Methods of treating parkinson's disease with t-type calcium channel modulators

Abstract

Described herein, in part, are methods useful for preventing and / or treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as Parkinson's disease, psychiatric disorders (e.g., mood disorder (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), seizures (e.g., absence seizures), epilepsy, or an epilepsy syndrome (e.g., juvenile myoclonic epilepsy). The present invention further comprises methods for modulating the function of a T-type calcium channel and methods of administering a titrated dosage of a T-type calcium channel antagonist.

Description

[0001] METHODS OF TREATING PARKINSON’S DISEASE WITH T-TYPE CALCIUM CHANNEL MODULATORS

[0002] RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application No. 63 / 761,427, filed on February 21, 2025 and U.S. Provisional Application No. 63 / 560,953, filed on March 4, 2024. The entire contents of each of the foregoing applications are hereby incorporated herein by reference.

[0004] BACKGROUND

[0005] Parkinson’s disease is a progressive degenerative disease of the central nervous system. The risk of developing Parkinson’s disease (PD) increases with age and afflicted invidivuals are usually adults over 40. PD occurs in all parts of the world and affects more than one million individuals in the United States alone.

[0006] While the primary cause of PD is not known, it is characterized by degeneration of dopaminergic neurons of the substantia nigra. The substantia nigra is a portion of the lower brain, or brain stem, that helps control voluntary movements. The shortage of dopamine in the brain caused by the loss of these neurons is believed to cause the observable disease symptoms.

[0007] The symptoms of PD vary from patient to patient. The most common symptom is a scarcity of movement, e.g., rigidity characterized by an increased stiffness of voluntary skeletal muscles. Additional symptoms include resting tremor, bradykinesia (slowness of movement), poor balance, and walking problems. Common secondary symptoms include depression, sleep disturbance, dizziness, stooped posture, dementia, and problems with speech, breathing, and swallowing. The symptoms become progressively worse and ultimately result in death.

[0008] T-type calcium channels are low-voltage activated ion channels that mediate the influx of calcium into cells. Aberrant function or activity of these ion channels is associated with several diseases or conditions, including central nervous system degenerative disorders (e.g., PD), psychiatric disorders (e.g., mood disorder (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), epilepsy, or an epilepsy syndrome (e.g., absence seizures and juvenile myoclonic epilepsy). In treating diseases or conditions related to aberrant function or activity of T-type calcium channels, the tolerability of potential pharmaceutical therapeutics is a factor to be considered. When investigating new therapeutics, tolerability is a clinically-defined term that refers to both patient (or study participant) and clinician (or investigator) input. Patient input includes patient’ willingness to continue taking the therapeutic, and clinician input is based on the clinician’s assessment of the severity and / or number of adverse effects and whether the patient should continue to be dosed with the therapeutic.

[0009] Accordingly, novel therapies, including effective therapeutic doses and / or dosage schedules that may benefit patients with diseases or conditions involving T-type calcium channels, e.g., PD, are needed.

[0010] SUMMARY

[0011] Described herein are methods of treating or preventing at least one symptom of Parkinson’s disease (PD) in a subject in need thereof, said methods comprising administering to said subject a T-type calcium channel (TTCC) blocker, such that at least one symptom of PD is treated or prevented in said subject.

[0012] In some embodiments, the TTCC blocker is compound of formula (I) represented by the following structure: or a pharmaceutically acceptable salt thereof. In some embodiments, the TTCC blocker is a compound of formula (II) represented by the following structure:

[0013] In some embodiments, the TTCC blocker is compound of formula (III) represented by the following structure: or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, treatment or prevention of the at least one symptom of PD in the subject is indicated by lack of an increase in the total score as measured according to the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS total score), as compared to the MDS-UPDRS total score measured prior to administration of the TTCC blocker to the subject.

[0015] In certain embodiments, the MDS-UPDRS total score is measured in the OFF state. In certain embodiments, the MDS-UPDRS total score is measured in the ON state.

[0016] In specific embodiments, the lack of an increase in the MDS-UPDRS total score comprises a lack of an increase in one or more of the following: a) MDS-UPDRS Part 1 score; b) MDS-UPDRS Part 2 score; c) MDS-UPDRS Part 3 score; and d) MDS-UPDRS Part 4 score.

[0017] In certain embodiments, the lack of an increase in the MDS-UPDRS total score comprises lack of an increase in the MDS-UPDRS Part 1 score. In certain embodiments, the lack of an increase in the MDS-UPDRS total score comprises lack of an increase in the MDS-UPDRS Part 2 score.

