Treatment methods for essential tremor

Abstract

The present disclosure relates to methods of treating essential tremor that comprise administering to a subject in need thereof compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the subject once daily at a dose of about 60 mg to about 100 mg; such that The Essential Tremor Rating Assessment Scale (TETRAS) performance score of said subject is decreased following administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, as compared to the TETRAS performance score of said subject prior to the administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

Description

1 / 105 Treatment methods for essential tremor Related Orders

[001] This application claims priority to U.S. Provisional Patent Application No. 63 / 542053, filed October 2, 2023; U.S. Provisional Patent Application No. 63 / 531467, filed August 8, 2023; U.S. Provisional Patent Application No. 63 / 467471, filed May 18, 2023; U.S. Provisional Patent Application No. 63 / 449676, filed March 3, 2023; and U.S. Provisional Patent Application No. 63 / 449528, filed March 2, 2023. The entire content of each of the foregoing applications is incorporated herein by reference. Background

[002] T-type calcium channels are low-voltage-gated ion channels that mediate calcium influx into cells. Aberrant function or activity of these ion channels is associated with various diseases or conditions, including psychiatric disorders (e.g., mood disorders such as major depressive disorder), pain, tremor (e.g., essential tremor), epilepsy, or an epileptic syndrome (e.g., absence seizures and juvenile myoclonic epilepsy).

[003] In the treatment of diseases or conditions related to aberrant function or activity of T-type calcium channels, the tolerability of potential pharmaceutical therapies is a factor to be considered. In investigations of new therapies, tolerability is a clinically defined term that relates to the contribution of the patient (or study participant) and the clinician (or investigator). The patient's contribution includes their willingness to continue taking the medication, and the clinician's contribution includes their assessment of the severity and / or number of adverse effects associated with the medication and a recommendation as to whether the patient should discontinue the medication. Petition 870250100953, dated 04 / 11 / 2025, page 7 / 143 2 / 105 continue taking the medication. Both parties may decide that the medication is intolerable and therefore discontinue administration of the dose.

[004] The assessment of tolerability may also be based on the relationship between the adverse effects that inform tolerability and the expected or perceived benefit. Consequently, for a therapeutic or therapeutic dose used to treat life-threatening diseases or conditions, a more severe or increased number of adverse events may be permitted before the therapeutic or therapeutic dose can be designated as intolerable, compared to a therapeutic or therapeutic dose used to treat less severe diseases or conditions.

[005] Essential tremor is a disorder with underlying aberrant T-type calcium channel function or activity that can affect an individual's ability to function in daily life, but is usually not fatal. Essential tremor can, however, have a significant impact on home life, work, social life, or any combination thereof. For example, individuals with essential tremor may have difficulty performing daily activities, including certain tasks or jobs that require motor skills, or may feel embarrassed by their tremor. Essential tremor is one of the most common movement disorders and is characterized by postural and / or kinetic tremors and, in some cases, impaired gait, along with some non-motor symptoms.Propranolol (a beta-blocker) and primidone (an anticonvulsant medication), which are currently used to treat essential tremor, are characterized by serious side effects and are ineffective in some patients. Consequently, additional methods of treating essential tremor are needed. SUMMARY Petition 870250100953, dated 04 / 11 / 2025, page 8 / 143 3 / 105

[006] Consequently, in some respects, the present invention provides methods of treating essential tremor comprising administering to an individual in need, for example, a human individual with essential tremor, a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or the pharmaceutically acceptable salt thereof, is administered to the individual once daily at a dose of about 60 mg to about 100 mg; such that the individual's Essential Tremor Rating Scale (TETRAS) performance score is decreased after administration of the compound of formula (I), compared with the individual's TETRAS performance score before administration of the compound of formula (I).

[007] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual in a dose of approximately 60 mg.

[008] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual in a dose of approximately 100 mg.

[009] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual after a period of initial titration.

[0010] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual at a dose of approximately 60 mg after an initial titration period; wherein said initial titration period Petition 870250100953, dated 04 / 11 / 2025, p. 9 / 143 4 / 105 comprises administering to the individual the compound of formula (I), or a pharmaceutically acceptable salt thereof, once daily at a dose of approximately 5 mg during a first period of time; followed by a dose of approximately 10 mg during a second period of time; followed by a dose of approximately 20 mg during a third period of time; followed by a dose of approximately 40 mg during a fourth period of time.

[0011] In some modalities, the first time period, the second time period, the third time period and the fourth time period each last 7 days.

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

[0013] In some modalities, the first time period, the second time period, the third time period, the fourth time period, the fifth time period and the sixth time period each last 7 days.

[0014] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual for at least 8 weeks. Petition 870250100953, dated 04 / 11 / 2025, p. 10 / 143 5 / 105

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

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

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

[0018] In some sports, the performance score TETRA comprises ADL subscore, and in which the ADL subscore is decreased by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of the compound of formula (I), compared with the individual's ADL subscore before administration of the compound of formula (I).

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

[0020] In some disciplines, the ADL sub-score is reduced by at least approximately 3 points after at least 8 Petition 870250100953, dated 04 / 11 / 2025, page 11 / 143 6 / 105 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0025] In some modalities, a sub-score for Petition 870250100953, dated 04 / 11 / 2025, page 12 / 143 7 / 105 minus one item assessed as part of the mADL subscale is reduced, wherein the said item is selected from the group consisting of: item 3 (drinking from a glass); item 4 (hygiene); item 5 (dressing); item 6 (pouring); item 7 (carrying something); item 8 (using keys); item 9 (writing); and item 11 (general disability).

[0026] In some sports, the performance score TETRAS comprises the mADL11 subscore, and where the mADL11 subscore is decreased by at least about 0.5 points, at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, or at least about 10 points after administration of the compound of formula (I), compared with the individual's ADL subscore before administration of the compound of formula (I).

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

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

[0029] In some modalities, the individual does not have intention tremor.

[0030] In some modalities, the individual is a human. Brief Description of the Figures

[0031] Figure 1 is a diagram illustrating the Phase 2 trial design for evaluating the efficacy and safety / tolerability of Petition 870250100953, dated 04 / 11 / 2025, page 13 / 143 8 / 105 titration of Compound 1 to 60 mg or 100 mg compared with placebo in participants with moderate to severe essential tremor (ET).

[0032] Figure 2 is a schematic listing of items that are included in the modified total score TETRAS and TETRAS.

[0033] Figure 3 is a diagram showing the patient's layout in the clinical trial described in Example 1.

[0034] Figure 4 is a table showing demographic data and initial patient assessment characteristics (mITT).

[0035] Figure 5 is a table showing the TEASs experienced by patients in the clinical trial described in Example 1.

[0036] Figure 6 is a table showing the TEAEs and the dose at the onset of the event.

[0037] Figure 7 is a table showing the discontinuations of Composite 1 in the mITT patient population.

[0038] Figure 8 is a bar graph showing the change in mADL and ADL scores for the mITT population treated with Compound 1 (ulixacaltamide) and placebo.

[0039] Figure 9 is a bar graph showing the change in mADL score on day 56 for patients who took ulixacaltamide (Compound 1) or placebo.

[0040] Figure 10 is a diagram showing the observed change in scores for individual items that were assessed as part of the mADL and ADL assessment compared to the baseline assessment.

[0041] Figure 11 is a bar graph showing the change in skinfold thickness adjusted for the change from placebo on day 56 for individual items that were assessed as part of the mADL assessment. Petition 870250100953, dated 04 / 11 / 2025, page 14 / 143 9 / 105

[0042] Figure 12 shows graphs illustrating the status of patients in the mITT population as measured using the PGI-C scale and the CGI-S scale.

[0043] Figure 13 is a diagram showing the results of the Pearson correlation assessment for the change from baseline in ADL and PS scores and other measures.

[0044] Figure 14 is a bar graph showing the change in mADL score on day 56 for each patient who took ulixacaltamide or placebo, when PS items (spirals - left and right and handwriting) are excluded from the assessment. Data from Figure 8 are also included in Figure 14 for comparison.

[0045] Figure 15 is a graph showing the change in mADL scores and mADL excluding PS scores (mADL11) at each scored time point. Figure 15 shows improvement in mADL scores and mADL excluding PS scores (mADL11) for ulixacaltamide vs. placebo after day 14.

[0046] Figure 16 is a graph and a table showing the outcome analysis for the mITT population.

[0047] Figure 17 is a bar graph showing the results of the post-hoc respondent analysis using the Method. MCID distribution in the mITT population.

[0048] Figure 18 is a bar graph showing mADL scores and mADL scores excluding PS in the mITT population, excluding patients with intention tremor.

[0049] Figure 19 is a diagram showing the change observed in scores for individual items that are assessed as part of the mADL assessment compared to the baseline assessment in patients who do not have intention tremor.

[0050] Figure 20 is a bar graph showing the change in placebo-adjusted mADL scores, excluding PS in Petition 870250100953, dated 04 / 11 / 2025, page 15 / 143 10 / 105 mITT patients without intention tremor for both dosage regimens tested (60 mg and 100 mg).

[0051] Figure 21 is a bar graph showing the change in mADL11 scores from baseline, by week of study from week 8 to week 14.

[0052] Figure 22 is a schematic showing the design of the phase 3 study to compare the efficacy and safety of ulixacaltamide (Compound 1) with placebo in participants aged 18 to 80 years who have a diagnosis of ET. Detailed Description Treatment methods for essential tremor

[0053] In some respects, the present invention provides methods of treating essential tremor comprising administering to an individual in need thereof the compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or the pharmaceutically acceptable salt thereof, is administered to the individual once daily at a dose of about 60 mg to about 100 mg; such that the individual's Essential Tremor Rating Scale (TETRAS) performance score is decreased after administration of the compound of formula (I), compared with the individual's TETRAS performance score before administration of the compound of formula (I).

[0054] As used in this document, an individual to whom administration is contemplated includes, but is not limited to, a human animal and a non-human animal. A non-human animal may be a mammal, such as a primate (e.g., a monkey). Petition 870250100953, dated 04 / 11 / 2025, page 16 / 143 11 / 105 cynomolgus or a rhesus monkey), cattle, a pig, a horse, a sheep, a goat, a rodent (e.g., a mouse or a rat), a cat, or a dog. In some embodiments, the individual is a non-human animal. In other embodiments, the individual is a human. In some embodiments, the individual is a male or female individual of any age group, such as a pediatric individual (e.g., infant, child, adolescent) or an adult individual (e.g., young adult, middle-aged adult, or elderly adult). The terms human and patient may be used interchangeably in this document.

[0055] In some modalities, the individual is a human. In some modalities, the individual has essential tremor. In some modalities, the individual does not have intention tremor.

[0056] As used in this document, and unless otherwise specified, the terms treat, treating, and treatment encompass an action that occurs while an individual suffers from the specified disease, disorder, or condition, for example, essential tremor, that reduces the severity of the disease, disorder, or condition, or slows or diminishes the progression of the disease, disorder, or condition (therapeutic treatment), and also encompass an action that occurs before an individual begins to suffer from a disease, disorder, or condition (prophylactic treatment).

[0057] Methods of the present invention comprise administering to an individual in need thereof the compound of formula (I): or a pharmaceutically acceptable salt (e.g., cocrystal) or solvate thereof.

[0058] As used in this document, the term salt Petition 870250100953, dated 04 / 11 / 2025, page 17 / 143 12 / 105 pharmaceutically acceptable refers to those salts that are, within good medical judgment, suitable for use in contact with human and minor animal tissues without toxicity, irritation, inappropriate allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compound of formula (I) include those derived from suitable inorganic and organic acids and bases.Examples of non-toxic and pharmaceutically acceptable acid addition salts are salts of an amino group 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 using other methods employed in the art, such as ion exchange.Other pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanopropionate, cyclamate, digluconate, dodecylsulfate, edisilate, ethanesulfonate, esilate, formate, fumarate, gentisate, glucoheptonate, glycerophosphate, gluconate, glucuronate, glutamate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrogen iodide, 2-hydroxyethanesulfonate, isethionate, ketoglutarate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, napadisilate, napsylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, oroate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, salts. Petition 870250100953, dated 04 / 11 / 2025, page 18 / 143 13 / 105 of valerate, stereoisomers thereof (e.g., enantiomers, diastereomers) and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counter-ions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0059] In certain embodiments, the compound of formula (I) is a salt of hydrochloric acid, for example, compound of formula (II):

[0060] The compound of formula (I) may also be referred to as N-((1-(2-( tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide, while formula (II) may be referred to as N-((1-(2-( tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide hydrochloride.

[0061] In some embodiments, the compound of formula (I) or formula (II) may also be referred to in this document as ulixacaltamide or Compound 1.

[0062] In some embodiments, the methods of the present invention comprise administering to an individual in need a crystalline form of the compound of formula (II), wherein the crystalline form exhibits a powder method X-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2 and 26.6±0.2. In some embodiments, the crystalline form exhibits a powder method X-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2 and 26.6±0.2. In some embodiments, the crystalline form exhibits a powder method X-ray diffraction pattern comprising peaks at the following angles of Petition 870250100953, dated 04 / 11 / 2025, p. 19 / 143 14 / 105 diffraction (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2 and 26.6±0.2. In some embodiments, the powder X-ray diffraction pattern was obtained using Cu Ka radiation. In some embodiments, the crystalline form has an onset melting point, as determined by differential scanning calorimetry, at approximately 226.6 °C.

[0063] In some embodiments, the methods of the present invention comprise administering to an individual in need a crystalline form of the compound of formula (II), wherein the crystalline form exhibits a powder method X-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2 and 17.8±0.2. In some embodiments, the crystalline form exhibits a powder method X-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2 and 20.5±0.2. In some embodiments, the crystalline form exhibits an X-ray diffraction pattern by the powder method comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2 and 21.2±0.2. In some embodiments, the powder X-ray diffraction pattern was obtained using Cu radiation. In certain embodiments, the crystalline form has an onset melting point, as determined by differential scanning calorimetry, at approximately 97.9, 131.6, 223.7, 83.8, 128.9, 168.9 or 224.4°C.

[0064] In some embodiments, the compound of formula (I), compound of formula (II) or crystalline form of the compound of formula (II) is administered to an individual in need according to methods of the present invention as part of a pharmaceutical composition that also comprises a modified-release polymer. The term modified-release polymer, as Petition 870250100953, dated 04 / 11 / 2025, page 20 / 143 15 / 105 used in this document refers to a polymer that is used in a composition (e.g., a tablet or capsule) to modify the rate of drug release after administration to an individual. For example, a modified-release polymer is used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, a modified-release polymer is a controlled-release polymer. For example, a modified-release polymer or a controlled-release polymer is an HPMC polymer. In some embodiments, a modified-release polymer may include hydrophilic matrix polymers (e.g., hypromellose, HPMC (hydroxypropylmethylcellulose)), hydrophobic matrix polymers (e.g., ethyl cellulose, etocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS100).

[0065] In some embodiments, the pharmaceutical composition comprising the compound of formula (I), the compound of formula (II) or the crystalline form of the compound of formula (II) comprises a diluent. The term diluent, as used in this document, refers to an excipient used to increase the weight and improve the uniformity of the contents. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starches and partially pregelatinized starches), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP) and sugar alcohols (e.g., sorbitol, xylitol and mannitol).

[0066] In some embodiments, the pharmaceutical composition comprising the compound of formula (I), the compound of formula (II) or the crystalline form of the compound of formula (II) comprises a glide. The term glide, as used in this document, refers to an excipient used to promote powder flow by reducing friction and cohesion between particles. For example, the Petition 870250100953, dated 04 / 11 / 2025, page 21 / 143 16 / 105 slip agents include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0067] In some embodiments, the pharmaceutical composition comprising the compound of formula (I), the compound of formula (II) or the crystalline form of the compound of formula (II) comprises a lubricant. The term lubricant, as used in this document, refers to an excipient used to prevent ingredients from clumping together and sticking to tablet punches or the capsule filling machine. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solid and the mold wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0068] In some embodiments, the pharmaceutical composition comprising the compound of formula (I), the compound of formula (II) or the crystalline form of the compound of formula (II) comprises a coating. The term coating, as used in this document, refers to an excipient, for example, to protect the tablet ingredients from deterioration by air moisture and to make large or unpleasant-tasting tablets easier to swallow.

[0069] The methods of the present invention for treating essential tremor comprise administering to an individual in need a titrated dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, such that the final or maintenance dosage (i.e., final dosage) exceeds an initial dosage or a dosage at which adverse events are likely to be experienced without titration (a maximum tolerated dosage achieved without titration). As used in this document, administering a tri-titrated dose refers to the practice of starting with Petition 870250100953, dated 04 / 11 / 2025, page 22 / 143 17 / 105 a low dosage and escalate to one or more higher dosages. The administration of titrated doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is described, for example, in WO 2021 / 222342 A1, the full content of which is incorporated herein by reference.

