, a hydrophilic matrix polymer, e.g., an HPMC polymer, a hydrophobic matrix polymer (e.g., ethyl cellulose / ethocel) or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)).

[0149] In other embodiments, dosage forms that can be used in the methods described herein can be dosage forms or compositions that include a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) and a modified release polymer (e.g., a controlled release polymer, a hydrophilic matrix polymer, e.g., an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose) or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100)), for example, 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)) when administered to a subject.

[0150] In some embodiments, the dosage form may include about 0.9 wt % to about 40 wt % (e.g., about 0.9 wt % to about 30 wt %, about 1 wt % to about 25 wt %, about 2 wt % to about 25 wt %, about 3 wt % to about 20 wt %, about 4 wt % to about 20 wt %, about 5 wt % to about 20 wt %, about 5 wt % to about 15 wt %, about 5 wt % to about 10 wt % or about 0.9 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19 wt %, about 20 wt %, about 25 wt %, about 20 wt %, about 2 %, about 9 weight %, about 10 weight %, about 11 weight %, about 12 weight %, about 13 weight %, about 14 weight %, about 15 weight %, about 16 weight %, about 17 weight %, about 18 weight %, about 19 weight %, about 20 weight %, about 21 weight %, about 22 weight %, about 23 weight %, about 24 weight %, about 25 weight %, about 26 weight %, about 27 weight %, about 28 weight %, about 29 weight %, about 30 weight %, about 40 weight %) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form comprises about 30 weight % to about 40 weight % of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)).

[0151] In some embodiments, the dosage form may include 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 certain embodiments, the dosage form contains 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 certain embodiments, the dosage form contains 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 certain embodiments, the dosage form contains 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 certain embodiments, the dosage form contains 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 certain embodiments, the dosage form contains 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 certain embodiments, the dosage form 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 certain embodiments, the dosage form 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)).

[0152] In other embodiments, dosage forms that can be used in the methods described herein can include 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 modified release 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)), for example, in an amount sufficient to modify the release rate of a compound of formula (I) or a pharmaceutically acceptable salt thereof (eg, a compound of formula (II)) when administered to a subject.

[0153] In other embodiments, the dosage form comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 5 mg to about 15 mg (e.g., about 10 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the dosage form comprises about 25 mg to about 35 mg (e.g., about 30 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form includes about 35 mg to about 45 mg (e.g., about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form includes about 45 mg to about 55 mg (e.g., about 50 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form includes about 55 mg to about 65 mg (e.g., about 60 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the dosage form includes about 65 mg to about 75 mg (e.g., about 70 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form includes about 75 mg to about 85 mg (e.g., about 80 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form includes about 85 mg to about 95 mg (e.g., about 90 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In some embodiments, the dosage form comprises about 95 mg to about 105 mg (e.g., about 100 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the dosage form comprises about 105 mg to about 115 mg (e.g., about 110 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the dosage form 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)).

[0154] In some embodiments, the dosage form comprises about 55 mg to 65 mg of a modified release polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 10 wt % to about 70 wt % of a modified release polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 50 wt % to about 60 wt % of a modified release polymer (e.g., an HPMC polymer).

[0155] 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 15mg to 40mg (e.g., about 15mg to about 25mg, about 20mg to about 25mg, about 25mg to about 30mg, about 30mg to about 40mg) of microcrystalline cellulose. In some embodiments, the dosage form comprises about 15mg to about 25mg of microcrystalline cellulose. In certain embodiments, the dosage form comprises about 30mg to about 40mg of microcrystalline cellulose. In some embodiments, the dosage form includes about 15% by weight to about 35% by weight (e.g., about 15% by weight to about 20% by weight, about 20% by weight to about 25% by weight, 25% by weight to about 30% by weight, 30% by weight to about 35% by weight) of microcrystalline cellulose.

[0156] In certain 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 certain embodiments, the dosage form further comprises a coating agent.

[0157] In some embodiments, about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof is released within 7 hours after administration to a subject. In certain embodiments, using USP apparatus type I, a medium containing 900 mL 0.1 M HCl and a paddle speed of 100 rpm, about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof is released within 7 hours.

[0158] In certain embodiments, after administration to a subject, the dosage form has a reduced C 20 compared to a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a modified release polymer, such as an HPMC polymer). max In certain embodiments, after administration to a subject, the dosage form has a greater t than a reference oral dosage form (e.g., a dosage form with any expected release rate profile, such as a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a modified release polymer, such as an HPMC polymer). max value.

[0159] In other embodiments, the dosage form is administered to the patient once a day. In certain embodiments, the dosage form is administered to the patient twice a day. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.

[0160] In some embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) 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.

[0161] In other embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) 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.

[0162] In certain embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) 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.

[0163] In some embodiments, a dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) comprising: about 3 wt % to about 8 wt % of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 53 wt % to about 64 wt % of an HPMC polymer.

[0164] In other embodiments, the dosage form that can be used in the methods described herein can be an oral (e.g., granular) composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and a modified release polymer (e.g., a controlled release polymer, such as an HPMC polymer as a hydrophilic matrix polymer).

[0165] In some embodiments, the composition includes 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 certain embodiments, the composition includes 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 certain embodiments, the composition includes 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 certain embodiments, the composition includes 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 certain embodiments, the composition includes 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 certain embodiments, the composition includes 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 certain 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 certain 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 certain 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)).

[0166] In some embodiments, the composition 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)). 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 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 25 mg to about 35 mg (e.g., about 30 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In other embodiments, the composition comprises about 35 mg to about 45 mg (e.g., about 40 mg) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)). In certain embodiments, the composition comprises about 45 mg to about 55 mg (e.g., about 50 mg) 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 55 mg to about 65 mg (e.g., about 60 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 65 mg to about 75 mg (e.g., about 70 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 75 mg to about 85 mg (e.g., about 80 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 85 mg to about 95 mg (e.g., about 90 mg) 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 95 mg to about 105 mg (e.g., about 100 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 105 mg to about 115 mg (e.g., about 110 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 115 mg to about 125 mg (eg, about 120 mg) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (eg, a compound of Formula (II)).

[0167] In some embodiments, the composition comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In other embodiments, the composition comprises about 15 m g to 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg g In some embodiments, the composition comprises about 15% to about 35% by weight (e.g., about 15% to about 20%, about 20% to about 25%, 25% to about 30%, 30% to about 35% by weight) microcrystalline cellulose.

[0168] In certain 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 certain embodiments, the composition further comprises a coating agent. In some embodiments, the compound of formula (I) or (II), including, for example, a compound of form C or form B, is stable in the formulation at about 25°C at 60% relative humidity for at least 24 months. In some embodiments, the compound is stable at about 25°C at 60% relative humidity for at least 36 months. In some embodiments, the compound is stable at about 25°C at 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at about 25°C at 60% relative humidity for at least 60 months. In some embodiments, the compound is stable at about 40°C at 75% relative humidity for at least 6 months.

[0169] In other embodiments of the oral dosage forms or compositions described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is a crystalline form. In certain embodiments, the crystalline form is a crystalline form as described herein, e.g., Form C or Form B.

[0170] Crystalline form of the compound of formula (II)

[0171] The crystalline form of the compound of formula (II) used in the methods as 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.

[0172] 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 other 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 certain embodiments, the crystalline form has Figure 1 In some embodiments, the XRPD pattern is obtained using Cu Ka radiation. In certain embodiments, the crystalline form has a melting point onset at about 226.6 °C as determined by differential scanning calorimetry. In certain embodiments, the crystalline form has a melting point onset at about 226.6 °C as determined by differential scanning calorimetry. Figure 2 Essentially the same differential scanning calorimetry curve as shown in .

[0173] The crystalline form of the compound of formula (II) used in the methods as 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.

[0174] 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 other 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 certain embodiments, the crystalline form has Figure 7 8. In some embodiments, the powder XRPD is obtained using Cu Ka radiation. In certain embodiments, the crystalline form has a melting point onset at about 97.9°C, 131.6°C, 223.7°C, 83.8°C, 128.9°C, 168.9°C, or 224.4°C as determined by differential scanning calorimetry. In some embodiments, the crystalline form has a differential scanning calorimetry curve substantially the same as that shown in FIG8.

[0175] Immediate release formulations

[0176] In some embodiments, a dosage form or composition that can be used in the methods described herein can be a dosage form or composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is released immediately after administration to a subject.

[0177] In other embodiments, the dosage form that can be used in the methods described herein can be an immediate release oral capsule comprising: about 15 mg to about 20 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)); and about 75 mg to 85 mg of a diluent; about 2 mg to 10 mg of a binder; about 1% to about 5% of a disintegrant; and about 0.1 mg to 5 mg of a lubricant.

[0178] Application

[0179] In certain embodiments, the dosage form is administered to the subject more than once per day (eg, twice per day, three times per day, or four times per day).

[0180] In some embodiments, the dosage form is administered to the subject once a day (e.g., one 20 mg tablet once a day, two 20 mg tablets once a day, or three 20 mg tablets once a day). gTablets). In some embodiments, the dosage form is administered to the subject twice a day (e.g., one 10 mg tablet twice a day, one 20 mg tablet twice a day, two 20 mg tablets twice a day, or three 20 mg tablets twice a day). In certain embodiments, the dosage form is administered to the subject every other day. In certain embodiments, about 1 mg to 60 mg, such as 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 the subject every day. In other embodiments, about 15 mg to 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject every day. In certain embodiments, about 30 mg to 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (II)) is administered to the subject every day.

[0181] In some embodiments, upon administration to a subject, the dosage form has a reduced C 20 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, a dosage form without a modified release polymer, e.g., an HPMC polymer). max In some embodiments, after administration to a subject, the dosage form has a greater t compared to a reference oral dosage form (e.g., a dosage form with any expected release rate profile, e.g., a modified release rate profile, a dosage form without a modified release rate profile, a dosage form without a modified release polymer, e.g., an HPMC polymer). max value.

[0182] Epilepsy and epileptic syndromes

[0183] The compositions described herein can be used to treat epilepsy and epileptic syndromes. Epilepsy is a central nervous system disorder in which nerve cell activity in the brain is disrupted, resulting in recurrent seizures that can manifest as abnormal movements, periods of abnormal behavior, sensations, and sometimes loss of consciousness. Seizure symptoms vary widely, from a simple blank stare for a few seconds to repeated twitching of an arm or leg during a seizure.

[0184] Epilepsy may involve generalized seizures, involving multiple areas of the brain, or partial or focal seizures. Generalized seizures involve all areas of the brain. People experiencing generalized seizures may cry or make some sounds, stiffen for several seconds to a minute, and then have rhythmic movements of arms and legs. Eyes may be open, and / or the person may not seem to be breathing and become blue. The recovery of consciousness may be gradual, and the person may feel confused in a few minutes to a few hours. The following are the main types of generalized seizures: tonic-clonic, tonic, clonus, myoclonus, myoclonus-tonic-clonic, myoclonus-atonia, atonia and absence (typical, atypical, myoclonus, eyelid myoclonus) seizures and epileptic spasms. In partial or focal seizures, only a part of the brain is involved, therefore only a part of the body is affected. Depending on the part of the brain with abnormal electrical activity, symptoms may be different.

[0185] As used herein, epilepsy includes generalized, partial, complex partial (e.g., a seizure involving only part of the brain but in which consciousness is impaired), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0186] The compositions described herein can also be used to treat epileptic syndromes. Severe syndromes with diffuse brain dysfunction caused at least in part by some aspects of epilepsy are also called epileptic encephalopathy. These are associated with frequent epileptic seizures and severe cognitive dysfunction (e.g., West syndrome) that are resistant to treatment.

[0187] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, severe myoclonic epilepsy of infancy (Dravet syndrome), Angelman syndrome, CDKL5 deficiency, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy or Glut1 deficiency syndrome. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Rege syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for hereditary generalized epilepsy (GGE) and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE), as discussed, for example, in Feng, YCA et al., "Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals," Am. J. Human Gen. 2019; 105(2): 267-282. In some embodiments, the epilepsy syndrome is epilepsy with myoclonic-atonic seizures (Doose syndrome) or myoclonic unstable epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spikes and waves in sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau-Kriffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0188] Absence seizures

[0189] Absence seizures are one of the most common types of seizures in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsy 2000). Absence seizures are relatively short-lived non-convulsive seizures characterized by the sudden loss of consciousness and responsiveness, usually lasting 10-30 seconds, and rapidly recovering normal consciousness without post-ictal confusion. In the accompanying EEG recording, epileptic seizures are characterized by the sudden occurrence and deviation of systemic 1-6Hz (e.g., 3Hz) peak and wave discharges. Absence seizures often occur multiple times a day, interrupting learning and psychosocial functions, and there is a risk of injury due to the frequent onset of loss of consciousness. Typically, absence seizures begin in childhood and are relieved in adolescence. However, in a few patients, they will continue to adulthood, and they often develop drug resistance and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures are often highly disabling, particularly by disqualifying the patient from obtaining a motor vehicle license or engaging in occupations and hobbies in which the seizure-related loss of arousal phases constitutes a safety risk, and are associated with severe psychosocial disability (Wirrell et al., 1997).

[0190] Although absence seizures are generally considered to be relatively "easy" to treat, randomized controlled trials in patients with childhood absence epilepsy have shown that even the most effective antiepileptic drugs, ethosuximide and valproate, only completely controlled seizures in 53% and 58% of patients, respectively, at 16 weeks (as assessed by video-EEG recordings) (Glauser et al., 2010), and in 45% and 44% at 12 months, respectively (Glauser et al., 2013). Lamotrigine, another AED commonly used to treat absence seizures, controlled seizures in only 29% of patients at 16 weeks and in 21% of patients at 12 months. In addition, both ethosuximide and valproate are often associated with intolerable side effects (occurring in 24% of patients treated with either of these drugs) (Glauser et al., 2010), and the latter is now generally considered contraindicated in girls and women of childbearing potential. Other treatment options for absence seizures are limited, with only benzodiazepines having established efficacy, and these drugs are often poorly tolerated due to sedation and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, with patients often treated with multiple medications that result in severe side effects and fail to achieve seizure control.

[0191] There is a large body of evidence that low-threshold (T-type) calcium channels play a role in the development and maintenance of absence seizures and are a key component of the oscillatory burst discharges that occur in thalamocortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the disclosure relates to methods for treating absence seizures using the compositions described herein. In certain embodiments, the absence seizure is a refractory absence seizure. In some embodiments, the absence seizure is refractory to anti-epileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0192] In some embodiments, the subject suffers from epilepsy. In some embodiments, the absence seizure is an atypical absence seizure. In some embodiments, the absence seizure comprises an adult absence seizure, a juvenile absence seizure, or a childhood absence seizure.

[0193] In some embodiments, the methods described herein further comprise identifying a subject suffering from absence seizures.

[0194] Genetic epilepsy

[0195] In some embodiments, the epilepsy or epilepsy syndrome is hereditary epilepsy or hereditary epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is hereditary systemic epilepsy. In some embodiments, epilepsy or epilepsy syndrome includes epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptic pediatric partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial epilepsy in infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy and KCNT1 epileptic encephalopathy.

[0196] In certain embodiments, the methods described herein further comprise identifying a subject having epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic pediatric partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) prior to administering a composition described herein.

[0197] In one aspect, the invention features a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic pediatric partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a composition described herein.

[0198] The compositions of the invention can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more of the following: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2 ,KCNQ3,KCNT1,KCTD7,LGI1,MEF2C,NHLRC1,PCDH19,PLCB1,PNKP,PNPO,PRICKLE1,PRICKLE2,PRRT2,RELN,SCARB2,SCN1A,SCN1B,SCN2A,SCN8A,SCN9A,S IAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24 and WWOX.

[0199] In some embodiments, the methods described herein further comprise identifying, prior to administration of the composition, that the subject has a mutation in one or more of: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1,KCTD7,LGI1,MEF2C,NHLRC1,PCDH19,PLCB1,PNKP,PNPO,PRICKLE1,PRICKLE2,PRRT2,RELN,SCARB2,SCN1A,SCN1B,SCN2A,SCN8A,SCN9A,SIAT9,SIK1,SLC13 A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H and CACNA1I.