[0018] In certain embodiments, the lack of an increase in the MDS-UPDRS total score comprises lack of an increase in the MDS-UPDRS Part 3 score. In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS- UPDRS subscale score for one or more of the following: tremor, bradykinesia, rigidity, posture and gait disorder. In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS-UPDRS subscale score for tremor. In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS-UPDRS subscale score for bradykinesia, rigidity, posture and gait disorder.

[0019] In certain embodiments, the lack of an increase in the MDS-UPDRS total score comprises lack of an increase in MDS-UPDRS Part 4 score.

[0020] In some embodiments, compound of formula (I) is administered at the dose of at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg or at least about 100 mg.

[0021] In some embodiments, compound of formula (I) is administered once daily.

[0022] In certain embodiments, a TTCC blocker, including, for example, a compound of formula (I), (II) or (III), is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or at least 7 or more weeks. In some embodiments, the TTCC blocker is administered to the subject for at least 21 days, at least 49 days, at least 77 days or at least 91 days. In some embodiments, the TTCC blocker is administered to the subject for at least 3 months, at least 6 months, at least 9 months or at least 12 months. In some embodiments, the TTCC blocker is administered to the subject for at least 3 years, at least 5 years or at least 10 years.

[0023] In some embodiments, the lack of an increase in the MDS-UPDRS total score or UPDRS total score comprises the decrease in the MDS-UPDRS total score of at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, at least 40 points, at least 45 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 75 points, at least 80 points, at least 85 points, at least 90 points, at least 95 points, at least 100 points, at least 105 points, at least 110 points, at least 115 points, at least 120 points, at least 125 points, at least 130 points, at least 135 points, at least 140 points, at least 145 points, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 205, at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, or at least 255 or more points..

[0024] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 1 score comprises a decrease in the MDS-UPDRS Part 1 score 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 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0025] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 2 score comprises a decrease in the MDS-UPDRS Part 2 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0026] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 score comprises a decrease in the MDS-UPDRS Part 3 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, at least 40 points, at least 45 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 75 points, at least 80 points, at least 85 points, at least 90 points, at least 95 points, at least 100 points, at least 105 points, at least 110 points, at least 115 points, at least 120 points, or at least 125 or more points.

[0027] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale score for tremor comprises a decrease in the MDS-UPDRS Part 3 subscale score for tremor of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, or at least 30 points .

[0028] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale score for bradykinesia comprises a decrease in the MDS-UPDRS Part 3 subscale score for bradykinesia of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points . In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale score for bradykinesia comprises a decrease in the MDS- UPDRS Part 3 subscale score for bradykinesia of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points. In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale score for rigidity comprises a decrease in the MDS-UPDRS Part 3 subscale score for rigidity 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 8 points, at least 10 points, at least 12 points, at least 14 points, or at least 16 points. In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale score for posture comprises a decrease in the MDS-UPDRS Part 3 subscale score for posture 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 8 points, at least 10 points, at least 12 points, at least 14 points, or at least 16 points. In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale score for gait postural instability comprises a decrease in the MDS-UPDRS Part 3 subscale score for gait postural instability of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 7 points, at least 10 points, or at least 15 points.

[0029] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 3 subscale for axial score comprises a decrease in the MDS-UPDRS Part 3 subscale axial score of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 7 points, at least 10 points, or at least 15 points.

[0030] In certain embodiments, the lack of an increase in the MDS-UPDRS Part 4 score comprises a decrease in the MDS-UPDRS Part 4 score of at least 1 point, at least 2 points, at least 4 points, at least 6 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0031] In some embodiments, the method does not result in moderate depressive symptoms or severe depressive symptoms in the subject as measured by Beck Depression Inventory - Second Edition (BDI-II).

[0032] In some embodiments, the method does not result in adverse events. In other embodiments, the method does not result in serious adverse events.

[0033] In some embodiments, the method does not result in moderate anxiety symptoms or severe anxiety symptoms as measured by Beck Anxiety Inventory (BAI).