[0070] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to an individual in the context of the present invention at a final dose (for example, 60 mg or 100 mg) after an initial titration period. The term initial titration period, when used in reference to the administration of a final dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, for example, a dose of about 60 mg or about 100 mg, refers to a period of time during which increasing doses that are lower than the final dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, are administered to an individual until the final dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is reached, for example, a dose of about 60 mg or about 100 mg.

[0071] For example, an initial titration period may comprise administering to an individual increasing doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, until a dose of approximately 60 mg is reached. In some embodiments, an initial titration period may comprise administering to an individual one or more doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of: a dose of approximately 5 mg, a dose of approximately 10 mg, a dose of approximately 20 mg, and a dose of approximately 40 mg. In some embodiments, an initial titration period may comprise administering to an individual Petition 870250100953, dated 04 / 11 / 2025, p. 23 / 143 18 / 105 of a dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 5 mg during a first time period; followed by a dose of about 10 mg during a second time period; followed by a dose of about 20 mg during a third time period; followed by a dose of about 40 mg during a fourth time period. In some embodiments, the first time period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days in duration. In some embodiments, the second time period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days in duration. In some modalities, the third time period can be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration.In some embodiments, the fourth time period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days in duration. In some embodiments, the first, second, third, and fourth time periods are each 7 days in duration. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once daily.

[0072] In another example, an initial titration period may comprise administering to an individual increasing doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, until a dose of about 80 mg is reached. In some embodiments, an initial titration period may comprise administering to an individual one or more doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of: a dose of about Petition 870250100953, dated 04 / 11 / 2025, p. 24 / 143 19 / 105 mg, a dose of approximately 10 mg, a dose of approximately 20 mg, a dose of approximately 40 mg, and a dose of approximately 60 mg. In some embodiments, an initial titration period may comprise administering to an individual a dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of approximately 5 mg during a first time period; followed by a dose of approximately 10 mg for a second time period; followed by a dose of approximately 20 mg during a third time period; followed by a dose of approximately 40 mg for a fourth time period; followed by a dose of approximately 60 mg during the fifth time period. In some embodiments, the first time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration.In some modalities, the second time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some modalities, the third time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some modalities, the fourth time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some modalities, the fifth time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some modalities, the first, second, third, fourth, and fifth time periods each last 7 days.In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once daily. Petition 870250100953, dated 04 / 11 / 2025, p. 25 / 143 20 / 105

[0073] In yet another example, an initial titration period may comprise administering to an individual increasing doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, until a dose of about 100 mg is reached. In some embodiments, an initial titration period may comprise administering to an individual one or more doses of the compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of: a dose of about 5 mg, a dose of about 10 mg, a dose of about 20 mg, a dose of about 40 mg, a dose of about 60 mg and a dose of about 80 mg.In some embodiments, an initial titration period may comprise administering to an individual a dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, of about 5 mg during a first time period; followed by a dose of about 10 mg during a second time period; followed by a dose of about 20 mg during a third time period; followed by a dose of about 40 mg during a fourth time period; followed by a dose of about 60 mg during a fifth time period; followed by a dose of about 80 mg during a sixth time period. In some embodiments, the first time period may be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days in duration.In some modalities, the second time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some modalities, the third time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some modalities, the fourth time period may be approximately 1 day. Petition 870250100953, dated 04 / 11 / 2025, page 26 / 143 21 / 105 approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some embodiments, the fifth time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some embodiments, the sixth time period may be approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately 5 days, approximately 6 days, or approximately 7 days in duration. In some embodiments, the first, second, third, fourth, fifth, and sixth time periods each have a duration of 7 days. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered once daily.

[0074] In certain aspects of all the modalities described herein, the administration time period, such as the first, second, third, fourth, fifth, or sixth time period, may vary from about 3 days to about 1 year. For example, the first, second, third, fourth, fifth, and / or sixth time period could be 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days, 63 days, 70 days, 77 days, 84 days, 91 days, 98 days, 105 days, 112 days, 119 days, 126 days, 133 days, 140 days, 147 days, 154 days, 161 days, 168 days, 175 days, 182 days, 189 days, 196 days, 203 days, 210 days, 217 days, 224 days, 231 days, 238 days, 245 days, 252 days, 259 days, 266 days, 273 days, 280 days, 287 days, 294 days, 301 days, 308 days, 315 days, 322 days, 329 days, 336 days, 343 days, 350 days, 357 days, 364 days, or 1 year in duration. In certain aspects of the modalities described in this document, the administration period, such as the seventh time period, may vary from approximately 3 to approximately 16 days, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 days. In other aspects of Petition 870250100953, dated 04 / 11 / 2025, p. 27 / 143 22 / 105 of the modalities described in this document, for example, the first, second, third, fourth, fifth, sixth or seventh administration time period may be longer than 14 days.

[0075] In certain aspects, the increase in dosage relative to the previous dose is not greater than 40 mg per day. For example, in certain embodiments, the second dose is increased by no more than 40 mg per day relative to the first dose, and in certain aspects, the third dose is increased by no more than 40 mg per day relative to the second dose. In other aspects, the increase in dosage relative to the previous dose is not greater than 20 mg per day. For example, in certain embodiments, the second dose is increased by no more than 20 mg per day relative to the first dose, and in certain embodiments, the third dose is increased by no more than 20 mg per day relative to the second dose. In some embodiments, the third dose is the maintenance or final dose.

[0076] In the context of the present invention, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered to an individual once, twice, or three times daily in a dose of up to about 120 mg (for example, from about 5 mg to about 120 mg, from about 10 mg to about 120 mg, from about 15 mg to about 120 mg, from about 20 mg to about 120 mg, from about 40 mg to about 120 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 15 mg to about 100 mg, from about 20 mg to about 100 mg, from about 40 mg to about 100 mg, from about 5 mg to about 80 mg, from about 10 mg to about 80 mg). mg, from about 15 mg to about 80 mg, from about 20 mg to about 80 mg, from about 40 mg to about 80 mg, from about 5 mg to about 60 mg, from about 10 mg to about 60 mg, from about 15 mg to about 60 mg, from about 20 mg to about 60 mg, or from about 40 mg to about 60 mg). In some Petition 870250100953, dated 04 / 11 / 2025, p. 28 / 143 23 / 105 modalities, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual once daily.

[0077] In some embodiments, methods of treating essential tremor in an individual in need within the context of the present invention comprise: (a) administer to the individual once daily for an initial period of time (e.g., 3, 4, 5, 6, 7, 8 or 9 days), 5 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); (b) administer to the individual once daily for a second period of time (for example, 3, 4, 5, 6, 7, 8 or 9 days), 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)); and (c) administer to the individual once daily for a third period of time (for example, 3, 4, 5, 6, 7, 8 or 9 days), 20 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)). In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual once daily.

[0078] In some embodiments, methods of treating essential tremor in an individual in need within the context of the present invention comprise: (a) administer to the individual for an initial period of time (e.g., 3, 5, 6, 7, 8 or 9 days), 20-40 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)); (b) administer to the individual for a second period of time (for example, 3, 5, 6, 7, 8 or 9 days), 20-60 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for Petition 870250100953, dated 04 / 11 / 2025, p. 29 / 143 24 / 105 example, the compound of formula (II)); and (c) administer to the individual for a third period (for example, 3, 4, 5, 6, 7, 8 or 9 days), 20-80 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)).

[0079] In some embodiments, the method further comprises (d) administering to the individual for a fourth period of time (for example, 3, 4, 5, 6, 7, 8 or 9 days), 20-100 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)).

[0080] In other embodiments, the method further comprises (e) administering to the individual for a fifth time period (for example, 3, 4, 5, 6, 7, 8 or 9 days), 20-120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)).

[0081] In certain embodiments, the method further comprises (f) administering to the individual for a sixth period of time (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 days), 20-120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)).

[0082] In certain embodiments, the method further comprises (g) administering to the individual for a seventh period of time (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, or more days), 20-120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)), as needed.

[0083] A physician may choose not to continue escalating the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, so that there may be fewer than the seven time periods described above. For example, there may be only 1, 2, 3, 4, 5 Petition 870250100953, dated 04 / 11 / 2025, p. 30 / 143 25 / 105 or 6 time periods of increasing dosages are necessary to achieve a desired appendetic effect. In some embodiments, the methods of the present invention comprise 2, 3, or 4 time periods of increasing dosages. In some embodiments, the methods of the present invention comprise 5 time periods of increasing dosages. In some embodiments, the methods of the present invention comprise 7 time periods of increasing dosages.

[0084] In some embodiments, the methods of the present invention comprise: (a) administering to the individual for a first period of time ranging from about 3 to about 9 days, about 5 mg to about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 20 mg or 40 mg per day; (b) administering to the individual for a second period of time ranging from about 3 to about 9 days, about 10 mg to about 100 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 40 mg, 60 mg or 80 mg per day; and (c) administer to the individual for a third period of time ranging from about 3 to about 9 days, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as 60 mg, 80 mg, 100 mg or 120 mg per day.

[0085] In some embodiments, the methods of the present invention comprise: (a) administering an initial dose of about 20 mg to about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual once daily for an initial period of time; (b) increasing the amount of the compound in the initial dose and administering one or more increased doses of the compound to the individual to reach a maximum titrated dose of about 80 mg to about 120 mg per day; and (c) Petition 870250100953, dated 04 / 11 / 2025, p. 31 / 143 26 / 105 administer the maximum titrated dose to the individual once daily, as needed.

[0086] In related embodiments, the dosage of the formula compound (I) may be adjusted up or down in increments of 1, 2, 3, 4, 5, 10, 15, 20 mg, as deemed necessary by a physician, depending on an individual's response to previous dosages of the formula compound (I).

[0087] In various embodiments of the invention, the methods described in this document comprise: (a) administering a first dose of 20 mg per day for a first period of 3 days, (b) administering a second dose of 40 mg per day for a second period of 3 days, (c) administering a third dose of 60 mg per day for a third period of 7 days; (d) administering a fourth dose of 80 mg per day for a fourth period of 7 days; (e) administering a fifth dose of 100 mg per day for a fifth period of 7 days; and (f) thereafter administering a sixth dose of 120 mg per day, as needed.In several other embodiments, the methods described in this document comprise (a) administering a first dose of 20 mg per day for an initial period of 3 days, (b) administering a second dose of 40 mg per day for a second period of 3 days, (c) administering a third dose of 80 mg per day for a third period of 3 days; and (d) administering a fourth dose of 120 mg per day, as needed.

[0088] In certain embodiments, a method of treating a disease or condition related to aberrant function or activity of T-type calcium channels in an individual in need thereof is described, comprising (a) administering to the individual for a first period of 3 days approximately 20 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administering to the individual for a second period of 3 days Petition 870250100953, dated 04 / 11 / 2025, p. 32 / 143 27 / 105 period of time of approximately 3 days approximately 40 mg per day of the compound; (c) administer to the individual for a third period of time of approximately 3 days approximately 60 mg per day of the compound; (d) administer to the individual for a fourth period of time of approximately 3 days approximately 80 mg per day of the compound; (e) administer to the individual for a fifth period of time of approximately 3 days approximately 100 mg per day of the compound; and (f) administer to the individual for a sixth period of time approximately 120 mg per day of the compound. Instead of every 3 days, doses may also be administered every 4, 5, or 6 days.

[0089] Also described in this document is a method of treating essential tremor in an individual who needs it, comprising: (a) administering to the individual during a first period of 7 days approximately 20 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administering to the individual during a second period of approximately 7 days approximately 40 mg per day of the compound; (c) administering to the individual during a third period of approximately 7 days approximately 60 mg per day of the compound; (d) administering to the individual during a fourth period of approximately 7 days approximately 80 mg per day of the compound; (e) administering to the individual during a fifth period of approximately 7 days approximately 100 mg per day of the compound; and (f) administering to the individual during a sixth period approximately 120 mg per day of the compound.

[0090] In some embodiments, the methods of the present invention comprise: (a) administering to the individual for a first period of time of 3 days about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administering to the individual for a second period of time of about 3 days about 80 mg per day of the compound; and (c) Petition 870250100953, dated 04 / 11 / 2025, p. 33 / 143 28 / 105 administer approximately 120 mg per day of the compound to the individual during a third period. Instead of every 3 days, doses can also be administered every 4, 5, or 6 days.

[0091] Also described in this document is a method of treating a disease or condition related to aberrant function or activity of a type T calcium channel in an individual who needs it, comprising (a) administering to the individual for a first period of 7 days about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administering to the individual for a second period of about 7 days about 80 mg per day of the compound; and (c) administering to the individual for a third period about 120 mg per day of the compound.

[0092] In certain embodiments, a method of treating a disease or condition related to aberrant function or activity of a T-type calcium channel in an individual requiring it is described, comprising (a) administering to the individual for a first period of 7 days about 20 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administering to the individual for a second period of about 7 days about 40 mg per day of the compound; (c) administering to the individual for a third period of about 7 days about 60 mg per day of the compound; (d) administering to the individual for a fourth period of about 7 days about 80 mg per day of the compound; (e) administering to the individual for a fifth period of about 7 days about 100 mg per day of the compound; (f) administering to the individual for a sixth period of about 14 days about 120 mg per day of the compound;and (g) thereafter administer to the individual approximately 1120 mg per day of the compound, as needed.;

[0093] A doctor may choose to stop escalating the dose of Petition 870250100953, dated 04 / 11 / 2025, page 34 / 143 29 / 105 compound of formula (I) or a pharmaceutically acceptable salt thereof, once the individual has demonstrated a desired therapeutic effect. At this point, the physician may choose that the individual continue the dose that the individual has been taking to achieve the desired therapeutic effect, or may choose that the individual decrease the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in order to maintain the desired therapeutic effect, reduce side effects, or both. Achieving a desired therapeutic effect may be observed by improvements, for example, in the individual's TETRA performance score, accelerometer performance score, or Archimedes spiral task test.

[0094] In some embodiments, methods of treatment of essential tremor provided by the present invention comprise administering to an individual in need a compound of formula (I), or a pharmaceutically acceptable salt thereof, such that the individual's Essential Tremor Rating Scale (TETRAS) performance score is decreased after administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, compared with the individual's TETRAS performance score before administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof. TETRAS was developed to quantify the severity of essential tremor and its impact on activities of daily living, as described in Elble et al., J. Neurol Neuromedicine (2016), 1(4):34-38, the full content of which is incorporated herein by reference.In certain modalities, treatment methods for essential tremor in an individual in need may result in a change in the individual's TETRAS performance score. (The performance score...) Petition 870250100953, dated 04 / 11 / 2025, page 35 / 143 30 / 105 TETRAS is assessed using the TETRAS scale, which consists of two sections: the performance subscale (TETRAS-PS) and the activities of daily living subscale (TETRAS-ADL). The TETRAS-PS section includes 9 items, as listed below: Item No. Item Description 1 Head tremor 2 Facial tremor 3 Voice tremor 4 Kinetic tremor 5 Lower limb tremor 6 Spiral extraction 7 Handwriting 8 Point approximation task 9 Standing

[0095] The TETRASADL or ADL subscale is a 12-item assessment of typical daily activities that are affected by tremor. As shown in Figure 2, activities in the TETRASADL subscale are assessed in the following functional domains: Item No. Item Description 1 Speaking 2 Feeding oneself (e.g., with a spoon) 3 Drinking from a cup 4 Hygiene (e.g., personal hygiene) 5 Dressing 6 Spilling 7 Carrying (e.g., food trays, plates, or similar) 8 Using keys 9 Writing 10 Working 11 General disability with the task most affected 12 Social impact

[0096] The impact on each function is classified on a scale of A 5-point Likert scale ranging from 0 to 4. The complete ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48. Petition 870250100953, dated 04 / 11 / 2025, page 36 / 143 31 / 105

[0097] The TETRAS-modified ADL subscore (mADL) is a composite sum of items 1 to 11 on the TETRAS-ADL subscale (omitting the social impact of item 12) and items 6 and 7 on the TETRAS-PS subscale (spiral and handwriting). The mADL score is adjusted so that response options 0 and 1 are combined into a single response of 0 = Normal, and scores of 2, 3, and 4 are adjusted to 1, 2, and 3, respectively. The total modified TETRAS score is the sum of the adjusted TETRAS-ADL and TETRAS PS items, with a possible range of 0 to 42, where higher values ​​represent a greater direct impact of tremor on activities of daily living. The items included in the total modified TETRAS score are illustrated in Figure 2.