[0200] The compositions of the invention can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more of the following: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNA JC5,DNM1,DOCK7,DYRK1A,EEF1A2,EFHC1,EHMT1,EPM2A,FARS2,FOLR1,FOXG1,FRRS1L,GABBR2,GABRA1,GABRB2,GABRB3,GABRG2,GAMT,GATM,GLRA1,G NAO1,GOSR2,GRIN1,GRIN2A,GRIN2B,HCN1,HNRNPU,IER3IP1,IQSEC2,ITPA,JMJD1C,KANSL1,KCNA2,KCNB1,KCNC1,KCNH2,KCNJ10,KCNMA1,KCNQ2,KCN Q3,KCNT1,KCTD7,LGI1,LIAS,MBD5,MECP2,MEF2C,MFSD8,MOCS1,MOCS2,MTOR,NEDD4L,NEXMIF,NGLY1,NHLRC1,NPRL3,NRXN1,PACS1,PCDH19,PIGA,PI GN,PIGO,PLCB1,PNKD,PNKP,PNPO,POLG,PPT1,PRICKLE1,PRIMA1,PRRT2,PURA,QARS,RELN,ROGDI,SATB2,SCARB2,SCN1A,SCN1B,SCN2A,SCN3A,SCN8A ,SCN9A,SERPINI1,SGCE,SIK1,SLC12A5,SLC13A5,SLC19A3,SLC25A12,SLC25A22,SLC2A1,SLC35A2,SLC6A1,SLC6A8,SLC9A6,SMC1A,SNX27,SPATA5,S PTAN1,ST3GAL5,STRADA,STX1B,STXBP1,SUOX,SYN1,SYNGAP1,SYNJ1,SZT2,TBC1D24,TCF4,TPK1,TSC1,TSC2,UBE3A,WDR45,WWOX,ZDHHC9,ZEB2,ABAT,ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN and RANBP2.,

[0201] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, D NAJC5,DNM1,DOCK7,DYRK1A,EEF1A2,EFHC1,EHMT1,EPM2A,FARS2,FOLR1,FOXG1,FRRS1L,GABBR2,GABRA1,GABRB2,GABRB3,GABRG2,GAMT,GATM,GLRA1 ,GNAO1,GOSR2,GRIN1,GRIN2A,GRIN2B,HCN1,HNRNPU,IER3IP1,IQSEC2,ITPA,JMJD1C,KANSL1,KCNA2,KCNB1,KCNC1,KCNH2,KCNJ10,KCNMA1,KCNQ2,KC NQ3,KCNT1,KCTD7,LGI1,LIAS,MBD5,MECP2,MEF2C,MFSD8,MOCS1,MOCS2,MTOR,NEDD4L,NEXMIF,NGLY1,NHLRC1,NPRL3,NRXN1,PACS1,PCDH19,PIGA,P IGN,PIGO,PLCB1,PNKD,PNKP,PNPO,POLG,PPT1,PRICKLE1,PRIMA1,PRRT2,PURA,QARS,RELN,ROGDI,SATB2,SCARB2,SCN1A,SCN1B,SCN2A,SCN3A,SCN8A ,SCN9A,SERPINI1,SGCE,SIK1,SLC12A5,SLC13A5,SLC19A3,SLC25A12,SLC25A22,SLC2A1,SLC35A2,SLC6A1,SLC6A8,SLC9A6,SMC1A,SNX27,SPATA5,S PTAN1,ST3GAL5,STRADA,STX1B,STXBP1,SUOX,SYN1,SYNGAP1,SYNJ1,SZT2,TBC1D24,TCF4,TPK1,TSC1,TSC2,UBE3A,WDR45,WWOX,ZDHHC9,ZEB2,ABAT,ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN and RANBP2.,

[0202] The compositions of the invention can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more of the following: ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD (CLN10), CTSF, DDX3X, DEPDC5, DNAJC5 (CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1 ,FOXG1,FRRS1L,GABBR2,GABRA1,GABRB2,GABRB3,GABRG2,GAMT,GATM,GLDC,GNAO1,GOSR2,GRIN1,GRIN2A,GRIN2B,HNRNPU,IQSEC2,KANSL1,KCNA2,KCNB1,KCNC1,KCNH1,KCNJ10,KCN MA1,KCNQ2,KCNQ3,KCNT1,KCTD7(CLN14),KDM6A,KIAA2022,LGI1,MAGI2,MBD5,MECP2,MEF2C,MFSD8(CLN7),NALCN,NGLY1,NHLRC1(EPM2B),NPRL3.NR2F1,NRXN1,PACS1,PCDH19,PIGA PIGO,PIGV,PLCB1,PNKP,PNPO,POLG,PPP2R5D,PPT1(CLN1),PRRT2,PURA,QARS,SATB2,SCARB2,SCN1A,SCN1B,SCN2A,SCN8A,SLC13A5,SLC19A3,SLC25A22,SLC2A 1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0203] In some embodiments, the methods described herein further comprise identifying that the subject has a mutation in one or more of: ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD (CLN10), CTSF, DDX3X, DEPDC5, DNAJC5 (CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1,FRRS1L,GABBR2,GABRA1,GABRB2,GABRB3,GABRG2,GAMT,GATM,GLDC,GNAO1,GOSR2,GRIN1,GRIN2A,GRIN2B,HNRNPU,IQSEC2,KANSL1,KCNA2,KCNB1,KCNC1,KCNH1,KCNJ10,KCN MA1,KCNQ2,KCNQ3,KCNT1,KCTD7(CLN14),KDM6A,KIAA2022,LGI1,MAGI2,MBD5,MECP2,MEF2C,MFSD8(CLN7),NALCN,NGLY1,NHLRC1(EPM2B),NPRL3.NR2F1,NRXN1,PACS1,PCDH19,PIGA PIGO,PIGV,PLCB1,PNKP,PNPO,POLG,PPP2R5D,PPT1(CLN1),PRRT2,PURA,QARS,SATB2,SCARB2,SCN1A,SCN1B,SCN2A,SCN8A,SLC13A5,SLC19A3,SLC25A22,SLC2A 1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0204] The compositions of the invention can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCN C1,KCNJ10,KCNQ2,KCNQ3,KCNT1,KCTD7,KIAA2022,LGI1,MECP2,MEF2C,MFSD8,NHLRC1,NRXN1,PCD H19,PIGA,PLCB1,PNKP,PNPO,POLG,PPT1,PRICKLE1,PRRT2,PURA,SCARB2,SCN1A,SCN1B,SCN2A,SCN 8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0205] In some embodiments, the methods described herein further comprise identifying that the subject has a mutation in one or more of: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCN C1,KCNJ10,KCNQ2,KCNQ3,KCNT1,KCTD7,KIAA2022,LGI1,MECP2,MEF2C,MFSD8,NHLRC1,NRXN1,PCD H19,PIGA,PLCB1,PNKP,PNPO,POLG,PPT1,PRICKLE1,PRRT2,PURA,SCARB2,SCN1A,SCN1B,SCN2A,SCN 8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0206] Mood disorders

[0207] Also provided herein are methods for treating mental disorders such as mood disorders, such as clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideas or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect for subjects suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or condition described herein (e.g., neuroendocrine diseases and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's Disease), women's health disorders or conditions).

[0208] Clinical depression is also known as major depressive disorder, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder and recurrent depression, and refers to a mental disorder characterized by a general and persistent low mood, with low self-esteem and loss of interest or pleasure in normally pleasurable activities. Some people with clinical depression have difficulty sleeping, lose weight, and generally feel anxious and irritable. Clinical depression affects how individuals feel, think and act, and may cause a variety of emotional and physical problems. Individuals with clinical depression may have difficulty carrying out daily activities, and feel as if life is not worth living.

[0209] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying spells, feeling restless, difficulty sleeping, extreme exhaustion (emotional and / or physical), changes in appetite, difficulty focusing, increased anxiety and / or worry, feelings of separation from the baby and / or fetus, and loss of interest in activities that were previously pleasurable.

[0210] Postpartum depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, loss of libido, crying attacks, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., refractory depression as described herein).

[0211] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy. Such depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression experience an increased risk of PND.

[0212] Atypical depression (AD) is characterized by increased emotional reactivity (e.g., abnormal anhedonia) and motivation, significant weight gain or increased appetite. Patients with AD may also have excessive sleep or sleepiness (hypersomnia), a sense of heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0213] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood that is more pronounced than sadness or loss, excessive weight loss, or excessive guilt.

[0214] Psychotic major depressive disorder (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0215] Catatonic depression refers to major depressive disorder that involves disturbances in motor behavior and other symptoms. The individual may become silent and catatonic, and be immobile or display meaningless or strange movements.

[0216] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes in the fall or winter.

[0217] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. These problems are less severe and tend to be more persistent (e.g., at least 2 years).

[0218] Double depression is defined as a period of severe depressed mood (dysthymia) lasting at least 2 years and marked by a phase of major depressive disorder.

[0219] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0220] Recurrent brief depressive disorder (RBD) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting 2 weeks or less, and usually less than 2-3 days.

[0221] Minor depressive disorder or minor depression means depression in which at least 2 symptoms are present for 2 weeks.

[0222] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During mania, individuals may feel or appear unusually happy, energetic, or irritable. They often make poorly thought-out decisions with little regard for the consequences. The need for sleep is often reduced. During depression, there may be tearfulness, poor eye contact with others, and a negative outlook on life. People with this condition have a high risk of suicide within 20 years, greater than 6%, while the incidence of self-harm is 30-40%. Other mental health issues such as anxiety disorders and substance use disorders are often associated with bipolar disorder.

[0223] Depression caused by a chronic medical condition means depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, chronic stress.

[0224] Treatment-resistant depression refers to a condition in which depression has been treated for an individual but the symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of an individual with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms but relapse. Refractory depression occurs in patients with depression who are resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or antianxiety drugs) and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0225] Postoperative depression refers to depressed feelings after surgical surgery (e.g., because of having to face the death of a person). For example, an individual may have persistent feelings of sadness or emptiness, a loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0226] A mood disorder associated with a condition or disorder of a woman's health refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a condition or disorder of a woman's health (eg, as described herein).

[0227] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual preoccupations with suicide. The range of suicidal ideation varies widely, from fleeting thoughts, for example, to extensive thoughts, detailed plans, role-playing, and / or incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social situations, preoccupying oneself with death, feeling confused or hopeless about a situation, increasing use of alcohol or drugs, doing dangerous or self-destructive things, and saying goodbye to people as if they were never to be seen again.

[0228] Symptoms of depression include persistent feelings of anxiety or sadness, helplessness, hopelessness, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, physical challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of vitality, poor self-esteem, lack of positive thoughts or plans, lethargy, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts and suicide attempts. The presence, severity, frequency and duration of symptoms can vary from case to case. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., by a mental status examination).

[0229] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, mood disorders, anxiety disorders, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0230] In some embodiments, the method comprises monitoring subjects with known depression scales, e.g., Hamilton depression (HAM-D) scale, Clinical Global Impression-Improvement Scale (CGI) and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by the reduction of the Hamilton depression (HAM-D) total score shown by the subject. The therapeutic effect can be evaluated during a specified treatment period. For example, the therapeutic effect can be determined by the decrease in the HAM-D total score relative to baseline after applying the composition described herein (e.g., 12, 24 or 48 hours after application; or 24, 48, 72 or 96 hours or more; or 1 day, 2 days, 14 days, 21 days or 28 days; or 1 week, 2 weeks, 3 weeks or 4 weeks; or 1 month, 2 months, 6 months or 10 months; or 1 year, 2 years or lifelong).

[0231] In some embodiments, the subject suffers from mild depressive disorder, for example, mild severe depressive disorder. In some embodiments, the subject has moderate depressive disorder, for example, moderate severe depressive disorder. In some embodiments, the subject has severe depressive disorder, for example, severe severe depressive disorder. In some embodiments, the subject has extremely severe depressive disorder, for example, extremely severe severe depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (that is, before treatment with the composition described herein) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between 14 and 18 and includes the end value. In some embodiments, the baseline HAM-D total score of the subject is between 19 and 22 and includes the end value. In some embodiments, the HAM-D total score of the subject before treatment with the composition described herein is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15 or 20. In some embodiments, the subject's HAM-D total score after treatment with a composition described herein is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a composition described herein is less than 10, 7, 5, or 3. In some embodiments, the decrease in HAM-D total score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a composition described herein. In some embodiments, the decrease from baseline HAM-D total score to the HAM-D total score after treatment with a composition described herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50). In some embodiments, the percentage decrease from baseline HAM-D total score to the HAM-D total score after treatment with a composition described herein is at least 50% (e.g., 60%, 70%, 80%, or 90%). In certain embodiments, the therapeutic effect is measured as a decrease in the HAM-D total score after treatment with a composition described herein relative to the baseline HAM-D total score.

[0232] In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect (e.g., as measured by reducing the HAM-D score within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day or within 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less). In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect within the first or second day of treatment with a composition described herein (e.g., as measured by a statistically significant reduction in the HAM-D total score). In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect within less than or equal to 14 days after initiating treatment with a composition described herein (e.g., as measured by a statistically significant reduction in the HAM-D total score). In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect within less than or equal to 21 days after initiating treatment with a composition described herein (e.g., as measured by a statistically significant reduction in the HAM-D total score). In some embodiments, the method for treating depressive disorders (e.g., major depressive disorders) provides a therapeutic effect (e.g., as measured by a statistically significant reduction in a HAM-D total score) within less than or equal to 28 days after starting treatment with a composition described herein. In certain embodiments, the therapeutic effect is a decline in the HAM-D total score from baseline after treatment with a composition described herein. In some embodiments, the HAM-D total score of the subject before treatment with a composition described herein is at least 24. In some embodiments, the HAM-D total score of the subject before treatment with a composition described herein is at least 18. In some embodiments, the HAM-D total score of the subject before treatment with a composition described herein is between 14 and 18 and includes the end value. In some embodiments, the decline in the HAM-D total score relative to the baseline HAM-D total score after treating a subject with a composition described herein is at least 10. In some embodiments, the decline in the HAM-D total score relative to the baseline HAM-D total score after treating a subject with a composition described herein is at least 15. In some embodiments, the HAM-D total score associated with treating a subject with a composition described herein does not exceed a number within the range of 6 to 8. In some embodiments, the HAM-D total score associated with treating a subject with a composition described herein is no greater than 7.

[0233] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression-Improvement Scale (CGI)) within 14, 10, 4, 3, 2, or 1 day or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., a major depressive disorder. In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score at the end of the treatment period (e.g., 14 days after administration) relative to baseline.

[0234] The therapeutic effect of major depressive disorder can be determined by the reduction of Montgomery-Asberg Depression Rating Scale (MADRS) scoring shown by the experimenter.For example, MADRS scoring can be in 4 days, 3 days, 2 days or 1 day; Or 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours or reduce in less time.MADRS is ten project diagnostic questionnaires (about obvious sadness, sadness reported, inner tension, sleep reduction, decreased appetite, concentration difficulties, fatigue, can not feel, pessimistic thoughts and suicidal thoughts), and psychiatrists use the questionnaire to measure the severity of the depressive episode of the patient with mood disorder.In some embodiments, the therapeutic effect is the decline of MADRS scoring from baseline at the end of the treatment period (for example, after applying 14 days).

[0235] pain

[0236] The dosage forms and compositions described herein can be used to treat pain. In certain embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain) or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In certain embodiments, the pain comprises migraine.

[0237] In certain embodiments, the methods described herein further comprise identifying a subject having pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine) prior to administering a dosage form or composition described herein (e.g., a dosage form or composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (II))).

[0238] Tremor

[0239] The methods described herein can be used to treat tremor, for example, the doses or compositions disclosed herein can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, or rubrosomal tremor. Tremor includes: genetic, degenerative, and congenital disorders, such as Wilson's disease (genetic), Parkinson's disease (degenerative), and essential tremor (congenital); metabolic diseases; peripheral neuropathies (with Charcot-Marie-Tooth, Roussy-Levy, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced (neuroleptics tricyclics, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor may be neurological and may be classified as physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor), primary orthostatic tremor, task- and position-specific tremor, dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (ie, red nucleus tremor), palatal tremor, toxic or drug-induced tremor, and psychogenic tremor. Tremor may be familial.

[0240] A tremor is an involuntary, rhythmic oscillation of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0241] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum or pathways, such as from tumors, stroke or other focal lesion diseases (e.g., multiple sclerosis) or neurodegenerative diseases.

[0242] Dystonic tremors occur in individuals affected by dystonia (a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful and abnormal postures or positions). Dystonic tremors may affect any muscle in the body. Dystonic tremors occur irregularly and can often be relieved by complete rest or certain sensory manipulations.

[0243] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild, and some are non-progressive, and can be slowly progressive, starting on one side of the body but usually affecting both sides. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease as a person ages, but the severity may increase. Aggravated emotions, stress, fever, physical fatigue, or low blood sugar may trigger tremors and / or increase their severity. Symptoms usually progress over time and can be obvious and persistent after they occur.

[0244] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs, and patients may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occur in patients with essential tremor.

[0245] Parkinson's disease tremor is caused by damage to structures in the brain that control movement. Parkinson's disease tremor is often seen as a "ball rolling" movement of the hands, which may also affect the jaw, lips, legs, and trunk. The onset of Parkinson's disease tremor usually begins after age 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0246] Rubrostral tremor is characterized by a coarse, slow tremor that can be present at rest, in posture, and with intent. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0247] In certain embodiments, the tremor is selected from essential tremor, Parkinson's disease tremor, or cerebellar tremor.

[0248] The efficacy 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., "An MDS-based evidence review of treatments for essential tremor," Movement Disorders.. 2019 Jul;34(7):950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor," Movement Disorders. 2013 Nov;28(13):1793-800; Deuschl G. et al., "Treatment of patients with essential tremor," Lancet Neurol. 2011;10:148–61; and Reich SG et al., "Essential Tremor: A review of the evidence for essential tremor." Tremor), Med. Clin. N. Am. 2019; 103: 351–356. The disclosure of the reference is incorporated herein in its entirety.

[0249] In some embodiments, the methods described herein reduce upper limb tremor scores by at least 25%, wherein the tremor scores can be converted to amplitudes compared to baseline. For example, in certain embodiments, as measured by the essential tremor assessment scale (TETRAS) upper limb score, the methods described herein reduce tremor amplitude by an average of about 40%, such as described in Elble, RJ, "Essential Tremor Assessment Scale (The Essential Tremor Rating Assessment Scale)", Journal of Neurology Neuromed. 2016; 1 (4): 34-38. In some embodiments, compared to baseline, the methods described herein reduce TETRAS performance scores by at least 25%. In some embodiments, as measured by TETRAS performance scores, compared to baseline, the methods described herein reduce symptom severity by an average of at least 35%.

[0250] Ataxia

[0251] Ataxia, including cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally related to the loss or failure of coordination. The patient showing ataxia may be difficult to adjust the power, range, direction, speed and rhythm involved in posture, balance and limb movement. For example, the ataxia of the trunk can cause the posture to sway and increase, and the center of gravity cannot be kept on the support bottom. The primary or secondary symptoms of ataxia and ataxic gait and tremor of the limbs may be accompanied by speech disorders, dysphagia, ventilation and speech abnormalities and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, thus seriously interfering with the activities of daily life.