[0034] In certain embodiments, the method results in a decrease in MDS-UPDRS Part 1 total score as compared to MDS-UPDRS Part 1 total score prior to administration of the TTCC blocker to the subject as assessed in the off state. In certain embodiments, the method results in a decrease in MDS-UPDRS Part 2 total score as compared to MDS-UPDRS Part 2 total score prior to administration of the TTCC blocker to the subject as assessed in the off state. In certain embodiments, the method results in a decrease in MDS-UPDRS Part 3 total score as compared to MDS-UPDRS Part 3 total score prior to administration of the TTCC blocker to the subject as assessed in the off state. In certain embodiments, the method results in a decrease in MDS- UPDRS Part 1 total score as compared to MDS-UPDRS Part 1 total score prior to administration of the TTCC blocker to the subject as assessed in the on state. In certain embodiments, the method results in a decrease in MDS-UPDRS Part 2 total score as compared to the MDS- UPDRS Part 2 total score prior to administration of the TTCC blocker to the subject as assessed in the on state. In certain embodiments, the method results in a decrease in MDS-UPDRS Part 3 total score as compared to the MDS-UPDRS Part 3 total score prior to administration of the TTCC blocker to the subject as assessed in the on state. In certain embodiments, the method results in a decrease in MDS-UPDRS Part 4 score as compared to MDS-UPDRS Part 4 score prior to administration of the TTCC blocker to the subject.

[0035] In some embodiments, treatment or prevention of at least one symptom of PD is measured according to the Beck Anxiety Inventory (BAI). In certain embodiments, the method results in a decrease in BAI score as compared to BAI score prior to administration of t he TTCC blocker to the subject.

[0036] In some embodiments, treatment or prevention of at least one symptom of PD is measured according to the Beck Depression Inventory, second edition (BDI-II). In certain embodiments, the method results in a decrease in BDI-II score as compared to BAI score prior to administration of the TTCC blocker to the subject.

[0037] In some embodiments, treatment or prevention of at least one symptom of PD is measured according to the Questionnaire for Impulsive Control Disorders in Parkinson’s Disease - Rating Scale (QUIP -RS). In certain embodiments, the method results in a decrease in QUIP- RS score as compared to QUIP -RS score prior to administration of the TTCC blocker to the subject.

[0038] In some embodiments, treatment or prevention of at least one symptom of PD is measured according to the Montreal Cognitive Assessment (MoCA). In certain embodiments, the method results in a decrease in MoCA score as compared to MoCA score prior to administration of the TTCC blocker to the subject.

[0039] In some embodiments, treatment or prevention of at least one symptom of PD is measured by the Patient Global Impression of Severity (PGI-S). In certain embodiments, the method results in a decrease in PGI-S score as compared to PGI-S score prior to administration of the TTCC blocker to the subject. In some embodiments, treatment or prevention of at least one symptom of PD is measured by the Motor Complications Assessment. In certain embodiments, the method results in a decrease dyskinesia as measured by the Motor Complications Assessment as compared to dyskinesia prior to administration of the TTCC blocker to the subject.

[0040] In some embodiments, treatment or prevention of at least one symptom of PD is measured by the Epworth Sleepiness Scale (ESS). In certain embodiments, the method results in a decrease in ESS score as compared to ESS score prior to administration of the TTCC blocker to the subject.

[0041] In some embodiments, treatment or prevention of at least one symptom of PD is measured by the Clinician Global Impression of Severity (CGI-S). In certain embodiments, the method results in a decrease in CGI-S score in the subject as compared to CGI-S score prior to administration of the TTCC blocker to the subject.

[0042] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Brief Description of the Figures, Detailed Description, Examples, and Claims.

[0043] BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 is a schematic of the clinical trial described in Example 1.

[0045] Figure l is a schematic representation of the use of a cylinder test to determine % paw asymmetry in the 6-OHDA rat model.

[0046] Figure 3, panel A is a bar graph showing % paw asymmetry measured in 6-OHDA rats after administration of vehicle or compound of formula (III) at 3 mg / kg and 10 mg / kg. Figure 3, panel B is a bar graph showing % paw asymmetry measured in 6-OHDA rats after administration of L-DOPA alone or in combination with compound of formula (III) at 3 mg / kg and 10 mg / kg.

[0047] Figure 4, panel A is a bar graph showing the number of abnormal involuntary movements (AIMs) measured in 6-OHDA rats after administration of vehicle or compound of formula (III) at 3 mg / kg and 10 mg / kg. Figure 4, panel B is a bar graph showing the number of AIMs measured in 6-OHDA rats after administration of L-DOPA alone or in combination with compound of formula (III) at 3 mg / kg and 10 mg / kg. Figure 5 is a graph showing total AIMs measured over 180 minutes in 6-OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone.