[0098] The modified ADL TETRAS excluding performance subscale score (mADL11) is a composite sum of items 1 to 11 of the TETRA-ADL subscale (social impact score of the omitted item 12 and items 6 and 7 of the TETRA-PS subscale). The score for each item is transformed into a 4-point scale from 0 to 3 with a total score range of 0 to 33.

[0099] In some modalities, a decrease in the TETRA performance score, for example, one or more of the ADL, mADL, or mADL11, is indicative of a desired therapeutic effect. In some modalities, a decrease in the TETRA performance score, for example, one or more of the ADL, mADL, or mADL11, is indicative of an improvement in essential tremor symptoms.

[00100] In some modalities, methods of treating essential tremor in an individual in need provided by the present invention may result in a decrease in the individual's TETRA performance score. Thus, in some modalities, an individual's TETRA performance score is decreased after administration of the compound of formula (I), or a salt Petition 870250100953, dated 04 / 11 / 2025, page 37 / 143 32 / 105 pharmaceutically acceptable, to the individual according to methods of the present invention, compared with the individual's TETRAS performance score before administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[00101] In some modalities, the TETRA performance score comprises ADL subscore, and an individual's ADL subscore is decreased by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about 4 points, at least about 4.5 points, at least about 5 points, at least about 5.5 points, at least about 6 points, at least about 6.5 points, at least about 7 points, at least about 7.5 points, at least about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points, or at least about 10 points after administration of the compound of formula (I), compared with the individual's ADL subscore before administration of the compound. from formula (I).In some embodiments, the ADL subscore is reduced by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the ADL subscore is reduced by at least about 3 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof to the individual.

[00102] In some modalities, the TETRA performance score comprises the mADL subscore, and an individual's mADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, by Petition 870250100953, dated 04 / 11 / 2025, page 38 / 143 33 / 105 less about less about less about less about less about less about about 2 points, 3 points, 4 points, 5 points, 6 points, 7 points, 8 points, at least at least at least at least at least at least about 2.5 about 3.5 about 4.5 about 5.5 about 6.5 about 7.5 about 8.5 points, by points, by points, by points, by points, by points, by points, at least about 9 points, at least about 9.5 points or at least about 10 points after administration of the compound of formula (I), compared with the individual's mADL subscore before administration of the compound of formula (I). In some embodiments, the mADL subscore is decreased by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof to the individual.In some embodiments, the mADL subscore is decreased by at least about 3 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the mADL subscore is decreased by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.

[00103] In some embodiments, within the context of the present invention, administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, to an individual in need of treatment for essential tremor leads to a decrease in a subscore for at least one item assessed as part of the mADL subscale. In some embodiments, the item is selected from the group consisting of: item 3 (drinking from a glass); item 4 (hygiene); item 5 (dressing); item 6 (pouring); item 7 (carrying something); Petition 870250100953, dated 04 / 11 / 2025, page 39 / 143 34 / 105 item 8 (using keys); item 9 (writing); and item 11 (general disability).

[00104] In some modalities, the TETRAS performance score comprises the mADL11 subscore, and an individual’s mADL11 subscore is decreased by at least about 0.5 points, at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points, or at least about 10 points, after administration of the compound of formula (I), compared with the individual’s mADL11 subscore before administration of the compound of formula (I). In some modalities, the mADL11 subscore is decreased by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.In some modalities, the mADL11 subscore is reduced by at least about 2.5 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

[00105] In some modalities, treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRA performance score. In some modalities, treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's ADL performance subscore. In some modalities, methods Petition 870250100953, dated 04 / 11 / 2025, page 40 / 143 Treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRA-mADL performance subscore. In some modalities, treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRA-mADL performance subscore of at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about less, about less, about less, about less, about less, about less, about less, about less. 3.5 points, by 4.5 points, by 5.5 points, by 6.5 points, by 7.5 points, by 8.5 points, at least approximately 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 9.5 points, or at least approximately 10 points. In some modalities, treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRASmADL performance subscore of 2 points or more. In some modalities, treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRASmADL performance subscore of 2 points or more. Petition 870250100953, dated 04 / 11 / 2025, page 41 / 143 36 / 105 individual's TETRA-mADL performance subscore of at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about less about less about less about less about less about less 3.5 points, by 4.5 points, by 5.5 points, by 6.5 points, by 7.5 points, by 8.5 points, at least about less about less about less about less about less about points, by points, by points, by points, by points, by points, at least about 9.5 points or at least 10 points when the compound of formula (I) is administered at a dose of about 60 mg once daily after an initial titration period.

[00106] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to an individual in need in the context of the present invention for at least 8 weeks, at least 12 weeks, at least 14 weeks, at least 52 weeks, at least 2 years, at least 3 years, at least 4 years, at least 5 years or at least 10 years.

[00107] In some modalities, methods of treating a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease in the individual's TETRA-mADL performance subscore of 2 points or more when the compound of formula (I) is administered at a dose of about 60 mg once daily after an initial titration period.

[00108] In some modalities, treatment methods for a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in a Petition 870250100953, dated 04 / 11 / 2025, page 42 / 143 37 / 105 individual in need, may result in a change, for example, a decrease in the individual's mADL11 performance subscore of 2 points or more when the compound of formula (I) is administered at a dose of about 60 mg once daily after an initial titration period.

[00109] In some modalities, methods of treating a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRA-mADL performance subscore of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points when the compound of formula (I) is administered at a dose of about 100 mg once daily after an initial titration period.

[00110] In some modalities, methods of treating a disease or condition related to aberrant function or activity of a T-type calcium channel, for example, essential tremor, in an individual in need, may result in a change, for example, a decrease, in the individual's TETRA-mADL performance subscore of 2 points or more when the compound of formula (I) is administered at a dose of about 100 mg once daily after an initial titration period.

[00111] In several respects, the methods described in this document result in a reduction of the EEG sigma frequency band during NREM sleep in the individual, such as a reduction of the NREM sigma frequency band from an initial assessment of approximately 0.4 to 0.7, such as approximately 0.5 to approximately 0.6, or approximately 0.5. In certain modalities, the methods described in this document Petition 870250100953, dated 04 / 11 / 2025, p. 43 / 143 38 / 105 results in a reduction of the EEG gamma frequency band during wakefulness in an EO condition or an EC condition in the individual, such as a reduction in the gamma frequency band compared to an initial assessment gamma frequency band of at least about 25%, such as, for example, a reduction of about 50%.

[00112] In certain embodiments, the methods described in this document result in a reduction of the EEG sigma frequency during NREM sleep and / or a reduction of the EEG gamma frequency band during an EO or EC condition in the individual when the individual is administered a dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, resulting in a Cmax of about 30 ng / mL to about 470 ng / mL, such as a Cmax ranging from about 30 to about 50 ng / mL, from about 80 to about 130 ng / mL, from about 130 to about 222 ng / mL, from about 180 to about 300 ng / mL, from about 230 to 380 ng / mL or from about 280 to about 470 ng / mL.In certain embodiments, the methods described in this document result in a reduction in EEG sigma frequency during NREM sleep and / or a reduction in EEG gamma frequency band during an EO or EC condition in the individual when the individual is administered a dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, resulting in an AUC24 ranging from about 490 ng*h / mL to about 5800 ng*h / mL, such as an AUC24 ranging from about 490 to 820 ng*h / mL, of about. 1220 to 2030 ng*h / mL, approximately 2000 to 3330 ng*h / mL, approximately 2440 to 4070 ng*h / mL, approximately 2820 to 4700 ng*h / mL, or approximately 3480 to 5800 ng*h / mL.

[00113] In certain modalities, the methods described in this document result in a sigma frequency reduction of NREM. Petition 870250100953, dated 04 / 11 / 2025, p. 44 / 143 39 / 105 in the individual when the individual is administered with a dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, resulting in a Cmax of about 5 ng / mL to about 470 ng / mL, such as a Cmax of about 180 to about 300 ng / mL. In certain embodiments, the methods described in this document result in a sigma frequency reduction of NREM in the individual when the individual is administered with a dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, resulting in a mean plasma concentration (Cave) during EEG recording (i.e., over a period of about 24 hours) of about 10 ng / mL to about 200 ng / mL, such as a Cave of about 12 to about 150 ng / mL.In certain embodiments, the methods described in this document result in a gamma frequency band reduction with EO or EC in the individual when the individual is administered with a dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, resulting in a Cmax of the compound of approximately, such as a Cmax of approximately 280 to approximately 470 ng / mL. In certain embodiments, the methods described in this document result in a gamma frequency band reduction with EO or EC in the individual when the individual is administered with a dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, resulting in a plasma concentration of approximately 75 ng / mL to approximately 310 ng / mL, such as a plasma concentration of approximately 90 to approximately 190 ng / mL.

[00114] Certain aspects of all titrated dosing schedule modalities described in this document allow for increasing the maximum titrated dose, including, for example, increasing the maximum titrated dose above 120 mg in one or more additional titration steps, provided the individual is able to safely tolerate it. Petition 870250100953, dated 04 / 11 / 2025, p. 45 / 143 40 / 105 is the highest dose.

[00115] In certain aspects of all titrated dosage regimens described in this document, the maximum titrated dosage achieved is greater than 20 mg, greater than 40 mg, such as approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, or approximately 220 mg. In certain aspects of the invention, the maximum dosage for an individual is, for example, 40 mg, 60 mg, or 80 mg if the individual has achieved a desired therapeutic result.

[00116] In certain aspects of all the titrated dosing schedule modalities described in this document, the maximum titrated dosage is achieved in 42 days or less, such as 31 days or less, 28 days or less, 18 days or less, 10 days or less, or 7 days or less. In certain modalities, the maximum titrated dosage is achieved in approximately 10 to approximately 42 days, such as approximately 36-42 days, approximately 22-28 days, approximately 16-18 days, approximately 10-12 days, or approximately 7-10 days. Dosage forms and compositions

[00117] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, the compound of formula (II), may be administered as part of a dosage form or in a pharmaceutical composition.

[00118] In some embodiments, the composition that may be used in a method described in this document may be a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and an excipient that functions to modify the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In Petition 870250100953, dated 04 / 11 / 2025, p. 46 / 143 41 / 105 In some embodiments, the pharmaceutical composition may be a swelling core technology formulation.

[00119] In certain embodiments, a dosage form that may be used in a method described in this document may be an oral dosage form comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); and a modified-release polymer (e.g., a controlled-release polymer, hydrophilic matrix polymers, e.g., an HPMC polymer, hydrophobic matrix polymers (e.g., ethylcellulose, etocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS100)).

[00120] In other embodiments, a dosage form that may be used in a method described in this document may be a dosage form or composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) and a modified-release polymer (e.g., a controlled-release polymer, hydrophilic matrix polymers, e.g., an HPMC polymer, hydrophobic matrix polymers (e.g., ethylcellulose, etocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS100)), for example, in an amount sufficient to modify the release rate of the compound of formula (I) or of a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) after administration to the individual.

[00121] In some embodiments, the dosage form comprises from about 0.9% by weight to about 40% by weight (for example, from about 0.9% by weight to about 30%, from about 1% by weight to about 25% by weight, from about 2% by weight to about 25% by weight, from about 3% by weight to about 20% by weight, from about 4% by weight to about 20% by weight, from about 5% by weight to about 20% by weight). Petition 870250100953, dated 04 / 11 / 2025, page 47 / 143 42 / 105 weight to about 20% by weight, from about 5% by weight to about 15% by weight, from about 5% by weight to about 10% by weight, or about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 40% by weight) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)). In some embodiments, the dosage form comprises about 30% by weight to about 40% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)).

[00122] In some embodiments, the dosage form comprises from about 14% by weight to about 25% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)). In some embodiments, the dosage form comprises from about 19% by weight to about 20% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)). In some embodiments, the dosage form comprises from about 21% by weight to about 22% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)). In some embodiments, the dosage form comprises from about 4% by weight to about 15% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)). In some embodiments, the dosage form Petition 870250100953, dated 04 / 11 / 2025, p. 48 / 143 43 / 105 comprises from about 4% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the dosage form comprises from about 4% by weight to about 5% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the dosage form comprises from about 5% by weight to about 6% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the dosage form comprises from about 9% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)).

[00123] In other embodiments, a dosage form that may be used in a method described in this document may be a dosage form or composition comprising from about 1 mg to about 120 mg (for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for for example, the compound of formula (II)) and a modified-release polymer (for example, a controlled-release polymer, hydrophilic matrix polymers, for example, an HPMC polymer, hydrophobic matrix polymers (for example, ethylcellulose, etocel), or polyacrylate polymers (for example, Eudragit RL100,Eudragit RS100), by, Petition 870250100953, dated 04 / 11 / 2025, page 49 / 143 44 / 105 example, in an amount sufficient to modify the release rate of the compound of formula (I) or of a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)) after administration to the individual.

[00124] In other embodiments, the dosage form comprises from about 4 mg to about 6 mg (e.g., about 5 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In certain embodiments, the dosage form comprises from about 15 mg to about 25 mg (e.g., about 20 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the dosage form comprises from about 5 mg to about 15 mg (e.g., about 10 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In other embodiments, the dosage form comprises from about 25 mg to about 35 mg (e.g., about 30 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).In certain embodiments, the dosage form comprises from about 35 mg to about 45 mg (e.g., about 40 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In certain embodiments, the dosage form comprises from about 45 mg to about 55 mg (e.g., about 50 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the dosage form comprises from about 55 mg to about 65 mg (e.g., about 60 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). Petition 870250100953, dated 04 / 11 / 2025, p. 50 / 143 45 / 105 other embodiments, the dosage form comprises from about 65 mg to about 75 mg (e.g., about 70 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In certain embodiments, the dosage form comprises from about 75 mg to about 85 mg (e.g., about 80 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In certain embodiments, the dosage form comprises from about 85 mg to about 95 mg (e.g., about 90 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the dosage form comprises from about 95 mg to about 105 mg (e.g., about 100 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).In other embodiments, the dosage form comprises from about 105 mg to about 115 mg (e.g., about 110 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In certain embodiments, the dosage form comprises from about 115 mg to about 125 mg (e.g., about 120 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[00125] In some embodiments, the dosage form comprises from about 55 mg to 65 mg of a modified-release polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises from about 10% by weight to about 70% by weight of the modified-release polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises from about 50% by weight to about Petition 870250100953, dated 04 / 11 / 2025, p. 51 / 143 46 / 105 60% by weight of the modified-release polymer (e.g., an HPMC polymer).

[00126] In some embodiments, the dosage form further comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the dosage form comprises from about 15 mg to 40 mg (for example, from about 15 mg to about 25 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 40 mg) of microcrystalline cellulose. In some embodiments, the dosage form comprises from about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises from about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises from about 15% to about 35% by weight (for example, from about 15% to about 20%, from about 20% to about 25%, from about 25% to about 30%, from about 30% to about 35% by weight) of microcrystalline cellulose.

[00127] In some embodiments, the dosage form further comprises a slider. In some embodiments, the slider comprises colloidal silicon dioxide. In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the dosage form further comprises a coating.

[00128] In some embodiments, approximately 80% of the compound of formula (I) or of a pharmaceutically acceptable salt thereof is released within 7 hours after administration to an individual. In certain embodiments, approximately 80% of the compound of formula (I) or of a pharmaceutically acceptable salt thereof is released within 7 hours of use of the USP type I apparatus, medium containing 900 mL of 0.1 M HCl and Petition 870250100953, dated 04 / 11 / 2025, p. 52 / 143 47 / 105 a blade speed of 100 rpm.

[00129] In some embodiments, the dosage form, after administration to an individual, has a lower Cmax value than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., modified release rate profile, a dosage form that does not have a modified release rate profile, e.g., an HPMC polymer). In some embodiments, the dosage form, after administration to an individual, has a higher tmax value than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., modified release rate profile, a dosage form that does not have a modified release rate profile, e.g., an HPMC polymer).

[00130] In some embodiments, the dosage form is administered to a patient once daily. In certain embodiments, the dosage form is administered to a patient twice daily. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.

[00131] In some embodiments, the dosage form that may be used in a method described in this document may be an oral dosage form (e.g., particulate) comprising: from about 15 mg to about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); and from about 55 mg to 65 mg of an HPMC polymer.

[00132] In other embodiments, the dosage form that may be used in a method described in this document may be an oral dosage form (e.g., particulate) comprising approximately Petition 870250100953, dated 04 / 11 / 2025, p. 53 / 143 48 / 105 of 14% by weight to about 25% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)); and of about 53% to about 64% by weight of an HPMC polymer.

