Therapeutic Methods Using T-Type Calcium Channel Modulators

Abstract

Disclosed herein, in part, is a method useful for treating a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as essential tremor, in a subject in need thereof, comprising administering a T-type calcium channel inhibitor in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. Also disclosed herein is a composition comprising a T-type calcium channel inhibitor and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] Disclosed herein is a method useful for treating a disease or condition associated with abnormal functioning of T-type calcium channels, such as essential tremor, in a subject in need thereof, comprising administering a T-type calcium channel inhibitor in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] Essential tremor (ET) is the most common movement disorder, affecting up to 7 million patients in the United States alone. As an action tremor, ET manifests during voluntary movement, thereby interfering with basic life functions, causing direct disability and impaired job performance. Approximately 50% of ET patients receive pharmacological therapy, but tremor is only partially controlled in these patients, and nearly half of medications are discontinued due to limited efficacy and / or poor tolerability.

[0003] Essential tremor, also known as essential tremor, is the most common type of tremor. In some patients, essential tremor may be mild and non-progressive, and in some patients, it may begin on one side of the body and progress slowly, typically affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremor may decrease with age, but the severity may increase. Increased emotion, stress, fever, physical exhaustion, or hypoglycemia may induce tremors and / or increase their severity. Symptoms generally progress over time and may be visible and persistent after onset.

[0004] Currently, propranolol, a beta blocker approved by the FDA in 1967, is the only approved therapy for ET in the United States. Propranolol, a nonselective beta blocker, is contraindicated for individuals with certain respiratory or cardiac problems, which are common comorbidities in the age group that often suffers from ET. Primidone, an anticonvulsant, can be used to control ET, but must be slowly titrated over six to eight weeks and can cause sedation and balance problems while accelerating osteoporosis with long-term use. Topiramate is another example of an anticonvulsant that can be used to treat ET, but patients often report unwanted side effects, including vision problems, cognitive problems, loss of appetite, and tingling sensations.

[0005] As a final-line treatment, thousands of ET patients in the United States choose invasive surgery each year. Interventions include Gamma Knife® surgery and focused ultrasound thalamotomy, in which a portion of the thalamus involved in the cerebellothalamocortical (CTC) pathway is removed, and deep brain stimulation (DBS), in which electrodes are implanted in the brain. These procedures are generally effective but can be associated with significant side effects and risks. Many patients who are eligible for surgical therapy do not choose to undergo these procedures.

[0006] Thus, there remains a significant unmet need for millions of ET patients who are currently not treated for ET or are underserved by existing treatment options. One recent strategy to treat ET is by administration of T-type calcium channel inhibitors. There is a large body of clinical, preclinical, and genetic evidence implicating T-type calcium channels in the CTC pathway as a major driver of ET. Successful development of T-type calcium channel modulators in ET will likely require pharmacokinetic (PK) properties with blunted Cmax and careful clinical trial design and endpoint selection. To this end, the compound of formula (I) shown below has been developed for the treatment of ET. [ka]

[0007] The compound of formula (I) is described, for example, in PCT Publication WO2009 / 146540, which is incorporated herein by reference. The safety profile, efficacy, tolerability, and pharmacokinetics of the compound of formula (I) in modified release formulations with and without dose titration have been evaluated as described in PCT Publication WO2021 / 222342, which is incorporated herein by reference. Given the potential of the compound of formula (I) to treat ET, strategies for further development of the compound of formula (I) for treating ET are an important goal. [Prior art documents] [Non-patent literature]

[0008] [Patent Document 1] International Publication No. 2009 / 146540 [Patent Document 2] International Publication No. 2021 / 222342 Summary of the Invention

[0009] 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 administering to the subject a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. In some variations, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with propranolol or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the disease or condition associated with abnormal function or activity of T-type calcium channels is essential tremor (ET).Accordingly, also disclosed herein is a method of treating ET in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the compound used to treat a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, is the hydrochloride salt (HCl) of the compound of formula (I), as shown below. [ka]

[0012] In some embodiments, the compound used to treat a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, is a crystalline form of the compound of formula (I), e.g., a crystalline HCl salt of the compound of formula (I). In some embodiments, the compound used to treat a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, is a polymorph of the crystalline salt of the compound of formula (I), e.g., a polymorph of the crystalline HCl salt of the compound of formula (I) described in WO2021007487A1, the entire contents of which are incorporated herein by reference.

[0013] In some embodiments, propranolol is administered as an HCl salt. In some embodiments, propranolol or a pharma- ceutically acceptable salt thereof is administered as the (S)-enantiomer. In certain embodiments, (S)-propranolol hydrochloride is administered in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In other embodiments, (R)-propranolol hydrochloride is administered in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., an HCl salt of a compound of formula (I), may be referred to as a "test drug" in the examples herein.

[0014] In some embodiments, a subject suffering from a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, has previously received a dosage regimen of propranolol or a pharma- ceutically acceptable salt thereof prior to administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, a subject suffering from a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, has previously received a dosage regimen of primidone or a pharma- ceutically acceptable salt thereof prior to administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and in some embodiments, a subject suffering from a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, has previously received a dosage regimen of topiramate or a pharma- ceutically acceptable salt thereof prior to administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0015] In some embodiments, a subject who has previously received a dosage regimen of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof has an active prescription for propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, and has been instructed by a physician to take propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof. After initiation of administration of a compound of formula (I) to a subject who has previously received a dosage regimen of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, the subject's active prescription of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof may be terminated or modified to adjust the dosage regimen or dosage of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, or the prescription may continue without change. In some embodiments, a subject previously receiving a dosing regimen of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof is administered a compound of formula (I) while the administration of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof to the subject is terminated. In some embodiments, a subject previously receiving a dosing regimen of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof is administered a compound of formula (I) in combination with propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof.

[0016] As disclosed herein, ET patients who were taking propranolol hydrochloride responded favorably (e.g., reduced tremor symptoms) to the HCl salt of the compound of formula (I) in a Phase 2 clinical trial designed to evaluate the efficacy, safety, and tolerability of the combination therapy without significant side effects. Thus, according to the present disclosure, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may serve as an adjunct therapy to at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. In some variations, propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof is administered to a subject chronically or as needed (PRN). For example, in certain embodiments, propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be administered PRN to a subject with mild ET symptoms prior to a situation / action in anticipation of the tremor(s) that the situation / action induces. In certain embodiments, propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be administered PRN to a subject based on the subject's self-determination that propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof will treat ET as needed. The subject's self-determination may be based, for example, on self-assessment of symptoms and / or data provided by an assessment device, e.g., wearable technology.

[0017] In one aspect, the disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, in a subject in need thereof, the method comprising administering to the subject 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 20 mg to about 100 mg, or about 20 mg to about 80 mg) of a compound of formula (I) or a pharma- ceutical acceptable salt thereof (e.g., an HCl salt) daily (e.g., once, twice, or three times), wherein the subject is concurrently taking at least one of propranolol, primidone, topiramate, or a pharma- ceutical acceptable salt thereof (e.g., propranolol HCl), i.e., the subject is administered a compound of formula (I) in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutical acceptable salt thereof, as described herein. In some embodiments, the subject is taking (S)-propranolol HCl.

[0018] In some embodiments, where the subject is or has been on a prescribed regimen of at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, the subject remains on the same dosage regimen of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof that the subject was on prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In other embodiments, the subject is administered a lower dose of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof than the subject was on prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof.

[0019] In another embodiment, a method for treating a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, in a subject in need thereof comprises administering a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) on a schedule comprising administering at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof (e.g., propranolol HCl), and titrating the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to a desired dosage level. For example, in some embodiments, the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof can be titrated from a starting dose of about 5 mg, about 10 mg, or about 20 mg per day, up to a maximum of about 120 mg per day. In some embodiments, the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof can be titrated from a starting dose of about 10 mg per day to a maximum dose of about 120 mg per day (e.g., about 20 mg per day, about 60 mg per day, about 80 mg per day, or about 100 mg per day). In some embodiments, the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof can be titrated from a starting dose of about 20 mg per day to a maximum dose of about 120 mg per day (e.g., about 40 mg per day, about 60 mg per day, about 80 mg per day, or about 100 mg per day). In some embodiments, each dose is administered in a modified or sustained release composition, as described herein.

[0020] In another aspect, the present disclosure provides a single oral composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof (e.g., propranolol HCl). In certain embodiments, a composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be formulated for once-daily administration. In some variations, the propranolol is (S)-propranolol, (R)-propranolol, or a mixture of (S)-propranolol and (R)-propranolol. In certain embodiments, the propranolol in the composition is (S)-propranolol HCl. In certain embodiments, the propranolol in the composition is (R)-propranolol HCl. In yet another embodiment, the propranolol in the composition is a mixture of (S)-propranolol and (R)-propranolol. In certain embodiments, the composition comprises at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, and a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the compounds are present in the composition in a weight ratio of about 1:10 to about 10:1. For example, the ratio of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof to a compound of formula (I) or a pharma- ceutically acceptable salt thereof can be about 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, or 10:1 by weight in the composition. It will be understood that all weights are based on the weight of the compound of formula (I) and propranolol, primidone, or topiramate, respectively.

[0021] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following disclosure. [Brief description of the drawings]

[0022] [Figure 1]FIG. 1 is a graph showing the percent change in modified Activities of Daily Living (ADL) scores compared to baseline Composite Upper Limb (CUL) scores for Part B participants, as discussed in Example 1.

[0023] [Diagram 2] FIG. 2 is a graph showing the percent change in Essential Tremor Rating Scale (TETRAS) CUL scores (top) and TETRAS ADL scores (bottom) compared to baseline CUL scores for Part B participants, as discussed in Example 1.

[0024] [Diagram 3] FIG. 3 is a graph showing the percent change in tremor amplitude compared to baseline CUL scores for Part A participants (left) and Part B participants (right), as discussed in Example 1.

[0025] [Figure 4-1] Panel A of Figure 4 is a bar graph showing tremor power measured in the 8-13 Hz band in harmaline-treated rats administered 1 mg / kg of a compound of formula (I) alone or in combination with 1 mg / kg or 3 mg / kg of propranolol. Panel B of Figure 4 is a bar graph showing tremor power measured in the 6-15 Hz band in harmaline-treated rats administered 1 mg / kg of a compound of formula (I) ("Test Drug") alone or in combination with 1 mg / kg or 3 mg / kg of propranolol. [Figure 4-2] Same as above.

[0026] [Diagram 5] FIG. 5 is a bar graph showing the sLMA as total distance traveled (mm) measured in rats treated with a compound of formula (I) ("Test Drug") and propranolol alone or in combination.