[0048] Figure 6, panel A is a bar graph showing total AIMs measured over 0-90 minutes postdose in 6-OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone. Figure 6, panel B is a bar graph showing total AIMs measured over 90-180 minutes post-dose in 6-OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone.

[0049] Figure 7 is a graph showing net contraversive rotations measured over 180 minutes in 6- OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone.

[0050] Figure 8 is a graph showing total AIMs measured over 180 minutes in 6-OHDA rats treated with 6 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine.

[0051] Figure 9, panel A is a bar graph showing total AIMs measured over 0-180 minutes postdose in 6-OHDA rats treated with 6 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine. Figure 9, panel B is a bar graph showing total AIMs measured over 0-90 minutes post-dose in 6-OHDA rats treated with 6 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine.

[0052] Figure 10 is a graph showing net contraversive rotations measured over 180 minutes in 6-OHDA rats treated with 6 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine.

[0053] DETAILED DESCRIPTION

[0054] This application discloses methods of preventing and / or treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as PD.

[0055] Also disclosed are the use of titrated dosage schedules for a compound of formula (I) or a pharmaceutically acceptable salt thereof to improve such methods of preventing and / or treating a disease or condition relating to aberrant function or activity of a T-type calcium channel. By using titrated dosage schedules, it was unexpectedly discovered that a titrated dose significantly larger than the maximum tolerated dose achieved without titration could be safely administered to a subject in need thereof. Similarly, by using a titrated dosage schedule, pharmacokinetic parameters, such as Cmax and AUC24, could be increased significantly beyond the Cmax and / or AUC24 values obtained when lower doses were administered without titration.

[0056] Thus, in one aspect of the present disclosure, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, the maximum tolerated Cmax without titration is less than 130 ng / mL, such as between 30 and 130 ng / mL, and / or the maximum tolerated AUC24 without titration is less than 2000 ng*h / mL, such as between 490 and 2000 ng*h / mL. Accordingly, in certain embodiments, by using the titrated dosage schedules disclosed herein, a Cmax is achieved that is greater than 130 ng / mL, such as ranging from about 180 to 300 ng / mL, from about 230 to 380 ng / mL, or from about 280 to 470 ng / mL and / or an AUC24 is achieved that is greater than 2000 ng*h / mL, such as from about 2440 to 4070 ng*h / mL, from about 2820 to 4700 ng*h / mL, or from about 3480 to 5800 ng*h / mL. In certain embodiments of the disclosure, there are provided methods of titrating an initial dosee to at least about 1.5 times the maximum tolerated Cmax and / or the maximum tolerated AUC24 achieved without titration, such as at least about 2 times, at least about 2.5 times, or at least about 3 times the maximum tolerated Cmax and / or AUC24 achieved without titration.

[0057] In other aspects of the disclosure, the maximum tolerated dose achieved without titration is less than 60 mg, such as about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg. In certain embodiments, the maximum titrated dosage is at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least at least about 110 mg, about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, or at least about 220 mg. In various embodiments, the maximum titrated dose is about 40 mg to about 80 mg.

[0058] In certain embodiments of the disclosure, there are provided methods of titrating an initial dosage to at least about 2 times the maximum tolerated dose achieved without titration or an initial dosage (e.g., about 2 times 10 mg, 20 mg, 30 mg, or 40 mg, for a maximum titrated dosage of about 20 mg, 40 mg, 60 mg, or 80 mg). In certain embodiments of the disclosure, there are provided methods of titrating the maximum tolerated dose without titration or an initial dosage to at least about 2.5 times, at least about 3 times, at least about 3.5 times, at least about 4 times, at least about 4.5 times, at least about 5 times, at least about 5.5 times, at least about 6 times, at least about 6.5 times, at least about 7 times, at least about 7.5 times, or at least about 8 times the maximum tolerated dose achieved without titration or the initial dosage.

[0059] In various embodiments, there are provided methods of titrating the maximum tolerated dosage without titration or an initial dosage to at least about 4 times (e.g., about 4 times 10 mg or 4 times 20 mg for a maximum titrated dosage of about 40 mg or 80 mg, respectively). In another embodiment, there are provided methods of titrating the maximum tolerated dosage achieved without titration or an initial dosage to at least about 8 times (e.g., about 8 times 10 mg).

[0060] Methods are provided for treating PD with or without titration.