[00133] In certain embodiments, the dosage form that may be used in a method described in this document may be an oral dosage form (e.g., particulate) comprising: from about 3 mg to about 8 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); and from about 55 mg to 65 mg of an HPMC polymer.

[00134] In some embodiments, the dosage form that may be used in a method described in this document may be an oral dosage form (e.g., particulate) comprising from about 3% by weight to about 8% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); and from about 53% to about 64% by weight of an HPMC polymer.

[00135] In other embodiments, a dosage form that may be used in a method described in this document may be an oral composition (e.g., particulate) comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); and a modified-release polymer (e.g., a controlled-release polymer, for example, an HPMC polymer as a hydrophilic matrix polymer).

[00136] In some embodiments, the composition comprises from about 0.9% by weight to about 40% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 14% by weight to about 25% Petition 870250100953, dated 04 / 11 / 2025, p. 54 / 143 49 / 105 by weight of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 19% by weight to about 20% by weight of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 21% by weight to about 22% by weight of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 4% by weight to about 15% by weight of compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 4% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)).In some embodiments, the composition comprises from about 4% by weight to about 5% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 5% by weight to about 6% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 9% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)).

[00137] In some embodiments, the composition comprises from about 1 mg to about 120 mg (for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 Petition 870250100953, dated 04 / 11 / 2025, p. 55 / 143 50 / 105 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg or approximately 120 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)). In certain embodiments, the composition comprises from approximately 4 mg to approximately 6 mg (for example, approximately 5 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)). In other embodiments, the composition comprises from about 15 mg to about 25 mg (for example, about 20 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)).In certain embodiments, the composition comprises from about 25 mg to about 35 mg (e.g., about 30 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In other embodiments, the composition comprises from about 35 mg to about 45 mg (e.g., about 40 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In certain embodiments, the composition comprises from about 45 mg to about 55 mg (e.g., about 50 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)). In some embodiments, the composition comprises from about 55 mg to about 65 mg (e.g., about 60 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)).In other embodiments, the composition comprises from about 65 mg to about 75 mg (for example, about 70 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, about 70 mg). Petition 870250100953, dated 04 / 11 / 2025, p. 56 / 143 51 / 105 example, the compound of formula (II)). In certain embodiments, the composition comprises from about 75 mg to about 85 mg (for example, about 80 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)). In certain embodiments, the composition comprises from about 85 mg to about 95 mg (for example, about 90 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)). In some embodiments, the composition comprises from about 95 mg to about 105 mg (for example, about 100 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, compound of formula (II)). In other embodiments, the composition comprises from about 105 mg to about 115 mg (for example, about 110 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)).In certain embodiments, the composition comprises from about 115 mg to about 125 mg (for example, about 120 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)).

[00138] In some embodiments, the composition comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In other embodiments, the composition comprises from about 15 mg to 40 mg (for example, from about 15 mg to about 25 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 40 mg) of microcrystalline cellulose. In some embodiments, the composition comprises from about 15% to about 35% by weight (for example, from about 15% to about 20%, from about 20% to about 25%, from 25% to about 30%, from 30% to about 35% by weight) of microcrystalline cellulose. Petition 870250100953, dated 04 / 11 / 2025, p. 57 / 143 52 / 105

[00139] In some embodiments, the composition comprises from about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the composition comprises from about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the composition further comprises a slider. In some embodiments, the slider comprises colloidal silicon dioxide. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the composition further comprises a coating. In some embodiments, the compound of formula (I) or (II), including, for example, the compound of Form C or Form B, is stable within the formulation at about 25 °C at 60% relative humidity for at least 24 months. In some embodiments, the compound is stable at about 25 °C at 60% relative humidity for at least 36 months.In some embodiments, the compound is stable at approximately 25°C and 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at approximately 25°C and 60% relative humidity for at least 60 months. In some embodiments, the compound is stable at approximately 40°C and 75% relative humidity for at least 6 months.

[00140] In other embodiments of the oral dosage forms or compositions described in this document, the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)) is a crystalline form. In certain embodiments, the crystalline form is a crystalline form as described in this document, such as Crystalline Form C or Crystalline Form B. In other embodiments, the crystalline form is Crystalline Form D. In certain embodiments, the crystalline form is a crystalline form described previously or contemporaneously as Crystalline Standard B, Crystalline Standard C, or Crystalline Standard D. Petition 870250100953, dated 04 / 11 / 2025, page 58 / 143 Crystalline Pattern B and Crystalline Pattern C are described, for example, in WO 2021 / 007487, the entire content of which is incorporated herein by reference. Crystalline Pattern D is characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one peak at the diffraction angle (2θ) selected from the group consisting of a peak at approximately 12.0°; a peak at approximately 15.6°; a peak at approximately 16.7°; a peak at approximately 19.8°; a peak at approximately 21.2°; a peak at approximately 24.1°; a peak at approximately 25.2°; a peak at approximately 27.3°; and a peak at approximately 30.2°. Crystalline form of the compound with formula (II)

[00141] A crystalline form of the compound of formula (II) used in the method as described in this document may exhibit an X-ray powder diffraction pattern (XRPD) comprising at least one peak selected from the peaks at the following diffraction angles (2θ): 26.6±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2, 11.5±0.2, 23.9±0.2, 18.3±0.2, 19.2±0.2, 18.5±0.2 or 20.0±0.2. In certain embodiments, a crystalline form of the compound of formula (II) described in this document may exhibit an XRPD pattern comprising peaks at the following diffraction angles (2θ): 16.2±0.2, 17.4±0.2 and 26.6±0.2.

[00142] In some embodiments, the crystalline form exhibits an XRPD pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 22.6±0.2 and 26.6±0.2. In other embodiments, the crystalline form exhibits an XRPD pattern comprising peaks at the following diffraction angles (2θ): 11.5±0.2, 16.2±0.2, 17.4±0.2, 18.3±0.2, 18.5±0.2, 19.2±0.2, 20.0±0.2, 22.6±0.2, 23.9±0.2 and 26.6±0.2. In some modes, the XRPD pattern was obtained using Cu radiation. In certain modes, the Petition 870250100953, dated 04 / 11 / 2025, page 59 / 143 The 54 / 105 crystalline form has an onset melting point, as determined by differential scanning calorimetry, at approximately 226.6°C.

[00143] A crystalline form of the compound of formula (II) used in the method as described in this document may exhibit an XRPD pattern comprising at least one peak selected from the peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2 or 21.2±0.2. In certain embodiments, a crystalline form of the compound of formula (II) described in this document may exhibit an XRPD pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2 and 17.8±0.2.

[00144] In some embodiments, the crystalline form exhibits an XRPD pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2 and 20.5±0.2. In other embodiments, the crystalline form exhibits an XRPD pattern comprising peaks at the following diffraction angles (2θ): 21.9±0.2, 18.5±0.2, 17.8±0.2, 10.2±0.2, 20.5±0.2, 25.2±0.2, 16.9±0.2, 24.2±0.2, 28.6±0.2 and 21.2±0.2. In some embodiments, XRPD by the powder method was obtained using Cu radiation. In certain embodiments, the crystalline form has an onset melting point, as determined by differential scanning calorimetry, of approximately 97.9°C, 131.6°C, 223.7°C, 83.8°C, 128.9°C, 168.9°C, or 224.4°C. Immediate-release formulations

[00145] In some embodiments, a dosage form or composition that may be used in a method described in this document may be a dosage form or composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, the compound of formula (II)), wherein the compound of formula (I) or a salt Petition 870250100953, dated 04 / 11 / 2025, page 60 / 143 55 / 105 pharmaceutically acceptable of the same (for example, the compound of formula (II)) is released immediately after administration to the individual.

[00146] In other embodiments, a dosage form that may be used in a method described in this document may be an immediate-release oral capsule comprising from about 15 mg to about 20 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); from about 75 mg to 85 mg of diluent; from about 2 mg to 10 mg of binder; from about 1% to about 5% of disintegrant; and from about 0.1 mg to 5 mg of lubricant. Administrations

[00147] In some modalities, the dosage form is administered to the individual more than once a day (for example, twice a day, three times a day, or four times a day).

[00148] In some embodiments, the dosage form is administered to the individual once daily (e.g., one 20 mg tablet once daily, two 20 mg tablets (or one 40 mg tablet) once daily, or three 20 mg tablets (or one 60 mg tablet) once daily). In some embodiments, the dosage form is administered to the individual twice daily (e.g., one 10 mg tablet twice daily, one 20 mg tablet twice daily, two 20 mg tablets twice daily, three 20 mg tablets twice daily). In some embodiments, the dosage form is administered to the individual on alternate days, twice weekly, or once weekly. In certain embodiments, doses of approximately 1 mg to 60 mg, such as 20 mg to 40 mg, of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is administered to the individual daily. In other Petition 870250100953, dated 04 / 11 / 2025, p. 61 / 143 In 56 / 105 embodiments, approximately 15 mg to 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)) is administered to the individual daily. In certain embodiments, approximately 30 mg to 40 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., compound of formula (II)) is administered to the individual daily.

[00149] In some embodiments, the dosage form, after administration to the individual, has a reduced Cmax value compared to a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., modified release rate profile, a dosage form that does not have a modified release rate profile, e.g., an HPMC polymer). In some embodiments, the dosage form, after administration to the individual, has a higher tmax value than a reference oral dosage form (e.g., a dosage form with any intended release rate profile, e.g., modified release rate profile, a dosage form that does not have a modified release rate profile, e.g., an HPMC polymer). Tremor

[00150] The methods described in this document can be used to treat tremor, for example, a dosage or composition described in this document can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, or rubral tremor. Tremor includes hereditary, degenerative, and idiopathic disorders, such as Wilson's disease (hereditary), Parkinson's disease (degenerative), and essential tremor (idiopathic); metabolic diseases; peripheral neuropathies (associated with regional pain syndrome). Petition 870250100953, dated 04 / 11 / 2025, page 62 / 143 57 / 105 complex, Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced (tricyclic neuroleptics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be neuropathic tremor, and can be classified into physiological tremor, potentiated physiological tremor, essential tremor syndromes (including classic essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, drug-induced tremor, and psychogenic tremor. Tremor can be familial tremor.

[00151] Tremor is a rhythmic and involuntary oscillation of one or more parts of the body (for example, hands, arms, eyes, face, head, vocal cords, trunk and / or legs).

[00152] Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after an intentional movement. Cerebellar tremor is caused by lesions or damage to the cerebellum or pathways resulting, for example, from a tumor, stroke, or other focal lesion disease (e.g., multiple sclerosis) or a neurodegenerative disease.

[00153] Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful and abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremors occur irregularly and can often be relieved by complete rest or certain sensory maneuvers.

[00154] Essential tremor or benign essential tremor is the most common type. Petition 870250100953, dated 04 / 11 / 2025, page 63 / 143 58 / 105 common tremor. Essential tremor can be mild and non-progressive in some, or it can be slowly progressive, starting on one side of the body but usually affecting both sides. Essential tremor can also be moderate or severe. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of the tremor may decrease as a person ages, but alternatively, the severity may increase. High emotion, stress, fever, other illnesses, physical exhaustion, or low blood sugar can trigger tremors and / or increase their severity. Symptoms usually evolve over time and may be noticeable and persistent after onset.

[00155] Orthostatic tremor is characterized by rapid rhythmic muscle contractions (e.g., greater than 12 Hz) that occur in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs, and the patient may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[00156] Parkinson's tremor is caused by damage to the structures within the brain that control movement. Parkinson's tremor is typically seen as a pill-rolling action of the hands that can also affect the chin, lips, legs, and trunk. The onset of Parkinsonian tremor typically begins after age 60. The movement starts in one limb or on one side of the body and may progress to include the other side.

[00157] Rubral tremor is characterized by a coarse, slow tremor that may be present at rest, in posture, and with intention. The tremor is associated with conditions affecting the red nucleus in the midbrain, such as a stroke.

[00158] In some modes, the tremor is selected from Petition 870250100953, dated 04 / 11 / 2025, page 64 / 143 59 / 105 essential tremor, Parkinson's tremor, or cerebellar tremor. In one modality, the tremor is essential tremor. In several modalities, essential tremor is with or without intentional tremor. In one modality, essential tremor does not have intentional tremor.

[00159] The efficacy of the compound or composition described in this document for treating essential tremor can be measured by the methods described in the technique, such as the methods described in the following references: Ferreira, JJ et al., MDS Evidence-Based Review of Treatments for Essential Tremor, Mov. Disord. July 2019; 34(7):950-958; Elble, R. et al., Task Force Report: Scales for Screening and Evaluating Tremor, Mov. Disord. November 2013; 28(13):1793-800; Deuschl G. et al., Treatment of patients with essential tremor, Lancet Neurol. 2011; 10:148-61; and Reich SG et al., Essential Tremor, Med. Clin. N. Am. 2019; 103:351-356. The disclosures of the references are incorporated herein in their entirety.

[00160] In some modalities, the methods described in this document result in at least a 25% reduction in upper limb tremor score, where the tremor score can be converted to amplitude, compared to an initial assessment. For example, in certain modalities, the methods described in this document result in approximately a 40% average reduction in tremor amplitude, as measured by the upper limb score of the Essential Tremor Rating Assessment Scale (TETRAS), described, for example, in Elble, RJ, The Essential Tremor Rating Assessment Scale, J. Neurol. Neuromed. 2016; 1(4):34-38. In some modalities, the methods described in this document result in at least a 25% reduction in the TETRAS performance score compared to the initial assessment. In some modalities, the methods described in this document result in at least a 35% reduction in the TETRAS performance score compared to the initial assessment. Petition 870250100953, dated 04 / 11 / 2025, page 65 / 143 60 / 105 average reduction in symptom severity compared to baseline assessment, as measured by the TETRAS performance score. Combined Therapy

[00161] In the context of the present invention, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered in combination with one or more other agents or therapies. For example, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered to an individual in combination with one or more medications for tremor. Exemplary tremor medications that may be administered in combination with the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the context of the present invention include propranolol, primidone, ^οηθ, diΘ, lofô, alprazolam, gabapentin, topiramate, topamax, neurontina, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, ^ηΘ, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide. In one embodiment, the tremor medication is propranolol. In another embodiment, the tremor medication is primidone.