[0252] As noted above, ataxia may be caused by a variety of underlying diseases and conditions in the patient, including cerebellar disorders and neurodegenerative diseases and diseases caused by chronic or long-term exposure to toxins. Symptoms of ataxia may be caused by a variety of diseases, disorders, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and long-term or chronic exposure to toxins (including drugs and alcohol), etc.; in one embodiment, for example, ataxia is the result of a metabolic disease, a neurodegenerative disease, a vascular disease, a neuromuscular disease, or a disease caused by long-term or chronic exposure to toxins. Diseases, disorders, syndromes and conditions that may result in ataxia symptoms that may be treated with the methods described herein include, but are not limited to, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (retinal tapetum lucidum), ... degeneration of the cerebellum parenchyma, autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar hypoplasia (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal conditions, autonomic dysfunction, balance disorders, tardive symptom syndrome, endocrine disorders, disorders caused by chronic exposure to toxins (e.g., alcohol, drugs, anticonvulsants, relaxants), fragile X / tremor ataxia syndrome, Friedreich's ataxia ataxia), frontal lobe dysfunction, hereditary disorders, granulomatous vasculitis of the central nervous system, Hallervorden-Spatz disease, hereditary motor and sensory neuropathies, hydrocephalus (e.g., low or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem responses, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller Fisher Syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonus-ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, Parkinson's disease (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe damage to the brain (e.g.,Caused by head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infections or brain tumors), spastic hemiparesis, spastic paraplegia 23, spastic paraplegia glaucoma precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular dystrophy-deafness), spinocerebellar ataxia (malformation), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal recessive 1), spinocerebellar ataxia (autosomal recessive 3), spinocerebellar ataxia (autosomal recessive 4), spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive, with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph disease type II), spinocerebellar ataxia (X-linked, 2), spinocerebellar ataxia (X-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellar degeneration (book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebral base artery insufficiency and diseases caused by vitamin deficiency, etc. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia and fragile X chromosome / tremor ataxia syndrome. In another specific embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X / ataxia tremor syndrome.

[0253] tinnitus

[0254] Provided herein are methods of treating tinnitus in a subject in need thereof, and the methods include administering a dosage form or composition as disclosed herein. Tinnitus is a condition in which the affected person perceives sounds in one or both ears or the head when no external sounds are present. Often referred to as "ringing" in the ears, tinnitus can occur intermittently or constantly, with the perceived volume ranging from low to painfully high. However, the perceived volume of tinnitus may vary from patient to patient, where an objective measure of the volume of tinnitus in one patient may be considered painful, but in another patient, the same volume may be considered subtle.

[0255] Sleep disorders

[0256] Provided herein are methods for treating or preventing sleep disorders (e.g., narcolepsy), comprising administering a dose or composition disclosed herein. For example, the sleep disorder can be a central disorder of narcolepsy, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia caused by a medical disorder, hypersomnia caused by a drug or substance, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0257] Combination therapy

[0258] The dosage forms or compositions described herein (e.g., for regulating T-type calcium ion channels) can be administered in combination with at least one other agent or therapy. The subject to whom the compounds disclosed herein are administered may suffer from a disease, disorder or condition or its symptoms that will benefit from treatment with another agent or therapy. In certain embodiments, these diseases or conditions may be associated with epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or hereditary epilepsy) or tremor (e.g., essential tremor).

[0259] Antiepileptic drugs

[0260] Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine acetate, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0261] Analgesics

[0262] Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opioids and morphine mimetics, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors. In view of the ability of the compounds disclosed herein to treat pain by inhibiting T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combinations with analgesics are particularly contemplated.

[0263] Tremor drugs

[0264] Medications for tremor included propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0265] Example

[0266] 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 should not be construed in any way as limiting their scope.

[0267] Example 1: Analysis of the crystallinity of the compound of formula (II) by X-ray powder diffraction

[0268] A polymorph screen of the compound of formula (II) was performed and a stable solid state form was identified, referred to as Form C. The crystallinity of Form C was analyzed by XRPD.

[0269] XRPD analysis was performed using a Bruker D8 ADVANCE and the following conditions.

[0270] Bragg Brentano geometric shapes.

[0271] 2θ range: 3° to 40°.

[0272] Step size: 0.02°.

[0273] Step time: 0.25 seconds.

[0274] Slit:0.3.

[0275] Sample rotation speed: 15rpm.

[0276] Copper K α radiation.

[0277] Use a Zero Background Silica filled sample holder.

[0278] XRPD of Form C of the compound of formula (II) shows Figure 1 The positions and relative intensities of the 10 most intense peaks of the XRPD pattern of Form C are shown in Table 1. The sample is highly crystalline and shows no evidence of any baseline shift indicating significant amorphicity.

[0279] Table 1. XRPD peak list of Form C (10 most intense reflections)

[0280] peak d-spacing °2θ Relative Strength % 1 3.3 26.6 100 2 5.5 16.2 94.2 3 5.1 17.4 93.5 4 3.9 22.6 73.8 5 7.7 11.5 58.6 6 3.7 23.9 50.8 7 4.8 18.3 47.5 8 4.6 19.2 44.7 9 4.8 18.5 42.4 10 4.4 20.0 41.1

[0281] Preparation of Form C

[0282] The free base solution of the compound of formula (I) was cooled to 0°C to 10°C over 1 hour. Ethyl acetate / HCl (10-12%, 53.5 L, prepared in-house from ethyl acetate and anhydrous HCl gas) was slowly added to the batch over 30 minutes while maintaining the temperature between 0°C and 10°C. The batch was warmed to 25°C to 30°C over 1.25 hours and held at that temperature for 4 hours. A vacuum (600-700 mmHg) was applied and the batch was distilled below 33°C for 6.25 hours, at which time the volume of the distillate was 115 L. The batch was cooled to 25°C to 30°C and diisopropyl ether (53.5 L, 5 volumes) was added. The batch was kept at 25°C to 30°C for 2 hours under stirring, then filtered through a Nutsche filter NF202 under a nitrogen atmosphere and sucked dry for 30 minutes. The filter cake was slurried / washed twice with diisopropyl ether (10.7 L, 1 volume) and sucked dry for 30 minutes to 1 hour. This material was dried in a vacuum dryer VD201 at 65°C to 70°C under vacuum (600-650 mmHg) for 12 hours until the water content of the filter cake did not exceed 2.0 wt % to give Form C of the compound of formula (II) (10.01 kg, 90% yield, 0.45% water, calculated on KF).

[0283] Polymorph screening identified another stable solid state form, referred to as Form B. The crystallinity of Form B was analyzed by XRPD.

[0284] XRPD analysis was performed using a Bruker D8 ADVANCE and the same conditions as described for Form C above.

[0285] XRPD of Form B of the compound of formula (II) showed Figure 7 The positions and relative intensities of the 10 most intense peaks of the XRPD pattern of Form B are shown in Table 2. The sample is highly crystalline and shows no evidence of any baseline shift indicating significant amorphicity.

[0286] Table 2. XRPD peak list of Form B (10 most intense reflections)

[0287]

[0288] Preparation of Form B

[0289] The material of the XRPD figure of form B is shown by ethyl acetate through controlled solvent evaporation preparation.The compound of formula (II) of about 200mg is placed in 30mL to 50mL glass bottle / beaker.Add 20mL ethyl acetate and sample vortex mixed / ultrasound process about one minute, until obtaining clear solution.Filter solution by syringe filter (DuraporePVDF 0.22 μm centrifugal filter from Millipore) to remove the potential seed of input solid form.Then solution is opened to environment and stirred 48 hours under ambient conditions.

[0290] Example 2: Thermal properties of Form C and Form B of the compound of formula (II)

[0291] Form C of the compound of formula (II) was further analyzed by DSC, TGA and HSM. The compound in Form C has a high melting point and does not undergo any physical or chemical changes below 180°C.

[0292] DSC

[0293] The DSC of Form C of the compound of formula (II) was analyzed using a Perkin Elmer Diamond DSC and the following conditions:

[0294] Aluminum pan under nitrogen purge gas.

[0295] Sample size: 1 to 5 mg.

[0296] Temperature range: -25℃ to 250℃.

[0297] Heating rate: 2℃ / min, 5℃ / min, 10℃ / min.

[0298] The DSC thermogram of Form C of the compound of formula (II) is shown in Figure 2 A summary of the data obtained is shown in Table 3. The thermogram obtained showed a single sharp endotherm due to the melting of Form C with an onset temperature of 226.6°C.

[0299] Table 3. DSC data obtained for Form C of the compound of formula (II)

[0300]

[0301] TGA

[0302] TGA analysis of Form C was performed using perkin elmer Pyris 1 and the following conditions:

[0303] Platinum pan under nitrogen purge gas.

[0304] Sample size: 2 to 4 mg.

[0305] Temperature range: ambient temperature to 300°C.

[0306] Heating rate: 10°C / min.

[0307] TGA thermal analysis diagram ( Figure 3 ) shows a weight loss of approximately 0.8% w / w when heated from ambient temperature to 150°C, indicating that Form C of the compound of Formula (II) is not a hydrate or solvate (theoretical weight loss for the monohydrate is 4.1% w / w).

[0308] Table 4. TGA data obtained for Form C of the compound of formula (II)

[0309]

[0310] HSM

[0311] HSM of Form C of the compound of Formula (II) was performed at ambient temperature to 300°C (without sample equilibration) at a heating rate of 10°C / min or 20°C / min. Figure 4 The HSM micrograph of Form C of the compound of formula (II) is shown. The experiment confirmed that the material remained unchanged until about 180°C. The material began to melt at about 201°C, and the melting of the final particles was completed at about 215°C. Figure 2 The endothermic event seen in the DSC thermogram of with an onset temperature of 227°C corresponds to melting.

[0312] Form B of the compound of formula (II) was further analyzed by DSC, TGA and HSM. Fig. 8A shows a DSC thermogram of Form B material at a heating rate of 10°C / min, and Figure 8BThe DSC thermogram of Form B at a heating rate of 2°C / min is shown. A summary of the data obtained is shown in Table 5 below. The DSC thermogram with a heating rate of 10°C / min shows three endothermic events. The first endothermic with an onset temperature of about 98°C can be attributed to the weight loss event seen in the TGA experiment (75°C to 125°C), which may be due to water or solvent loss. The slower heating rate of 2°C / min is used to study the thermal events observed at higher temperatures. The DSC thermogram recorded at a heating rate of 2°C / min shows four main events: three endothermic events and one exothermic event. The first endothermic event (onset temperature 84°C) may be due to water or solvent loss. The second event (onset temperature 129°C) is due to the melting of the dehydrated or desolvated form of the compound. An exothermic event (onset temperature 169°C) is observed after this melting, which corresponds to the crystallization seen in HSM (possibly producing Form B material). The final endothermic event (onset temperature 224°C) is shown as melting by HSM and corresponds to the melting of Form C material.

[0313] Table 5. DSC data obtained for Form B of the compound of formula (II) 10°C / min heating rate

[0314]

[0315] 2℃ / min heating rate

[0316]

[0317] The TGA thermogram of Form B material is Fig. 9 The results are shown in Table 6. A summary of the data obtained is shown in Table 6. The TGA thermogram shows a typical stepwise weight loss of about 4.0% w / w for a hydrate in the temperature range of 75°C to 125°C. The theoretical weight of the monohydrate is 4.1%, indicating that Form B is a possible hydrate. It is unlikely to be a solvate because it comes from a different solvent and different solvates are unlikely to produce the same diffraction pattern. This weight loss event corresponds to the first endotherm observed in the DSC thermogram of Form B. A significant weight loss of about 17% w / w was observed in the temperature range of 195°C to 300°C. Inspection of the experimental residue showed that it was a brown material, indicating that degradation had occurred. Hot stage microscopy confirmed melting at about 200°C and then decomposition.

[0318] Table 6. TGA data obtained for Form B of the compound of formula (II)

[0319] event Weight reduction 1 4.0%w / w(75℃ to 125℃) 2 17.4% w / w (195℃ to 300℃)

[0320] The HSM of the Form B material shows that the appearance of the material remains unchanged up to 128°C. The material begins to melt at 128°C and the melting of the final particles is complete at a temperature of about 135°C (see Fig.10 ). This confirms that the event observed in DSC with an onset temperature of 227 °C is caused by melting. Recrystallization from the melt is observed between 161 °C and 175 °C, while the color change of the melt as well as the melting of the recrystallized solid are observed simultaneously between 189 °C and 195 °C. The degradation of the compound can occur differently during HSM when compared to DSC. HSM was performed under an air atmosphere; DSC was performed under an inert atmosphere of nitrogen. Therefore, oxidation processes can occur during HSM, while oxidation processes do not occur during DSC.

[0321] Example 3: Modified Release Tablet Formulation of the Compound of Formula (II)

[0322] Preparation

[0323] In Phase 1, single ascending dose studies of the immediate-release ("IR") capsules, CNS-related events and psychiatric-related adverse events were the most frequently reported adverse events and generally occurred at the time of maximum plasma concentration (T max ). In a subsequent cohort of the same study, 40 mg IR capsules administered as four 10-mg doses at 2-hour intervals reduced mean C max The values ​​were reduced by about 50% of those observed after a single oral 40-mg dose of the compound of formula (II), and mild headache and mild somnolence were the only adverse events reported after divided doses. In view of these findings, a modified release ("MR") tablet formulation of the compound of formula (II) was developed in an attempt to reduce the C for a given dose while maintaining the overall AUC. max .

[0324] The composition of the immediate release capsule of the compound of formula (II) is provided in Table 7 below.

[0325] Table 7. Formulations of compounds of formula (II) for immediate release capsules

[0326]

[0327] Three initial tablet formulations of the compound of formula (II) (Form C) having different release rate profiles were prepared: (1) Formulation 1 (wherein approximately 80% of the compound of formula (I) is released within 2 hours after administration to a subject); (2) Formulation 2 (wherein approximately 80% of the compound of formula (I) is released within 5 hours); and (3) Formulation 3 (wherein approximately 80% of the compound of formula (I) is released within 7 hours). The compositions of Formulations 1-3 are shown in Table 8. Each tablet contains 20 mg of the compound of formula (II).

[0328] Table 8. Formulations of compounds of formula (II) for modified release tablets

[0329]

[0330] Preparation method

[0331] The method for preparing modified-release tablets comprises six sequential steps: 1) screening of all ingredients (compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., formula (II)) and excipients); 2) blending the compounds with excipients (including intragranular lubrication); 3) roller compaction (including grinding); 4) extragranular lubrication; 5) tableting; and 6) tablet coating.

[0332] Example 4: Pharmacokinetic studies and adverse events reported after single-dose administration of modified-release tablets

[0333] Modified release tablets of the compound of formula (II) were developed in an attempt to mitigate some of the adverse effects observed with the immediate release capsule formulation of the compound of formula (II). In a Phase 1 study, three modified release tablet formulations of the compound of formula (II) were evaluated relative to the immediate release capsule formulation of the compound of formula (II) under fasting conditions in healthy volunteers. max Lower and t max Delay.

[0334] The Phase 1 study is a randomized, open-label, 4-way crossover study. Eligible subjects are randomly assigned to 1 of 4 treatment sequences and receive a single 20-mg dose of an immediate-release capsule formulation of the compound of formula (II) (compound of formula (II)) and a single 20-mg dose of the following 3 modified-release tablet formulations of the compound of formula (II): Formulation 1 (80% release rate within 2 hours), Formulation 2 (80% release rate within 5 hours), and Formulation 3 (80% release rate within 7 hours) in the fasting state. Study treatments are administered in 4 separate study visits, with each visit separated from the previous one by a minimum 1-week washout period.

[0335] Figure 5Shown are the mean concentration-time profiles of the compound of formula (II) following a single 20-mg oral dose of modified-release tablets and immediate-release capsules of Formulations 1-3 of the compound of formula (II).

[0336] After administration of 20 mg of the compound of formula (II) in the fasting state, before 0.75 hours after administration of each modified release tablet formulation of the compound of formula (II) in the fasting state and after administration of the immediate release capsule formulation, the plasma concentration of the compound of formula (I) is quantifiable ( Figure 5 ). max After that, the plasma concentration of the compound of formula (II) decreased in a biphasic manner after administration of both the immediate release capsule and the Formulation 1 tablet in the fasting state. The plasma concentration reached C max The compound of formula (II) remained quantifiable for at least 36 hours after administration of the immediate release capsule and formulation 1 tablets and for the duration of the 48 hour sampling period after administration of formulation 2 and formulation 3 tablets.

[0337] The fed formulation 3 tablets reached C max The compound of formula (II) remained quantifiable for the duration of the 48-hour sampling period after administration of formulation 3 tablets in the fed state. Figure 5 ).

[0338] Table 9 summarizes the median t for the immediate release capsule, Formulation 1 tablet (release rate of 2 hours), Formulation 2 tablet (release rate of 5 hours), and Formulation 3 tablet (release rate of 7 hours). max , the observed geometric mean C max , observed geometric mean AUC 最后 and AUC inf Modified release formulations with longer release rates provide delayed t relative to immediate release capsules. max value and reduced C max concentration, while maintaining the AUC 最后 Estimated overall exposure. T values ​​observed for all formulations at approximately 8 to 10 hours 1 / 2 There is no evidence that absorption rate affects t 1 / 2 Among the three modified-release tablet formulations, the AUC 最后 The relevant within-subject variability was similar.

[0339] Table 9. Geometric Mean Pharmacokinetic Parameters (CV% Geometric Mean) of the Compound of Formula (II) Following a Single Oral 20 mg Dose of Modified Release Tablets and Immediate Release Capsules (Study Phase 1)

[0340]

[0341]

[0342] Abbreviation: AUC 外推 , the percentage of the area extrapolated after the last quantifiable plasma concentration; AUC inf , the area under the plasma concentration-time curve from the time of administration to infinity; AUC 最后 , the area under the plasma concentration-time curve from the time of administration to the last measurable concentration; C max , maximum (peak) plasma drug concentration; Cl / F, apparent plasma clearance after oral administration; CV%, coefficient of variation expressed as a percentage; t1 / 2, terminal elimination half-life; MR-modified release, t lag , the time before the first measurable (non-zero) concentration; t max , the time to reach the maximum (peak) plasma drug concentration; V z / F, apparent volume of distribution after oral administration. 1 Median (range).