[0061] Definitions

[0062] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0063] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0064] As used herein, the term “refractory” refers to a disease, disorder, or condition that does not readily yield or respond to therapy or treatment, or is not controlled by a therapy or treatment. In some embodiments, a disease, disorder, or condition described herein is refractory (e.g., refractory epilepsy, refractory absence seizures, refractory Parkinson’s disease) and does not respond to standard therapy or treatment.

[0065] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human” and “patient” may be used interchangeably herein.

[0066] The terms “disease”, “disorder”, and “condition” are used interchangeably herein. As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”) or achieves beneficial or desired clinical results. The beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of the condition, disorder, or disease; delay in onset or slowing of the condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the subject; and enhancement or improvement of the condition, disorder, or disease. Treatment includes eliciting a clinically-significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0067] As used herein, the terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

[0068] As used herein, the term “adverse event”, or “AE”, refers to any untoward medical occurrence in a patient or clinical trial participant, temporally associated with the use of a drug, whether or not considered related to the drug. The term “adverse event” therefore encompasses any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of drug, whether or not considered related to the drug.

[0069] As used herein, the term “serious adverse event”, or “SAE”, refers to any untoward medical occurrence that, at any dose of a drug: a) results in death; or b) is life-threatening; or c) requires inpatient hospitalization or prolongation of existing hospitalization; or d) results in persistent disability / incapacity; or e) is congenital anomaly or birth defect; or f) is an important medical event, z.e., an event that may not be immediately life-threatening or result in death or hospitalization but may j eopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed above.

[0070] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, 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 cd.. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic 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 by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, cyclamate, digluconate, dodecyl sulfate, edisylate, ethanesulfonate, esylate, formate, fumarate, gentisate, glucoheptonate, glycerophosphate, gluconate, glucoronate, glutamate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, ketoglutarate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, napadisylate, napsylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, oroate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, stereoisomers thereof (e.g., enantiomers, diastereomers) and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. In certain embodiments, a compound of Formula (I) is a hydrochloric acid salt.

[0071] The term “modified-release polymer” refers to a polymer that is used in a formulation (e.g., tablets and capsules) to modify the release rate of the drug upon the administration to a subject. For example, a modified-release polymer is used to dissolve a drug over time in order to be released slower and steadier 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 (hydroxyl -propyl methylcellulose)), hydrophobic matrix polymers (e.g., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS 100).

[0072] The term “diluent” as used herein refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starches, and partially pregelatinized starches), anhydrous lactose, lactose monohydrate, di -calcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol and mannitol)).

[0073] The term “glidanf ’ as used herein refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0074] The term “lubricant” as used herein refers to an excipient used to prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solid and die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0075] The term “coating” as used herein refers to an excipient to protect tablet ingredients from deterioration by moisture in the air and make large or unpleasant-tasting tablets easier to swallow. These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents. Methods of treating a disease or condition relating to aberrant function or activity of a T- type calcium channel

[0076] In all aspects, the present disclosure provides a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as Parkinson’s disease (PD), in a subject in need thereof, the method comprising administering (e.g., once, twice, three times) daily to the subject a therapeutically effective amount of a T-type calcium channel (TTCC) blocker. Exemplary TTCC blockers that may be used in the methods of the present disclosure are described, e.g., in U.S. Patent No. 8,377,968, the entire contents of which are hereby incorporated herein by reference.

[0077] In one aspect, the present disclosure provides a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as Parkinson’s disease, in a subject in need thereof, the method comprising administering (e.g., once, twice, three, or four times) daily to the subject a therapeutically effective amount of the compound of formula (I): or a pharmaceutically acceptable salt (e.g., co-crystal) or solvate thereof, for example, a compound of formula (II):

[0078] Compound of formula (I) may also be referred to as N-(( l -(2-( / c / 7-butylamino)-2- oxoethyl)piperidin-4-yl)methyl)-3 -chi oro-5 -fluorob enzami de, while compound of formula (II) may be referred to as 7V-((l-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5- fluorob enzami de hydrochloride. Compound of formula (I) may also be referred to herein as “compound 1”. Compound of formula (II) may also be referred to herein as “compound 2”. Compound of formula (I) and / or compound of formula (II) may also be referred to herein as “ulixacaltamide”.