[00162] In one embodiment, tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, chlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide. EXAMPLES

[00163] In order for the modalities described in this document to be more fully understood, the following examples are Petition 870250100953, dated 04 / 11 / 2025, p. 66 / 143 61 / 105 established. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting their scope. Example 1: Phase 2 Trial to Evaluate the Efficacy of the Compound of Formula (I) in the Treatment of Adults with Essential Tremor

[00164] This trial is a Phase 2 trial to evaluate the efficacy and safety / tolerability of titration of Compound 1 to 60 mg or 100 mg compared with placebo in participants with moderate to severe ET. ET severity in this study was defined by the eligibility criteria in items 6 and 7 of the TETRAS-ADL, CGI-S, and TETRAS-PS. This dose-range determination study is comprised of three parts. The first part was randomized, double-blind (DB), and placebo-controlled; the second part was an optional extension consisting of an initial DB extension period followed by an open-label extension (OL) period. Additionally, there was also a third part available to those completing the Day 99 visit, which consisted of a blinded crossover period (referred to as the crossover period) after re-randomization for 6 weeks, after which all participants would receive the open-label formula (I).In part one of the study, eligible participants were randomized to 1 of 2 dose levels of Compound 1 (60 mg or 100 mg) or to placebo. The primary objective of this study was to evaluate the efficacy of Compound 1 compared with placebo after 56 days (end of the randomized, DB, placebo-controlled portion) of dosing in participants with ET with moderate to severe tremor using modified ADL as the primary efficacy endpoint. Secondary and exploratory objectives include additional efficacy assessments, an evaluation of safety and tolerability, and determination of plasma concentrations of formula (I) and its. Petition 870250100953, dated 04 / 11 / 2025, page 67 / 143 62 / 105 metabolites. The phase 2 assay design is illustrated in Figure 1. Objective Primary Outcomes • To evaluate the efficacy of Compound 1 compared to placebo in participants with ET • Change from baseline assessment to Day 56 in modified ADL Secondary Efficacy • To further evaluate the efficacy of Compound 1 compared to placebo in participants with ET • Change from baseline assessment to Day 56 in clinical global molding severity (CGI-S) • Clinical Global Impression of Improvement (CGI-I) scores on Day 56 • Change from baseline assessment to Day 56 in the following: o TETRAS-ADL score o Total TETRAS Performance Subscale (PS) score o TETRAS Upper Limb (UL) score (TETRASPS item 4) o Combined TETRAS Upper Limb (CUL) score (sum of TETRAS-PS items 4, 6, 7, and 8) • Patient Global Impression of Change (PGI-C) scores on Day 56 • Change of the initial assessment to the 14th,28 and 42 in the following: the modified ADL, the CGI-S, the total TETRAS-ADL score, the TETRAS-UL score, the TETRAS-CUL score, and the CGI-I and PGI-C scores on Days 14, 28, and 42. Petition 870250100953, dated 04 / 11 / 2025, page 68 / 143 63 / 105 Objective Outcomes • Change from baseline assessment to Day 42 in the total TETRA-PS score Safety • To assess the safety and tolerability of Compound 1 (both in the DB and extension portions of the study) compared to placebo (in the DB portion of the study) in participants with ET • Incidence and severity of adverse events, including discontinuation of the study medication due to adverse events • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in electrocardiogram (ECG) parameters • Incidence of suicidal ideation or behavior as measured by the Columbia Suicide Risk Assessment Scale (C-SSRS) Exploratory Efficacy • To assess the efficacy of Compound 1 in participants with ET in the extension portion of the study • Change from baseline assessment to Days 70, 84, 99, 129, 159, 189, 279,369 and 459 following: Modified ADL, CGI-S, Total TETRASADL score, Total TETRAS-PS score, TETRAS-UL score, TETRAS-CUL score • CGI-I and PGI-C scores on Days 70, 84, 99, 129, 159, 189, 279, 369, and 459 • Assess the efficacy of the compound in participants with ET in the crossover part of the study • Change of rerandomization visit to 7, 14, 21, 28, 35, and 42 days after rerandomization in: TETRAS ADL response status, Petition 870250100953, dated 04 / 11 / 2025, page 69 / 143 64 / 105 Objective Outcomes • TETRA ADL PK • To determine plasma concentrations of Compound 1 and its metabolites in participants with ET • Plasma concentrations of Compound 1 and metabolites over time

[00165] Participants who continued to meet all clinical trial entry criteria on Day 1 were randomized to receive DB treatment with Compound 1 or placebo every morning (QAM) from Day 1 to Day 56. Participants were randomized to 1 of 2 fixed-dose regimens or placebo in a 1:1:1 ratio. No dose adjustments were allowed. Table 1 Administration sequence by regimen for the double-blind portion of the study Dosage Sequence - Double-blind Part of the Study Days with 5 mg dose Days with 10 mg dose Days with 20 mg dose Days with 40 mg dose Days with 60 mg dose Days with 80 mg dose Days with 100 mg dose Regimen 1 (active drug) 7 7 7 7 7 7 14 Regimen 2 (active drug) 7 7 7 7 28 - - Placebo Dosed with placebo every day during the Intervention Period (56 days) Table 2 Dosing sequence by regimen for the initial double-blind extension portion of the study. Petition 870250100953, dated 04 / 11 / 2025, page 70 / 143 65 / 105 Treatment assignment in the double-blind part of the study. Dose administration sequence - Initial extension part of the DB study. Days with 5 mg dose. Days with 10 mg dose. Days with 20 mg dose. Days with 40 mg dose. Days with 60 mg dose. Days with 80 mg dose. Days with 100 mg dose. Regimen 1 Compound 1 100 mg - - - - - - 43. Regimen 2 Compound 1 60 mg - - - - - 7 36. Placebo 7 7 7 7 7 7 1 DB = double-blind; OL = open character. Table 3 Dosage sequence by regimen for the cross-period Dosage Sequence Regimen - Crossover Period Period 1 (3 weeks) Period 2 (3 weeks) Days with 20 mg dose Days with 40 mg dose Days with 60 mg dose Days with 20 mg dose Days with 40 mg dose Days with 60 mg dose Active drug Maintain OL extension dose before rerandomization Placebo1 Assigned to placebo Placebo1 3 4 14 1. Participants will be assessed every 7 days. If a participant receiving placebo meets the criteria to restart the medication, the participant will be restarted with a dose regimen of 20 mg for 3 days, 40 mg for 4 days, and 60 mg for the remainder of the period. If a participant receiving placebo in Period 1 restarts the active medication, the dose will be 60 mg for the 3 weeks in Period 2. In Period 2, if the participant receiving placebo does not restart the medication before the end of the period, they will undergo dose titration in the open-label extension. Petition 870250100953, dated 04 / 11 / 2025, page 71 / 143 66 / 105

[00166] During the Intervention Period (Day 1 to Day 56), participants who chose to discontinue dosing or were required to discontinue dosing entered the Safety Follow-up Period. All participants were asked to return to the clinic for the safety follow-up visit 14 days after their last dose of the study medication, except those who opted to enroll in the optional extension portion of the study (see below).

[00167] On Day 1, participants received 6 tablets of the study drug QAM and TETRAS-PS, TETRAS-ADL and CGI-S were performed prior to dose administration. Additional assessments performed prior to dosing included pharmacokinetic (PK) sampling.

[00168] Participants continued taking 6 tablets of the QAM study drug during the DB portion of the study.

[00169] On days 14, 28, 42, and 56, participants returned to the clinic for pharmacokinetic, dosage, efficacy, and safety sample collection. The primary efficacy assessments at these visits included TETRAS-PS, TETRAS ADL, CGI-S, CGI-I, and PGI-C.

[00170] On Days 7, 21, 35, and 54, participants received a phone call from the on-site team to inquire about adverse events and changes in concomitant medications.

[00171] After completion of the DB portion of the study, participants could choose to enter the extension portion of the study. Participants who chose to enter the extension began receiving the study drug OL for up to 12 months, or the start of the crossover period, after an initial 43-day DB extension period, whichever occurred first. During this initial DB extension period, participants who received placebo or 60 mg in the DB portion of the study Petition 870250100953, dated 04 / 11 / 2025, page 72 / 143 67 / 105 titrated up to 100 mg of the DB form using the same dose titration regimen as in the DB portion of the study. Participants who received 100 mg in the DB portion of the study continued to receive 100 mg blinded until all participants were receiving 100 mg of Compound 1 QAM from Day 99. Participants who were unable to tolerate fixed-dose titration to 100 mg during the initial DB extension period were discontinued from the study and asked to attend the safety follow-up visit / EOS-E. After the Initial DB Extension Period, participants received flexible doses of Compound 1 (20-100 mg) QAM at the Investigator's discretion during the OL Extension Period until the start of the crossover period. Participants who consented to participate in the separate LTSS could terminate participation in the current study after completing the treatment termination visit and participate in the LTSS at any time during the OL extension period.

[00172] Participants who opted not to continue in the extension proceeded directly to the Day 57 to Day 70 safety follow-up period. The safety follow-up period lasted 14 days for participants in the DB portion of the study and lasted until 14 days after the last dose of Compound 1 for participants in the extension portion of the study. Participants who could not tolerate the titration dose of the initial DB extension period in the extension portion of the clinical study were discontinued from the clinical study so as not to compromise the blinded nature of this initial DB extension period and completed a safety follow-up visit.

[00173] Compound 1 was supplied as 5 mg and 20 mg modified-release tablets. A matching placebo was also provided. Compound 1 was administered orally via QAM with or Petition 870250100953, dated 04 / 11 / 2025, page 73 / 143 68 / 105 without food and provided in pre-packaged containers to participants. During the DB portion of the study and the initial blinded extension period, participants receiving Compound 1 received 6 tablets (a combination of Compound 1 and corresponding placebo tablets, depending on the assigned dose level). Participants in the placebo group received 6 corresponding placebo tablets. At the Day 1 / initial assessment study visit, the study medication was dispensed from Interactive Response Technology (IRT), and the in-clinic dose was taken from Day 1 of Kit A at the visit. At subsequent study visits, the in-clinic dose was the last dose withdrawn from Wallet B card dispensed at the previous study visit.

[00174] Compound 1 (20 mg potency) was provided to participants in OL bottles at the Day 99 clinical visit so that open-label dosing could begin the following day (Day 100) to initiate the open-label extension period. The tablet quantity varied depending on the dose level and formulation used.

[00175] At the rerandomization visit for the crossover period and every 7 days in this part of the study, the treatment regimen was assigned by the IRT and dispensed by the center pharmacist for direct participant delivery (DTP). In the crossover period of the study, all participants were centrally assigned to randomization to remain on the current Compound 1 or placebo regimen using an IRT. After 3 weeks, participants who received placebo were switched to Compound 1 following the regimen described in Table 3. The treatment regimen assigned by the IRT was based on Tetras ADL response criteria after day 7.

[00176] In the DB portion of the study, eligible participants were randomized to receive 1 of 2 dosage regimens of the Compound. Petition 870250100953, dated 04 / 11 / 2025, page 74 / 143 69 / 105 (60 mg or 100 mg) or placebo, administered orally via QAM. Fixed titration regimens were used (Table 1). Participants were not allowed to adjust the number of tablets per day.

[00177] All participants who continued into the extension portion of the study participated in an initial 43-day DB extension period so that all participants could be titrated to the 100 mg dose in a blinded manner (Table 2) before receiving open-label, flexible doses of Compound 1 (20-100 mg) for up to 12 months (Days 100-459) during the OL extension period.

[00178] Selected items from TETRAS-ADL and TETRAS-PS (or TETRAS-CUL, as appropriate) were scored in a modified manner and combined to create a modified total TETRAS score. Items 1-11 in the TETRAS ADL subscale and items 6 and 7 from TETRAS-PS were used, with scoring adjusted so that response options 0 and 1 were combined into a single response of 0 = Normal. Additionally, scores 2, 3, and 4 were adjusted to 1, 2, and 3, respectively. The modified total TETRAS score was the sum of these adjusted TETRAS-ADL and TETRAS-PS items, with a possible range of 0 to 42, where higher values ​​represent a greater direct impact of tremor on activities of daily living. The items included in the modified total TETRAS score are illustrated in Figure 2. Results

[00179] Compound 1 was well tolerated in the study, with no new safety findings. Most adverse events were of mild to moderate severity, consistent with previous findings. There was a higher proportion of individuals who discontinued in the Compound 1 group at 17% versus in the placebo group at 11%. Figure 3 is a diagram showing patient readiness for the clinical study. Figure 4 is a table showing demographic data and characteristics. Petition 870250100953, dated 04 / 11 / 2025, page 75 / 143 70 / 105 of the patient's initial assessment (mITT). Figure 5 is a table showing the TEASs experienced by patients in the clinical study. Figure 6 is a table showing the TEAEs and the dose at the onset of the event. Figure 7 is a table showing discontinuations of Compound 1 in the mITT patient population.

[00180] The primary efficacy measure in this clinical study was the change from baseline in mADL at day 56. The effect of ulixacaltamide on individual mADL items was determined by calculating the placebo-adjusted fold change at Day 56 in mADL for individual mADL items. Secondary efficacy measures included change in Clinical Global Impression - Severity (CGI-S) score, Patient Global Impression - Change (PGI-C) score, total TETRA-ADL score, TETRA-UL score, TETRA-CUL score, and TETRA-PS score.

[00181] Figure 8 is a bar graph showing the change in mADL and ADL scores for the mITT population treated with Compound 1 (ulixacaltamide) and placebo. As shown in Figure 8, Compound 1 demonstrated a numerical difference vs. placebo in mADL with a mean difference of 1.57 systolic pressure (p = 0.126). Participants treated with Compound 1 demonstrated a mean improvement from baseline in ADL scores, with a mean reduction of 3.6 points compared to baseline (n=78) and clinically and statistically different from the placebo group (n=38) (p = 0.026) on day 56. Modified ADL scores in participants treated with Compound 1 (mean decrease of 2.69 points, n=78) also showed improvement compared to placebo (mean decrease of 0.88 points, n=38). For the secondary outcome, the change in the TETRA-ADL, nominal statistical significance was achieved with a [mean difference of LS 2.53 ep = 0.026]. Petition 870250100953, dated 04 / 11 / 2025, page 76 / 143 71 / 105

[00182] Figure 9 is a bar graph showing the change in mADL score on day 56 for patients who took ulixacaltamide (Compound 1) or placebo. Figure 9 indicates that more patients taking ulixacaltamide showed improvements in mADL scores compared to patients taking placebo.

[00183] Figure 10 is a diagram showing the observed change in scores for individual items that were assessed as part of the mADL and ADL assessment compared to baseline. Figure 11 is a bar graph showing the placebo-adjusted fold change at day 56 for individual items that were assessed as part of the mADL assessment. As shown in Figures 10 and 11, patients showed improvements in nearly all components of the ADL assessment, but showed little or no improvement in the additional components that were added to the mADL assessment. Ulixacaltamide demonstrated a consistent effect compared to placebo for 8 of 11 ADL-Scoring Items. For the TETRA PS, dominant handwriting, and left- and right-hand spirals items, patients treated with ulixacaltamide demonstrated less improvement than those who received placebo.

[00184] Figure 12 shows graphs illustrating patient status in the mITT population as measured using the PGI-C and CGI-S scales. As shown in Figure 12, patients and investigators reported greater overall improvement in status with Compound 1 compared with placebo using the PGI-C scale (47% improved) and the CGI-S scale (42% improved). Statistically significant nominal improvements were observed on both PGI-C and CGI-S scales.

[00185] To assess the correlations between different outcomes in Petition 870250100953, dated 04 / 11 / 2025, page 77 / 143 In the 72 / 105 study, Pearson correlations were calculated for the change from baseline in ADL and PS scores, as well as other measures. The change from baseline in total scores for participants in the placebo group was used to calculate r values ​​for the five assessments shown. Figure 13 is a diagram showing the results of the Pearson correlation assessment for the change from baseline in ADL and PS scores and other measures. The results shown in Figure 13 are consistent with the pattern of clinical discordance between ADL and PS assessments. ADL showed no correlation with item 4 of PS nor with total PS. Interestingly, ADL shows a higher correlation with patient-reported status than PS assessments, while PS assessments show a higher correlation with physician-reported status than ADL.

[00186] Figure 14 is a bar graph showing the change in mADL score on day 56 for each patient who took ulixacaltamide or placebo, when PS items (spirals - left and right and handwriting) are excluded from the assessment. Data from Figure 8 are also included in Figure 14 for comparison. As shown in Figure 14, in a post hoc analysis, when excluding the PS items from mADL, ulixacaltamide demonstrated a nominal and statistically significant improvement compared to placebo on Day 56 (mITT) [mean difference of LS 1.81 ep = 0.042].

[00187] In the post-hoc analysis of responders using the minimum clinically important difference distribution method, for the mITT population, patients who received ulixacaltamide were determined to have higher response rates compared to patients who received placebo for mADL and mADL excluding PS items. Considering an SD threshold of 0.5, more than 50% of participants treated with ulixacaltamide had a Petition 870250100953, dated 04 / 11 / 2025, page 78 / 143 73 / 105 improvement of at least 2 points in their total score. When using a more stringent threshold of 1 SD, approximately 40% of participants treated with ulixacaltamide have an improvement of at least 4 points in their total score.

[00188] Figure 15 is a graph showing the change in mADL scores and mADL excluding PS scores (mADL11) at each scored time point. Figure 15 shows improvement in mADL scores and mADL excluding PS scores (mADL11) for ulixacaltamide vs. placebo after day 14.

[00189] Figure 16 is a graph and a table showing the outcome analysis for the mITT population.

[00190] Figure 17 is a bar graph showing the results of the post-hoc respondent analysis using the MCID Distribution Method in the mITT population. The results shown in Figure 17 demonstrate that patients taking ulixacaltamide had higher response rates compared to patients taking placebo, as assessed by mADL score and mADL item score excluding PS.

[00191] Patients who participated in the clinical study included those with intention tremor. The effect of ulixacaltamide in the population of patients without intention tremor was analyzed. Figure 18 is a bar graph showing mADL scores and mADL scores excluding PS in the mITT population, excluding patients with intention tremor. Figure 19 is a diagram showing the observed change in scores for individual items that are assessed as part of the mADL assessment compared to baseline in patients without intention tremor. Figures 18 and 19 demonstrate that there is a greater improvement in mADL-scored items compared to baseline in patients with ET who do not have intention tremor. Petition 870250100953, dated 04 / 11 / 2025, page 79 / 143 74 / 105

[00192] Figure 20 is a bar graph showing the change in placebo-adjusted mADL scores, excluding PS, in mITT patients without intention tremor for the two dosing regimens tested (60 mg and 100 mg). Figure 20 demonstrates that there is a consistent effect observed in both dosing regimens tested in mITT patients without intention tremor.

[00193] Ulixacaltamide has also demonstrated benefit for patients using propranolol. Specifically, 48% of patients using propranolol and ulixacaltamide in this phase 2 trial achieved an improvement of at least 3 points in mADL11 compared to 25% for patients using propranolol and placebo.