[0027] [Figure 6]FIG. 6 is a graph showing the sLMA measured as total distance traveled (mm) over time in rats treated with a compound of formula (I) ("Test Drug") and propranolol alone or in combination.

[0028] [Figure 7] FIG. 7 is a bar graph showing the tremor scores measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug, i.e., the compound of formula (I).

[0029] [Figure 8] FIG. 8 is a bar graph showing the distance traveled (mm) from 0 to 5 minutes measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug, i.e., the compound of formula (I).

[0030] [Figure 9] FIG. 9 is a bar graph showing the mean latency drop measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug, i.e., the compound of formula (I).

[0031] [Figure 10] FIG. 10 is a bar graph showing the mean latency to drop (seconds) measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug, i.e., the compound of formula (I).

[0032] [Figure 11]FIG. 11 is a bar graph showing the distance traveled (mm) from 0 to 30 minutes in rats treated with harmaline (30 mg / kg), propranolol at 3 mg / kg and the test drug, i.e., the compound of formula (I), at 1 mg / kg and 3 mg / kg.

[0033] [Figure 12] FIG. 12 is a bar graph showing the distance traveled (mm) from 0 to 30 minutes in rats treated with harmaline (30 mg / kg), propranolol at 10 mg / kg and the test drug, i.e., the compound of formula (I), at 1 mg / kg and 3 mg / kg.

[0034] [Figure 13] FIG. 13 is a bar graph showing the same data as in FIGS. 11 and 12, and also showing the results of statistical comparisons between different groups of rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] I. Definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms having commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference to what is commonly understood in the art.

[0036] Throughout this disclosure, various aspects of the claimed subject matter are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, when a range of values ​​is provided, unless the context clearly indicates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the disclosure, subject to any specifically excluded limit within the stated range. When a stated range includes one or both of the limits, ranges excluding one or both of those included limits are also included in the disclosure. In some embodiments, two opposing open-ended ranges are provided for a property, and such descriptions contemplate that a combination of those two ranges is provided herein. For example, in some embodiments, a characteristic may be described as being greater than about 10 units and the characteristic may be described (e.g., in a separate context) as being less than about 20 units, and thus a range of about 10 units to about 20 units is described herein.

[0037] As used herein, the term "about" refers to a normal error range for the respective value, which is readily known in the art. With reference to "about," a value or parameter herein includes (and describes) a variation directed to the value or parameter itself. For example, a description that refers to "about X" includes the description of "X."

[0038] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0039] The term "release modifying polymer" refers to a polymer used in formulations (e.g., tablets and capsules) to modify the release rate of a drug upon administration to a subject. For example, release modifying polymers are used to dissolve a drug over time so that it is released more slowly and / or more steadily into the bloodstream. For example, the release modifying polymer is a sustained release polymer. For example, the release modifying polymer or sustained release polymer is a hydroxy-propylmethylcellulose (HPMC) polymer. In some embodiments, the release modifying polymer can include a hydrophilic matrix polymer (e.g., hypromellose, HPMC (hydroxyl-propylmethylcellulose)), a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit RL100, Eudragit RS100).

[0040] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, 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 of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, lauryl sulfate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, lauryl sulfate, cyclopentanepropionate, cyclopentanepropionate, cyclopentanepropionate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, lauryl sulfate ... dodecyl sulfate, cyclopentanepropionate, dodecyl sulfate, Examples of salts that can be used include urate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and stereoisomers thereof (e.g., enantiomers, diastereomers).Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0041] The term "refractory" refers to a disease, disorder, or condition that does not readily succumb or respond to a therapy or treatment, or is not controlled by a therapy or treatment. In some embodiments, the disease, disorder, or condition described herein is refractory (e.g., refractory epilepsy or refractory absence seizures) and does not respond to standard therapies or treatments. For example, according to the present disclosure, in some embodiments, a patient taking propranolol no longer responds to propranolol.

[0042] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human" and "patient" are used interchangeably herein, while the term "subject" can refer to a human or a non-human animal.

[0043] As used herein, a "subject in need thereof" is a subject having a disease, disorder, or condition associated with abnormal function or activity of T-type calcium channels. In some embodiments, a "subject in need thereof" is a subject having essential tremor (ET). In some embodiments, a "subject in need thereof" is a subject having ET that is refractory or has become refractory to treatment with propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof.

[0044] The term "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0045] The terms "treat", "treating", and "treatment" contemplate actions taken while a subject is suffering from a specified disease, disorder, or condition to reduce the severity or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions taken before a subject begins to suffer from a specified disease, disorder, or condition ("prophylactic treatment" or "prevention" of a specified disease, disorder, or condition). The terms "treat", "treating", and "treatment" also refer to reversing, alleviating, arresting, or ameliorating a disease, e.g., ET, or at least one clinical symptom of a disease, e.g., ET, or inhibiting the progression of a disease or at least one clinical symptom of a disease, e.g., ET.

[0046] As used herein, the term "coating" refers to an excipient that protects tablet ingredients from deterioration due to moisture in the air and / or makes large or unpleasant tasting tablets easier to swallow.

[0047] As used herein, the term "diluent" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dibasic calcium phosphate (DCP), and sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0048] As used herein, the term "lubricant" refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, lubricants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0049] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping together and / or sticking to tablet punches or capsule filling machines. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solids and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0050] In some embodiments, the methods provided by the present disclosure comprise administering to a subject in need thereof a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof. As used herein, the term "in combination" refers to the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof to a subject in need thereof, whereby the subject has an effective prescription for the compound of formula (I) or a pharmaceutically acceptable salt thereof and an effective prescription for at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof and has been instructed by a physician to take the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof. In some embodiments, the term "in combination" also refers to the administration of the compound of formula (I) or its pharmaceutically acceptable salt and at least one of propranolol, primidone, topiramate, or its pharmaceutically acceptable salt to a subject in need thereof over the same period of time. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and at least one of propranolol, primidone, topiramate, or its pharmaceutically acceptable salt may be administered in combination to a subject in need thereof according to the same administration schedule or according to different administration schedules, respectively. For example, in some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and at least one of propranolol, primidone, topiramate, or its pharmaceutically acceptable salt may be administered to a subject in need thereof once a day, for example, in the morning, over the same period of time. In other embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered to a subject once a day, for example in the morning, and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be administered to a subject in need thereof two or three times a day over the same period of time.In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be administered simultaneously as part of a new pharmaceutical composition to a subject in need thereof. In other embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be administered simultaneously or in combination within minutes or hours to a subject in need thereof as part of different pharmaceutical compositions.

[0051] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The invention is not intended to be limited in any way by the above exemplary recitation of substituents.

[0052] II. Methods of Treating T-Type Calcium Channel Diseases or Conditions In one aspect, there is provided 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 a subject a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof.

[0053] Also disclosed herein, in certain embodiments, is a method of treating ET in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or a pharma- ceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof.

[0054] The disclosure also includes administering a deuterium-enriched compound of formula (I) or a pharma- ceutically acceptable salt in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof (e.g., propranolol HCl) to treat a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, in a subject in need thereof. For example, in one embodiment, the deuterium-enriched compound is represented by formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1a , R 1b , R 2a , R 2b , R6, and R7 are each independently hydrogen or deuterium; Each of R3, R4, and R5 is -C(R a )3, and each R a are independently hydrogen or deuterium; n is an integer selected from 0 to 9, m is an integer selected from 0 to 3.

[0055] In another embodiment, the deuterium-enriched compound has the formula (II-A): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1a , R 1b , R 2a , R 2b , R6, and R7 are each independently hydrogen or deuterium; Each of R3, R4, and R5 is -C(R a )3, and each R a are independently hydrogen or deuterium; n is an integer selected from 0 to 9, m is an integer selected from 0 to 3; and In the formula, R 1a , R 1b , R2a , R 2b , R6, R7, and R a At least one of the atoms is deuterium.

[0056] In another embodiment, the deuterium-enriched compound has the formula (II-B): [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1a , R 1b , R 2a , R 2b and R7 are each deuterium; Each of R3, R4, and R5 is -C(R a )3, and each R a are independently hydrogen or deuterium; m is an integer selected from 0 to 3; R 6a , R 6b , R 6c , and R 6d at least one of is deuterium, and R 6e , R 6f , R 6g , R 6h Each of is independently hydrogen or deuterium.

[0057] In another embodiment, the deuterium-enriched compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0058] It will be understood that any reference to a compound of Formula (I) for the treatment of essential tremor applies equally to the deuterium-enriched compounds described herein (e.g., compounds of Formula (II), Formula (II-A), and Formula (II-B), as well as the compounds in the preceding paragraph).

[0059] In some embodiments, the compound used to treat a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, is the HCl salt of a compound of formula (I), as shown below. [ka]

[0060] In one aspect, the disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, in a subject in need thereof, the method comprising administering to the subject 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 20 mg to about 100 mg, or about 20 mg to about 80 mg) of a compound of formula (I) or a pharma- ceutical acceptable salt thereof (e.g., an HCl salt) daily (e.g., once, twice, or three times), wherein the subject is concurrently taking at least one of propranolol, primidone, topiramate, or a pharma- ceutical acceptable salt thereof (e.g., propranolol HCl), i.e., the subject is administered a compound of formula (I) in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutical acceptable salt thereof, as described herein.

[0061] In some such embodiments, the subject has taken a daily dose of about 10 mg to about 1000 mg of at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. For example, in certain embodiments, the subject has taken a daily dose of about 20 mg to about 200 mg of propranolol or a pharma- ceutically acceptable salt thereof, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In other such embodiments, the subject has taken a dose of about 20 mg to about 100 mg / day of propranolol or a pharma- ceutically acceptable salt thereof, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In other such embodiments, the subject has taken a dose of about 20 mg to about 40 mg / day of propranolol or a pharma- ceutically acceptable salt thereof, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject has taken a dose of about 10 mg to about 1000 mg / day of primidone, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In other such embodiments, the subject has taken a dose of about 12.5 mg to about 750 mg / day of primidone, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.In other such embodiments, the subject has taken, for example, a dose of about 50 mg to about 250 mg / day of primidone at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In other such embodiments, the subject has taken, for example, a dose of about 10 mg to about 400 mg / day of topiramate at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In other such embodiments, the subject has taken, for example, a dose of about 25 mg to about 200 mg / day of topiramate at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In other such embodiments, the subject has been taking a dose of about 10 mg to about 50 mg per day of topiramate, for example, at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks, or at least 1 week prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments where the subject has received a regimen of at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, the subject may remain on the same dosage regimen of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof that was received prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof. In other embodiments where the subject has received a regimen of at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, the subject may be administered a lower dose of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof than was received prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof. For example, if a subject was administered 20 mg of propranolol HCl once daily prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof, the subject may be administered a dose of 10 mg of propranolol HCl once daily after initiation of administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject is administered a dose of propranolol, primidone, or topiramate in combination with the compound of formula (I) or a pharma- ceutically acceptable salt thereof, the dose of propranolol, primidone, or topiramate being about 5% to about 90% less than the dose of propranolol, primidone, or topiramate the subject received prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the dose of propranolol, primidone, or topiramate is about 10% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, or about 40% to about 50% less than the dose of propranolol, primidone, or topiramate that the subject received prior to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof.In certain embodiments, the dose of propranolol, primidone, topiramate is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% less than the dose of propranolol, primidone, topiramate that the subject received prior to the compound of Formula (I) or a pharma- ceutically acceptable salt thereof.