[0343] Of the 18 subjects who received a single oral 20-mg dose of the three modified-release tablet formulations (Formulations 1-3) or IR capsules in the fasting state (see Example 4), 17 subjects (94.4%) experienced at least one adverse event following administration of any of the formulations (see Table 10 below). At least one drug-related adverse event was reported in 15 of the 18 subjects (83.3%). No serious or severe adverse events were reported, and no subject discontinued treatment with study drug due to an adverse event.

[0344] The expected lower C of the compound of formula (I) for MR tablets relative to IR capsules maxConsistent with the exposure, the percentage of subjects experiencing at least one adverse event and the percentage of subjects experiencing at least one drug-related adverse event were less after administration of each MR tablet than after administration of the IR capsule (Table 10). Among the MR tablets, the percentage of subjects experiencing any adverse event and the percentage of subjects experiencing any drug-related adverse event were the lowest for formulation 3. At least one adverse event was reported in 33.3% of subjects after administration of formulation 3 tablets, in 44.4% of subjects after administration of formulation 2, in 61.1% of subjects after administration of formulation 1 tablets, and in 72.2% of subjects after administration of the IR capsule. At least one drug-related adverse event was reported in 16.7% of subjects after administration of formulation 3 tablets, in 44.4% of subjects after administration of formulation 2, in 44.4% of subjects after administration of formulation 1 tablets, and in 72.2% of subjects after administration of the IR capsule.

[0345] The increase in the percentage of subjects experiencing any adverse event and any drug-related adverse event was concentration-dependent and was generally associated with the ranking of Cmax (formulation 3 < formulation 2 < formulation 1 < IR capsule).

[0346] Table 10. Overall summary of treatment-emergent adverse events (safety population) after a single oral 20-mg dose of tablets (formulations 1 - 3) and immediate-release capsules in the fasting state

[0347]

[0348] Abbreviations: IR = immediate release, MR = modified release, SAE = serious adverse event, TEAE = treatment-emergent adverse event

[0349] 1 Drug-related adverse events are those for which the investigators evaluated the association with the study drug as far as possible, to the best of their ability, or as much as possible.

[0350] Example 5: Pharmacokinetic study of modified-release tablets at single and multiple escalating doses

[0351] There was a 2-part, phase 1, double-blind, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics (including KSS, KDT, SQSQ, and 24-hour EEG recordings) of single escalating (Part A: 20 mg, 40 mg, and 60 mg) and multiple escalating (Part B: 20 mg and 40 mg for 8 days) doses of a 20-mg tablet (formulation 3) in healthy participants. Based on the results of this trial, as Fig.16As shown, after a single oral dose of a 20 mg tablet (Formulation 3), exposure to the compound of Formula (I) increased with dose over the dose range of 20 mg to 60 mg. After a single oral dose of a 20 mg tablet formulation (Formulation 3), C max The variability of AUC and AUC increased with increasing dose ( Fig.16 ).

[0352] In this study, single and multiple doses (daily for 8 days) of 20 and 40 mg were well tolerated. Adverse events for the 20 mg and 40 mg doses were transient and the incidence was similar to that of placebo. The following TEAEs were observed, all of which were mild to moderate:

[0353] For the 40 mg dose (n=6), the following neurological TEAEs were observed: somnolence (33.3%), headache (33.3%), and dizziness (33.3%). TEAEs also included fatigue (33.3%) and hot flashes (33.3%). The following adverse events were also observed: ECG application site rash, EEG application site skin reaction, nausea, blurred vision, thermal burns (accidental), and euphoria, each of which was observed in 16.7% of the subjects.

[0354] For the 20 mg dose (n=6), the following neurologic disorder TEAEs were observed: somnolence (16.7%) and headache (33.3%), as well as nausea (33.3%), fatigue (16.7%), vomiting (16.7%), and dry throat (16.7%).

[0355] For placebo (n=4), the following neurologic TEAEs were observed: headache (25%), somnolence (25%), and dizziness (25%) as well as fatigue (50%) and nausea (25%).

[0356] A single 60 mg dose administered to 6 healthy volunteers was not tolerated. Nausea occurred in 5 of the 6 participants, and vomiting occurred in 3 of the 6 participants. In the multiple-dose 20 mg and 40 mg groups, three subjects reported nausea, with one subject also reporting vomiting; these events were mild in severity and resolved by day 1 of dosing. No subjects reported nausea or vomiting after day 1 of dosing. Although the single 60 mg dose was poorly tolerated, the mean peak drug levels observed in the 40 mg group after eight days of treatment (138 ng / mL) were greater than the mean peak drug levels observed at a single 60 mg dose on day 1 (130 ng / mL) ( Fig.16 ). Therefore, when a 60 mg dosage form is administered to a patient at an initial dose, repeated administration of a 40 mg dosage form achieves a C associated with intolerable adverse effects. max However, repeated administration of the 40 mg dosage form was safely tolerated.

[0357] Table 11. Geometric Means (Geometric CV%) after a Single Oral Dose of 20 mg Tablet Formulation 3 (Part A)

[0358]

[0359]

[0360] AUC 24 = Area under the plasma concentration-time curve from the time of administration to 24 hours after administration, AUC inf = Area under the plasma concentration-time curve from the time of administration to infinity, AUC 最后 = the area under the plasma concentration-time curve from the time of administration to the last measurable concentration, C max = maximum (peak) plasma drug concentration, CL / F = apparent total clearance of drug from plasma after oral administration, CV% = coefficient of variation, %AUC 外推 = area under the plasma concentration-time curve extrapolated from time t to infinity as a percentage of the total area under the curve, MR = modified release, t1 / 2 = elimination half-life, t lag = delay time, t max = time of maximum (peak) plasma drug concentration, V z / F = apparent volume of distribution at the end of the period after oral administration. 1 Median (range). 2 n=5.

[0361] The pharmacokinetic properties of multiple 20 mg and 40 mg doses of the 20 mg tablet (Formulation 3) were determined on days 1 and 8 of dosing, as shown in Table 12. Based on the results of this trial, exposure to the compound of formula (II) increased with increasing dose over the dose range of 20 to 40 mg after once daily administration of the 20 mg tablet formulation for 8 days. max The variability of C and AUC increased over the dose range studied. Steady state was achieved before the fifth day of repeated daily administration in the 20 to 40 mg dose range. max An increase of approximately 2 times.

[0362] Table 12: Geometric mean (geometric CV%) plasma pharmacokinetic parameters following single and multiple oral doses of 20 mg tablet formulation (Formulation 3) (Part B)

[0363]

[0364]

[0365] Abbreviation: AUC 24 = Area under the plasma concentration-time curve from the time of administration to 24 hours after administration, AUC τ = the area under the plasma concentration-time curve during the administration interval, C avg = average drug concentration during multiple dose administration, C max = maximum (peak) plasma drug concentration, C min = minimum plasma drug concentration, CL / F = apparent total clearance of drug from plasma after oral administration, CV% = coefficient of variation, MR = modified release, NA = not applicable, NC = not calculated, RacAUC = AUC from τ,ss and AUC τ Calculated cumulative ratio, Rac C max =From C max,ss Calculated cumulative ratio, ss = steady state, t1 / 2 = elimination half-life, t lag = delay time, t max = time of maximum (peak) plasma drug concentration, V z / F = apparent volume of distribution at the end of the period after oral administration. 1 Median (range). 2 Labeled as AUC on day 1 24

[0366] Example 6: Modified Release Tablet Formulations 4 and 5 of the Compound of Formula (I)

[0367] Formulations 4 and 5, provided as coated matrix modified release (MR) tablets, are designed to release approximately 80% of the drug substance within 7 hours. The composition of the clinical batches of the products (Formulations 4 and 5) is shown in Table 13. Each active tablet will contain drug substance equivalent to 5 or 20 mg of the compound of formula (I), corresponding to approximately 5.475 mg or 21.90 mg of the compound of formula (II), respectively.

[0368] Table 13. Formulations of a compound of formula (I) in a modified release tablet containing 5 mg or 20 mg of the compound of formula (I)

[0369]

[0370] a About the amount of free base adjusting formula (I)

[0371] b The amount of microcrystalline cellulose (Avicel PH101) is compensated according to the amount of formula (I)

[0372] The dissolution method used to evaluate the release was a chromatographic assay using USP apparatus type I. The dissolution parameters and high performance liquid chromatography (HPLC) conditions used to evaluate the release were shown below.

[0373] Table 14. Dissolution parameters

[0374]

[0375] Table 15. Chromatographic conditions

[0376]

[0377]

[0378] Table 16. Gradient program

[0379] Time (minutes) Mobile phase-A% Mobile phase-B% 0.00 67 33 1.50 67 33 4.00 55 45 4.10 67 33 8.00 67 33

[0380] Preparation method

[0381] Modified release tablets are prepared by screening and blending excipients (including lubricants). The blend is granulated by rolling and grinding the ribbon compact. The granules are lubricated and then compressed into tablets. The tablets are then coated with a film coating.

[0382] Many quality attributes are monitored in-process, during release testing and in terms of stability. These include hardness, friability, appearance, assay, related substances, content uniformity, moisture content and dissolution.

[0383] Table 17 provides additional modified release formulations (Formulations 6-9).

[0384] Table 17. Formulations of a compound of formula (I) for modified release tablets containing 10 mg, 15 mg, 30 mg and 40 mg of the compound of formula (I)

[0385]

[0386]

[0387] a About the amount of free base adjusting formula (I)

[0388] b The amount of microcrystalline cellulose (Avicel PH101) is compensated according to the amount of formula (I)

[0389] Following administration of a single 5 mg dose of the compound of formula (II) (Formulation 4) to healthy volunteers, plasma concentrations of the free base of the compound of formula (I) (i.e., the compound of formula (II)) were quantifiable until 0.50 hours after administration of the modified release tablet formulation of the compound of formula (II). The plasma concentration reached C maxThe levels of the compound of formula (I) as a free base (i.e., the compound of formula (II)) remained quantifiable for the duration of the 24-hour sampling period following administration of the 5 mg dose of Formulation 4. Fig.11 Mean (± SD) concentrations following a single oral dose of 5 mg tablet Formulation 4 are shown.

[0390] Table 18. Geometric Means (Geometric CV%) after a single oral dose of 5 mg tablet Formulation 4

[0391]

[0392] AUC 24 = the area under the plasma concentration-time curve from the time of administration to 24 hours after administration, C max = maximum (peak) plasma drug concentration, CV% = coefficient of variation, MR = modified release, t lag = delay time, t max = time of maximum (peak) plasma drug concentration. 1 Median (range).

[0393] Example 7: Long-term stability of the compound of formula (II) (Form C) in formulation

[0394] The drug product is chemically and physically stable for up to 48 months at 25°C / 60% RH (Table 19), or for up to 6 months at accelerated conditions (40°C / 75% RH) (Table 20). Based on currently available stability data, 20 mg of drug product (Formulation 3) packaged in a 40 cc high density polyethylene (HDPE) bottle has a shelf life of 60 months when stored between 20°C and 25°C according to the United States Pharmacopeia (USP) definition of controlled room temperature. Based on the excellent stability of at least 48 months for the 20 mg drug product and the substantially same composition of the 5 mg drug product, the 5 mg drug product (Formulation 4) packaged in a 40 cc high density polyethylene (HDPE) bottle has a shelf life of 24 months when stored between 20°C and 25°C.

[0395] The stability study of MR tablets including the compound of Formula II (containing Form C) was conducted at 25°C / 60% RH. The batch size was 10,000 tablets. Each film-coated tablet contained 20 mg of the compound of Formula II. The tablets were packaged in 40cc HDPE bottles with CRC caps containing 30 tablets (Table 19).

[0396] Table 19. Stability study data of MR tablet formulation 3 (containing 20 mg of the compound of formula (II)) at 25°C / 60% over 48 months

[0397]

[0398]

[0399] NMT-not to exceed; RH-relative humidity

[0400] The stability study of MR tablets including the compound of Formula II (containing Form C) was conducted at 40°C / 75% RH. The batch size was 10,000 tablets. Each film-coated tablet contained 20 mg of the compound of Formula II. The tablets were packaged in 40cc HDPE bottles with CRC caps containing 30 tablets (Table 20).

[0401] Table 20. Stability study data of MR tablet formulation 3 (containing 20 mg of the compound of formula (II)) under accelerated conditions

[0402]

[0403] NMT-not to exceed; RH-relative humidity

[0404] A stability study of Formulation 4 tablets comprising 5 mg of the compound of formula (II) (containing Form C) was conducted at 25°C / 60% RH. The batch size was 30,000 tablets. The tablets were packaged in 40cc HDPE bottles with CRC caps containing 30 tablets (Table 21).

[0405] Table 2 1.5 mg tablets (Formulation 4) stability study data at 25°C / 60% RH for 3 months

[0406]

[0407]

[0408] Example 8: Evaluation of Safety, Tolerability, Pharmacokinetics, and Efficacy of Ascending Multiple Oral Doses in Adults with Generalized Epilepsy Syndromes with Absence Seizures

[0409] This open-label multiple ascending dose trial will primarily evaluate the safety and tolerability of 20 mg daily and 40 mg daily (20 mg twice daily) doses of the 20 mg modified-release tablet (Formulation 3) as an adjunct to standard of care. Secondary objectives include characterizing the pharmacokinetics, pharmacodynamics (sigma frequency power during NREM sleep), and effects of the tablet (Formulation 3) on seizure frequency.

[0410] Subjects

[0411] The subjects of this study were males or females aged 18 to 60 years. The subjects had a clinical diagnosis of an epilepsy syndrome (including, but not limited to, childhood absence seizures, juvenile absence seizures, juvenile myoclonic epilepsy, or Jeavons syndrome) in which the absence seizures met the revised classification of epilepsy seizures of the International League Against Epilepsy (2017), persisted despite documented trials with at least one standard anti-epileptic treatment, and had a history and electrographic evidence of absence epilepsy.

[0412] Methodology:

[0413] Each participant will complete 3 study phases: screening, treatment period (up to 2 dose levels, then tapering), and safety follow-up. All participants will undergo two weeks of dosing of the compound of formula (II), followed by tapering, as follows:

[0414] Dose Level 1: 20 mg daily (Formulation 3) for 7 days and up to 14 days if 20 mg twice daily is not tolerated.

[0415] Dose Level 2: 20 mg (Formulation 3) twice a day for 7 days.

[0416] Tapering: If the participant tolerates 20 mg twice a day for the full 7 days, the taper will be 20 mg per day for 2 days (Days 15 and 16), followed by 20 mg every other day for 5 days (Days 17, 19, and 21). If the participant tolerates only 20 mg once a day, the taper will be 20 mg every other day for 7 days (Days 15 to 21).

[0417] Safety and Tolerability

[0418] Safety variables included clinical laboratory evaluations, physical examination, vital signs, 12-lead ECG, C-SSRS, and adverse event (AE) assessments, including event type, frequency, severity, severity, timing, and relationship to IP.

[0419] Pharmacokinetics

[0420] Pharmacokinetic parameters will include: maximum observed concentration (C max ) and the maximum observed concentration at steady state (C max，SS ), C max Time (T max ) and C max，SS Time (T max，SS ), the area under the concentration-time curve during the dosing interval (AUC tau or AUC SS), total clearance at steady state (CLSS). If available, other parameters will be calculated, such as half-life, accumulation, and volume of distribution at steady state (VSS).

[0421] Effectiveness

[0422] Efficacy was assessed as follows: a) number of seizures from participant-reported seizure diaries, including absence seizures, generalized tonic-clonic seizures, and myoclonic seizures, b) EEG measures of seizure activity and pharmacodynamic effects of compounds of Formula (I), including: seizure density (number of bilaterally synchronized symmetric spike discharges of approximately 2.5-5 Hz>3 seconds in an approximately 24-hour period, including seizures induced by photostimulation and hyperventilation), mean seizure duration (mean duration of 2.5-5 Hz discharges greater than 3 seconds in duration over a 24-hour period), cumulative seizure duration (product of seizure density and mean seizure duration), total time with 2.5-4 Hz spike discharges following hyperventilation and photostimulation challenges, and c) overall severity as measured by CGI-S and CGI-I scores.

[0423] Example 9: Evaluation of the efficacy, safety, tolerability and pharmacokinetics of a compound of formula (I) or a pharmaceutically acceptable salt thereof in essential tremor

[0424] A randomized controlled trial was conducted to investigate the efficacy, safety and tolerability of the compound of formula (I) in essential tremor. Each patient completed 3 study phases: screening, treatment period (21 or 28 days) and safety follow-up.

[0425] Patients were men and women aged 18 to 75 years who had been diagnosed with essential tremor for at least 3 years. Patients received a stable dose of 1 tremor medication throughout the clinical trial. Patients with clinical evidence of psychogenic tremor, a history of other medical, neurological, or psychiatric conditions that could explain or cause the tremor, previous magnetic resonance-guided focused ultrasound or surgical intervention for essential tremor, or botulinum toxin injections for essential tremor within 6 months before screening were excluded from the study.

[0426] Patients received orally 20 mg of a compound of formula (I) (Formulation 3) once a day for 14 days and twice a day for 7 days (Part A) or orally 20 mg of a compound of formula (I) (Formulation 3) once a day for 14 days and twice a day for 14 days or placebo (Part B).

[0427] The efficacy of compounds of formula (I) on upper limb tremor was assessed at baseline by TETRAS upper limb score on Day 21 (Part A) and Day 28 (Part B).