[00194] For the first time, items 1-11 of the modified TETRA ADL (mADL11), excluding performance subscale (PS) items, have been identified as reliable and clinically significant measures of treatment effectiveness in ET. For example, distribution methods and anchor-based analysis confirmed that a significant score difference (MSD) of approximately two or more points in mADL11 is an indicator of effective ET treatment for a patient. Example 2. Open-label extension of the phase 2 study.

[00195] After completion of the initial 8-week double-blind treatment phase of the Phase 2 study described in Example 1, eligible patients had the option to continue their access to Compound 1 in an open-label extension (OLE) phase. Participants who continued in the open-label extension (OLE) phase remained blinded for an initial six-week phase.

[00196] In the extension portion of the study, effectiveness measures include analysis of the change from the initial assessment to Day 70, Petition 870250100953, dated 04 / 11 / 2025, page 80 / 143 75 / 105 84, 99, 129, 159, 189, 279, 369 and 459 in modified ADL, CGI-S, total TETRAS-ADL score, total TETRAS-PS score, total TETRAS UL score, TETRAS CUL score and CGI-I and PGI-C scores on Days 70, 84, 99, 129, 159, 189, 279, 369 and 459.

[00197] There was no change in overall safety results during 14 weeks of treatment with Compound 1.

[00198] A total of 65 patients who completed the double-blind portion of the phase 2 study described in Example 1 were eligible to participate in OLE and completed the week 14 assessment. Figure 21 is a bar graph showing the change in mADL11 scores from baseline, by study week from week 8 to week 14. Patients who were eligible and continued in Composite 1 (n=39) showed an additional mean improvement in mADL11 of 1.7 points from 3.09 at Week 8 (95% CI: 0.98, 5.2) to 4.81 (95% CI: 2.38, 7.23) after 14 weeks of treatment. Patients who switched from placebo to Compound 1 treatment during the initial 6-week OLE period (n=26) experienced a mean improvement in mADL11 of 3.15 points from 1.21 at Week 8 (95% CI: -1.04, 3.46) to 4.36 (95% CI: 1.68, 7.05). Randomized withdrawal substudy

[00199] The open-label protocol was modified to better evaluate the criteria to be used in the next randomized withdrawal study in Phase 3 (as described in Example 3). In this study, patients were re-randomized in a blinded manner to receive placebo or continue to receive Compound 1. Twenty-one patients who completed assessments at week 14 of the open-label extension were eligible to participate in the blinded study.

[00200] Patients were assessed weekly for a total of 6 weeks, with 11 patients assigned to Composite 1 and 10 Petition 870250100953, dated 04 / 11 / 2025, page 81 / 143 76 / 105 patients were assigned to placebo during the initial 3-week period, crossing over to placebo or Compound 1 for an additional 3-week period. Blinded rescue was triggered for patients using placebo if the loss in mADL11 exceeded 2 points at any timepoint.

[00201] Patients who switched from Compound 1 to placebo experienced a mean weekly loss of effect in their mADL11 of 47% (mean loss of effect of -1.15 points / week), compared to a 6% improvement in mean overall change per week (mean improvement of 0.16 points / week) for periods receiving Compound 1. Additionally, 10 patients assigned to placebo met the rescue criteria to restart Compound 1.

[00202] 85% of patients who received Compound 1 (17 of 20% and 52% who received placebo maintained their mADL11 within 3 points compared to baseline, confirming the definition of patient stability to be used in the Phase 3 program. No new safety signals emerged and there was no change in the overall safety outcomes observed in the 8-week double-blind treatment phase.

[00203] The subgroup results corroborated a number of design elements proposed for the next Phase 3 randomized withdrawal study, including response criteria and feasibility of rescuing patients with Composite 1. Example 3. Phase 3 Study to Evaluate the Efficacy of the Compound in Formula (1) in the Treatment of Adults with Essential Tremor Overview

[00204] This Phase 3 study is a three-part, randomized, double-blind, placebo-controlled, fixed-dose (after titration) study that will compare the efficacy and safety of Compound 1 with Petition 870250100953, dated 04 / 11 / 2025, page 82 / 143 77 / 105 placebo in participants aged 18 to 80 years who have a diagnosis of ET. The primary objective of the parallel design (PD) of Study 1 is to evaluate the change from baseline in mADL11 score for Compound 1 compared with placebo after 12 weeks (84 days) of treatment. The primary objective of the randomized withdrawal (RW) of Study 2 is to evaluate maintenance of response by measuring the proportion of participants who maintain a response after RW. Other efficacy assessments in Studies 1 and 2 include clinical-severity global molding (CGI-S), patient-severity global molding (PGI-S), patient-severity global molding change (PGI-C), and Archimedes spiral design. The primary objective of the long-term safety Study 3 (LTSS) is to evaluate the long-term safety of up to approximately 1 year of treatment with Compound 1. The safety and tolerability of Compound 1 will be evaluated in all 3 studies.

[00205] This is a decentralized phase 3 clinical trial using a combination of home visits and telehealth, consisting of 3 concurrent studies including a randomized, placebo-controlled PD study, a DB RW study, and an LTSS study. The studies in this trial are designed to evaluate the efficacy and / or safety of Compound 1 in participants aged 18–80 years who have a diagnosis of ET and have had symptoms for at least 3 years. Participants in the PD of Study 1 and RW of Study 2 will be informed about all 3 studies and must agree during informed consent that, if deemed eligible, they will be assigned to the PD of Study 1 or RW of Study 2 and transferred to the LTSS of Study 3. A specific informed consent form (ICF) will be used for phase 2 OLE participants who are transferred to the LTSS of Study 3. Petition 870250100953, dated 04 / 11 / 2025, page 83 / 143 78 / 105 • In Study 1 PD, participants will receive 12 weeks (84 days) of Compound 1 or a matching placebo in a DB fashion. • In the Study 2 RW, participants will receive 8 weeks (56 days) of Compound 1 in a DB manner before entering a 4-week DB RW period, where responders will undergo RW and non-responders will continue treatment with Compound 1. Responsive participants in the RW period who subsequently meet the predefined relapse criteria will be transferred to the Study 3 LTSS with blinded dose titration, as described in Table 6. • In Study 3, LTSS participants will receive up to a total of approximately 1 year of Compound 1, which includes any prior study dose administration.

[00206] Compound 1 will be titrated to 60 mg over a 2-week period (Table 8). Following the initial assessment visit, participants will administer Compound 1 or placebo every morning (QAM) at home before their scheduled home health or telehealth visits, as applicable. Dose adjustments will not be permitted. Participants who complete the Study 1 PD or Study 2 RW (complete all assessments by Day 84), meet the predefined relapse criteria in the Study 2 RW, or complete a Phase 2 EOT visit may be transferred to the Study 3 LTSS, with Day 84 assessments transferred from their respective studies.

[00207] The duration of Studies 1 PD and 2 RW may be up to 18 weeks, including the screening period (Table 4) and the treatment and safety follow-up (SFU) periods (Table 5 and Table 6). The duration of the LTSS will be up to approximately 1 year (Table 7).

[00208] Figure 22 is a diagram showing the design of Petition 870250100953, dated 04 / 11 / 2025, page 84 / 143 79 / 105 phase 3 study. Table 4 Central studies: screening period Study Period Description Screening period: 4 weeks with weekly visits, as described below: • Home health visit: Day -21 • Telehealth visits: Day -28, Day -21, Day -14 and Day -7 Table 5 Study 1 PD: Intervention and safety follow-up periods Study Period Description Baseline Visit Day 1: Home health visit and telehealth visit Treatment Period Duration of 12 weeks • Titration period: 2 weeks o Week 1 (Days 1 to 7) 20 mg of QAM or placebo o Week 2 (Days 8 to 14) 40 mg of QAM or placebo • Maintenance period: 10 weeks o Week 3 to Week 12 (Days 15 to 84) 60 mg of QAM or placebo Safety follow-up period 2 weeks (14 days) after the last dose of the study medication for those who complete the study and choose not to participate in the LTSS of Study 3 or discontinue treatment prematurely for any reason. Abbreviations: LTSS = Long-Term Safety Study; QAM = Every Morning. Petition 870250100953, dated 04 / 11 / 2025, page 85 / 143 80 / 105 Table 6 Study2 RW: Intervention and safety follow-up periods Study Period Description Baseline Visit Day 1: Home health visit and telehealth visit Intervention Period DB: Initial RW period Duration of 8 weeks • Titration Period: 2 weeks o Week 1 (Days 1 to 7) 20 mg QAM o Week 2 (Days 8 to 14) 40 mg QAM • Maintenance Period: 6 weeks o Week 3 to Week 8 (Days 15 to 56) 60 mg QAM Intervention Period DB: RW period Duration of 4 weeks • Compound 1 Randomized Respondent Cohort: Randomized 1:1 to continue treatment with Compound 1 at its current dose (60 mg) or transition to placebo. o Relapse Group: Transfer to the LTSS of Study 3 and maintain Compound 1 or initiate 2-week titration from placebo to 60 mg.• Non-Randomized Cohort: Remain in Compound 1 60 mg Safety follow-up period 2 weeks (14 days) after the last dose of the study medication for those who complete the study and choose not to participate in the LTSS of Study 3 or discontinue treatment prematurely for any reason. Abbreviations: DB = double-blind; LTSS = long-term safety study; QAM = every morning; RW = random withdrawal. Petition 870250100953, dated 04 / 11 / 2025, page 86 / 143 81 / 105 Table 7 Study 3 LTSS: Intervention and safety follow-up periods Study Period Description Initial LTSS Assessment Day 84: Telehealth visit for Phase 2 OLE participants, following informed consent and investigator review of the most recent OLE safety assessments. Study 1 and 2 participants who are transferred to the LTSS will enter Day 84a. Intervention Period: Up to approximately 1 year in duration, with DB administration of Compound 1 until Week 14. • Blinded titration period: 2 weeks o Days 84 to 90: 20 mg QAM (or maintain 60 mg) o Days 91 to 97: 40 mg QAM (or maintain 60 mg) • Maintenance period: 50 weeks o Day 99 to approximately 1 year: 60 mg QAM Safety follow-up period: 2 weeks (14 days) after the last dose of the study medication for those who complete the study and choose not to continue in the Study 3 LTSS or discontinue treatment prematurely for any reason. Abbreviations: DB = double-blind; set = end of treatment; LTSS = long-term safety study; OLE = open-label extension; PD = parallel design; QAM = every morning; RW = random withdrawal. For transferred participants, the Day 84 / EOT assessments should be transferred from the Study 1 PD or Study 2 RW as the initial LTSS assessment. bA blinded titration period will occur during the first two weeks of the LTSS study for participants transferred from Studies 1 and 2. During this blinded titration period, participants will either titrate from their placebo dose to 60 mg over a 2-week period or maintain their 60 mg dose.

[00209] Eligible participants will be randomized to receive oral Compound 1 or placebo QAM. Fixed-titration regimens will be used, as described in Table 8.

[00210] Dose adjustments will not be allowed. Petition 870250100953, dated 04 / 11 / 2025, page 87 / 143 82 / 105 Table 8. Sequence of dose administration during the intervention period by treatment group. Intervention Period Study Titration Maintenance Study 1 PD Week 1 (7 days) Week 2 (7 days) Week 3 to Week 12 (70 days) Study 2 RW Initial Period Random Withdrawal Week 3 to Week 8 (42 days) Week 9 to Week 12 (28 days) Study 3 LTSS Week 1 (7 days) b Week 2 (7 days) b Maintenance Week 3c up to 1 year Treatment Dose Compound 1 20 mg 40 mg 60 mg Placebo Matching Placebo Study Duration Study 1 PD 84 days Study 2 RW 84 days Study 3 LTSS Up to approximately 1 year LTSS = long-term safety study; OLE = open-label extension; PD = parallel design; RW = random withdrawal. In Study 2, after 6 weeks of maintenance dose administration, participants who meet the response criteria will receive either placebo or ulixacaltamide for several weeks. The remaining participants will continue receiving ulixacaltamide. (b) Only for participants who are not currently receiving ulixacaltamide (i.e., are receiving placebo in the PD of Study 1 or RW of Study 2 before entering the LTSS of Study 3). For participants transferred from the PD of Study 1 and RW of Study 2, dose administration throughout the first 2 weeks of the LTSS of the study will remain blinded. Participants entering the LTSS of Study 3 after completing the PD of Study 2 or RW of Study 2 will remain on a 60 mg dose or begin titration of ulixacaltamide to 60 mg, as defined in the schedule above. Participants entering the LTSS of Study 3 of PRAX-944-222 OLE will remain on 60 mg or titrate over a two-week period to 60 mg as follows: if their current dose is greater than 60 mg, they will reduce their dose directly to 60 mg, and if less than 60 mg, based on the titration schedule described above, with a dose increase every 7 days based on their dose (i.e., 20 or 40 mg).

[00211] The objectives and outcomes for PD in Study 1 are Petition 870250100953, dated 04 / 11 / 2025, page 88 / 143 83 / 105 described below (Table 9). Table 9 Objectives and outcomes for PD of Study 1 Objectives Primary Outcomes Efficacy • To evaluate the efficacy of Compound 1 compared to placebo in participants with ET • Change from baseline assessment to day 84 in mADL11 Secondary Outcomes Efficacy • To better assess the efficacy of Compound 1 compared to placebo in participants with ET over time • Proportion of participants who responded to ulixacaltamide, as defined by the change in mADL11 score after 12 weeks (84 days) of treatment • Change from baseline assessment to day 84 in: o TETRA-ADL o PGI-C o CGI-S o PGI-S • Proportion of participants who responded to ulixacaltamide, as defined by the change in mADL11 score after 14, 28, 56, and 70 days of treatment • Change from baseline assessment to day 14, day 28, day 56, and day 70 in: o mADL11 Tetras-ADL, PGI-C, CGI-S, PGI-S, Archimedes' Spiral of the Dominant Hands (Day 1, Day 56, Day 84) Safety Petition 870250100953, dated 04 / 11 / 2025, page 89 / 143 84 / 105 • To evaluate the safety of Compound 1 compared to placebo in participants with ET • Incidence and severity of adverse events, including discontinuation of the study medication due to adverse events • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in ECG parameters • The incidence of C-SSRS measured suicidal ideation or behavior • Changes in BDI-II and BAI Exploratory Clinical Pharmacology • To determine plasma concentrations of Compound 1 in participants with ET • Plasma concentrations of Compound 1 AE = Adverse Event; BAI = Beck Anxiety Index; BDI-II = Beck Depression Inventory - Second Edition; CGI-S = Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = Electrocardiogram; ET = Essential Tremor; mADL11 = Modified Tetras-ADL items 1 to 11 with modified scoring; PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; Tetras-ADL = Essential Tremor Rating Scale - Activities of Daily Living.

[00212] The objectives and outcomes for RW in Study 2 are described below (Table 10). Table 10 Objectives and outcomes for RW of Study 2 Objectives Primary Outcomes Efficacy • To assess the maintenance of response efficacy in Compound 1 in the RW portion of the study • The proportion of participants who maintain the response, as defined by the change in mADL11 score, after RW Secondary Outcomes Efficacy • To better assess efficacy • Change since baseline Petition 870250100953, dated 04 / 11 / 2025, pp. 90 / 143 85 / 105 Continuous Compound 1 throughout the initial RW time (Day 56) through Day 63, Day 70, Day 77, and Day 84 thereafter: mADL11, TETRA-ADL, PGI-C, CGI-S, PGI-S • Dominant-hand Archimedes spiral (Day 1, Day 56, Day 84) Safety • To assess the safety of Compound 1 in participants with ET • Incidence and severity of adverse events, including discontinuation of the study medication due to adverse events • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in ECG parameters • The incidence of C-SSRS measured suicidal ideation or behavior • Changes in BDI-II and BAI Exploratory Clinical Pharmacology • To determine plasma concentrations of Compound 1 in participants with ET • Plasma concentrations of Compound 1 AE = adverse event; BAI = Beck Anxiety Index; BDI-II = Beck Depression Inventory - Second Edition; CGI-S = Clinical Global Impression of Severity;CSSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; ET = essential tremor; mADL11 = modified TETRA-ADL items 1 to 11 with modified scoring; PGIC = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; RW = random withdrawal; TETRA-ADL = Essential Tremor Rating Scale - Activities of Daily Living. Petition 870250100953, dated 04 / 11 / 2025, pp. 91 / 143 86 / 105

[00213] The objectives and outcomes for the LTSS of Study 3 are described below (Table 11). Table 11 Objectives and outcomes for the LTSS of Study 3 Objective Primary Outcomes • To evaluate the long-term safety of Compound 1 in participants with ET • Incidence and severity of AEs • Changes in vital sign measurements • Changes in clinical laboratory results • Changes in ECG parameters • The incidence of C-SSRS measured suicidal ideation or behavior AE = adverse event; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; ET = essential tremor. Background and Rationale for the Clinical Trial

[00214] Compound 1 is a novel small molecule being developed for the treatment of essential tremor (ET) that is a selective, state-dependent, high-affinity inhibitor of T-type calcium ion channels (Ca2+). Composed of 3 isoforms (CaV3.1, CaV3.2, and CaV3.3), T-type Ca2+ channels are widely expressed throughout the brain, especially in the cerebellothalamo-cortical (CTC) circuit. Aberrant bursts in the CTC circuit occur at the same frequency as upper limb tremor in ET.