[0063] In certain embodiments in which the subject has received a regimen of at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof, propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof may be administered to the subject PRN (if necessary). In certain embodiments in which the subject has received a regimen of propranolol or a pharma- ceutically acceptable salt thereof prior to administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof, propranolol or a pharma- ceutically acceptable salt thereof may be administered to the subject PRN.

[0064] In another embodiment, a subject suffering from a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, taking at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof (e.g., propranolol HCl) is administered a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) on a schedule that includes titrating the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to a desired dosage level. For example, in some embodiments, the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is titrated from a starting dose of about 5 mg per day to a maximum dose of about 120 mg per day. In other embodiments, the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is titrated from a starting dose of about 10 mg per day to a maximum dose of about 120 mg per day (e.g., about 20 mg per day, about 60 mg per day, about 80 mg per day, or about 100 mg per day). In other embodiments, the dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is titrated at a starting dose of about 20 mg per day to a maximum dose of about 120 mg per day (e.g., titrated in 20 mg increments from about 20 mg per day to about 40 mg per day, about 60 mg per day, about 80 mg per day, about 100 mg per day, or about 120 mg per day).

[0065] In one embodiment, a subject suffering from a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, who is taking at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, is (a) administering to a subject about 5 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) once daily for a first period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more); (b) administering to the subject about 10 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) once daily for a second period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more); and (c) administering to the subject about 20 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) per day once daily for a third period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more).

[0066] In another embodiment, a subject suffering from a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, taking at least one of propranolol, primidone, topiramate, or a pharma- ceutical acceptable salt thereof, is (a) administering to a subject about 20 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) for a first period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more); (b) administering to the subject about 40 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) for a second period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more); and (c) administering to the subject about 60 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) per day for a third period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more).

[0067] In some embodiments, the method further includes (d) administering to the subject about 80 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) for a fourth period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more).

[0068] In other embodiments, the method further comprises (e) administering to the subject about 100 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) for a fifth period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more).

[0069] In certain embodiments, the method further includes (f) administering to the subject about 120 mg per day of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) for a sixth period of time (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more).

[0070] In some embodiments, the subject is a human. In some embodiments, the subject is a human and is 10-100 years old, e.g., 10-30 years old, 15-45 years old, 18-55 years old, 10-80 years old, 15-75 years old, 40-90 years old, 50-80 years old, 60-75 years old, or 25-65 years old. In some embodiments, the subject is a human and is 18-55 years old.

[0071] In some embodiments, the subject has ET with onset at age 30 or less, 40 or less, 50 or less, 60 or less, 70 or less, or 80 or less. In some embodiments, the subject has ET with onset at age 10-90 years, 30-60 years, 40-80 years, or 50-75 years.

[0072] In some embodiments, a subject suffering from a disease or condition associated with abnormal function or activity of a T-type calcium channel, such as ET, also suffers from another disorder, including a disease or condition associated with abnormal function or activity of another T-type calcium channel. In some such embodiments, the other disorder is selected from the group consisting of a psychiatric disorder (e.g., a mood disorder (e.g., major depressive disorder)), pain, tremor, seizures (e.g., absence seizures), and epilepsy or epilepsy syndrome (e.g., juvenile myoclonic epilepsy).

[0073] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) can be administered to a subject suffering from a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, that has become refractory to treatment with propranolol or a pharma- ceutically acceptable salt thereof. In other embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) can be administered to a subject suffering from a disease or condition associated with abnormal function or activity of T-type calcium channels, such as ET, that has become refractory to other first-line treatments, such as primidone and / or topiramate.

[0074] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce tremor severity by at least about 20% as measured by the Essential Tremor Rating Scale (TETRAS). As used herein, the term "TETRAS" refers to a scale developed to quantify the severity of ET and its impact on daily activities. It includes an Activities of Daily Living (ADL) category and an Activity category. The ADL category has 12 items rated from 0 to 4, and the Activity category has 9 items rated from 0 to 4. See, e.g., Elble, RR, The Essential Tremor Rating Assessment Scale, J.Neurology Neuromed. 2016,1(4):34-38.

[0075] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce tremor severity by at least about 30% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce tremor severity by at least about 40% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce tremor severity by at least about 50% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce tremor severity by at least about 60% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce tremor severity by about 20% to about 70% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce tremor severity by about 30% to about 50% as measured by TETRAS.

[0076] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) can reduce upper limb tremor amplitude by at least about 20% when measured by the Essential Tremor Rating Scale (TETRAS) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) can reduce upper limb tremor amplitude by at least about 30% when measured by TETRAS when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) can reduce upper limb tremor amplitude by at least about 40% when measured by TETRAS when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce upper extremity tremor amplitude by at least about 50% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce upper extremity tremor amplitude by at least about 60% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce upper extremity tremor amplitude by about 20% to about 70% as measured by TETRAS.In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce upper extremity tremor amplitude by about 30% to about 50%, as measured by TETRAS.

[0077] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude of the right or left hand when tracing an Archimedes spiral by at least about 20% as measured by the Essential Tremor Rating Scale (TETRAS). In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude of the right or left hand when tracing an Archimedes spiral by at least about 30% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude when tracing an Archimedes spiral with the right or left hand by at least about 40% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude when tracing an Archimedes spiral with the right or left hand by at least about 50% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude when tracing an Archimedes spiral with the right or left hand by at least about 60%, as measured by TETRAS.In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude when tracing an Archimedes spiral with the right or left hand by about 20% to about 70% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce the tremor amplitude when tracing an Archimedes spiral with the right or left hand by about 30% to about 50% as measured by TETRAS.

[0078] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce handwriting tremor amplitude by at least about 20% as measured by the Essential Tremor Rating Scale (TETRAS). In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce handwriting tremor amplitude by at least about 30% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce handwriting tremor amplitude by at least about 40% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce handwriting tremor amplitude by at least about 50% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce handwriting tremor amplitude by at least about 60% as measured by TETRAS. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can reduce handwriting tremor amplitude by about 20% to about 70% as measured by TETRAS.In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can reduce tremor amplitude in handwriting by about 30% to about 50%, as measured by TETRAS.

[0079] In other embodiments, other suitable measures for assessing the efficacy of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof include measuring TETRAS Activities of Daily Living (ADL) and Modified Activities of Daily Living (mADL) scores.

[0080] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can improve activities of daily living by at least about 20% as measured by TETRAS ADL. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can improve activities of daily living by at least about 30% as measured by TETRAS ADL. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can improve activities of daily living by at least about 40% as measured by TETRAS ADL. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can improve activities of daily living by at least about 50% as measured by TETRAS ADL. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can improve activities of daily living by at least about 60% as measured by TETRAS ADL. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof can improve activities of daily living by about 20% to about 70% as measured by TETRAS ADL.In some embodiments, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt), when administered in combination with at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, can improve activities of daily living by about 30% to about 50% as measured by TETRAS ADL.

[0081] The Clinical Global Impression-I (CGI-I) (Guy 1976) assesses the clinician's impression of the participant's functioning before and after starting a study drug. Using their own overall clinical experience with this patient population, the clinician should rate the current severity of the participant's essential tremor symptoms on a 7-point scale ranging from 1 (normal, not ill at all) to 7 (one of the most severely ill patients). Thus, in some embodiments, the methods of the invention result in a decrease in CGI-I score compared to, for example, pre-treatment, baseline.

[0082] The Patient Global Impression-Change (PGI-C) assesses the improvement (or worsening) of the participant. Participants are required to rate their condition compared to baseline (day 0) on a 7-point scale of 1 (much improved) to 7 (much worse). The assessment is made regardless of whether the participant believes the improvement / worsening is drug-related or unrelated. In some embodiments, the method results in a reduction in the PGI-C score compared to baseline. The Columbia Suicide Severity Rating Scale (C-SSRS) assesses suicidal thoughts and behaviors in participants participating in clinical trials of centrally acting drugs. The C-SSRS consists of five questions addressing suicidal behaviors and five questions addressing suicidal ideation, with sub-questions assessing severity. The tool is administered by interview with the participant (by a trained operator / interviewer) and takes approximately 5-10 minutes to complete. In some embodiments, the method results in a reduction in suicidal thoughts and / or behaviors compared to pre-treatment suicidal thoughts and / or behaviors. In other embodiments, the method does not result in a change in the patient's C-SSRS score compared to the pre-treatment C-SSRS score.

[0083] The Beck Depression Profile Inventory (BDI-II) is a list of 21 common symptoms of depression (Beck et al 1996). Each item is scored on a 4-point Likert scale (score range is 0-3). The time frame of the assessment is the previous month or since the last assessment. The BDI-II is divided into two subscales: affective and somatic. Subscale scores are calculated as the sum of the items comprising each subscale. The total score is calculated as the sum of all 21 items and ranges from 0 to 63. A total score of 0-13 indicates minimal depressive symptoms. A total score of 14-19 indicates mild depressive symptoms. A total score of 20-28 indicates moderate depressive symptoms. A total score of 29-63 indicates severe depressive symptoms. The BDI-II is assessed at screening to exclude participants with moderate to severe depressive symptoms. Thus, in some embodiments, the methods do not result in moderate or severe depressive symptoms in the subject as measured by BDI-II.