[0428] The efficacy of compounds of formula (I) on other measures of tremor severity was assessed at baseline by TETRAS performance subscale scores and TETRAS performance individual items on Day 21 (Part A) and Day 28 (Part B).

[0429] The safety and tolerability of the compound of formula (I) was evaluated by a comprehensive analysis of the following endpoints: patient- and clinician-reported adverse events, vital signs, clinical laboratory results, electrocardiogram (ECG), and Columbia-Suicidality Severity Rating Scale (C-SSRS) at baseline, on Day 1, Day 7, Day 14, Day 21, and Day 28 (Part B only).

[0430] Example 10: Evaluation of the efficacy, safety, tolerability and pharmacokinetics of compounds of formula (I) in essential tremor

[0431] A non-randomized, non-controlled and open-label trial was conducted to study the efficacy, safety, tolerability and pharmacokinetics of the compound of formula (I) in adults with essential tremor. Patients were males and females aged between 18 and 75 years and had been diagnosed with essential tremor (e.g., isolated tremor syndrome with bilateral UL action tremor lasting at least 3 years as defined by the Movement Disorders Society or the MDS Tremor Working Group). The bilateral composite score of the patient's TETRAS UL project was required to be ≥10, as confirmed by the on-site investigator and the central video review.

[0432] Each patient completed 3 study periods: screening, treatment period (14 days), and safety follow-up. A video of the TETRAS performance subscale was completed during the screening period. Patients were on a stable dose of 1 previously prescribed tremor medication throughout the clinical trial, which was acceptable.

[0433] Patients with clinical evidence of psychogenic tremor, a history of other medical, neurological, or psychiatric conditions that could explain or cause the tremor, previous magnetic resonance-guided focused ultrasound or surgical intervention for essential tremor, or botulinum toxin injections for essential tremor within 6 months before screening were excluded from the study.

[0434] Each patient received 20 mg of the compound of formula (I) (one tablet of Formulation 5) orally once a day in the morning (QAM) for 7 days and 40 mg of the compound of formula (I) (two 20 mg tablets of Formulation 5) orally once a day in the morning (QAM) for 7 days (a total of 14 consecutive days).

[0435] The primary efficacy endpoint for compounds of formula (I) was upper limb tremor assessed at baseline, day 7, and day 14 by the Essential Tremor Rating Assessment Scale (TETRAS) upper limb item score (item #4).

[0436] The efficacy of compounds of formula (I) on other measures of tremor severity was assessed at baseline, day 7, and day 14 by TETRAS performance subscale scores, TETRAS performance individual items, and accelerometer.

[0437] The efficacy of compounds of formula (I) may also be assessed by Clinical Global Impression-Severity (CGI-S), Clinical Global Impression-Improvement (CGI-I) and Patient Global Impression of Change (PGI-C).

[0438] The safety and tolerability of the compound of formula (I) was assessed by comprehensive analysis of the following endpoints: adverse events reported by patients and clinicians (e.g., dizziness or headache), vital signs, clinical laboratory results, electrocardiogram (ECG), and Columbia Suicide Severity Rating Scale (C-SSRS) at baseline, on Day 1, Day 7, Day 14, and Day 21. Six participants have completed this study. Preliminary field data for 6 patients showed that tremor severity was stable between screening and baseline visits. In addition, tremor reduction was observed at both dose levels, which appears to be superior to standard of care agents.

[0439] Compared with baseline, after applying 20mg (formulation 5) for 7 days (day 7), the average upper limb tremor score of TETRAS item 4 was reduced, and after applying 40mg (two 20mg formulations 5) for another 7 days (day 14), a further reduction was observed. The average baseline TETRAS-UL score was 12.4 (its range was 10 to 15, corresponding to moderate disease). On the 14th day, the upper limb tremor score was reduced by at least 25% compared with baseline. For example, within 14 days of administration, a mean reduction of 2.83 points was observed in the TETRAS upper limb score, which is equivalent to an average reduction of about 40% (e.g., 42%) in the tremor amplitude. The TETRAS-UL score of the primary endpoint of the study of three participants was reduced by more than or equal to 4 points, which is equivalent to a reduction of more than 50% in the upper limb tremor amplitude. It is worth noting that after 7 days of removal, the upper limb score increased compared with the upper limb score on the 14th day mentioned above, indicating a gradual return to baseline dysfunction.

[0440] Compared to baseline, the mean TETRAS performance score decreased after administration of 20 mg (formulation 5) for 7 days (day 7), and a further decrease was observed after administration of 40 mg (two 20 mg tablets of formulation 5) for another 7 days (day 14), with an average decrease of 6.25 points on day 14. On day 14, the TETRAS performance score decreased by at least 25% compared to baseline. According to the six participants who completed the study, the full TETRAS-PS improved, with an average reduction of at least 35% (e.g., 36%) in symptom severity from baseline to day 14. It is worth noting that after 7 days of washout, the performance score increased compared to the physical fitness score on day 14 mentioned above, indicating a gradual return to baseline functional impairment. Based on the six participants who completed this study, the TETRAS upper limb score correlated with the TETRAS performance score.

[0441] Figure 6 The reduction of tremor in the Archimedes spiral task was confirmed with the administration of a compound of formula (I) (formulation 5). The Archimedes spiral task is used in the art to identify essential tremor in patients, as described in, for example, Michalec, M et al., "The Spiral Axis as a Clinical Tool to Distinguish Essential Tremor from Dystonia Cases", Parkinsonism Relat. Disord. 2014; 20(5): 541-544. Figure 6 As shown, patients demonstrated a visible reduction in essential tremor between, for example, baseline (Day 1) spirals and Day 7 and Day 14 spirals.

[0442] Fig.15 Data for TETRAS UL and TETRAS PS, i.e., the five patients who completed this study, are shown. Fig.15 As shown, both mean TETRAS UL and mean TETRAS PS decreased between baseline scores and scores on Days 7 and 14.

[0443] The compound of formula (I) (Formulation 5) was safe and well tolerated. There were no SAEs and no severe AEs. Most AEs were mild, transient, and resolved without intervention. All five participants recruited completed the full dosing regimen. There were no clinically significant ECG or laboratory abnormalities. There was no change in C-SSRS.

[0444] Emerging data indicate that the compound of formula (I) is well tolerated and can reduce upper limb tremor amplitude and improve activities of daily living (ADL), such as writing skills. Physician rating scales, accelerometer-based tremor assessment tools, and patient symptom rating scales have consistently demonstrated a reduction in symptoms with administration of the compound of formula (I) (Formulation 5). In addition, anecdotal evidence from participants suggests that once-lost abilities, such as carrying a tray with food or beverages, can be restored after taking the compound of formula (I) (Formulation 5).

[0445] Example 11: Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of the compound of formula (I) in a within-participant ascending dose paradigm

[0446] The trial was conducted to study the safety, tolerability, pharmacokinetics and pharmacodynamics of the compound of formula (I) in healthy participants. Each participant completed 3 study periods: screening, treatment period (12 days or 31 days) and safety follow-up.

[0447] Participants were healthy men and women between the ages of 18 and 55. Participants who had or had any psychiatric, medical, or surgical condition that could compromise the safety of the participant or interfere with the absorption, distribution, metabolism, or excretion of the study drug were excluded from the study.

[0448] In Part A, an open-label trial was conducted. Patients received 5 mg of a compound of formula (I) (Formulation 4) daily for 4 days (Day 1 to Day 4), followed by 10 mg (2 x 5 mg Formulation 4) daily for 4 days (Day 5 to Day 8), and 20 mg (Formulation 5) daily for 4 days (Day 9 to Day 12).

[0449] In Part B, a randomized controlled trial was conducted. Patients received 20 mg of a compound of formula (I) (Formulation 5) or matching placebo daily for 3 days (Day 1 to Day 3), 40 mg daily for 3 days (Day 4 to Day 6), 60 mg daily for 7 days (Day 7 to Day 13), 80 mg daily for 7 days (Day 14 to Day 20), 100 mg daily for 7 days (Day 21 to Day 27), and 120 mg daily for 4 days (Day 28 to Day 31). Patients were allowed to receive a compound of formula (I) daily at each of the 60 mg, 80 mg, and 100 mg dose levels for an extended period of up to 2 days.

[0450] Table 22 summarizes the activities carried out in Part A during the trial.

[0451] In Part A, the pharmacodynamic effects of compounds of Formula (I) are assessed at baseline on Days 1, 4, 5, 8, 9, 12, and 13 as assessed by changes in quantitative electroencephalography (qEEG).

[0452] In Part A, the pharmacokinetics of the compound of formula (I) were evaluated by quantifying the level of the compound in plasma by liquid chromatography / mass spectrometry (LC / MS). Blood samples were collected at the following predetermined time points for pharmacokinetic analysis: Day 1, Day 5, and Day 9: pre-dose (within 60 minutes before dosing) and 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours after dosing; Days 2 to 4, Days 6 to 8, and Days 10 to 12: pre-dose (within 60 minutes before dosing); and Day 13: before discharge (at approximately the same time as the pre-dose sample was collected). The sample collection window is as follows: ±2 minutes for <1 hour after dosing; ±5 minutes for 1 to 3 hours after dosing; ±10 minutes for 4 to 12 hours after dosing.

[0453] The pharmacokinetic parameters measured for the compounds of formula (I) include but are not limited to the area under the plasma concentration-time curve (AUC t ), AUC inf , AUC tau , maximum (peak) plasma drug concentration (C max ), time to reach maximum (peak) plasma drug concentration (t max ), terminal elimination half-life (t 1 / 2 ), apparent plasma clearance after oral administration (Cl / F) and apparent volume of distribution based on the terminal phase (Vd / F).

[0454] In Part A, the safety and tolerability of the compound of formula (I) as assessed by a comprehensive analysis of the following endpoints (as shown in Table 22 below) were assessed at baseline and at multiple times between Day 1 and Day 13: adverse events reported by patients and clinicians, physical examinations, vital signs, clinical laboratory results, electrocardiograms (ECGs), electroencephalograms (EEGs), and Columbia Suicide Severity Rating Scale (C-SSRS). After completing all study assessments and arranging safety follow-up visits by telephone call on Day 17 (± 1 day), the patient was discharged on Day 13.

[0455] Table 22. Schedule of activities for Part A

[0456]

[0457]

[0458] aHepatitis B, hepatitis C and HIV.

[0459] bSymptom-oriented physical examination.

[0460] c CBC, clinical chemistry, coagulation (screening only), urinalysis, and urine albumin. Collected on dosing days prior to dosing.

[0461] dSerum hCG at screening and urine hCG on Days -1 and 13, if applicable.

[0462] e Urine creatinine and KIM-1. Collected on day 1 before dosing.

[0463] fOral temperature, respiratory rate, supine blood pressure, and pulse rate will be obtained as follows: Screening; Day -1; Day 1, 5, and 9: before dosing (within 60 minutes before dosing) and 0.25 hours, 1 hour, 2 hours, 3 hours, and 4 hours (±15 minutes) after dosing; Days 2 to 4, 6 to 8, and 10 to 12: 2 hours after dosing (±15 minutes); Day 13: prior to discharge.

[0464] g Three replicates at screening only. Baseline: any time; During intervention period: 2 hours (±15 minutes) after dosing.

[0465] h During the intervention period, C-SSRS was performed before drug administration.

[0466] iThe entire trial process from signing the informed consent until the end of the trial.

[0467] k 24-hour EEG, including PSG. Day -1 (baseline): after confirmation of eligibility until 1 hour before dosing on Day 1; Days 4 and 8: 2 hours before dosing until 2 hours before dosing on the next day; Day 12: 2 hours before dosing until approximately 22 hours after dosing.

[0468] NOTE: If vital signs assessments are scheduled at the same nominal time points as other assessments, follow this order: obtain PK samples, vital signs, ECG and qEEG, and vital signs assessments as close to the scheduled time points as possible.

[0469] Table 23 summarizes the activities carried out in Part B during the trial.

[0470] In Part B, the safety and tolerability of the compound of formula (I) as assessed by a comprehensive analysis of the following endpoints (as shown in Table 23 below) were assessed at baseline and at pre-determined time points from day 1 to day 33: adverse events reported by patients and clinicians, physical examinations, vital signs, clinical laboratory results, ECG, EEG, and C-SSRS. After completing all study assessments and arranging safety follow-up by telephone call on day 36 (± 1 day), the patient was discharged on day 33. The pharmacokinetics of the compound of formula (I) were assessed by LC / MS quantification of the levels of the compound in plasma and urine. Blood samples for pharmacokinetic analysis were collected at the following predetermined time points: Day 1, Day 4, Day 7, Day 14, Day 21, and Day 28: pre-dose (within 60 minutes pre-dose) and 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours post-dose; Day 2, Day 3, Day 5, Day 6, Days 8 to Day 13, Day 15 to Day 20, Day 22 to Day 27, and Day 29 to Day 31: pre-dose (within 60 minutes pre-dose); Day 32: at approximately the same time as the Day 31 sample was obtained; and Day 33: prior to discharge (at approximately the time the pre-dose sample was collected). The sample collection windows are as follows: for <1 hour after dosing, ±2 minutes; for 1 to 3 hours after dosing, ±5 minutes; for 4 to 12 hours after dosing, ±10 minutes. Urine samples were collected for pharmacokinetic analysis at the following predetermined time points: Day 1: pre-dose only; and Days 3, 6, 10, 17, 24, and 31: 0 hours to 6 hours, 6 hours to 12 hours, 12 hours to 24 hours, and urine volume was recorded. The pharmacokinetic parameters determined for the compounds of formula (I) include, but are not limited to, AUC t , AUC inf , AUC tau , C max ,t max ,t 1 / 2 , CL / F and Vd / F.

[0471] Table 23: Timeline of activities for Part B

[0472]

[0473]

[0474]

[0475]

[0476] aHepatitis B, hepatitis C and HIV.

[0477] bSymptom-oriented physical examination.

[0478] cClinical laboratories included CBC, clinical chemistry, coagulation (screening only), urinalysis, and urine albumin. Collected on dosing days prior to dosing.

[0479] dSerum hCG at screening and urine hCG on Day -1 and Day 33 or at discharge, if applicable.

[0480] e Urine creatinine and KIM-1. Obtained before dosing on Day 1. Collected before dosing on dosing day.

[0481] fContains oral temperature, respiratory rate, supine blood pressure, and pulse rate obtained as follows: Screening; Day -1; Day 1, Day 4, Day 7, Day 14, Day 21, and Day 28: before dosing (within 60 minutes before dosing) and 0.25 hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 12 hours (±15 minutes) after dosing; Day 2, Day 3, Day 5, Day 6, Days 8 to Day 13, Days 15 to Day 20, Days 22 to Day 27, and Days 26 to Day 31: 2 hours after dosing (±15 minutes); Day 32: in the morning; Day 33: prior to discharge.

[0482] g Three replicates at Screening only; Baseline: any time; During Intervention Period: 2 hours (±15 minutes) after dosing.

[0483] hStarting on the morning of Day 6 before dosing and continuing through Day 33.

[0484] i During the intervention period, C-SSRS was performed before drug administration.

[0485] jThe entire trial process from signing the informed consent to the end of the trial.

[0486] m 24-hour EEG, including PSG. Day -1 (baseline): after confirmation of eligibility until 1 hour before dosing on Day 1; Days 10, 17, 24, and 31: 2 hours before dosing until 2 hours before dosing on the next day, or until approximately 22 hours after dosing on Day 32.

[0487] nDay -1 (baseline): 12:00 noon (±3 hours); Days 10, 17, 24, and 31: 4 hours after dosing (±15 minutes); Days 11, 18, and 25: prior to dosing; Day 32: at approximately the same time as Day 25. Each qEEG acquisition period consists of 5 minutes with eyes open followed by 5 minutes with eyes closed. Note: If vital signs assessments are scheduled at the same nominal time points as other assessments, the following sequence should be followed: obtain PK samples, vital signs, ECG, and qEEG, and vital signs assessments as close to the scheduled time points as possible.

[0488] Following administration of a single 5 mg dose of the compound of formula (I) to healthy volunteers, plasma concentrations of the compound of formula (I) were quantifiable 0.50 hours after administration of the compound. Following repeated administration of a titration regimen of a modified release tablet formulation of the compound of formula (I) comprising 4 days of 5 mg (Days 1-4), 4 days of 10 mg (Days 5-8), and 4 days of 20 mg (Days 9-12), detectable pre-dose concentrations of the free base of the compound of formula (I) were observed. Upon reaching C max After 100 mg, the plasma concentration reaches a stable level and then begins to decline over the dosage interval. During the 24-hour sampling period duration after administration of a single 5 mg tablet (Formulation 4), 2 x 5 mg tablet (Formulation 4) on the 5th day (10 mg), and 1 x 20 mg tablet (Formulation 5) on the 9th day (20 mg), the compound of formula (I) remains quantifiable. Dose normalization of the concentration after repeated administration of the modified release tablet formulation of the compound of formula (I) results in comparable dose normalized exposure between 2 x 5 mg tablet (Formulation 4) and 1 x 20 mg tablet (Formulation 5), which indicates the interchangeability of 5 mg tablet (Formulation 4) with 20 mg tablet (Formulation 5).

[0489] Table 24. Geometric Means (Geometric CV%) after Repeated Administration of a Single Oral Dose of 5 mg Tablet Formulation 4 (Day 1), 2 x 5 mg Tablet Formulation 4 (Day 5), and 20 mg Tablet Formulation 5 (Day 9)

[0490]

[0491] AUC 24 = the area under the plasma concentration-time curve from the time of administration to 24 hours after administration, C max = maximum (peak) plasma drug concentration, CV% = coefficient of variation, MR = modified release, t lag = delay time, t max = time of maximum (peak) plasma drug concentration. 1 Median (range).

[0492] Fig.13 Shown are mean (± SD) concentrations following a single oral dose of 5 mg tablet Formulation 4 (Day 1), oral dose of 10 mg (2 x 5 mg tablet Formulation 4) (Day 5), and oral dose of 20 mg tablet Formulation 3 (Day 9) after repeated administration.