[00215] Tension is the most common adult movement disorder, affecting up to 2% of the United States (US) population, with an estimated actual prevalence of approximately 7 million Americans. Tension is characterized by postural and kinetic tremor of 6 to 12 Hz (i.e., tremor during voluntary movement) in the upper extremities. The most characteristic clinical feature is kinetic tremor of the arms and hands, but tremor may also occur in the head and voice as the disease progresses and, less commonly, Petition 870250100953, dated 04 / 11 / 2025, page 92 / 143 87 / 105 in the face, legs, and trunk. Emerging evidence corroborates the understanding that ET represents a heterogeneous syndrome and diagnosis requires further differentiation based on medical history and neurological examination.

[00216] ET has a significant impact on several dimensions of patients' daily functioning, especially writing, eating, and drinking. Functional disability has been reported in over 70% of patients with ET and has been associated with comorbid anxiety and depression.

[00217] Despite being one of the most common movement disorders, TS often remains undertreated or untreated, in part due to the limited number of treatments available. Propranolol and primidone are the medications most frequently used to treat TS. Pranolol is the only orally administered treatment approved by the FDA indicated for the treatment of TS. Pranolol was originally developed and approved for hypertension in 1967 and was approved for the treatment of TS in 1986 based on a 2-week clinical study that included only 9 patients and evaluated a limited dose range of 40 mg to 80 mg three times daily. As the scientific understanding of TS matured and clinical experience with propranolol was gained, propranolol emerged as an inadequate and poorly tolerated treatment, leaving a serious unmet medical need for patients with TS.Propranolol in the treatment of tetanus torticollis (TT) has limited efficacy with side effects (e.g., bradycardia) that frequently lead to discontinuation. The 2011 American Academy of Neurology TT treatment guideline states that not all patients improve with or tolerate primidone and propranolol. Our most recent data indicate that, for patients receiving pharmacotherapy, more than 40% discontinue all options. Petition 870250100953, dated 04 / 11 / 2025, pp. 93 / 143 88 / 105 pharmacological responses after 2 years of treatment. Thus, although there is at least one approved therapy, the medications currently available for ET do not meet the needs of most patients.

[00218] The results of the Phase 2 studies with ulixacaltamide (see Examples 1 and 2) corroborate the efficacy and safety of ulixacaltamide in patients with ET. The Phase 2 trials demonstrated reduced modified ADL scores (mADL) (i.e., reduced tremor symptoms) at daily doses ranging from 20 to 120 mg for up to 56 days. In the double-blind (DB) portion of the Phase 2 study, the rescored TETRA-ADL score of items 1-11 (mADL11) decreased more in participants randomized to Compound 1 compared with placebo after 56 days of dosing, with least squares mean scores (LSM standard error [SE]) of (2.69 [0.81]) compared with placebo (-0.87 [0.95]). The difference in LSM treatment (95% confidence interval [CI]) was -1.82 (95% CI: -3.565, -0.066; with a nominal p-value < 0.05). In the phase 2 extension period, 20 participants completed a 6-week blinded crossover period.Participants were randomized in a blinded manner to 3 weeks of Compound 1 60 mg or placebo. Rescue treatment (Compound 1) was offered to participants if their mADL11 worsened by a predefined threshold. During the crossover period, maintenance of response was observed in 17 of 20 participants who received Compound 1 compared with 11 of 21 participants who received placebo, with a chi-square p-value of 0.0249 and 0.0388 when adjusted for propranolol use, family history, and intention tremor (IT). None of the participants treated with Compound 1 and 9 of 21 participants treated with placebo qualified for and received rescue treatment within the 3-week period. No new participants. Petition 870250100953, dated 04 / 11 / 2025, pp. 94 / 143 89 / 105 safety signals were identified during this part of the study.

[00219] Throughout the clinical development program, Compound 1 was generally well tolerated after up to 129 days of daily administration at doses ranging from 5 to 120 mg, demonstrating a favorable safety profile following a titration schedule. No deaths or serious adverse events (SAEs) considered by the sponsor to be related to the study drug were reported following administration of Compound 1. Similarly, no suicide attempts or pregnancies were reported following administration of Compound 1.

[00220] This Phase 3 study is a three-part, randomized, DB, placebo-controlled, fixed-dose (after titration) study that will compare the efficacy and safety of Compound 1 with placebo in participants aged 18 to 80 years who have a diagnosis of ET. The primary objective of the parallel design (PD) of Study 1 is to assess the change from baseline in mADL11 score for Compound 1 compared with placebo after 12 weeks (84 days) of treatment. The primary objective of the randomized withdrawal (RW) of Study 2 is to assess maintenance of response by measuring the proportion of participants who maintain a response after RW. Other efficacy assessments in Studies 1 and 2 include Clinical Global Impressions-Severity (CGI-S), Patient Global Impression-Severity (PGI-S), Patient Global Impression-Change (PGI-C), and Archimedes spiral design.The primary objective of the Long-Term Safety Study 3 (LTSS) is to evaluate the long-term safety of up to approximately 1 year of treatment with Compound 1. The safety and tolerability of ulixacaltamide will be evaluated in all 3 studies. General Design

[00221] This trial is a decentralized, Phase 3 clinical trial, Petition 870250100953, dated 04 / 11 / 2025, page 95 / 143 90 / 105 of multiple studies, evaluating the safety and efficacy of Compound 1 in ET. The study includes two separate, concurrent pivotal phase 3 studies, with all participants undergoing a screening process. This concurrent study design promotes a more homogeneous study population and ensures blinded study assignment and treatment group allocation throughout the PD of Study 1 and RW of Study 2, an objective that could not be met if the RW of Study 2 were conducted in isolation.

[00222] The study consists of 3 simultaneous, decentralized studies, including 2 central DB placebo-controlled studies and one LTSS in participants with ET, as follows:

[00223] Study 1 PD: A 12-week, randomized, DB, placebo-controlled PD study to evaluate the change from baseline in mADL11 score for Compound 1 compared with placebo after 12 weeks (84 days) of treatment.

[00224] Study 2 RW: A 12-week, DB, placebo-controlled RW study to evaluate the efficacy and maintenance of response and durability of effect in participants responding to Compound 1 and safety.

[00225] Study 3 LTSS: An LTSS to evaluate the long-term safety of Compound 1 for up to approximately 1 year. The first 2 weeks of the LTSS will include a 2-week blinded titration period for participants who are transferred from Study 1 PD and Study 2 RW to maintain blinding for those studies. The remainder of the study will be open-label. Participants enrolled in the open-label extension (OLE) of Phase 2 may be transferred to the LTSS of Study 3 and will begin titration over a 2-week period to 60 mg or continue taking the 60 mg dose.

[00226] Both central studies include a screening period. Petition 870250100953, dated 04 / 11 / 2025, pp. 96 / 143 91 / 105 and all 3 studies have intervention and safety follow-up periods. There are two types of study visits: home health visits and telehealth visits. Home health visits will be conducted by a trained research nurse who travels to the participant's home. The investigator and / or research team will participate in home health visits remotely with audiovisual communication. The telehealth visit will be a remote visit by the investigator and / or research team. The investigator will supervise all visits. In addition to home health visits and telehealth, the study medication will be delivered directly to participants. Screening / initial assessment periods

[00227] The main screening assessments include medical history, demographics, previous and concomitant medications, physical and neurological examination, drug / alcohol screening, pregnancy screening, clinical laboratory assessments, electrocardiogram (ECG), vital signs, Columbia Suicide Severity Rating Scale (C-SSRS), and assessments of ET severity using the Essential Tremor Rating Scale - Activities of Daily Living (TETRAS-ADL).

[00228] The Screening Period for participants not exposed to Compound 1 will last 28 days. After all screening assessments are completed and a participant is deemed eligible for the study, randomization will occur between Day -7 and Day -3 to allow time for delivery of the assigned study medication to the participant's home.

[00229] Participants will complete the TETRAS-ADL assessment 3 times during screening (on Day -28, Day -14 and Day -7).

[00230] Phase 2 OLE participants will not need to complete this screening process, but the investigator must review the Petition 870250100953, dated 04 / 11 / 2025, p. 97 / 143 92 / 105 most recent safety assessments for these participants approximately 1 week prior to their first LTSS study visit. If safety concerns are identified, the investigator will review with the sponsor to determine if the participant is eligible to continue Compound 1 in the LTSS. Throughout the intervention periods in Studies 1 PD, 2 RW, or 3 LTSS, participants who choose or need to discontinue study medication should have an early discontinuation (ED) visit scheduled as soon as possible. If participants choose not to participate in the Study 3 LTSS after completion of the Study 1 PD or Study 2 RW, they should enter the 14-day safety follow-up period. Participants who prematurely discontinue the Study 1 PD or Study 2 RW will not be eligible to participate in the LTSS.

[00231] Participants will self-administer ulixacaltamide or placebo every morning (QAM) at home prior to their scheduled home health or telehealth visits, as applicable. Key efficacy assessments will be conducted at selected visits based on study assignment and include TETRASADL, PGI-C, PGI-S, CGI-S, and Archimedes spiral design. Drug concentration samples (on Day 56 and Day 70) will be collected concurrently with clinical laboratory assessments, following the correct collection order. Study 1 PD

[00232] All participants assigned to Study 1 PD who continue to meet all clinical trial entry criteria on Day 1 will receive DB treatment with Compound 1 or placebo from Day 1 to Day 84, using a fixed-dose regimen (after titration).

[00233] In the initial assessment (Day 1), participants will receive 1 tablet of the study medication during the health visit. Petition 870250100953, dated 04 / 11 / 2025, pp. 98 / 143 93 / 105 at home and then self-administer the QAM from Day 2 to Day 84. Assessments for CGI-S, PGI-S, and Archimedes spiral will be performed in that order before dose administration.

[00234] For participants randomized to Compound 1, the titration period will consist of a 20 mg dose of QAM during Week 1 (Days 1 to 7) and a 40 mg dose of QAM during Week 2 (Days 8 to 14). On Day 15, these participants will enter the maintenance period, receiving a 60 mg dose of QAM until the end of the intervention period (Day 84). No dose adjustments will be allowed.

[00235] Participants who complete the PD of Study 1 may be transferred to the ongoing LTSS of Study 3 with Day 84 assessments conducted from the PD of Study 1. Study 2 RW

[00236] All participants assigned to RW in Study 2 who continue to meet all clinical trial inclusion criteria on Day 1 will enter the initial RW period. Initial period of RW

[00237] During the initial RW period, participants will receive Compound 1 during the home health visit on Day 1 and will self-administer it from Day 2 to Day 56. These participants will be blinded as to whether they are participating in this study or the PD of Study 1 and will therefore receive Compound 1 in a DB manner.

[00238] On Day 1 (initial assessment), participants will complete the CGI-S, PGI-S, and Archimedes spiral assessments in that order before dose administration.

[00239] All participants will undergo a titration period consisting of a 20 mg dose of QAM during Week 1 (Days 1 to 7) and a 40 mg dose of QAM during Week 2 (Days 8 to 14). On Day 15, these participants will enter the Petition 870250100953, dated 04 / 11 / 2025, pp. 99 / 143 94 / 105 maintenance period, receiving a 60 mg dose of QAM until the end of the intervention period (Day 56). No dosage adjustments will be allowed. RW period

[00240] Based on predefined selection criteria, a subset of participants who are responsive to Compound 1 will be randomized 1:1 to continue Compound 1 or receive placebo in a DB manner. No tapering of Compound 1 is required before initiating placebo. Participants who do not meet these criteria will remain on Compound 1 at 60 mg for the remainder of the study. Study visits will be conducted weekly throughout the RW period, as described in the SoA.

[00241] Participants who complete the RW of Study 2 may be transferred to the ongoing LTSS of Study 3 with Day 84 assessments conducted from the PD of Study 2.

[00242] Participants who meet the criteria for worsening tremor (according to the predefined relapse criterion) during RW will be transferred to the LTSS of Study 3. Final assessments conducted in RW of Study 2 will be conducted on Day 84 of LTSS of Study 3. Study 3 LTSS

[00243] Participants receiving placebo in Studies 1 PD or 2 RW will undergo a DB titration period consisting of a 20 mg dose of QAM during the first week (Days 84 to 90) and a 40 mg dose of QAM during the second week (Days 91 to 97) (Table 9). Participants who were receiving 60 mg of Compound 1 in a central study when switching to the LTSS will remain on the 60 mg dose throughout the blinded titration period. On Day 15, all participants will enter the period Petition 870250100953, dated 04 / 11 / 2025, pages 100 / 143 95 / 105 participants will be in the open-label maintenance phase, receiving a 60 mg dose of QAM for the remainder of the study. Participants in the Phase 2 OLE (Example 2) will be transferred to the Study 3 LTSS at a dose of 60 mg or titrated over a 2-week period to 60 mg, if appropriate, based on their current dose. No dose adjustments will be permitted in the Study 3 LTSS. Scientific Justification for the Clinical Trial Design

[00244] This Protocol includes 2 simultaneous central DB studies designed to better evaluate the favorable efficacy and safety profiles of Compound 1 demonstrated throughout the Phase 2 program. A multi-study protocol offers several benefits over a traditional single-study protocol. The shared study infrastructure allows for greater efficiency in enrollment, operations, data collection and management, as well as overall resource utilization across the three studies. Furthermore, simultaneous study enrollment ensures a more homogeneous participant population across the two central Phase 3 studies (Study 1 PD and Study 2 RW). By initiating Study 1 PD and Study 2 RW simultaneously under one protocol, Compound 1 treatment administration in the Initial RW Period of Study 2 RW will be blinded, resulting in a more accurate determination of Compound 1 responders.Finally, all PD (Professional) participants from Study 1 and RW (Responsible Worker) participants from Study 2 can enter the LTSS directly, allowing for a seamless transition from the participant perspective and the continuous collection of safety data from the sponsor perspective.

[00245] The PD of Study 1 and the RW of Study 2 will be conducted using 2 different study designs. The PD of Study 1 is similar to the Phase 2 trial described in Example 1, but extends the total treatment period to 12 weeks to allow for assessment of chronic treatment. The RW design of Study 2 was Petition 870250100953, dated 04 / 11 / 2025, pages 101 / 143 The 96 / 105 score was chosen for several reasons. First, the durability of the effect will be further confirmed in the RW arm designed to evaluate a defined subpopulation of ulixacaltamide responders. The RW design is expected to be useful since ET is known to be heterogeneous; and given this heterogeneity (i.e., unique patient characteristics, genotype / etiology, or phenotype), there are likely to be subpopulations of ET participants who will respond more favorably to treatment than other subpopulations. The RW design identifies this subpopulation, its response to treatment, and therefore will lead to a better understanding of the responder population. Furthermore, participants will be assessed weekly during the RW period, and those who meet the predefined relapse criterion will be transferred to the LTSS of Study 3. This limits the placebo duration for those who are true responders.

[00246] The intervention periods in Studies 1 PD and 2 RW are up to 12 weeks in duration, including the 2-week titration. A 2-week titration period is considered appropriate based on the tolerability observed in Phase 2. Furthermore, a 10-week maintenance treatment period at the 60 mg dose is considered sufficient to establish the durability of the chronic dosing effect. This is corroborated by evidence of a treatment effect as early as 2 weeks in the Phase 2 studies. In Phase 2, the change in LSM mADL11 score from baseline showed a treatment effect relative to placebo of 1.44 on Day 28, with the effect sustained throughout the remainder of the study (Day 56). A favorable treatment effect of 1.03 mADL11 points relative to placebo was observed as early as the first assessment point (Day 14) in participants without intention tremor (IT).

[00247] In the Phase 2 OLE study (Example 2), the requirement of Petition 870250100953, dated 04 / 11 / 2025, pp. 102 / 143 97 / 105 rescue treatment in the placebo group was observed within the 3-week crossover period, suggesting a rapid washout without drug effect and further supporting the 4-week RW period chosen for RW in Study 2.