[0084] The Beck Anxiety Inventory (BAI) is a brief measure of anxiety with particular attention to somatic symptoms of anxiety, developed as a measure aimed at differentiating between anxiety and depression (Beck et al 1988). The BAI includes 21 questions about general symptoms of anxiety that the subject may have experienced in the past week (including the day the BAI was administered). General symptoms of anxiety include numbness and tingling, sweating not due to fever, and fear of the worst happening. It is designed for individuals aged 17 years and older and takes 5-10 minutes to complete. Each response is scored on a scale value from 0 (not at all) to 3 (severe). A higher total score indicates more severe anxiety symptoms. Standardized cutoffs are as follows: 0-7: minimal, 8-15: mild, 16-25: moderate, 26-63: severe. Thus, in some embodiments, the method does not result in moderate or severe anxiety symptoms as measured by the BAI.

[0085] III. Dosage Forms and Compositions In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (eg, an HCl salt) may be formulated into a dosage form or pharmaceutical composition.

[0086] In some embodiments, the compositions that may be used in the methods described herein may be pharmaceutical compositions that include a compound of formula (I) or a pharma- ceutically acceptable salt thereof and an excipient that functions to modulate the release rate of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0087] In certain embodiments, the dosage form that can be used in the methods described herein may be an oral dosage form that includes the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) and at least one release modifying polymer. The at least one release modifying polymer includes, but is not limited to, sustained release polymers, hydrophilic matrix polymers such as HPMC polymers, hydrophobic matrix polymers such as ethylcellulose and Ethocel, and polyacrylate polymers such as Eudragit RL100 and Eudragit RS100. The at least one release modifying polymer is typically present in an amount sufficient to modify the release rate of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) upon administration to a subject.

[0088] In some embodiments, the composition or dosage form comprises from about 0.9% to about 40% by weight (e.g., from about 0.9% to about 30% by weight, from about 1% to about 25% by weight, from about 2% to about 25% by weight, from about 3% to about 20% by weight, from about 4% to about 20% by weight, from about 5% to about 20% by weight, from about 5% to about 15% by weight, from about 5% to about 10% by weight, or from about 0.9% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8 ...8% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1% by weight, about 1 %, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 40% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the dosage form comprises about 30% to about 40% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt).

[0089] In some embodiments, the composition or dosage form may comprise about 14% to about 25% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 19% to about 20% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 21% to about 22% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 4% to about 15% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 4% to about 10% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 4% to about 5% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 5% to about 6% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt). In some embodiments, the composition or dosage form comprises about 9% to about 10% by weight of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt).

[0090] In other embodiments, a composition or dosage form that may be used in the methods described herein may be a dosage form or composition comprising about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and in some embodiments, the composition or dosage form may further comprise at least one release modifying polymer (e.g., a sustained release polymer, a hydrophilic matrix polymer such as an HPMC polymer, a hydrophobic matrix polymer such as ethylcellulose and Ethocel, and a polyacrylate polymer such as Eudragit RL100 and Eudragit RS100). Typically, the at least one release modifying polymer is present in an amount sufficient to modify the release rate of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) upon administration to a subject.

[0091] In other embodiments, the composition or dosage form comprises about 4 mg to about 6 mg (e.g., about 5 mg) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt). In certain embodiments, the composition or dosage form comprises about 15 mg to about 25 mg (e.g., about 20 mg) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt). In some embodiments, the composition or dosage form comprises about 5 mg to about 15 mg (e.g., about 10 mg) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt). In other embodiments, the composition or dosage form comprises about 25 mg to about 35 mg (e.g., about 30 mg) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt). In certain embodiments, the composition or dosage form comprises about 35 mg to about 45 mg (e.g., about 40 mg) of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt).

[0092] In some embodiments, the composition or dosage form comprises about 55 mg to about 65 mg of a release-modifying polymer (e.g., an HPMC polymer). In some embodiments, the composition or dosage form comprises about 10% to about 70% by weight of a release-modifying polymer (e.g., an HPMC polymer). In some embodiments, the composition or dosage form comprises about 50% to about 60% by weight of a release-modifying polymer (e.g., an HPMC polymer).

[0093] In some embodiments, the composition or dosage form further comprises at least one diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the composition or dosage form comprises about 15 mg to about 40 mg of microcrystalline cellulose (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg). In some embodiments, the composition or dosage form comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the composition or dosage form comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the composition or dosage form comprises 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, or 30% by weight to about 35% by weight).

[0094] In some embodiments, the composition or dosage form further comprises at least one lubricant. In some embodiments, the lubricant comprises colloidal silicon dioxide. In some embodiments, the composition or dosage form further comprises at least one lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the composition or dosage form further comprises at least one coating agent.

[0095] In some embodiments, about 80% of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is released within 7 hours upon administration to a subject. In certain embodiments, about 80% of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is released within 7 hours as measured by using a USP apparatus type I, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

[0096] In some embodiments, the composition or dosage form, upon administration to a subject, exhibits a reduced Cmax relative to a reference oral dosage form (e.g., a composition or dosage form having any intended release rate profile, including a modified release rate profile, a dosage form or dosage form that does not have a modified release rate profile, or a composition or dosage form that does not have a release modifying polymer, e.g., an HPMC polymer).max In some embodiments, the composition or dosage form, upon administration to a subject, has a t value that is greater than a reference oral dosage form (e.g., a composition or dosage form having any intended release rate profile, including a modified release rate profile, a dosage form or dosage form that does not have a modified release rate profile, or a composition or dosage form that does not have a release modifying polymer, e.g., an HPMC polymer). max It has a value.

[0097] In other embodiments, the composition or dosage form is administered to a patient once a day. In certain embodiments, the composition or dosage form is administered to a patient twice a day. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.

[0098] In some embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form comprising about 15 mg to 25 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 55 mg to 65 mg of an HPMC polymer.

[0099] In other embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form comprising about 14% to about 25% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 53% to about 64% by weight of an HPMC polymer.

[0100] In certain embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form comprising about 3 mg to 8 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 55 mg to 65 mg of an HPMC polymer.

[0101] In some embodiments, a dosage form that may be used in the methods described herein may be an oral dosage form comprising about 3% to about 8% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 53% to about 64% by weight of an HPMC polymer.

[0102] In other embodiments, a dosage form that may be used in the methods described herein may be an oral (e.g., microparticle) composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and a release-modifying polymer (e.g., a sustained release polymer, such as an HPMC polymer or a hydrophilic matrix polymer).

[0103] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is stable in a composition at about 25°C and 60% relative humidity for at least 24 months. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is stable in a composition at about 25°C and 60% relative humidity for at least 36 months. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is stable in a composition at about 25°C and 60% relative humidity for at least 48 months. In other embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is stable in a composition at about 25°C and 60% relative humidity for at least 60 months. In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is stable in a composition at about 40°C and 75% relative humidity for at least 6 months.

[0104] In another aspect, provided herein is an oral (e.g., microparticle) composition comprising about 15 mg to 25 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 55 mg to about 65 mg of HPMC.

[0105] In other embodiments, a composition that may be used in the methods described herein may be an oral (e.g., microparticle) composition comprising about 14% to about 25% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 53% to about 64% by weight of an HPMC polymer.

[0106] In certain embodiments, a composition that may be used in the methods described herein may be an oral (e.g., microparticle) composition comprising about 3 mg to about 8 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 55 mg to about 65 mg of HPMC.

[0107] In some embodiments, a composition that may be used in the methods described herein may be an oral (e.g., microparticle) composition comprising about 3% to about 8% by weight of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), and about 53% to about 64% by weight of an HPMC polymer.

[0108] In another aspect, the disclosure provides a fixed dose oral composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., HCl salt) and at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof (e.g., propranolol HCl). In certain embodiments, the fixed dose composition may be formulated for once-daily administration. In some variations, the propranolol in the fixed dose composition is (S)-propranolol, (R)-propranolol, or a mixture of (S)-propranolol and (R)-propranolol. In certain embodiments, the propranolol in the fixed dose composition is (S)-propranolol HCl. In certain embodiments, the propranolol in the fixed dose composition is (R)-propranolol HCl. In still other embodiments, the propranolol in the fixed dose composition is a mixture of (S)-propranolol and (R)-propranolol. In certain embodiments, the fixed dose composition comprises at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof, and a compound of formula (I) or a pharma- ceutically acceptable salt thereof, present in the composition in a weight ratio of about 1:10 to about 10:1. For example, the ratio of at least one of propranolol, primidone, topiramate, or a pharma- ceutically acceptable salt thereof to a compound of formula (I) or a pharma- ceutically acceptable salt thereof can be about 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, or 10:1 by weight. It will be understood that all weights are based on the weight of the compound of formula (I) and at least one of propranolol, primidone, or topiramate.

[0109] Immediate-release formulations In some embodiments, a dosage form or composition that may be used in the methods described herein may be a dosage form or composition that includes a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), where the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is released immediately after administration to a subject.

[0110] In other embodiments, a dosage form that can be used in the methods described herein can be an immediate release oral capsule containing about 15 mg to about 20 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt), as well as about 75 mg to about 85 mg of at least one diluent, about 2 mg to about 10 mg of at least one binder, about 1% to about 5% of at least one disintegrant, and about 0.1 mg to about 5 mg of at least one lubricant.

[0111] Administration In some embodiments, the dosage form or composition is administered to a subject more than once a day (e.g., twice a day, three times a day, or four times a day). In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate or a pharma- ceutically acceptable salt thereof are administered in separate pharmaceutical compositions. In certain embodiments, each composition is orally administered to a subject in need thereof once a day.

[0112] In some embodiments, the dosage form or composition is administered to the subject once a day (e.g., one 20 mg tablet per day, two 20 mg tablets per day, or three 20 mg tablets per day). In some embodiments, the dosage form or composition is administered to the subject twice a day. In some embodiments, the dosage form or composition is administered to the subject every other day. In certain embodiments, about 1 mg to about 40 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is administered to the subject daily. In other embodiments, about 15 mg to about 25 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is administered to the subject daily. In certain embodiments, about 30 mg to about 40 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., an HCl salt) is administered to the subject daily. EXAMPLES

[0113] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as limiting the scope thereof in any manner.

[0114] Example 1: Phase 2 Clinical Trial Evaluating the Efficacy, Safety, Tolerability, and Pharmacokinetics of Compound of Formula (I) in Adults with Essential Tremor This multicenter clinical trial evaluated the efficacy, safety, tolerability, and PK of the HCl salt compound of formula (I) in participants aged 18 years or older with signs and symptoms consistent with ET, beginning before age 65 and lasting at least 3 years. The clinical trial was conducted in two parts (Part A and Part B). Both parts consisted of three periods: screening, intervention, and safety follow-up periods.

[0115] Part A of the clinical trial was open-label and evaluated the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity. Daily dose levels of the HCl salt compound of Formula (I) were titrated at 20 mg (days 1-7) to 40 mg (days 8-14).