[0079] In one aspect, the present disclosure provides a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as Parkinson’s disease, in a subject in need thereof, the method comprising administering (e.g., once, twice, three times) daily to the subject a therapeutically effective amount of the compound of formula (III): or a pharmaceutically acceptable salt thereof. Compound of formula (III) may also be referred to herein as “compound 3”.

[0080] In one aspect, the present disclosure provides a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as Parkinson’s disease, in a subject in need thereof, the method comprising administering (e.g., once, twice, three times) daily to the subject a therapeutically effective amount of any of the compounds disclosed in, for example, U.S. Patent No. 8,377,968, the entire contents of which are expressly incorporated herein by reference.

[0081] Disclosed herein are methods of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel, comprising administering a titrated dose such that the end or maintenance dosage exceeds an initial dosage or a dosage at which adverse events are likely to be experienced absent titration (a maximum tolerated dosage achieved without titration). As used herein, administering a titrated dose refers to the practice of beginning with a low dosage and escalating to one or more higher dosages. For example, in certain embodiments, disclosed herein is a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need thereof comprising (a) administering a first dose, such as a dose of about 5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject for a first period of time; (b) increasing the amount of the compound in the first dose and administering one or more increased doses of the compound to the subject to arrive at a maximum titrated dose; and (c) administering the maximum titrated dose of the compound to the subject. Typically, each dose is administered daily, preferably once a day.

[0082] For instance, in certain embodiments, step (b) comprises increasing the first dose to a second dose, such as for example, a dose of about 10 mg, and administering the second dose of the compound to the subject for a second period of time, wherein following administration of the second dose of the compound for the second period of time. In certain embodiments, step (b) may further comprise increasing the second dose to a third dose, such as a dose ranging from about 20 mg, and administering the third dose of the compound to the subject for a third period of time.

[0083] Also disclosed herein are embodiments further comprising increasing the third dose to a fourth dose, such as a dose of about 40 mg, and administering the fourth dose of the compound to the subject for a fourth period of time. In certain aspects, the methods disclosed herein may further comprise increasing the fourth dose to a fifth dose, such as a dose of about 60 mg, and administering the fifth dose of the compound to the subject for a fifth period of time. In certain aspects, the methods disclosed herein may further comprise increasing the fifth dose to a sixth dose, such as a dose of about 80 mg, and administering the sixth dose of the compound to the subject for a sixth period of time. In certain aspects, the methods disclosed herein may further comprise increasing the sixth dose to a seventh dose, such as a dose of about 100 mg, and administering the seventh dose of the compound to the subject for a seventh period of time.

[0084] Also disclosed herein is a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need of treatment comprising (a) administering to the subject for a first period, about 5 mg to about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administrating to the subject for a second period, about 10 mg to about 100 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and (c) administrating to the subject for a third period, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Typically, each of the first period, second period, and third period range from about 3 to about 9 days. However, shorter or longer periods of time may be used depending on the subject and / or the judgement of a physician.

[0085] Also disclosed herein is a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need of treatment comprising (a) administering to the subject for a first period, about 5 mg to about 40 mg per day of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (b) administrating to the subject for a second period, about 10 mg to about 100 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof; (c) administrating to the subject for a third period, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof; (d) administrating to the subject for a fourth period, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof; (e) administrating to the subject for a fifth period, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof; (f) administrating to the subject for a sixth period, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and (g) administrating to the subject for a seventh period, about 20 mg to about 120 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Typically, each of the first period, second period, third period, fourth period, fifth period, and sixth period range from about 3 to about 9 days, and the seventh period ranges from about 7 days to about 30 days. However, shorter or longer periods of time may be used for each period depending on the subject and / or the judgement of a physician.

[0086] In certain embodiments, the subject does not experience adverse events at any of the dosage levels in the titrated dosage schedule. In certain embodiments, absent administering a first dosage level for a first dosing period (e.g., about 5 mg to about 40 mg), the subject would experience adverse events at the second dosage level administered during the second dosing period (e.g., about 10 mg to about 100 mg, such as at least about 60 mg to about 100 mg). In certain embodiments, absent administering the first and second dosage level during the first and second dosing period, a subject would experience adverse events at the third dosage level administered during the third dosing period (e.g., about 20 mg to about 120 mg, such as at least about 60 mg to about 120 mg).