[00248] The presence of TI is of special interest because it is a distinct type of action tremor observed in some individuals with ET that may be associated with other unique neurological conditions. TI is characterized by a coarse tremor of high amplitude and low frequency that worsens with movement toward a target, as opposed to the action or postural tremor otherwise observed in ET, where the frequency and amplitude of the tremor are more consistent along the trajectory of the movement. Because TI may be associated with a diagnosis other than ET, participants with TI will be assessed during screening to determine if there is a possible cerebellar etiology other than ET. Only participants determined by the central reviewer of the Eligibility Review Committee (ERC) as having TI associated with ET (ET with TI) and not an alternative etiology for TI will be included in the study.Functional, physiological, and anatomical data suggest that ET with IT may represent a unique clinical manifestation that could create a potentially confounding effect in terms of outcome measures in clinical studies based on functional activities. Therefore, this subpopulation could confound the measurement and interpretation of the primary outcome measure, ADL performance. Based on this, participants with IT will only be included if IT is determined to be associated with ET and not an alternative etiology. Participants assigned to Studies 1 PD or 2 RW will be stratified for the presence of ET with IT. Participants determined to have ET with IT will be included in the sensitivity analyses of Study 1 PD and Study 2 RW. Petition 870250100953, dated 04 / 11 / 2025, pp. 103 / 143 98 / 105

[00249] The primary outcomes for Study 1PD and Study 2 RW are based on mADL11 (TETRAS-ADL items 1-11 with transformed scores 0-3). In the Phase 2 trial described in Example 1, the primary assessment point was mADL (TETRAS-ADL items 1-11 + Performance [PS] subscale items 6 and 7 with transformed scores 0-3). Although the mADL score was reduced in the Phase 2 studies, careful analysis of the data from the Phase 2 study described in Example 1 revealed that the PS items (Archimedean spirals and cursive handwriting) and ADL item 12 (social impact) did not have sufficient sensitivity, reliability, specificity, and / or clinical significance to assess the severity of ET. Thus, in line with FDA feedback, the mADL11 score was chosen as the primary efficacy endpoint for PD in Study 1 and as a secondary endpoint for RW in Study 2. The Archimedes spiral dominant hand test will be analyzed as a secondary endpoint.

[00250] This is a decentralized clinical trial. The reduced burden of a decentralized study would increase the engagement of participants without access to research clinics, the participation of older participants who are limited by transportation (and other issues, e.g., mobility, etc.), and younger participants who are potentially still working and need a more convenient clinical trial schedule. This will improve the engagement, recruitment, inclusion, and retention of study participants not only from a significantly diverse clinical population but may also increase investigator diversity, which is important for clinical trials in the US. Furthermore, home-based collection of efficacy assessments is ideal, as the study assessments are functionally relevant ADLs that focus on participants' daily experiences and Petition 870250100953, dated 04 / 11 / 2025, pages 104 / 143 99 / 105 disability associated with ET. The Phase 2 crossover study shows that a decentralized study can be effectively and safely conducted for participants with moderate to severe ET, and TETRA-ADL can be assessed by telehealth with consistency in mADL11 observed at multiple consecutive time points. Given this, these assessments are feasible to collect, and bias can be reduced through collection by a decentralized investigator. Finally, a decentralized trial is appropriate given the well-tolerated and well-characterized safety profile of Compound 1, as observed in the Phase 2 study, as described in Example 1. Compound 1 has stable characteristics that allow for direct patient transport, simple drug administration, and simple safety monitoring appropriate for a decentralized trial. Definition of clinical trial termination

[00251] A participant is considered to have completed Studies 1 PD and 2 RW when they have been transferred to Study 3 LTSS or have completed an SFU or ED visit. LTSS completion of Study 3 will occur when participants have completed their last planned assessment, as shown in the SoA. The study may be terminated at any time by the sponsor. Justification for the Dose

[00252] Ulixacaltamide, when administered as the modified-release (MR) formulation in the context of titration, demonstrated a favorable safety profile in healthy participants and patients with ET throughout the Phase 2 development program at doses ranging from 5 to 120 mg for up to 129 days.

[00253] In the Phase 2 trial described in Example 1, participants were randomized to placebo or 60 or 100 mg of Compound 1. When assessing the change from baseline versus placebo in the mADL11 outcome, the magnitude of the benefit was Petition 870250100953, dated 04 / 11 / 2025, pages 105 / 143 100 / 105 was broadly similar between participants in the 60 mg or 100 mg Compound 1 groups. No additional benefit was observed by increasing the dose to 100 mg and no significant difference in the safety profile between the 60 mg and 100 mg groups. Thus, the risk / benefit ratio for the 60 mg dose is ideal without the need to evaluate additional maintenance doses below 60 mg.

[00254] The effect of a high-fat, high-calorie meal on the pharmacokinetics of Compound 1 was evaluated in healthy participants who had previously received Compound 1 under fasting conditions in a Phase 1 trial. The effect of a high-fat, high-calorie meal on the PK of Compound 1 was evaluated at the 120 mg dose level after healthy adult participants had titrated to achieve steady-state exposure. Following administration of the 120 mg dose in either the fed or fasted state, the maximum plasma drug concentration (emax) and AUCt values ​​were similar. Based on this analysis, Compound 1 can be administered without regard to food. Administration of the drug under study

[00255] Compound 1 will be provided as 20 mg, 40 mg, and 60 mg modified-release tablets. A matching placebo will also be provided. The study drug is administered by oral QAM with or without food and will be provided to participants in pre-packaged bottles. Participants receiving ulixacaltamide will receive 1 tablet of the study drug per day. Participants in the placebo group will receive one matching placebo tablet per day. For each home health / telehealth visit, the dose should be taken from the previously dispensed bottle. The interactive response technology (IRT) system may dispense replacement bottles if needed. Petition 870250100953, dated 04 / 11 / 2025, pages 106 / 143 101 / 105 required.

[00256] Eligible participants will be randomized to receive oral Compound 1 or placebo daily. Fixed-titration regimens will be used for all 3 studies, starting with 20 mg for 7 days, then 40 mg for 7 days, followed by a maintenance dose of 60 mg (note that participants who received placebo in Study 1 PD and Study 2 RW will require blinded titration after transfer to Study 3 LTSS). Dose adjustments will not be permitted. Effectiveness assessments

[00257] All TETRA-ADL assessments throughout the study will be conducted by a trained and qualified investigator. Baseline CGI-S, PGI-S, and Archimedes spiral assessments on Day 1 (initial assessment) should be conducted pre-dose. Essential Tremor Rating Scale

[00258] The TETRAS was developed by the Tremor Research Group (TRG; www.tremorresearchgroup.org) to quantify the severity of ET and its impact on ADLs. The full scale has 2 sections, the Performance and ADL subscales. This study will only collect TETRAS-ADL. Activities of Daily Living at TETRAS

[00259] The TETRAS-ADL subscale is a 12-item assessment of typical activities of daily living (ADL) that are affected by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, emptying, carrying, using keys, writing, working, general disability, and social activity. The impact on each function is rated on a 5-point Likert scale from 0 to 4. The full ADL subscale score is calculated as the sum of all 12 items and ranges from 0 to 48. Modified Activities of Daily Living from TETRA 11 Petition 870250100953, dated 04 / 11 / 2025, pp. 107 / 143 102 / 105

[00260] The mADL11 score is a composite sum of items 1 to 11 (social impact score of item 12) of the TETRASADL subscale. The score for each item is transformed into a 4-point scale from 0 to 3 with a total score range of 0 to 33. The TETRASADL will be collected and the mADL11 will be used for data analysis purposes. Overall clinical impression

[00261] Clinical Global Impressions (CGI) scales are commonly used measures of symptom severity and response in clinical studies (Guy 1976). The CGI scale will be used in this clinical study. Overall clinical impression - severity

[00262] The CGI-S assesses the physician's impression of the participant's current disease status. The clinician should use their total clinical experience with this patient population and rate the participant's current TE severity on a 7-point scale, from 1 (normal, not ill at all) to 7 (among the most extremely ill patients). Overall impression of the patient Overall impression of the patient - Change

[00263] The PGI-C assesses the participant's improvement (or worsening). The participant must rate their condition relative to the baseline assessment (pre-dose on day 1) on a 7-point scale, from 1 (much better) to 7 (much worse). In all cases, the assessment must be made regardless of whether the participant believes the improvement / worsening is related to the drug or not. Overall impression of the patient - severity

[00264] The PGI-S assesses the participant's perception of their current disease status. The participant must rate their clinical condition on a 7-point scale from 1 (not present) to 7 (extremely severe). Petition 870250100953, dated 04 / 11 / 2025, pages 108 / 143 103 / 105 Archimedes in a spiral

[00265] Participants will draw Archimedean spirals with their dominant hand on a fixed, unlined, standard-sized (letter) paper that includes pre-formed spiral designs. A specific pen (for standardization across all drawings) will be provided for use. Participants will be instructed to draw a spiral without crossing the lines on the pre-formed spiral template using their dominant hand, without practice and without leaning on their forearm, wrist, or dominant hand. Descriptive analyses will be used to summarize the findings. Equivalents and Scope

[00266] In the claims, articles such as a, an, or aeo may mean one or more of a, unless otherwise indicated or otherwise evident from the context. Claims or descriptions that include or are among one or more members of a group are considered satisfied if one, more than one, or all members of the group are present in, used in, or otherwise relevant to a particular product or process, unless otherwise indicated or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present, is used, or is otherwise relevant to a particular product or process. The invention includes embodiments in which more than one, or all members of the group are present, used in, or otherwise relevant to a particular product or process.

[00267] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms of one or more of the listed claims are introduced into another claim. For example, any claim that depends on another claim. Petition 870250100953, dated 04 / 11 / 2025, pp. 109 / 143 104 / 105 may be modified to include one or more limitations found in any other claim that depends on the same base claim. Where elements are presented as lists, for example, in Markush group format, each subgroup of elements is also described and any element(s) may be removed from the group. It should be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist of, or essentially consist of, such elements and / or features. For simplicity, these embodiments have not been specifically set forth in haec verba in this document. It is also noted that the terms comprising and containing are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are provided, outcomes are included.Furthermore, unless otherwise indicated or evident from the context and understanding of a person skilled in the art, the values ​​that are expressed as intervals may assume any specific value or subinterval within the intervals indicated in different embodiments of the invention, down to the tenth of a unit of the lower limit of the interval, unless the context clearly indicates otherwise.

[00268] This application refers to various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the present descriptive report, the descriptive report shall prevail. Furthermore, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are considered known to a person skilled in the art, Petition 870250100953, dated 04 / 11 / 2025, pp. 110 / 143 105 / 105 in the art, they can be excluded even if the exclusion is not explicitly stated in this document. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of the prior art.

[00269] Persons skilled in the art will recognize or be able to verify the use of no more than routine experimentation of many equivalents to the specific embodiments described in this document. The scope of the present embodiments described in this document is not intended to be limited to the above Description, but is instead as set forth in the appended claims. Persons skilled in the art will appreciate that various alterations and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. Petition 870250100953, dated 04 / 11 / 2025, pp. 111 / 143

Claims

1 / 6 CLAIMS 1. A method for treating essential tremor, characterized in that it comprises administering to an individual in need of the compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual once daily at a dose of about 60 mg to about 100 mg; such that the Essential Tremor Rating Scale (TETRAS) performance score of said individual is decreased after administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, compared with the TETRAS performance score of said individual before administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. Method according to claim 1, characterized in that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual in a dose of about 60 mg.

3. Method according to claim 1, characterized in that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual in a dose of about 100 mg.

4. Method according to any one of claims 1 to 3, characterized in that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to said individual after an initial titration period. Petition 870250100953, dated 04 / 11 / 2025, pp. 112 / 143 2 / 6 5. Method according to claim 4, characterized in that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to said individual at a dose of about 60 mg after an initial titration period; wherein said initial titration period comprises administering to the individual the compound of Formula (I), or a pharmaceutically acceptable salt thereof, once daily at a dose of about 5 mg during a first time period; followed by a dose of about 10 mg during a second time period; followed by a dose of about 20 mg during a third time period; followed by a dose of about 40 mg during a fourth time period.

6. Method according to claim 5, characterized in that the first time period, the second time period, the third time period and the fourth time period each have a duration of 7 days.

7. Method according to claim 4, characterized in that the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered to said individual at a dose of about 100 mg after an initial titration period; wherein said initial titration period comprises administering to the individual the compound of Formula (I), or a pharmaceutically acceptable salt thereof, once daily at a dose of about 5 mg during a first time period; followed by a dose of about 10 mg during a second time period; followed by a dose of about 20 mg during a third time period; followed by a dose of about 40 mg during a fourth time period; followed by a dose of about 60 mg Petition 870250100953, dated 04 / 11 / 2025, page 113 / 143 3 / 6 for a fifth time period, followed by a dose of about 80 mg for a sixth time period.

8. Method according to claim 7, characterized in that the first time period, the second time period, the third time period, the fourth period, the fifth period and the sixth period each have a duration of 7 days.

9. Method, according to any one of claims 1 to 8, characterized in that the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual for at least 8 weeks.

10. Method, according to any one of claims 1 to 8, characterized in that the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual for at least 12 weeks.

11. Method, according to any one of claims 1 to 8, characterized in that the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual for at least 14 weeks.

12. Method, according to any one of claims 1 to 8, characterized in that the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to the individual for at least 52 weeks.

13. Method, according to any one of claims 1 to 12, characterized in that the TETRA performance score comprises the ADL subscore, and in that the ADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, as per Petition 870250100953, dated 04 / 11 / 2025, p.114 / 143 4 / 6 less about less about less about less about about about 4 points, 5 points, 6 points, 7 points, 8 points, at least at least at least at least about 4.5 about 5.5 about 6.5 about 7.5 about 8.5 points, by points, by points, by points, by points, at least about 9 points, at least about 9.5 points or at least about 10 points after administration of the compound of formula (I), compared with the individual's ADL subscore before administration of the compound of formula (I).

14. Method according to claim 13, characterized in that the ADL subscore is decreased by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

15. Method according to claim 13, characterized in that the ADL subscore is decreased by at least about 3 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

16. Method, according to any one of claims 1 to 12, characterized in that the TETRA performance score comprises the mADL subscore, and in that the mADL subscore is reduced by at least about 0.5 points, at least about 1 point, at least about 1.5 points, at least about 2 points, at least about 2.5 points, at least about 3 points, at least about 3.5 points, at least about less about less about less about 4 points, of 5 points, of 6 points, of 7 points, at least at least at least at least about 4.5 about 5.5 about 6.5 about 7.5 points, by points, by points, by points, by Petition 870250100953, dated 04 / 11 / 2025, p.115 / 143 5 / 6 less about 8 points, at least about 8.5 points, at least about 9 points, at least about 9.5 points or at least about 10 points after administration of the compound of formula (I), compared with the sub-score of said individual's ADL before administration of the compound of formula (I).

17. Method according to claim 16, characterized in that the mADL subscore is decreased by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

18. Method according to claim 17, characterized in that the mADL subscore is decreased by at least about 3 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

19. Method according to claim 16, characterized in that the mADL subscore is decreased by at least about 4 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

20. A method, according to any one of claims 16 to 19, characterized in that a subscore for at least one item assessed as part of the mADL subscale is reduced, wherein said item is selected from the group consisting of: item 3 (drinking from a cup); item 4 (hygiene); item 5 (dressing); item 6 (pouring); item 7 (carrying something); item 8 (using keys); item 9 (writing); and item 11 (disability in general).

21. Method, according to any one of claims 1 to 12, characterized in that the TETRA performance score comprises the mADL11 subscore, and in Petition 870250100953, dated 11 / 04 / 2025, p. 116 / 143 6 / 6 that the mADL11 subscore is decreased by at least about 0.5 points, at least about 1 point, at least about 2 points, at least about 3 points, at least about 4 points, at least about 5 points, at least about 6 points, at least about 7 points, at least about 8 points, at least about 9 points or at least about 10 points after administration of the compound of formula (I), compared with the individual's ADL subscore before administration of the compound of formula (I).

22. Method according to claim 19, characterized in that the mADL11 subscore is decreased by at least about 2 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

23. Method according to claim 19, characterized in that the mADL11 subscore is decreased by at least about 2.5 points after at least 8 weeks of administration of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

24. A method, according to any one of claims 1 to 23, characterized in that the individual in question does not have intentional tremor.

25. Method, according to any one of claims 1 to 24, characterized in that the individual in question is a human. Petition 870250100953, dated 04 / 11 / 2025, pp. 117 / 143

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