[0116] Part B of the clinical trial consisted of both an open-label titration phase and a randomized, double-blind, placebo-controlled washout phase. Part B assessed the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity and duration of effect. During the open-label titration phase, daily dose levels of the HCl salt compound of formula (I) were titrated from 20 mg (days 1-3) to 40 mg (days 4-7) to 60 mg (days 8-14) to 80 mg (days 15-21) to 100 mg (days 22-28) to 120 mg (days 29-42) or to the maximum tolerated dose. During the randomized, double-blind, placebo-controlled washout phase, participants were maintained on their final open-label dose or switched to placebo for an additional 14 days (days 43-56).

[0117] Participants who received study drug in Part A were not eligible for Part B.

[0118] Screening / Baseline Period The screening period for Parts A and B spanned a maximum of 28 days (days -28 to -1). Participants who discontinued primidone were allowed an additional 14 days (i.e., a total of 42 days) of screening.

[0119] Primary screening assessments included medical history, demographics, physical examination, drug screen, clinical laboratory assessments and pregnancy serum testing for women of childbearing potential, 12-lead ECG, vital signs, C-SSRS, assessment of ET severity using the TETRAS performance subscale (including a video on independent review of eligibility), and a review of concomitant medications. To be eligible, participants who may have been taking prohibited medications had to have adequately discontinued those medications for at least 5 half-lives or 14 days (whichever was longer) prior to the first dose of study drug.

[0120] For those participants who require the additional 14 days of the screening period to discontinue primidone, all or part of the screening assessments may need to be repeated.

[0121] For Part A, participants completed a baseline assessment (Day 0). Day 0 (baseline) activities were matched with Day 1 activities, provided that baseline activities were completed before dosing and dosing occurred on the morning of Day 1. Additionally, baseline efficacy assessments were conducted pre-dosing on either Day 0 or Day 1, but not on both days to avoid learning effects.

[0122] For Part B participants, the TETRAS upper extremity items were also completed using accelerometry at screening and via telehealth on day -2 of the screening period. A screening telehealth visit was required to allow participants to successfully complete the TETRAS upper extremity assessment via telehealth and provide a pre-dose measurement. Additional assessments at Part B screening included the TETRAS ADL and the Clinical Global Impression Score (CGI-S), which measures disease severity.

[0123] Intervention period Part A. On Day 1, participants received a 20 mg dose of study medication administered in the morning. Participants remained at the clinic under medical observation for approximately 6 hours. TETRAS performance assessments were conducted pre-dose and 6 hours post-dose. After the first dose, participants continued QAM administration at home after breakfast until Day 7. Participants returned to the clinic on Day 7 for efficacy testing at the 20 mg dose level. On Day 8, the dose was increased to 40 mg QAM after breakfast until Day 14. Participants returned to the clinic on Day 14 for efficacy testing at the 40 mg dose level. Participants who consented to any additional PK sampling stayed overnight at the clinic on Days 1, 7, and 14.

[0124] Primary safety measures included clinical laboratory assessments, 12-lead ECG, C-SSRS, and vital signs. Primary efficacy assessments included TETRAS performance subscale, TETRAS upper extremity using accelerometry, CGI, and PGI-C. Blood samples were obtained for determination of study drug plasma concentrations using validated biochemical analytical methods and may also be used for method development and / or metabolite characterization.

[0125] Part B. Open-label titration phase On day 1, participants received a dose of 20 mg study medication on an empty stomach (at least 1 hour before breakfast). Participants remained at the clinical site under medical observation for approximately 6 hours. TETRAS performance assessments were conducted pre-dose and 6 hours (±2 hours) after dosing. For dosing days 2-41, participants were instructed to administer the QAM at least 1 hour before breakfast at home. Participants continued to take the study medication 20 mg QAM at home until day 3. On day 3, participants received a call from site staff to inquire about adverse events (AEs) and concomitant medications, confirm dose escalation, and receive a reminder regarding the number of study medication tablets to be taken from days 4-7. On day 4, participants were titrated to 40 mg QAM until day 7 and returned to the clinic for safety evaluations and efficacy testing. On day 8, participants were titrated to 60 mg QAM until day 14. On day 14, participants received a call from site staff with questions regarding AEs and concomitant medications, confirmation of dose titration, and a reminder regarding the number of study medication tablets participants should take from days 15 to 21. On day 15, participants were titrated to 80 mg QAM until day 21 and returned to the clinic for safety evaluations and efficacy testing. On day 22, participants were titrated to 100 mg QAM until day 28. On day 28, participants received a call from site staff with questions regarding AEs and concomitant medications, confirmation of dose titration, and a reminder regarding the number of study medication tablets participants should take from days 29 to 42. On day 29, participants were titrated to 120 mg QAM until day 42 and returned to the clinic for safety evaluations and efficacy testing. The day 42 dose was taken at the clinic. On day 35, participants received a call from site staff with questions regarding AEs and concomitant medications. On Day 41, participants completed the TETRAS Performance Upper Limb Assessment via a telehealth visit. If at any point during the open-label titration phase the participant did not tolerate the titration and returned to a lower dose level, the participant could continue according to the schedule outlined above, but further dose changes were not permitted. Participants could only change to a lower dose level once, and no dose changes were permitted after Day 36.

[0126] Double-blind randomized washout period On Day 42, participants completed the final clinic visit of the open-label titration phase. Participants received their dose of study medication on an empty stomach (at least 1 hour before breakfast) at the clinic. Participants remained at the clinical site under medical observation for approximately 6 hours. TETRAS performance assessments were conducted pre-dose and 6 hours (±2) post-dose.

[0127] After day 42, participants either continued to receive study drug at their current dose or switched to placebo, depending on randomization. Randomization in a 1:1 fashion was completed anywhere between days 37 and 42.

[0128] Participants were instructed to receive their assigned blinded treatment QAM (at least 1 hour before breakfast) on days 43 through 56. On day 56 (the last day of dosing), participants returned to the clinic for safety assessments and efficacy testing.

[0129] In both periods, primary safety measures included clinical laboratory assessments, 12-lead ECG, C-SSRS, and vital signs. Primary efficacy assessments included TETRAS performance subscale, TETRAS upper extremity using accelerometry, CGI, PGI-C, TETRAS ADL subscale, QUEST, BDI-II, and BAI. Blood samples were obtained for determination of study drug and metabolite plasma concentrations.

[0130] Safety follow-up period Part A. The safety follow-up period was from Day 15 to Day 21. At the end of the safety follow-up period, participants returned to the clinic on Day 21 (± 1 day) for their final clinical trial evaluation.

[0131] Part B. The safety follow-up period was from Day 57 to Day 70. At the end of the safety follow-up period, participants returned to the clinic on Day 70 for their final clinical trial evaluation.

[0132] Number of participants Part A. In Part A of the study, seven participants received the study drug.

[0133] Part B. In part B of the study, 17 participants received study drug for an initial 42 days and were then randomized (1:1) to receive either the maximum tolerated dose of study drug or placebo for an additional 2 weeks.

[0134] Clinical trial duration Participants participated in the clinical trial for the following time intervals, as set forth in Tables 1 and 2 below. [Table 1] [Table 2]

[0135] Test product, reference therapy, and administration MR7 tablets of 20 mg of the HCl salt compound of formula (I) or a matching placebo were administered orally and provided to participants in prepackaged containers.

[0136] Dose / Route / Regimen Part A. All participants received study medication, 20 mg QAM orally for 7 days (days 1-7) and 40 mg QAM orally for 7 days (days 8-14).

[0137] Part B. Open-label titration. The titration schedule for study drug was as follows: 20mg QAM for 3 days (days 1-3) 40mg QAM for 4 days (days 4-7) 60 mg of QAM for 7 days (days 8-14), 80mg QAM for 7 days (days 15-21) 100 mg of QAM for 7 days (days 22-28), and 120mg QAM for 14 days (days 29-42).

[0138] Double-blind randomized washout. Participants were randomized to either continue study drug orally QAM at their maximum tolerated dose or switch to placebo orally QAM for 14 days (Days 43-56).

[0139] Objectives and Evaluation Items To evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of the study medication in adults with ET. [Table 3] [Table 4-1] [Table 4-2]

[0140] Results and Observations The following table provides representative demographics of the ET population: [Table 5]

[0141] Referring to Table 5 above, six participants in Part A received propranolol and five participants in Part B received propranolol. [Table 6] [Table 7] [Table 8-1] [Table 8-2] [Table 9] [Table 10] [Table 11]

[0142] Adverse events Treatment-emergent adverse events (TEAEs) were mild to moderate in severity and consistent with the program's safety profile, as shown in the table below.

[0143] Overall, 85.7% of participants in Part A and 88.2% of participants in the open-label titration phase of Part B experienced at least one TEAE during the study, with 57.1% and 70.6% of participants, respectively, experiencing a TEAE that was deemed related to study drug (see Table 12 below). A smaller percentage of participants experienced a TEAE during the randomized washout period of Part B (20% in the placebo group and 16.7% in the study drug group).

[0144] Across the study, most TEAEs were mild or moderate in severity. A single severe TEAE of increased ET after randomization was experienced by participants randomized to placebo.

[0145] TEAEs leading to study drug discontinuation occurred in six participants in the open-label titration phase of Part B and one participant in Part A. All of these AEs were mild or moderate in intensity and resolved, with five of these precipitating events occurring within the first 2 days of 20 mg study drug treatment. One mild SAE, a cyst, was experienced by a participant in the open-label titration phase of Part B and was considered unrelated to study drug. [Table 12]

[0146] Overall, the most commonly experienced TEAEs in Part A were dizziness (four participants, 57.1%) and headache (three participants, 42.9%), with all TEAEs except for one headache experienced by participants receiving 20 mg of study medication. [Table 13]

[0147] Overall, the most commonly experienced TEAEs during the open-label titration phase of Part B were constipation (6 participants, 35.3%) and psychiatric and cognitive disorders (4 participants each, 23.5%) (see Table 14 below). The highest incidence of TEAEs during the open-label titration phase of Part B occurred with doses of study drug ≤ 60 mg. [Table 14]

[0148] Preliminary Part B data showing modified Activities of Daily Living (ADL) scores compared to baseline Composite Upper Limb (CUL) scores are provided in Figure 1. TETRAS CUL and TETRAS ADL are provided in Figure 2. TETRAS CUL is provided in Figure 3.