[0493] Fig.14 Shown are the mean (± SD) dose normalized concentrations following single oral dosing of 5 mg tablet Formulation 4 (Day 1), oral dosing of 10 mg (2 x 5 mg tablet Formulation 4) (Day 5), and oral dosing of 20 mg tablet Formulation 5 (Day 9) after repeated administration.

[0494] In Part A of the study, a 5 mg tablet formulation was evaluated in a dose escalation pattern from 5 mg to 20 mg per day within a participant. In Part B, doses between 20 mg and 120 mg per day were evaluated in a within-participant dose escalation titration design. Dosing of Part A and Part B of the study has been completed. By incorporating a titrated dosing regimen, it was surprisingly found that the compound of Formula (I) was well tolerated at dose levels up to and including 120 mg per day, which is more than twice the dose that was not tolerated when administered without titration (see Example 4). In addition, by using a titrated dosing regimen, it was also surprisingly found that pharmacokinetic values, such as C max and AUC 24 , can increase pharmacokinetic values ​​by at least about 2-3 fold above those obtained with lower doses that were not tolerated when administered without titration (see Example 4). There were no SAEs and no severe AEs. Most AEs were mild, transient, and resolved without intervention. There were no treatment-related ECG or EEG abnormalities. To date, safety laboratory values ​​were generally within normal limits and there were no dose-dependent deviations from the normal range. Since the highest dose tested was well tolerated in the titration regimen, a maximum tolerated dose was not identified, indicating that even higher doses and / or pharmacokinetic parameters can be achieved and safely tolerated.

[0495] Table 25 - Pharmacokinetic data from Part B dose escalation study

[0496]

[0497]

[0498] AUCτ = area under the plasma concentration-time curve during the dosing interval; C max = maximum (peak) plasma drug concentration; t max = time to reach maximum (peak) plasma concentration after drug administration

[0499] a The single-dose study interval was 24 hours (AUC 24 )

[0500] b This study day represents the first day of dosing at this dose level.

[0501] Eight participants completed Part A and Part B each. No severe or serious adverse events were reported by the participants, and no clinically adverse changes in safety laboratory tests, vital signs, ECG or EEG were observed. A summary of treatment-emergent adverse events is provided below in Table 26 (Part A) and Table 27 (Part B).

[0502] Table 26 - Treatment-emergent adverse events associated with dose increases of 5 to 20 mg in 2 or more participants (Part A)

[0503]

[0504] MedDRA = Medical Dictionary for Regulatory Activities; TEAE = Treatment Emergent Adverse Event

[0505] Table 27 - Treatment-emergent adverse events associated with dose increases of 20 to 120 mg in 2 or more participants (Part B)

[0506]

[0507]

[0508] MedDRA = Medical Dictionary for Regulatory Activities; TEAE = Treatment Emergent Adverse Event

[0509] As shown above, at the highest dose of 120 mg, there were a few AEs, including 1 event of toxic sensation and 1 event of medical device site contact dermatitis. No treatment-related ECG or EEG abnormalities were observed. Safety laboratory values ​​were generally within normal limits, and there were no dose-dependent deviations from the normal range. There were no treatment-emergent abnormalities in renal function or exploratory renal biomarkers (KIM-1), and no treatment-emergent changes in C-SSRS were observed.

[0510] Overall, the data indicate that doses up to 120 mg with titration were well tolerated and were not associated with AEs observed in previous studies with administration of the compound of Formula (II) without titration, such as the nausea and vomiting observed with a single dose of the 60 mg tablet or with administration of 40 mg of the immediate release formulation of the compound of Formula (II) discussed above.

[0511] Example 12 - Food Effects

[0512] The effect of a high-fat, high-calorie meal on the pharmacokinetics of the compound of formula (II) following a single 20 mg dose of Formulation 5 was evaluated in an open-label, sequential manner in participants who had previously received a 20 mg dose of Formulation 5 under fasting conditions.

[0513] Co-administration of Formulation 5 with a high-fat, high-calorie meal resulted in a modest increase in AUC (14% to 15%) compared to the fasting state, and C max The increase was 49%, as shown in Table 28 below. Relative to the fasting state, when co-administered with a high-fat, high-calorie meal, the t max Delayed from 4.0 hours to 5.0 hours.

[0514] Table 28 - Evaluation of Formula (II) Exposure to Co-administration of a High Fat / High Calorie Meal Following a Single 20 mg Oral Dose

[0515]

[0516] AUC 最后 = Area under the plasma concentration-time curve AUC from time zero to the last measurable concentration ∞ = the area under the plasma concentration-time curve from time zero to infinity; C max = Maximum (peak) plasma drug concentration

[0517] Example 13 - Pharmacodynamic and EEG sleep studies

[0518] like Fig.12 As shown, administration of both a 20 mg tablet of the compound of formula (II) and a 40 mg tablet of the compound of formula (II) resulted in a decrease in NREM Σ bands compared to placebo control. As part of the protocol described in Example 11 above, the effects of multiple doses over a wider dose range (Part A: 5 mg, 10 mg, 20 mg; Part B: 60 mg, 80 mg, 100 mg, 120 mg) on ​​Σ band EEG power during NREM sleep were also evaluated. 24-hour EEG / PSG recordings were performed one day before (baseline day) and one day after dosing on Days 4, 8, and 12 (for Part A) or Days 10, 17, 24, and 31 (for Part B). Part B also included placebo-treated participants for statistical comparison. A significant dose-dependent decrease in Σ band EEG power during NREM sleep from baseline was observed within each dose range tested until the decrease reached a plateau after Day 17, as shown in Figure 11. Fig.17Statistical analysis of the data from Part B achieved significant differences in sigma-band EEG power relative to placebo-treated subjects at each dose level (ie, decreases until a plateau corresponding to 80 mg administration).

[0519] Table 29 - NREM Σ Power Ratios Relative to Baseline

[0520]

[0521] Further effects on gamma band EEG power were observed at higher doses. For Part B of the study described in Example 11 above, there was a dose-related decrease in gamma power starting at 60 mg and continuing to 120 mg. It appears that the maximum effect in the gamma decrease was not reached.

[0522] The pharmacokinetic / pharmacodynamic (PKPD) effects of administering a compound of formula (II) on EEG were also assessed. Recordings of NREMΣ absolute power were reported as single summary values ​​for a single sleep night after each dose on pre-specified days (baseline and days 4, 8, and 12 of Part A of Example 11, and days 10, 17, 24, and 31 of Part B, as described in Tables 22 and 23 above). Each NREMΣ absolute power value was compared with the model-predicted mean plasma concentration (C ave ) pairing. For example, if the EEG recording period of an individual is from 6:00 a.m. on the 4th day to 6:00 a.m. on the 5th day, the corresponding C ave The PKPD data were analyzed in a mixed effects modeling framework using nonlinear mixed effects modeling (NONMEM) software. The change in baseline NREMΣ absolute power, designated as the outcome and primary explanatory variable, was C of the compound of formula (II). ave .

[0523] Each individual was also assessed for eye open (EO) and eye closed (EC) gamma absolute power at specific time points during the study day. These data were analyzed in a conventional population PKPD modeling framework that relates the model-predicted compound concentration at a certain time point to the corresponding EO or EC gamma absolute power at that time point.

[0524] Generating C for NREMΣ absolute power using population PK model ave and concentrations for EO and ECγ absolute power. For NREMΣ absolute power, C was calculated for each dose level on the last day of the EEG acquisition interval. aveFor EO and ECγ absolute power, concentrations at 4 h post-dose and 23.75 h post-dose were generated on the last day for each dose level. The corresponding EEG responses were then generated using the NREMΣ absolute power and the final population PKPD models for EO and ECγ absolute power.

[0525] For NREMΣ absolute power, the C ave After that, the signal appears to decrease maximally. Fig.18 , which shows NREMΣ absolute power versus average concentration, where the individual trajectories are represented by solid thin lines in part A and dashed thin lines in part B, as described in Example 11.

[0526] For EOγ absolute power, titration up to >300 ng / mL C (t) The signal appears to decrease maximally after the last dose of 120 mg. Fig.19 , which shows EOγ absolute power versus concentration, where the individual trajectories are represented by the solid thin line in part A and the dashed thin line in part B, as described in Example 11.

[0527] For ECγ absolute power, titrate up to a C corresponding to >300 ng / mL. (t) The signal appears to decrease the most after the final dose of 120 mg (titrated to 120 mg). As with the EO gamma absolute power, simulations indicate that the decrease in signal is greatest after the final dose of 120 mg. Fig. 20 , which shows ECγ absolute power versus concentration, where each trajectory is represented by a solid thin line in part A and a dashed thin line in part B, as described in Example 11.

[0528] Example 14 - Evaluation of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Dose Titration of a Compound of Formula (I) in a Within-Participant Ascending Dose Paradigm

[0529] This single-center, multi-part, Phase 1, randomized, double-blind, placebo-controlled clinical trial will evaluate the safety, tolerability, and pharmacokinetics of a compound of formula (I) titrated up to 120 mg in healthy male and female participants aged 18 to 54 years and participants aged 55 to 75 years. Specific endpoints will include the incidence and severity of AEs, changes in vital sign measurements, changes in clinical laboratory results, changes in ECG parameters, and the incidence of suicidal thoughts or behaviors measured by C-SSRS. For pharmacokinetic endpoints, plasma concentrations over time will be measured, as well as AUC t , AUC tau , C max and t maxIn addition, the C between age groups will be measured max and AUC tau The screening period for Part A and B will be up to 29 days (Day -29 to Day -1), with a baseline visit on Day -1. Screening assessments will include medical history, demographics, vital signs, physical examination (including height and weight), drug screen, viral serology tests, clinical laboratory tests, ECG, and C-SSRS assessment. All study drug administrations in both Part A and B will be performed in the fasting state; no food or drink, except water, will be allowed for at least 10 hours before dosing.

[0530] In Part A of this study, a titration scheme of reaching a 120 mg dosage in less than 28 days, such as 14 days or shorter, 12 days or shorter, 10 days or shorter or 7 days or shorter will be explored. Specifically, on the one hand, an initial daily dose of 20 mg or a matching placebo will be applied every day for 3 days (Day 1 to Day 3), followed by 40 mg every day for 3 days (Day 4 to Day 6), 80 mg every day for 3 days (Day 7 to Day 9) and 120 mg every day for 5 days (Day 10 to Day 14). For all queues, the titration scheme comprising the dose level studied will be fixed in each corresponding queue before starting administration, wherein the maximum dose level is 120 mg, and each dose level increment is no more than 60 mg, such as no more than 40 mg.

[0531] In Part B of this study, the same titration scheme described in Part A of this example and Part B of Example 11 above will be explored in healthy elderly participants aged 55 to 75 years. Specifically, on the one hand, an initial daily dose of 20 mg or a matching placebo will be administered daily for 3 days (Day 1 to Day 3), followed by 40 mg per day for 3 days (Day 4 to Day 6), 60 mg per day for 7 days (Day 7 to Day 13), 80 mg per day for 7 days (Day 14 to Day 20), 100 mg per day for 7 days (Day 21 to Day 27), and 120 mg per day for 4 days (Day 28 to Day 31). Patients will be allowed to receive a compound of Formula (I) at each of the 60 mg, 80 mg, and 100 mg dose levels daily for an extended period of up to 2 days.

[0532] Example 15 - Determination of the voltage dependence of calcium channel inhibition of formula (II)

[0533] The voltage dependence of the calcium channel isoforms was determined by comparing the activity at rest (Tonic Block) and half-inactivated (Voltage Dependent Block) voltages of different concentrations of Formula (II). First, 2 x 10 6 Preparation of hCa-containing cells 2 days after inoculation v 3.1、hCa v 3.2 or hCa v 3.3 HEK-293 cells expressing calcium channel isoforms; then approximately 6 x 10 6 Cells were collected from each cell. The collected cells were washed once in DPBS for about 30 minutes, and 1 mL of 1x (0.05%) trypsin-EDTA was added, vortexed, and allowed to stand on the cells for about 4 minutes. 10 mL of warm DMEM high-glucose medium supplemented with 10% fetal bovine serum, 2 mM sodium pyruvate, 10 mM HEPES, and 400 mg / mL G418 was added, and the cells were ground until a single cell suspension was added. The cells were placed in a 250 mL centrifuge tube with 30 mL of warm culture medium and gently shaken at 28 ° C for about 1 hour. Then 5 mL of cell aliquots (1x 10 6 Cells) were centrifuged at 100x for 2 minutes and the supernatant was removed. Next, 100 ml of external recording solution was added to the remaining cell pellet and triturated 20 times to achieve a single cell suspension.

[0534] Formula (II) (420.35 g / mol, supplied as a powder) was prepared in DMSO stock solution and the current inhibition potency (IC 50 ). Immediately before the assay, Formula (II) was diluted with DMSO to 300x the specified final concentration. All studies were performed at room temperature using the Molecular Devices PatchXpress automated patch clamp platform.

[0535] To measure hCa from a resting, closed state (tonic block) v 3.1、hCa v 3.2 and hCa v 3.3 Peak current, current was called by depolarizing pulses from -120 mV (non-inactivating holding potential) to -25 mV (10 milliseconds) at a frequency of 0.1 Hz. Peak current was defined as the peak inward current during period 1 when no leak subtraction was applied. Current stability was monitored and the potency of each compound was determined using concentration response curves. Compounds were tested at the maximum concentration that produced >85% block or solubility issues (e.g., compound precipitation).

[0536] Pharmacology was measured during period 1. The percentage of inhibition was calculated as: 100*((([Step 2+Step 5] / 2)–Step 3) / (Step 2+Step 5 / 2)), where Step 2 is the peak current measured at baseline, Step 5 is the current measured during the wash period, and Step 3 is the peak current measured during compound application. All calculations were performed using the average of the final 3 consecutive currents in each experimental procedure. The concentration response curves were fitted to the Hill equation to obtain IC50, slope, minimum response, and maximum response fitting parameters.

[0537] To calculate hCa from the semi-inactivated state (voltage-dependent block) v 3.1,hCa v 3.2, and hCa v 3.3 Peak currents Currents were first called by depolarizing pulses to -25 mV (10 ms) at a frequency of 0.1 Hz from the noninactivating holding potential (-120 mV). After the current amplitude became stable, the midpoint mean of the steady-state inactivation for each cell was determined using a series of 9,900 ms conditioning steps to bring the voltage before the test pulse (ranging from V hold The cells were then depolarized to -25 mV (10 ms) (-120 mV to -40 mV) to determine the extent of inactivation. The holding command potential was then set to produce approximately 50% inactivation (V 0.5 ) voltage. From this V 0.5 Potential, a voltage step of -25 mV (10 ms) was used to evoke peak current. Voltage steps to -120 mV (50 ms) were used to evoke tail current and monitor cell integrity.

[0538] The effect of the compounds on peak current amplitude was monitored using the voltage protocol described above and eluted after reaching steady state as determined by the PatchXpress stability script. Elution was performed with an original holding potential of -120 mV to promote reversal of state-dependent interactions. The holding potential was reset to the previously determined half-inactivation potential (V 0.5 ) and the peak current from this holding potential was measured to determine the washout current used to calculate inhibition. Pharmacology was measured during period 1 and percent inhibition was calculated as discussed above for tonic blockade.

[0539] It was found that formula (II) was generated by hCa v 3.1、hCa v 3.2 and hCa vConcentration-dependent inhibition of peak calcium current expressed by 3.3 channels. The extent of tonic block and voltage-dependent block was similar for all channels, consistent with the comparable potency of each isoform. Compounds of formula (II) were 2- to 4-fold more potent for voltage-dependent block than for tonic block, suggesting that they are effective for all hCa v Voltage-dependent inhibition of 3 isotypes. The results are shown below in Table 30 (tonic block) and Table 31 (voltage-dependent block).

[0540] Table 30 - Inhibition of tonic blockade of hCav3.x by formula (II)

[0541]

[0542] Table 31 - Inhibition of voltage-dependent blockade of hCav3.x by formula (II)

[0543]

[0544] The compounds of formula (II) exhibited concentration- and voltage-dependent inhibition of peak currents generated by hCav3.1, hCav3.2, and hCav3.3 channels. The potency of voltage-dependent blockade ranged from 172 nM to 341 nM and was 2- to 4-fold higher than the potency of tonic (resting) blockade measured. Specifically, for hCa v 3.1、hCa v 3.2 and hCa v 3.3, and the tonic block / voltage-dependent block (TB / VDB) ratios were 3.8, 2.0, and 4.0, respectively.

[0545] Example 16: Evaluation of the efficacy, safety, tolerability and pharmacokinetics of Formula (I) in adults with essential tremor

[0546] A two-part trial (Part A and Part B as described below) was conducted to investigate the efficacy, safety, tolerability, and pharmacokinetics of the compound of formula (I) in adult patients with essential tremor (ET). Each participant completed three study periods: screening, treatment period (14 days or 56 days), and safety follow-up.

[0547] Participants were males and females aged 18 years and older with a clinical diagnosis of ET. Participants with a history of any other medical, neurological or psychiatric illness that could explain or cause the tremor were excluded. Participants previously treated with Formula (I) in any clinical trial (including Part A of the current trial for participants enrolled in Part B) were also excluded.

[0548] In Part A, an open-label trial was conducted in which patients received 20 mg of the compound of formula (I) (Formulation 5) daily for 7 days (Day 1 to Day 7) followed by 40 mg (Formulation 5) daily for 4 days (Day 8 to Day 14).