[0149] Discussion and Conclusion The study was conducted in two parts and enrolled adult male and female participants with a clinical diagnosis of ET for at least 3 years at screening and age at onset younger than 65 years. Part A was open-label and evaluated the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity. Daily dose levels were titrated from 20 mg to 40 mg. Part B consisted of both an open-label titration phase and a randomized, double-blind, placebo-controlled washout phase. Part B evaluated the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity and the duration of its effect. Daily dose levels were titrated from 20 mg to a maximum of 120 mg during the open-label phase. During the randomized, double-blind, placebo-controlled washout phase, participants were maintained at their final open-label dose or switched to placebo.

[0150] Effectiveness The aim of this study was to evaluate the efficacy of the study drug on upper limb tremor in participants with ET.

[0151] Part A Open Label Study In Part A, administration of study drug resulted in a significant reduction (i.e., improvement) in the primary efficacy parameter, TETRAS upper extremity score, on Day 7 (7 days after administration of 20 mg QAM), which was further reduced on Day 14 (another 7 days after administration of 40 mg QAM). These improvements were observed in upper extremity tremor amplitude, along with reductions in upper extremity tremor amplitude of 23.9% and 42.8%, respectively.

[0152] Similar improvements were observed for the composite upper limb and TETRAS performance subscale total scores. Improvements for all TETRAS performance subscale derived measures (including the upper limb score and the composite upper limb score) were most pronounced in participants with an upper limb score ≥ 10 at baseline.

[0153] As expected, all TETRAS performance subscale derived scores returned to near pretreatment baseline levels after a 1-week washout period on Day 21. This finding supports the need for continued study drug administration to achieve efficacy.

[0154] Part B: Open-label dose-finding period In the open-label titration phase of Part B, reductions (i.e., improvements) in TETRAS upper extremity scores were observed as early as 7 days after administration of 20 mg of study drug. Mean improvements became increasingly more pronounced over time until Day 42, when participants were titrated to their maximum tolerated dose (ranging from 20 to 120 mg of study drug). In Part A, similar improvements occurred for all TETRAS performance subscale derived measures (including upper extremity and composite upper extremity scores), with improvements most pronounced in participants with an upper extremity score ≥ 10 at baseline.

[0155] TETRAS ADL and mADL scores also decreased as early as day 7 with continued improvement observed through day 42. These findings, coupled with improvements in quality of life measures such as QUEST, CGI-I, CGI-S, and PGI-C, support functional improvement in ET symptom severity during the titration phase (days 7 and 21) and continued to improve after participants received 2 weeks of stable dosing at either 120 mg study drug or the maximum tolerated dose on day 42. Comparable improvements in ADL, mADL, and quality of life measures were observed in participants with upper extremity scores ≥ 10 at baseline, reflecting functional improvements in participants across the range of ET severity levels at baseline.

[0156] Part B randomized washout period Part B randomized washout revealed increases (i.e., worsening) in TETRAS composite upper extremity and performance subscale total scores at Day 56 compared with randomization baseline at Day 42 that were greater in the placebo group compared with the study drug group, indicating maintenance of effect in consecutively treated participants. Changes in upper extremity scores from randomization baseline from Day 42 to Day 56 were comparable between the placebo and study drug groups.

[0157] Comparison of mADL scores at day 42 with randomization baseline revealed an increase (i.e., worsening) in mADL total scores at day 56 that was greater in the placebo group compared to test drug, with an LS mean difference between treatment groups (test drug minus placebo) of -8.439, with a 95% CI less than zero (-15.3856, -1.4916), indicating a nonzero change from baseline. Similar trends were observed for ADL scores over the same time frame. QUEST, CGI-I, and CGI-S scores also worsened compared to randomization baseline for those randomized to the placebo group, supporting sustained efficacy in the test drug group.

[0158] All TETRAS performance subscale derivations, TETRAS ADL derivations and quality of life measures returned to near pretreatment baseline levels after a 1-week washout period on day 70, supporting the need for continued study drug administration to achieve sustained efficacy.

[0159] Quality of life, severity of symptoms, anxiety and depression Quality of life as measured by QUEST and symptom severity as measured by CGI-I and PGI-C improved for participants receiving study drug from pre-dose baseline to Day 56 in Part B. BAI scores shifted (i.e., improved) from mild to minimal anxiety during the open-label titration phase of Part B. The majority of participants in both treatment groups had BDI-II scores reflecting minimal depressive symptoms from pre-dose baseline to Day 70, with no clinically meaningful change over time.

[0160] Pharmacokinetics Measurable study drug plasma concentrations were obtained for all participants 1 hour after dosing. Steady-state exposure was achieved on Day 42, with similar study drug plasma concentrations on Day 56 (379.4 ng / mL vs. 344.1 ng / mL), consistent with the characterized PK profile of study drug. After 56 days of daily dosing, a 14-day washout period resulted in undetectable study drug plasma concentrations.

[0161] safety The safety profile of study drug was similar between Part A and the open-label titration phase of Part B. In these study portions, most participants experienced at least one TEAE, all of mild to moderate intensity. One mild SAE, a cyst, was experienced by a participant in the open-label titration phase of Part B, which was considered unrelated to study drug. Seven participants experienced AEs that led to study drug discontinuation, although two of the AEs were considered unrelated (anxiety and cyst), four of the AEs occurred during the first 2 days on the 20 mg dose of study drug, and three of the participants experiencing these AEs were participants at sites that ultimately discontinued due to repeated enrollment of ineligible subjects.

[0162] During the randomized washout period of Part B, only one participant in each of the study drug and placebo groups experienced a TEAE. Thus, as expected, TEAEs were less frequent in participants titrated to the maximum tolerated dose. Given that all AEs leading to discontinuation occurred during titration, treatment with study drug will be initiated at lower dose levels (5 mg and 10 mg) with a 1-week dosing interval in future studies, followed by titration to the maximum tolerated dose for each participant. Focusing on early tolerability to allow participants to reach a stable and effective dose remains a focus of the clinical development program.

[0163] The most common TEAEs in Part A were dizziness and headache, with all but one event of headache occurring with the lower 20 mg dose of study drug. The most common TEAEs in the open-label titration phase of Part B were constipation, cognitive impairment, and psychiatric disorders, with the highest overall incidence of TEAEs occurring with doses ≤ 60 mg of study drug. The AE constipation observed in Part B may suggest that continuous administration of T-type calcium channel blockers such as study drug may affect colonic motility, as described for nifedipine and verapamil, but requires further investigation. No TEAE had an onset date during the randomized washout period of Part B in more than one participant. However, all participants receiving study drug in the randomized washout period of Part B continued to experience some ongoing AEs that occurred during the open-label titration period, most commonly constipation in three participants and photosensitivity / photophobia in two participants.

[0164] Drug-related TEAEs experienced by ≥2 participants included dizziness (3 participants in Part A and 6 participants in the open-label titration phase of Part B), cognitive impairment (4 participants in the open-label titration phase of Part B), and paresthesia (2 participants in the open-label titration phase of Part B). All of these events were mild or moderate in severity.

[0165] conclusion In this study, study drug significantly reduced upper extremity tremor in participants with ET at Day 7, as assessed by TETRAS Upper Extremity score, with continued improvement at Day 14. These findings were supported by similar improvements in TETRAS performance subscales, TETRAS ADL, mADL, and measures across the open-label titration phases of Parts A and B.

[0166] Overall, the study drug was generally safe and well tolerated at doses up to 120 mg. The accelerated titration regimen used in this study resulted in a third participant discontinuing during the titration period. Therefore, a more gradual titration regimen will be used to enhance the early tolerability of the study drug in future studies.

[0167] Example 2: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Clinical Trial to Evaluate the Tolerability, Safety, and Efficacy of Compound of Formula (I) in the Treatment of Adults with Essential Tremor This multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial was conducted to evaluate the efficacy, safety, and tolerability of the HCl salt compound of formula (I) in participants aged 18 years or older who had a diagnosis of essential tremor (ET) and had been symptomatic for at least 3 years. Participants were randomized to receive either the HCl salt compound of formula (I) or a matching placebo for 56 days.

[0168] The clinical trial will consist of three study periods: screening / baseline, intervention, and safety follow-up.

[0169] Screening / Baseline Period The screening period was of maximum 28 days duration (days -28 to -1) but could be extended by an additional 14 days (days -42 to -1) for participants who needed to discontinue primidone. To be eligible, participants who were taking primidone at screening had to successfully discontinue this medication at least 14 days before the first dose of study medication.

[0170] Primary screening assessments included medical history, demographics, previous and concomitant medications, physical examination, drug / alcohol screen, clinical laboratory assessment, 12-lead ECG, vital signs, C-SSRS, and assessment of ET severity using TETRAS PS (including video recorded for independent eligibility review), TETRAS ADL, and CGI-S.

[0171] Intervention period Participants who continued to meet all clinical trial entry criteria on Day 1 were randomized to receive double-blind treatment with the HCl salt compound of Formula (I) or placebo every morning (QAM) from Day 1 through Day 56. To allow for titration in the two treatment regimens in the HCl salt compound of Formula (I) group (120 mg and 60 mg), participants were randomized in a 1:1:1:1 ratio to one of three fixed dose regimens or placebo.

[0172] Throughout the intervention period (days 1–56), participants who chose to or were forced to discontinue treatment entered the follow-up period if they did not withdraw their consent to participate.

[0173] Participants were administered six tablets of study medication QAM on day 1. TETRAS PS, TETRAS ADL, Essential Tremor Performance-Based Test (ET Performance-Based Test), CGI-S, QUEST, BDI-II, BAI, and mobile phone-based video tremor task were administered pre-dose. Additional assessments, including pharmacokinetic (PK) sampling, were performed pre-dose.

[0174] Participants continued to take six tablets of the study drug QAM throughout the entire trial. On days 14, 28, 42, and 56, participants returned to the clinic for safety and efficacy assessments. On days 14, 28, 42, and 56, participants took the study drug QAM at the clinic after pre-dose PK sampling and any pre-dose assessments were collected. Primary efficacy assessments at these visits included selection of the following assessments: TETRAS PS or CUL assessments, TETRAS ADL, QUEST, ET performance-based tests, BAI, BDI-II, CGI-S, CGI-I, and PGI-C. On days 7, 43, 44, 54, and 55, participants performed Archimedes spiral diagrams and handwriting samples at home. On days 43, 44, 54, and 55, participants performed a mobile phone-based video tremor task. On days 7, 21, 35, and 54, participants received a telephone call from site staff inquiring about AEs and changes in concomitant medications.

[0175] Safety follow-up period The safety follow-up period was from Day 57 to Day 70. At the end of the safety follow-up period, participants returned to the study site on Day 70 (± 1 day) for their final clinical trial evaluation.

[0176] Number of participants Approximately 112 participants were randomized (approximately 28 in each of the four groups), achieving approximately 88 evaluable participants (ie, 22 per treatment group). Clinical trial duration [Table 15]

[0177] Inclusion criteria Among the list of inclusion criteria, to be eligible to participate in this clinical trial, participants had a clinical diagnosis of ET at screening, including: A. Bilateral upper extremity action tremor syndrome; b. Persistence for at least 3 years c. With or without tremors elsewhere (e.g., in the head, voice, or legs), d. If the symptoms and signs are judged by the subject to be attributable to a diagnosis of ET, the subject may also have one or more of the following ET plus signs: i. mild dystonic postures, ii. Mild resting tremor in the setting of advanced ET and in the absence of other features of Parkinson's disease, iii. Intention tremor, iv. Mild increase in difficulty treading.

[0178] Eligible participants at screening also had a TETRAS upper extremity score of ≥10 (i.e., the sum of bilateral upper extremity items 4a, 4b, and 4c) as assessed by the investigator at screening and baseline.

[0179] If currently receiving any medication for ET, eligible participants were on a stable dose of any of these medications for ET for 1 month prior to screening and were willing to maintain a stable dose throughout the study. If receiving primidone for ET, eligible participants were willing and able to discontinue 14 days prior to Day 1.

[0180] Test product, reference therapy, and administration The HCl salt compound of formula (I) was provided as a 20 mg modified release tablet. A matching placebo was also provided. The study drug was administered orally and was provided to the participants in a prepackaged container. All participants were administered 6 tablets per day. Participants in one study drug group received a combination of the HCl salt compound of formula (I) and a matching placebo tablet, with the number of each tablet type depending on the assigned dosing regimen and study day. Participants in the placebo group were administered 6 tablets of the matching placebo on all dosing days.

[0181] Dose / Route / Regimen Eligible participants were randomized to receive one of three study drug dosing regimens (20 mg, 60 mg, or 120 mg) or placebo QAM orally. This randomized, double-blind, placebo-controlled, dose-ranging clinical trial assigned participants to receive 56 days of treatment with either study drug or placebo every morning. A fixed titration regimen was used to achieve dose levels higher than 20 mg (i.e., 60 mg and 120 mg). Participants were not allowed to adjust the number of tablets per day. See Table 16 below for dosing regimens. [Table 16]

[0182] Objectives and Evaluation Items The objectives and endpoints are summarized in the table below. [Table 17-1] [Table 17-2]

[0183] Example 3. Effect of the HCl salt of the compound of formula (I) alone or in combination with propranolol on tremor activity in rats This study seeks to evaluate the effect of the HCl salt of compound of formula (I) ("Test Drug") (1 mg / kg, i.p.), administered alone or in combination with propranolol (1 and 3 mg / kg, i.p., 20 min prior) on harmaline (10 or 30 mg / kg, i.p.)-induced tremor activity measured using a piezoelectric plate in male Sprague-Dawley (SD) rats.

[0184] Male SD rats had a body weight of approximately 250 g at the time of testing. Rats were fed ad libitum and maintained on a 12:12 light / dark cycle throughout the study. N=15 in each group. Harmaline and propranolol were each formulated in saline using a volume of 5 ml / kg body weight. The vehicle for the test drugs (1 mg / kg) was 0.5% methylcellulose / 0.1% Tween®-80 in water. See table below.

[0185] Table 18 provides doses for the first study based on the protocol described in this Example. Table 19 provides adjusted doses for the repeat (second) study based on the protocol described in this Example. [Table 18] [Table 19] method 1) Rats were acclimated in a standard laboratory animal facility for at least 5–7 days prior to use. 2) Rats were placed in a Plexiglas chamber with a piezoelectric plate attached to the bottom to transmit tremor behavior to an electronic signal. The tremor electrical signal was amplified 100× by AM Systems (model 1700), digitized by a CED-micro 1401 at a sampling rate of 512 Hz, and saved in "smr" format for offline analysis using Spike-2 software (version 7.07). 3) Because this sensitivity level allows the system to detect generally all tremor signals, naive rats were placed in the testing chamber one day prior to the first testing day to ensure that baseline spontaneous activity was within the range of 3,000-10,000 uv. 4) The experiment included seven groups (7 × 15 = 105 rats) and was conducted for seven days with balanced group placement each day. 5) Animals were randomly assigned to each treatment group across study days. 6) On each test day, each rat was given an acclimation session of at least 30 min in the testing room. 7) Prior to testing, rats were placed in the testing chamber for 5 minutes to ensure baseline activity was within acceptable limits (3000-10000 uv). 8) Rats were orally dosed with test compound and vehicle (60 min) and then intraperitoneally administered propranolol 20 min prior to harmaline injection. 9) Rats were then maintained in the testing chambers and allowed 20 min of baseline recording (-20 to 0 min) prior to harmaline (30 mg / kg) treatment (pre-harmaline). Eight rats were tested simultaneously by using the eight testing chambers in a counterbalanced order. 10) After 20 min of baseline recording (-20 to 0 min), each rat was intraperitoneally administered harmaline (30 mg / kg). 11) The after-effects of harmaline were measured for 20 minutes (10 to 30 minutes). 12) Immediately after completing the tremor recording, the rats were transferred to a designated necropsy room close to the procedure room. The rats were then anesthetized with CO2 and blood was collected via the left ventricle (approximately 90 minutes after harmaline). 13) Animals were sacrificed and relevant tissues were removed and kept in dry ice for immediate dissection. Piezoelectric plate signal analysis 1) Force spectrum density analysis: The electrical tremor signals were processed using a fast Fourier transform (FFT) with a bin resolution of 0.5 Hz. ·PZ force density was calculated from 20 min before and 20 min after harmaline injection (10–30 min) in the frequency range of 1–40 Hz. · Non-normalized force density after harmaline administration plotted in 0.5 Hz bins. Changes in force density following harmaline administration were normalized to 1) the mean of the 10-min baseline, and 2) the mean of the 20-min baseline for each rat in 0.5 Hz bins. The mean force density over the 8–13 Hz and 9–12 Hz bands was expressed as the percentage change relative to the baseline value separately and plotted as a bar graph. The average maximum force density over the 8–13 Hz band in 0.5 Hz bins was calculated and plotted as a bar graph. 2) Force-time analysis: Electrical tremor signals were processed with a fast Fourier transform (FFT) in 1-minute time bins through the frequency ranges 8–13 Hz and 9–12 Hz. Normalized mean force density over the 8–13 Hz band and in the 9–12 Hz band from 20 min before harmaline to 20 min after harmaline administration in 1 min bins were plotted as line graphs. Raw normalized mean force density data from individual animals in each group were collected across the 8–13 Hz band and in the 9–12 Hz band from 20 min before harmaline to 20 min after harmaline administration. Changes in force density after harmaline administration were normalized to 1) the mean of the 10-min baseline, and 2) the mean of the 20-min baseline for each rat in 1-min time bins. For each rat, the area under the force-time curve (AUC) over a 20-minute period following harmaline administration was calculated and the mean AUC was plotted as a bar graph. Eugenic EEG frequencies were collected over time from pre-harmaline to 20 min post-harmaline.

[0186] Plasma and brain tissue sample collection (90 minutes after administration of the test compound) was evaluated in 15 test rats, see table below. [Table 20]

[0187] N=15 in each group. Plasma and brain tissue samples were taken immediately after harmaline test. Number of plasma samples: 5×15=75. Number of brain tissue samples: 5×15=75.

[0188] result The results of the study are shown in Figures 4-6. Specifically, Panel A of Figure 4 is a bar graph showing tremor power measured in the 8-13 Hz band in harmaline-treated rats administered 1 mg / kg of the compound of formula (I) alone or in combination with 1 mg / kg or 3 mg / kg of propranolol. Panel B of Figure 4 is a bar graph showing tremor power measured in the 6-15 Hz band in harmaline-treated rats administered 1 mg / kg of the compound of formula (I) alone or in combination with 1 mg / kg or 3 mg / kg of propranolol. The results shown in Figure 4, Panels A and B, show that the compound of formula (I) significantly reduces harmaline-induced tremor when administered alone or with coadministration of propranolol. Furthermore, the plasma and brain concentrations of the compound of formula (I) and propranolol were consistent with those measured in previous studies.

[0189] Figure 5 is a bar graph showing sLMA as total distance traveled (mm) measured in rats treated with the compound of formula (I) and propranolol alone or in combination. Figure 6 is a bar graph showing sLMA as total distance traveled (mm) over time measured in rats treated with the compound of formula (I) and propranolol alone or in combination. The results shown in Figures 5 and 6 show that the compound of formula (I) or propranolol alone or in combination does not significantly reduce total sLMA in rats. Plasma and brain tissue concentrations of the compound of formula (I) and propranolol were consistent with those measured in previous studies. Example 4. Effect of Formula (I) and Propranolol in the Rat sLMA Assay The purpose of this study was to determine the effects of the compound of formula (I) and propranolol alone and in combination on rat locomotor activity (sLMA). Both propranolol and the compound of formula (I) were tested at 1 mg / kg of the compound of formula (I) and 3 mg / kg of propranolol. Rat sLMA was measured from 0 to 30 minutes (0 minutes is 60 minutes after administration of the compound of formula (I) and 20 minutes after administration of propranolol). [Table 21]

[0190] Figure 5 is a bar graph showing sLMA as total distance traveled (mm) measured in rats treated with the compound of formula (I) and propranolol alone or in combination. Figure 6 is a bar graph showing sLMA as total distance traveled (mm) over time measured in rats treated with the compound of formula (I) and propranolol alone or in combination. The results shown in Figures 5 and 6 show that the compound of formula (I) or propranolol alone or in combination does not significantly reduce total sLMA in rats. Plasma and brain tissue concentrations of the compound of formula (I) and propranolol were consistent with those measured in previous studies.

[0191] Example 5. Effects of the compound of formula (I) (1, 3, and 10 mg / kg, orally administered) or propranolol on multiple endpoints using harmaline in SD rats: tremor assessment, open field, rotarod, and wire grip tests As outlined in Table 22 below, six groups of male SD rats were each administered a dose of either vehicle, Formula (I), or propranolol, followed by saline or harmaline, and then subjected to tremor assessment followed by three ADL-like measurements, including the open field, rotarod, and wire grip tests. [Table 22]

[0192] Twenty minutes after administration of harmaline or saline, rats were subjected to a tremor assessment using the scoring criteria outlined in the table below. [Table 23]

[0193] The results of the experiment are shown in Figure 7. Specifically, Figure 7 is a bar graph showing the tremor scores measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug. As shown in Figure 7, rats administered 30 mg / kg harmaline exhibited a mean tremor score that was significantly higher than the mean tremor score of rats administered only vehicle and saline. Also shown in Figure 7, rats administered 10 mg / kg propranolol exhibited a mean tremor score that was significantly lower than the mean tremor score of rats administered only vehicle and harmaline. Administration of the compound of formula (I) to rats at doses of 1, 3, and 10 mg / kg significantly reduced the mean tremor score compared to rats administered only vehicle and harmaline.