[0549] In Part B, an open-label titration phase and a randomized, double-blind, placebo-controlled trial were conducted. During the open-label titration phase, patients received 20 mg of the compound of formula (I) (Formulation 5) daily for 3 days (Day 1 to Day 3), 40 mg daily for 4 days (Day 4 to Day 7), 60 mg daily for 7 days (Day 8 to Day 14), 80 mg daily for 7 days (Day 15 to Day 21), 100 mg daily for 7 days (Day 22 to Day 28), and 120 mg daily for 14 days (Day 29 to Day 42). During the withdrawal phase, patients continued to receive the current dose of (I) or switched to placebo according to randomization for 14 days (Day 43 to Day 56).

[0550] Table 32 summarizes the activities carried out in Part B during the trial.

[0551] In Part B, the safety and tolerability of the compound of formula (I) as assessed by a comprehensive analysis of the following endpoints are evaluated at a predetermined time point at the 1st day to the 70th day at baseline (as shown in Table 32 below): adverse events, physical examinations, vital signs, clinical laboratory results, ECG and C-SSRS reported by patients and clinicians. Patients are scheduled to undergo a safety follow-up visit in the clinic on the 70th day (± 1 day) to conduct the final clinical trial assessment. Efficacy assessments include TETRAS performance subscales, TETRAS upper limbs assessed using accelerometers, CGI, PGI-C, TETRAS ADL subscales, QUEST, BDI-II and BAI (Table 32).

[0552] Table 32: Timeline of activities for Part B

[0553]

[0554]

[0555] ADL = activities of daily living; AE = adverse event; BAI = Beck Anxiety Inventory; BDI = Beck Depression Inventory; CBC = complete blood count; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; C-SSRS = Columbia-Suicidality Severity Rating Scale; ECG = electrocardiogram; Meds = medications; PGI-C = Patient Global Impression of Change; PK = pharmacokinetics; QAM = every morning; QUEST = Quality of Life Questionnaire for Essential Tremor; TETRAS = Essential Tremor Rating Assessment Scale.

[0556] *Performed on Day -1.

[0557] a Urine samples are used to assess selected drugs and breath samples are used for alcohol screening.

[0558] b Vital signs included pulse rate, respiratory rate, body temperature, and blood pressure. Blood pressure was measured once after the participant had been lying down for at least 5 minutes and once after the participant had been standing for at least 2 minutes. On Day 1, vital signs were measured before dosing, 2 hours (±30 minutes), and 6 hours (±30 minutes) after dosing.

[0559] cIncludes CBC, clinical chemistry, coagulation factors, viral serology screen, urinalysis, and urine albumin. Coagulation factors and viral serology screen are collected only at screening.

[0560] d Three measurements were performed at Screening only; for all other time points, a single measurement was acceptable.

[0561] e TETRAS was completed at screening and at an undetermined time on Day 70. On other days, the following schedule was followed: Day 1: before and 6 (± 2) hours after the 20 mg QAM dose, Day 7: 6 (± 2) hours after the 40 mg QAM dose, Day 21: 6 (± 2) hours after the 80 mg (or highest tolerated dose) QAM dose, Day 42: before and 6 (± 2) hours after the 120 mg (or highest tolerated dose) QAM dose, Day 56: 6 (± 2) hours after the dose

[0562] f The TETRAS performance assessment is video recorded for center review. The local assessor scores the TETRAS performance assessment the same as captured in the video for center review. An independent conformity assessment is also conducted on the screening video.

[0563] g Kinesia ONE assessments were completed immediately after the TETRAS performance assessments (including pre- and post-dose assessments on Days 1 and 42). Two Kinesia ONE assessments were performed after each TETRAS performance assessment, with at least 30 minutes between each. All 3 movements in the upper extremity task (subtasks 4a, 4b, and 4c) were performed with both arms, first with the right arm and then with the left arm.

[0564] hFor visits where multiple TETRAS assessments were performed, the TETRAS ADL subscale was assessed only once. On Day 1, the ADL subscale was completed prior to dosing. On Day 42, the ADL subscale was completed 6 (± 2) hours after the QAM dose.

[0565] iBlood samples were collected at the following time points on Days 1 and 42: pre-dose and 0.5, 1, 2, 4, and 6 hours post-dose. A 6-hour post-dose sample was collected immediately after completion of the second Kinesia ONE assessment. When the pharmacokinetic sampling time point coincided with the TETRAS performance time point or the accelerometer-based assessment time point, the last pharmacokinetic sample was obtained. On Days 7, 21, and 56; samples were collected 2 hours post-dose. Blood collection was completed at an undetermined time on Day 70.

[0566] j Participants were randomized (1:1) to receive placebo or Formula (I) from Day 43 to Day 56. Randomization occurred from Day 37 to Day 42.

[0567] kOn days 1 and 42, participants were administered study medication in the clinic on an empty stomach (at least 1 hour before breakfast, which was provided by the center), and were observed in the clinic for approximately 6 hours before discharge. On all other days, participants were asked to receive study medication at home in the morning at least 1 hour before breakfast. The escalation schedule was as follows: 20 mg, days 1 to 3; 40 mg, days 4 to 7; 60 mg, days 8 to 14; 80 mg, days 15 to 21; 100 mg, days 22 to 28; and 120 mg, days 29 to 42. Participants received blinded study medication on days 43 to 56. During the blinded treatment period, participants received the same number of tablets per day as during days 36 to 42.

[0568] Table 33 provides a summary of baseline demographics for patients enrolled in Part B.

[0569] Table 33. Patients Enrolled in Phase 2 Represent a Broad Range of ET Populations

[0570]

[0571] *Center 704 was excluded due to protocol deviation

[0572] Fig.21 The mean change from baseline in modified ADL before and after cessation of dosing of Formula (I) as described in Example 16 is shown.

[0573] Fig. 22 The mean change in improved ADL from Day 42 to Day 57 following cessation of dosing of Formula (I) as described in Example 16 is shown.

[0574] Fig.23 Shown are mean changes from baseline in tremor obtained using tremor amplitude analysis before and after discontinuation of dosing of Formula (I) as described in Example 16.

[0575] Fig.24 Shown are mean changes in tremor obtained using tremor amplitude analysis from Day 42 to Day 56 following cessation of dosing of Formula (I) as described in Example 16.

[0576] Fig.25 The Archimedean screw tasks from patients before Formula (I) administration (Day 1 Baseline), during Formula (I) administration (Day 42), and during placebo administration (Day 56) are shown.

[0577] In Part A of the study, the 20 mg tablet formulation was evaluated with a dose escalation pattern of 20 mg per day for 7 days to 40 mg per day for 7 days. In Part B, doses between 20 and 120 mg per day were evaluated in an ascending titration design followed by continued dosing or weaning with placebo. Dosing for Parts A and B of the study has been completed.

[0578] The results of Part B strongly demonstrate the efficacy of Formula (I) when administered to subjects with essential tremor (ET), as evidenced by a significant effect on activities of daily living after 42 days of treatment with Formula (I), and this efficacy was maintained for patients who remained in the active experimental group after randomization, but not for patients randomized to placebo. ( Figure 21-22 In addition, tremor measurements using accelerometers ( Figure 23-24 ) and the functional data of the patients before administration of Formula (I), during administration of Formula (I) and during administration of placebo ( Fig.25 ) is consistent with the finding that formula (I) is effective in treating ET.

[0579] TETRAS upper limb score (Part A)

[0580] In Part A, the TETRAS upper limb score (LS mean [95% CI]) on Day 7 was reduced (i.e., improved) relative to the pre-dose baseline (-1.427 [-4.4375, 1.5845]), and the upper limb tremor amplitude was reduced by 23.9%. It was further reduced on Day 14 (-2.912 [-4.2779, -1.5466]), and the 95% CI showed that the change relative to baseline was not zero, and the upper limb tremor amplitude was reduced by 42.8% (Table 34) ( Fig.26 ). In the follow-up on day 21, i.e., 1 week after stopping the administration of formula (I), the upper limb score was still reduced relative to the pre-drug baseline (-1.183 [-2.7734, 0.4064]), and the upper limb tremor amplitude was reduced by 20.3%.

[0581] TETRAS upper limb score (Part B)

[0582] During the open-label titration phase of Part B, the TETRAS upper limb score on Day 7 improved relative to the pre-dose baseline (LS mean [95% CI]) (-0.967 [-2.1795, 0.2447]), and the upper limb tremor amplitude decreased by 16.9% (Table 35) ( Fig. 27 ). There was a further decrease on day 21 (-1.143 [-2.1269, -0.1598]) (upper limb tremor amplitude decreased by 19.7%) and day 42 (-2.090 [-3.8223, -0.3585]), with 95% CI showing that the change relative to baseline was not zero, and the upper limb tremor amplitude decreased by 33.0% (Table 35) ( Fig. 27 ).

[0583] In the randomized withdrawal phase of Part B, comparison with the randomized baseline on Day 42 showed that the TETRAS upper limb score on Day 56 increased (i.e., worsened), with comparable efficacy between the placebo group (0.969 [-2.4752, 4.4139]) and the Formula (I) group (0.716 [-2.4290, 3.8619]), and the upper limb tremor amplitude increased by 17.0% and 12.8%, respectively, with the LS mean difference (95% CI) between the treatment groups (Formula (I)-placebo) being -0.253 (-4.9188, 4.4129) (Table 36) ( Fig.28 At the 70th day follow-up, 2 weeks after dosing was discontinued in both treatment groups, the upper limb scores in the placebo group (1.969 [-0.2731, 4.2118]) and the Formula (I) group (1.653 [-0.4283, 3.7347]) increased to levels above the randomized baseline (i.e., worsened relative to the randomized baseline on Day 42), with increases in the combined upper limb tremor amplitude of 31.5% and 27.2%, respectively.

[0584] In the open-label titration phase of Part B, the LS mean reductions in upper-limb tremor amplitude in the subset of participants with a predose baseline upper-limb score of ≥10 were 22.9% on Day 7 and 26.7% on Day 21. These reductions from predose baseline were greater than those observed in the full analysis set. The reduction in upper-limb tremor amplitude, as measured by accelerometer, was also greater in this subgroup compared with the full analysis set. No significant differences in upper-limb tremor amplitude were observed in this subgroup during the randomized withdrawal phase of Part B compared with the full randomized withdrawal analysis set.

[0585] TETRAS combined upper limb score

[0586] In Part A, the composite TETRAS upper limb score (LS mean [95% CI]) on Day 7 was reduced (i.e., improved) relative to the pre-dose baseline (-1.667 [-5.8826, 2.5476]), and the composite upper limb tremor amplitude was reduced by 16.0%. It was further reduced on Day 14 (-4.239 [-8.3234, -0.1546]), and the 95% CI showed that the change relative to the baseline was not zero, and the composite upper limb tremor amplitude was reduced by 35.8% (Table 34). In the follow-up on Day 21, i.e., 1 week after stopping the administration of Formula (I), the composite upper limb score increased to close to the pre-dose baseline level (-0.278 [-4.0192, 3.4625]), and the composite upper limb tremor amplitude was reduced by 2.9%.

[0587] In the open-label titration phase of Part B, the TETRAS composite upper limb score on Day 7 was improved relative to the pre-dose baseline (LS mean [95% CI]) (-0.909 [-2.9414, 1.1234]), and the composite upper limb tremor amplitude decreased by 9.1%. It was further reduced on Day 21 (-1.320 [-2.8986, 0.2589]) and Day 42 (-1.882 [-4.8650, 1.1014]), and the composite upper limb tremor amplitude decreased by 12.9% and 17.9%, respectively (Table 35).

[0588] During the randomized withdrawal phase of Part B, comparison with the randomized baseline on Day 42 showed that the TETRAS composite upper limb score on Day 56 increased (i.e., worsened), with the placebo group (3.420 [-1.6327, 8.4732]) being greater than that in the Formula (I) group (1.525 [-3.0887, 6.1378]), and the composite upper limb tremor amplitude increased by 30.1% and 14.7%, respectively, and the LS mean difference (95% CI) between the treatment groups (Formula (I)-placebo) was -1.896 (-8.7365, 4.9451) (Table 36). At the 70-day follow-up, 2 weeks after dosing was stopped, the combined upper limb scores in the placebo group (4.120 [-0.0017, 8.2422]) and the Formula (I) group (3.156 [-0.6797, 6.9924]) increased to levels above the randomized baseline (i.e., worsened relative to the randomized baseline on Day 42), and the combined upper limb tremor amplitude increased by 35.0% and 28.1%, respectively.

[0589] TETRAS performance subscale total score and individual scores

[0590] The trends observed in the TETRAS Upper Limb and Combined Upper Limb scores were similar to those observed in the TETRAS Performance Subscale Total Score and individual Performance Subscale items, including Item 6 (Drawing an Archimedean spiral with both hands) and Item 7 (Handwriting) (Tables 34, 35, 36), including greater reductions in tremor amplitude in the subgroup of participants with baseline Upper Limb scores ≥10.

[0591] Modified Activities of Daily Living Score [Part B only]

[0592] In the open-label titration phase of Part B, the mADL score on Day 7 decreased (i.e., improved) relative to the pre-dose baseline (LS mean [95% CI]) (-2.862 [-4.9674, -0.7571]). The score remained largely stable on Day 21 (-2.812 [-5.7299, 0.1065]), and then further decreased on Day 42 (-6.669 [-10.0333, -3.3042]), and the 95% CI for all time points after dosing showed that the change relative to baseline was not zero (Table 35).

[0593] In the randomized withdrawal phase of Part B, the comparison with the randomized baseline on day 42 showed that the total mADL score on day 56 increased (ie, worsened), and the placebo group (9.789 [4.7981, 14.7796]) was greater than the formula (I) group (1.350 [-3.2686, 5.9691]), and the LS mean difference (95% CI) between the treatment groups (formula (I)-placebo) was -8.439 (-15.3856, -1.4916) (Table 36). At the follow-up on day 70, 2 weeks after stopping dosing, the mADL scores of the placebo group (7.589 [1.0775, 14.1001]) and the formula (I) group (4.353 [-1.8456, 10.5507]) increased to a level above the randomized baseline (ie, worsened relative to the randomization on day 42).

[0594] During the Part B open-label titration phase, the subset of participants with a predose baseline upper extremity score ≥10 had reductions in mADL (LS mean [95% CI]) relative to predose baseline at Day 7 (-3.011 [-5.4324, -0.5891]) and Day 21 (-3.773 [-6.9613, -0.5848]). These reductions were comparable to those observed in the full analysis set. During the Part B randomized withdrawal phase, no significant differences in mADL were observed for this subgroup compared with the full randomized withdrawal analysis set.

[0595] TETRAS Activities of Daily Living

[0596] In the open-label titration phase of Part B, the TETRAS ADL score on Day 7 (-1.986 [-4.8142, 0.8417]) decreased (i.e., improved) relative to the pre-dose baseline (LS mean [95% CI]). The ADL score decreased further on Day 21 (-3.475 [-7.0260, 0.0756]) and then decreased again on Day 42 (-8.207 [-12.5655, -3.8481]), and the 95% CI on Day 42 showed that the change relative to baseline was not zero (Table 35).

[0597] In the randomized withdrawal phase of Part B, the comparison with the randomized baseline on day 42 showed that the TETRAS ADL score on day 56 increased (i.e., worsened), and the placebo group (10.455 [4.1039, 16.8060]) was greater than the formula (I) group (0.877 [-5.0097, 6.7629]), and the LS mean difference (95% CI) between the treatment groups (formula (I)-placebo) was -9.578 (-18.9020, -0.2546) (Table 36). At the follow-up on day 70, 2 weeks after stopping dosing, the TETRAS ADL scores of the placebo group (9.255 [1.8118, 16.6981]) and the formula (I) group (3.267 [-3.9333, 10.4677]) increased to a level above the randomized baseline (i.e., worsened relative to the randomization on day 42).

[0598] During the Part B open-label titration phase, the subset of participants with a predose baseline upper extremity score ≥10 had reductions in ADL (LS mean [95% CI]) relative to predose baseline at Day 7 (-2.222 [-5.7665, 1.3220]) and Day 21 (-4.444 [-8.6856, -0.2033]). These reductions were comparable to those observed in the full analysis set, as described above. No significant differences in ADL were observed for this subgroup during the Part B randomized withdrawal phase compared with the full randomized withdrawal analysis set.

[0599] Accelerometer-based TETRAS analysis

[0600] The accelerometer (Kinesia ONE) TETRAS assessments were generally consistent with those performed in the clinic. Tables 37, 38, and 39 summarize the accelerometer upper extremity scores for Part A, the open-label titration phase of Part B, and the randomized withdrawal phase of Part B, respectively.

[0601] Fig.29 , Fig.30 and Fig.31 Accelerometer-based TETRAS scores for Part A, the open-label titration phase of Part B, and the randomized withdrawal phase of Part B are depicted graphically, respectively.

[0602] Tables 40 and 41 provide the accelerometer-based TETRAS scores for participants with a predose baseline upper extremity score ≥ 10 during the open-label titration and randomized withdrawal phases of Part B, respectively.

[0603] TETRAS Analysis for Video Review

[0604] The video-reviewed TETRAS assessments were generally consistent with those performed in the clinic. Tables 42, 43, and 44 summarize the video-reviewed TETRAS performance subscale total scores for Part A, the open-label titration phase of Part B, and the randomized withdrawal phase of Part B.

[0605] The upper extremity scoring values ​​from the video review were generally consistent with those performed in the clinic, and are summarized in Tables 45, 46, and 47 for Part A, the open-label titration phase of Part B, and the randomized withdrawal phase of Part B, respectively.

[0606] QUEST total score [Secondary efficacy analysis]

[0607] During the open-label titration phase of Part B, the QUEST total score on Day 7 (-0.561 [-7.7823, 6.6611]) significantly decreased (i.e., improved) relative to the pre-dose baseline (LS mean [95% CI]), then decreased further on Day 21 (-5.933 [-12.1961, 0.3310]), and decreased again on Day 42 (-8.203 [-17.9048, 1.4991]).