[0194] Fifteen minutes after tremor assessment, rats were subjected to the open field test. FIG. 8 is a bar graph showing the distance traveled (mm) from 0 to 5 minutes measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug. As shown in FIG. 8, rats administered 30 mg / kg harmaline showed a significant reduction in distance traveled in the open field test compared to rats administered vehicle and saline only. Also shown in FIG. 8, rats administered the compound of formula (I) at doses of 3 and 10 mg / kg showed a significantly attenuated decrease in harmaline-induced distance traveled compared to rats administered vehicle and harmaline only.

[0195] One day before injection of the compound of formula (I) or vehicle, rats were trained on the rotarod moving at 8 rpm for 5 min. After 15 min of the open field test, rats were subjected to the rotarod test. The speed of the rotarod was increased from 10 rpm to 60 rpm within the first 5 min of the test. Figure 9 is a bar graph showing the mean latency to fall in the rotarod test measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug. As shown in Figure 9, rats administered 30 mg / kg harmaline showed significant motor impairment measured as a reduction in the latency to fall compared to rats administered vehicle and saline only. Also shown in Figure 9, rats administered the compound of formula (I) at doses of 3 and 10 mg / kg showed a significant attenuation of motor impairment (increased latency to fall) compared to rats administered vehicle and harmaline only. In contrast, rats treated with 10 mg / kg propranolol showed no significant amelioration of harmaline-induced motor impairment compared with rats treated with vehicle and harmaline alone.

[0196] Fifteen minutes after the rotarod test, the rats were subjected to a wire grip test using a wire 80 cm long and 7 mm in diameter, placed at a height of 50 cm. Figure 10 is a bar graph showing the mean time to fall (seconds) measured in rats administered 30 mg / kg harmaline and also administered 10 mg / kg propranolol or 1 mg / kg, 3 mg / kg, or 10 mg / kg of the test drug. As shown in Figure 10, rats administered 30 mg / kg harmaline showed a significant reduction in the time to fall compared to rats administered vehicle and saline only. Also shown in Figure 10, rats administered propranolol as a reference compound showed a significant reduction in motor injury (increased time to fall) compared to rats administered vehicle and saline only. Rats administered the compound of formula (I) at doses of 1, 3, and 10 mg / kg showed a significantly attenuated decrease in harmaline-induced fall time compared to rats administered vehicle and harmaline only.

[0197] conclusion The results of this study showed that administration of 30 mg / kg harmaline successfully induced tremor activity and induced motor impairment in three ADL-like measures, including a significant reduction in distance traveled in the open field test and in the time to fall in both the rotarod and wire-grip tests in male SD rats. Administration of propranolol had no effect on either locomotor activity in the open field (low locomotor activity) or harmaline-induced reduction in the time to fall in the rotarod test in male SD rats, respectively. In contrast, rats administered propranolol showed a significant inhibition of harmaline-induced tremor activity in the wire-grip test, and a significant attenuation of harmaline-induced motor impairment, compared to rats administered vehicle and harmaline only.

[0198] Rats administered the compound of formula (I) at doses of 1, 3, and 10 mg / kg, respectively, showed significant inhibition of tremor activity and significant effects in each of the three ADL-like measures. Formula (I) significantly attenuated harmaline-induced decreases in distance traveled in the open field test and latency to fall in the rotarod test, compared to rats administered vehicle and harmaline alone.

[0199] Example 6. Co-administration of a compound of formula (I) with propranolol in harmaline-induced hypolocomotion in rats Two harmaline model studies were conducted using sLMA as an ADL-like endpoint. In each of the two sLMA studies, male SD rats were grouped into five groups according to the following table. In the first study, groups 3, 4, and 5 received 3 mg / kg propranolol and a compound of formula (I) (test drug) at a dose of 1 mg / kg or 3 mg / kg. In the second study, groups 3, 4, and 5 received 10 mg / kg propranolol and a test drug at a dose of 1 mg / kg or 3 mg / kg. [Table 24]

[0200] The rats were then subjected to an open field test for 30 minutes. The total distance traveled was measured. The results are shown in Figures 11-13. Specifically, Figure 11 is a bar graph showing the distance traveled (mm) from 0 to 30 minutes for rats treated with harmaline (30 mg / kg), propranolol at 3 mg / kg, and test drug at 1 mg / kg and 3 mg / kg. As shown in Figure 11, there was a significant attenuation of harmaline-induced hypolocomotion in rats administered both propranolol and test drug at 3 mg / kg compared to rats administered only vehicle and harmaline in the first study. Figure 12 is a bar graph showing the distance traveled (mm) from 0 to 30 minutes for rats treated with harmaline (30 mg / kg), propranolol at 10 mg / kg, and test drug at 1 mg / kg and 3 mg / kg. Figure 13 shows the same data as in Figures 11 and 12, and is a bar graph showing the results of a statistical comparison between different groups of rats, including data from the same study from 30 mg / kg harmaline and 1 and 3 mg / kg test drug only (without propranolol). As shown in Figure 12, in the second study, rats administered 10 mg / kg propranolol and 3 mg / kg test drug also showed significantly increased locomotor activity compared to harmaline and vehicle only control rats, and as shown in Figure 13, was the group of rats whose locomotor activity was closest to that of rats administered saline only. Rats treated with 3 or 10 mg / kg propranolol, along with 3 mg / kg test drug, showed a significant attenuation of harmaline-induced hypolocomotion (compared to rats treated with harmaline and vehicle), whereas 3 mg / kg test drug alone (without propranolol) was not significantly different from rats treated with harmaline and vehicle only. Thus, these results indicate that co-administration of a compound of formula (I) with propranolol may result in enhanced activity in attenuating harmaline-induced hypolocomotion.

[0201] Equivalence and Scope In the claims, articles such as "a," "an," and "the" can mean one or more, unless otherwise indicated to the contrary or clear from the context. A claim or specification containing "or" between one or more elements of a group is deemed to be satisfied if one, more than one, or all of the group elements are present in, employed in, or relevant to a given product or process, unless otherwise indicated to the contrary or clear from the context. Thus, the claims include embodiments in which exactly one element of a group is present in, employed in, or relevant to a given product or process. The claims or specifications also include embodiments in which two or more, or all of the group elements are present in, employed in, or relevant to a given product or process.

[0202] Moreover, the embodiments encompass all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be amended to include one or more limitations found in any other claim that is dependent on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. In general, when the present embodiments are described as including certain elements and / or features, it should be understood that a particular embodiment consists of, or consists essentially of, such elements and / or features. For purposes of brevity, those embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Additionally, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can be considered to be any specific value or subrange within the described ranges of different embodiments of the invention, to one tenth of the unit of the lower limit of the range, unless the context clearly indicates otherwise.

[0203] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed known to those of ordinary skill in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0204] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above detailed description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. 1. A composition for use in the treatment of a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, comprising a compound of formula (I): 【Chemistry 11】 or a pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof.

2. 2. The composition for use according to claim 1, wherein the disease or condition is essential tremor (ET).

3. 2. The composition for use according to claim 1, wherein the compound of formula (I) is an HCl salt.

4. 4. The composition for use according to claim 3, wherein said use comprises administering said compound of formula (I) in combination with propranolol or a pharmaceutically acceptable salt thereof.

5. 5. The composition for use according to claim 4, wherein the propranolol is administered as the HCl salt.

6. 5. The composition for use according to claim 4, wherein said use comprises administering propranolol as the (S)-enantiomer, the (R)-enantiomer, or a mixture thereof.

7. 10. The composition for use according to claim 1, wherein the subject was taking a dosage regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof prior to treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof.

8. 8. The composition for use according to claim 7, wherein the dosing regimen of at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, is not changed after treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof has begun.

9. 2. The composition for use according to claim 1, wherein said use comprises administering to said subject said compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose of from about 5 mg to about 120 mg.

10. 2. The composition for use according to claim 1, wherein said use comprises administering to said subject said compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose of from about 20 mg to about 80 mg.

11. A composition for use according to claim 1, wherein said use comprises titrating the compound of formula (I) or a pharmaceutically acceptable salt thereof upward from a starting dose to a final dose during administration.

12. 12. The composition for use according to claim 11, wherein the starting dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 10 mg to about 40 mg once daily.

13. 12. The composition for use according to claim 11, wherein the starting dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 20 mg once daily.

14. 12. The composition for use according to claim 11, wherein the final dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from about 80 mg once a day to about 120 mg once a day.

15. 15. The composition for use according to claim 14, wherein the final dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 120 mg once a day.

16. The composition for use according to claim 11, wherein the final dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 60 mg once a day.

17. The composition for use described in claim 11, wherein the use further comprises administering to the subject at least one intermediate dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof between the initial dose and the final dose, wherein the intermediate dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is greater than the initial dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof but less than the final dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

18. 10. The composition for use of claim 1, wherein the subject is refractory to at least one of propranolol, primidone, topiramate, or pharmaceutically acceptable salts thereof.

19. A composition for use according to claim 1, wherein the use comprises daily administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, respectively.

20. A composition for use according to claim 1, wherein the use comprises daily administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and administering at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof as needed.

21. A composition for use according to claim 7, wherein the use comprises administering to the subject a dose of propranolol, primidone, or topiramate that is about 5% to 90% less than the dose of propranolol, primidone, or topiramate that the subject was taking prior to treatment with the compound of formula (I) or a pharmaceutically acceptable salt thereof.

22. 22. The composition for use according to any one of claims 1 to 21, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is a deuterium-enriched compound of formula (I) or a pharmaceutically acceptable salt thereof.

23. The deuterium-enriched compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the deuterium-enriched compound of formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (II-A): or a compound of formula (II-B):

23. The composition for use according to claim 22, wherein the compound is

24. (i) Formula (I): or a pharmaceutically acceptable salt thereof, and (ii) at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof; 1. A fixed dose composition for oral administration comprising:

25. (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (ii) propranolol or a pharmaceutically acceptable salt thereof 25. The fixed dose composition of claim 24, comprising:

26. 26. The fixed-dose composition of claim 25, comprising the HCl salt of the compound of formula (I) and the HCl salt of propranolol.

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