[0608] In the randomized withdrawal phase of Part B, the comparison with the randomized baseline on Day 42 showed that the QUEST total score on Day 56 in the placebo group increased (i.e., worsened) (5.106 [-7.3675, 17.5787]), while the Formula (I) group continued to improve (-1.322 [-12.9588, 10.3140]). At the follow-up on Day 70, 2 weeks after stopping dosing, the QUEST total scores of the placebo group (10.542 [-2.9626, 24.0474]) and the Formula (I) group (1.741 [-11.0530, 14.5340]) increased to a level above the randomized baseline (i.e., worsened relative to the randomization on Day 42).

[0609] No significant differences in QUEST scores were observed among participants with a predose baseline upper extremity score ≥10 compared with the full analysis set of the open-label titration and randomized withdrawal phases of Part B.

[0610] Clinical overall impression

[0611] In Part A, 4 participants (66.7%) had no change in CGI-I scores from pre-dose baseline at Day 7. On Day 14, 5 participants (83.3%) had a slight improvement in CGI scores, 1 participant (16.7%) had a great improvement in CGI scores, and no participant was assessed as having no change in symptoms or worsening symptoms (Table 48).

[0612] During the open-label titration phase of Part B, from day 7 to day 42, the number of participants with CGI-I scores reflecting no change from predose baseline decreased (four participants [33.3%] vs. three participants [27.3%]), whereas the number of participants with much improved symptoms increased (one participant [8.3%] vs. four participants [36.4%]).

[0613] During the Part B randomized withdrawal phase, the majority of participants (60.0% to 83.3%) in both treatment groups had CGI-I scores reflecting no change in symptoms on Days 56 and 70 from the randomized baseline of Day 42.

[0614] In addition, CGI-S scores supported the categorical CGI-I results. No significant differences in CGI-S or CGI-I scores were observed for participants with a predose baseline upper extremity score ≥10 compared with the full analysis set of the open-label titration and randomized withdrawal phases of Part B.

[0615] Patient's overall impression of change

[0616] In Part A, 2 participants (33.3%) had minimal improvement in PGI-C scores from pre-dose baseline at Day 7, and 5 participants (83.3%) had an increase in PGI-C scores at Day 14. No participant was assessed as having no change in symptoms or worsening symptoms at Day 14 (Table 49).

[0617] During the open-label titration phase of Part B, the number of participants with PGI-C scores reflecting no change from predose baseline decreased from day 7 to day 42 (seven participants [53.8%] vs. four participants [36.4%]), whereas the number of participants with much improved symptoms increased (one participant [7.7%] vs. three participants [27.3%]).

[0618] During the Part B randomized withdrawal phase, the majority of participants (50.0% to 80.0%) in both treatment groups had PGI-C scores reflecting no change in symptoms on Days 56 and 70 from the randomized baseline of Day 42.

[0619] No significant differences in PGI-C scores were observed among participants with a predose baseline upper extremity score ≥10 compared with the full analysis set of the open-label titration and randomized withdrawal phases of Part B.

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627] Table 37. Accelerometer-Based Upper Limb Scores: Observations by Time Point, Change from Baseline, and Percent Change from Baseline—Part A

[0628]

[0629]

[0630]

[0631] Table 38. Accelerometer-Based Upper Extremity Scores: Observations by Time Point, Change from Baseline, and Percent Change from Baseline - Part B Open-Label Titration Phase

[0632]

[0633]

[0634]

[0635] Table 39. Accelerometer-Based Upper Limb Scores: Observations and Changes by Time Point - Part B Randomized Withdrawal

[0636]

[0637]

[0638]

[0639]

[0640]

[0641] Table 40. Accelerometer-Based Upper Extremity Scores: Observations by Time Point, Change from Baseline, and Percent Change from Baseline - Part B Open-Label Titration Phase

[0642]

[0643]

[0644]

[0645]

[0646] Table 41. Accelerometer-based upper extremity scores: observations and changes by time point – Part B

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653] Table 42. TETRAS Performance Subscale Total Score by Video Review: Observations by Time Point, Change from Baseline, and Percent Change from Baseline – Part A

[0654]

[0655]

[0656]

[0657] Table 43. TETRAS Performance Subscale Total Score by Video Review: Observation by Time Point, Change from Baseline, and Percent Change from Baseline – Part B Open-Label Titration Phase

[0658]

[0659]

[0660]

[0661] Table 44. TETRAS Performance Subscale Total Score by Video Review: Observations and Changes by Time Point – Part B

[0662]

[0663]

[0664]

[0665]

[0666]

[0667] Table 45. TETRAS Upper Extremity Scores by Video Review: Observations by Time Point, Change from Baseline, and Percent Change from Baseline – Part A

[0668]

[0669]

[0670]

[0671] Table 46. TETRAS Upper Extremity Score by Video Review: Observation by Time Point, Change from Baseline, and Percent Change from Baseline – Part B Open-Label Titration Phase

[0672]

[0673]

[0674]

[0675] Table 47. TETRAS upper extremity scores by video review: observations and changes by time point – Part B

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683] CGI-I = Clinical Global Impression-Improvement; FAS = Full Analysis Set; OLT = Open-Label Titration; PGI-C = Patient Global Impression of Change; RWAS = Randomisation Withdrawal Analysis Set; RWD = Randomisation Withdrawal.

[0684] a Change from pre-dose baseline.

[0685] b Change from randomization baseline.

[0686] A summary of treatment-emergent adverse events (Part B) is provided in Table 50 below. One serious adverse event (AE) of essential tremor was reported by one patient randomized to placebo after Day 42. All other adverse events were mild to moderate.

[0687] Table 50 – Treatment-emergent adverse events (TEAES) in >1 participant

[0688]

[0689] *Serious AE - essential tremor in patients randomized to placebo after Day 42.

[0690] Eleven participants completed Part B. Treatment-emergent adverse events that led to dose titration reductions (Table 51) or discontinuations (Table 52) were mild to moderate. The Part B protocol allowed patients to reduce dose titration once. In Part B, four of the 14 participants had their titration reduced and three of the 14 participants discontinued administration of Formula (I).

[0691] Table 51 – Treatment-emergent adverse events leading to detitration

[0692] Confusion 1 Poor concentration 1 Postural dizziness 1 Paresthesias 1 Lethargy 1

[0693] Table 52 - Treatment-emergent adverse events associated with discontinuation of Formula (I)

[0694]

[0695]

[0696] All reported by the same patient.

[0697] As shown above, at the highest dose of 120 mg, adverse events were rare.

[0698] Overall, the data showed that titrated doses up to 120 mg were well tolerated. The data also showed that ET patients generally improved, as shown by the significant effect on activities of daily living (ADL) 42 days after administration of Formula (I), which was maintained for patients who continued to be given Formula (I) after randomization, but not for patients who were given placebo after randomization. In addition, these data demonstrate the efficacy of Formula (I) in treating ET patients, as shown by the improvement of TETRAS scores when given Formula (I) and the rebound of symptoms after stopping treatment with Formula (I).

[0699] Equivalent programs and scope

[0700] In the claims, articles such as "a," "an," and "the" may mean one or more unless indicated to the contrary or otherwise obvious from the context. Claims or descriptions containing "or" between one or more members of a group are deemed to be satisfied if one, more than one, or all of the members of the group are present in, used in, or otherwise related to a specified product or process, unless indicated to the contrary or otherwise obvious from the context. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to a given product or method. The invention includes embodiments in which more than one or all of the members of the group are present in, used in, or otherwise related to a given product or method.

[0701] In addition, the present invention encompasses all variations, combinations and arrangements, wherein one or more limitations, elements, clauses and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim that is subordinate to another claim can be modified to include one or more limitations found in any other claim that is subordinate to the same basic claim. In the case where the elements are presented as a list, for example, in the Markush group format, each subgroup of the elements is also disclosed, and any element can be removed from the group. It should be understood that, in general, in the case where the present invention or aspects of the present invention are referred to as including specific elements and / or features, certain embodiments of the present invention or aspects of the present invention are composed of such elements and / or features, or are substantially composed of such elements and / or features. For simplicity, those embodiments are not specifically described in this article with such words. It should also be noted that the terms "include" and "contain" are intended to be open, and allow the inclusion of additional elements or steps. In the case of giving a range, the endpoints are included. In addition, unless otherwise indicated or otherwise obvious from the context and understanding of one of ordinary skill in the art, values ​​expressed as ranges can be assumed in different embodiments of the present invention to any specific value or sub-range within the range, to the tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0702] This application relates to various granted patents, published patent applications, journal articles and other publications, which are all incorporated herein by reference. If there is a conflict between any incorporated reference and this specification, the specification shall prevail. In addition, any specific embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if they are not explicitly set forth herein. For any reason, any specific embodiment of the present invention may be excluded from any claim, whether or not it is related to the existence of the prior art.

[0703] Those skilled in the art will recognize or be able to determine many equivalents to the specific embodiments described herein using no more than routine experimentation. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but is as set forth in the appended claims. It will be appreciated by those of ordinary skill in the art that various changes and modifications may be made to this specification without departing from the spirit or scope of the invention as defined by the following claims.

Claims

1. A method for 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 a first dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a first period of time, wherein after administration of the first dose of the compound for the first period of time, the subject's maximum plasma drug concentration (C max ) ranges from about 30 ng / mL to about 130 ng / mL and / or the area under the plasma concentration-time curve (AUC 24 ) ranges from about 490 ng*hr / ml to about 2030 ng*hr / ml; (b) increasing the amount of the compound in the first dose and administering one or more increasing doses of the compound to the subject to reach a maximum titrated dose; as well as (c) administering to the subject the maximum titrated dose of the compound to maintain a C in the subject in the range of about 280 ng / mL to about 470 ng / mL. max and / or an AUC ranging from about 3480 ng*hr / ml to about 5800 ng*hr / ml 24 .

2. The method of claim 1, wherein the first period of time ranges from about 3 days to about 9 days.

3. The method of claim 1 or 2, wherein step (b) comprises increasing the first dose to a second dose, and administering the second dose of the compound to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's C max The range is about 80 ng / mL to about 300 ng / mL and / or AUC 24 The range is about 1220 ng*hr / ml to about 4070 ng*hr / ml.

4. The method according to claim 1 or 2, wherein step (b) comprises: The first dose is increased to a second dose, and the second dose of the compound is administered to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's C max The range is from about 80 ng / mL to about 220 ng / mL and / or AUC 24 ranges from about 1220 ng*hr / ml to about 3330 ng*hr / ml; and The second dose is increased to a third dose, and the third dose of the compound is administered to the subject for a third period of time, wherein after administering the third dose of the compound for the third period of time, the subject's C max The range is from about 180 ng / mL to about 380 ng / mL and / or AUC 24 The range is about 2440 ng*hr / ml to about 4700 ng*hr / ml.

5. The method according to any one of claims 1 to 4, wherein the second dose is increased by no more than 40 mg relative to the first dose, and wherein the third dose is increased by no more than 40 mg relative to the second dose.

6. The method of claim 3, 4 or 5, wherein the second time period and the third time period range from 3 days to 9 days.

7. The method of claim 1, wherein step (b) comprises: The first dose is increased to a second dose, and the second dose of the compound is administered to the subject for a second period of time, wherein after administering the second dose of the compound for the second period of time, the subject's C max The range is about 80 ng / mL to less than 130 ng / mL and / or AUC 24 A range of about 1220 ng*hr / ml to less than 2030 ng*hr / ml; The second dose is increased to a third dose, and the third dose of the compound is administered to the subject for a third period of time, wherein after administering the third dose of the compound for the third period of time, the subject's C max The range is 130 ng / mL to less than 220 ng / mL and / or AUC 24 The range is 2000 ng*h / mL to less than 3330 ng*h / mL; The third dose is increased to a fourth dose, and the fourth dose of the compound is administered to the subject for a fourth period of time, wherein after administering the fourth dose of the compound for the fourth period of time, the subject's C max The range is 180 ng / mL to less than 300 ng / mL and / or AUC 24 The range is 2440 ng*h / mL to less than 4070 ng*h / mL; The fourth dose is increased to a fifth dose, and the fifth dose of the compound is administered to the subject for a fifth period of time, wherein after administering the fifth dose of the compound for the fifth period of time, the subject's C max The range is 230 ng / mL to less than 380 ng / mL and / or AUC 24 ranged from 2820 ng*hr / mL to less than 4700 ng*hr / mL, and The fifth dose is increased to a sixth dose, and the sixth dose of the compound is administered to the subject for a sixth period of time, wherein after administering the sixth dose of the compound for the sixth period of time, the subject's C max The range is 230 ng / mL to less than 380 ng / mL and / or AUC 24 The range was 2820 ng*hr / mL to less than 4700 ng*hr / mL.

8. The method of claim 7, wherein the first time period, the second time period, the third time period, the fourth time period, the fifth time period, and the sixth time period range from 3 days to 14 days.

9. The method according to any one of claims 1 to 8, wherein the first dose is 20 mg per day.

10. The method according to any one of claims 1 to 9, wherein the maximum titrated dose is 120 mg per day.

11. The method according to any one of claims 1 to 9, wherein each dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject daily.

12. 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, the method comprising: (a) administering to the subject a first dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount ranging from about 5 mg per day to about 40 mg per day for a first period of time; (b) increasing the amount of the compound in the first dose and administering one or more increasing doses of the compound to the subject to reach a maximum titrated dose; as well as (c) administering to said subject said maximum titrated dose of said compound in an amount ranging from about 20 mg per day to about 120 mg per day.

13. The method of claim 12, wherein the first period of time is 3 days.

14. The method of claim 12 or claim 13, wherein in step (b) the one or more increasing doses of the compound are administered for a period of 3 to 14 days.

15. The method of any one of claims 12 to 14, wherein during the first period of time, the compound is administered in an amount ranging from about 20 mg per day to about 40 mg per day.

16. The method of any one of claims 12 to 15, wherein step (b) comprises increasing the first dose to a second dose, and administering the second dose of the compound to the subject in an amount ranging from about 40 mg per day to about 80 mg per day for a second period of time.

17. The method of any one of claims 12 to 15, wherein step (b) comprises increasing the first dose to a second dose, and administering the second dose of the compound to the subject in an amount ranging from about 40 mg per day to about 60 mg per day for a second period of time; and The second dose is increased to a third dose, and the third dose of the compound is administered to the subject in an amount ranging from about 60 mg per day to about 100 mg per day for a third period of time.

18. The method of any one of claims 17, further comprising increasing the third dose to a fourth dose, and administering the fourth dose of the compound to the subject in an amount of about 80 mg per day for a fourth period of time.

19. The method of claim 12, wherein the first period of time is 3 days and the compound is administered in an amount of about 20 mg per day, and wherein step (b) comprises increasing the first dose to a second dose and administering the second dose of the compound to the subject in an amount of about 40 mg per day for a second period of time.

20. The method of claim 17 or claim 18, wherein the third period of time is 7 days and the compound is administered in an amount of about 60 mg per day.

21. The method of claim 16, wherein the second period of time is 3 days, and the compound is administered in an amount of about 40 mg per day, and the method further comprises: In step (b), increasing the second dose to a third dose, and administering the third dose of the compound to the subject in an amount of about 60 mg per day for a third period of time; increasing the third dose to a fourth dose, and administering the fourth dose of the compound to the subject in an amount of about 80 mg per day for a fourth period of time; as well as increasing the fourth dose to a fifth dose, and administering the fifth dose of the compound to the subject in an amount of about 100 mg per day for a fifth period of time, increasing the fifth dose to a sixth dose, and administering the sixth dose of the compound to the subject in an amount of about 120 mg per day for a sixth period of time, wherein the maximum titrated dose of the compound is about 120 mg per day.

22. The method according to any one of claims 1 to 21, wherein the pharmaceutically acceptable salt is the hydrochloride salt of formula (II).

23. The method according to any one of claims 1 to 22, wherein the disease or condition associated with abnormal function or activity of a T-type calcium channel is a psychiatric disorder, pain, tremor, seizure, epilepsy or an epileptic syndrome.

24. The method of claim 23, wherein the disease or condition associated with abnormal function or activity of a T-type calcium channel is tremor.

25. The method of claim 24, wherein the disease or condition associated with abnormal function or activity of a T-type calcium channel is essential tremor.

26. The method of any one of claims 1 to 25, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a modified release dosage formulation comprising at least one modified release polymer.

27. The method of claim 26, wherein about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof is released within 7 hours after administration to the subject.

28. The method of claim 26 or 27, wherein the modified release polymer is hydroxypropyl methylcellulose, ethyl cellulose or a polyacrylate polymer.

29. The method of any one of claims 26 to 28, wherein the modified release polymer is hydroxypropyl methylcellulose.

30. The method of any one of claims 1 to 29, wherein the method causes a reduction in the EEG sigma band during NREM sleep of the subject.

31. The method of claim 30, wherein the ratio of the EEG sigma band decrease to the EEG sigma band baseline during NREM sleep of the subject ranges from about 0.4 to about 0.

7.

32. The method of any one of the preceding claims, wherein the subject's TETRAS performance score is reduced by at least 25%.

33. The method of any of the preceding claims, wherein the subject's accelerometer performance score improves by at least 20%.

34. The method of any of the preceding claims, wherein the subject improves on an Archimedean Screw Task test.

35. The method according to any one of the preceding claims, wherein the compound of formula (I) is administered to the subject for a period of at least 3 months.

36. The method according to any one of the preceding claims, wherein the compound of formula (I) is administered to the subject for a period of at least 6 months.

37. The method according to any one of the preceding claims, wherein the compound of formula (I) is administered to the subject for a period of at least 9 months.

38. The method according to any one of the preceding claims, wherein the compound of formula (I) is administered to the subject for a period of at least 1 year.

39. The method according to any one of the preceding claims, wherein the compound of formula (I) is administered to the subject for a period of at least 5 years.

40. The method according to any one of the preceding claims, wherein the compound of formula (I) is administered to the subject for a period of at least 10 years.

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