[0087] In certain embodiments, wherein a subject would be likely to experience adverse events at the second dosage level administered during the second dosing period absent administering the first dosage level during the first dosing period, the dosage may continue to be titrated to a dosage level that is greater than the second dosage level administered during the second dosing period, such as a dosage level that is at least about 25% greater, at least about 50% greater, at least about 75% greater, at least about 100% greater, at least about 125% greater, at least about 150% greater, at least about 175% greater, at least about 200% greater, at least about 250% greater, or at least about 300% greater than the dosage level at which adverse events are likely to occur without titration.

[0088] In certain aspects of all embodiments disclosed herein, the time period of administration, such as the first, second, third, fourth, fifth, or sixth period of time, may range from about 3 to about 9 days, such as, for example, 3, 4, 5, 6, 7, 8, or 9 days. In certain aspects of the embodiments disclosed herein, the time period of administration, such as the seventh period of time, may range from about 3 to about 30 days, such as, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. In other aspects of the embodiments disclosed herein, of the time periods, e.g., the first, second, third, fourth, fifth, sixth, or seventh time period of administration may extend beyond 14 days.

[0089] In certain aspects, the dosage increase relative to the prior dose does not increase more than 40 mg per day. For instance, in certain embodiments, the second dose is increased no more than 40 mg per day relative to the first dose, and in certain aspects, the third dose is increased no more than 40 mg per day relative to the second dose.

[0090] In another aspect, the present disclosure provides a method of treating a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need thereof, the method comprising administering (e.g., once, twice, three times) daily to the subject up to about 120 mg (e.g., 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, 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) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0091] In another aspect, the present disclosure provides a method of treating a disease or condition relating to aberrant function or activity of T-type calcium channels in a subject in need thereof, the method comprising: (a) administrating to the subject once daily for a first period (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));

[0092] (b) administrating to the subject once daily for a second period (e.g., 3, 4, 5, 6, 7, 8, or 9 days), 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)); and

[0093] (c) administrating to the subject once daily for a third period (e.g., 3, 4, 5, 6, 7, 8, or 9 days), 20 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0094] In some embodiments, the method further comprises (d) administering to the subject for a fourth period (e.g., 3, 4, 5, 6, 7, 8, or 9 days), 40 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0095] In other embodiments, the method further comprises (e) administering to the subject for a fifth period (e.g., 3, 4, 5, 6, 7, 8, or 9 days), 60 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0096] In certain embodiments, the method further comprises (f) administering to the subject for a sixth period (e.g., 3, 4, 5, 6, 7, 8, or 9 days), 80 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0097] In certain embodiments, the method further comprises (g) administering to the subject for a seventh period (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more days), 100 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) as needed.

[0098] In certain embodiments, the method further optionally comprises (h) administering to the subject for an eighth period (e.g., 3, 4, 5, 6, or 7 days) 50 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) as needed.

[0099] In certain embodiments, the method further optionally comprises (i) administering to the subject for a ninth period (e.g., 3, 4, 5, 6, or 7 days) 25 mg per day of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) as needed. In some embodiments, the subject is a human of age from birth to 100 years of age, such as from 10 to 90 years, from 20 to 70 years, from 18 to 55 years, or from 55-75 years of age.

[0100] In other embodiments, the disease or condition relating to aberrant function or activity of a T-type calcium channel is selected from the group consisting of Parkinson’s disease (PD), psychiatric disorders (e.g., mood disorder (e.g., major depressive disorder)), pain, tremor (e.g., essential tremor), seizures (e.g., absence seizures), and epilepsy or an epilepsy syndrome (e.g., juvenile myoclonic epilepsy). In an embodiment, the disease or condition relating to aberrant function or activity of a T-type calcium channel is Parkinson’s disease (PD).

[0101] In certain aspects of all embodiments of titrated dosing schedules disclosed herein, it is possible to increase the maximum titrated dose, including, for example, increasing the maximum titrated dose above 120 mg in one or more additional titration steps, provided the subject is able to safely tolerate the higher dose.

[0102] In certain aspects of all of the embodiments of titrated dosing schedules disclosed herein, the maximum titrated dosage achieved is greater than 20 mg, greater than 40 mg, greater than 60 mg, such as about 80 mg, about 100 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, or about 220 mg.

[0103] In some embodiments, methods of the present disclosure comprise administering to a subject in need thereof a titrated dose of a TTCC blocker, e.g., compound of formula (I), (II) or (III). In some embodiments, the maximum titrated dose is 60 mg per day or 100 mg per day. In one embodiment, the maximum titrated dose is 60 mg per day.

[0104] In certain aspects of all of the embodiments of titrated dosing schedules disclosed herein, the maximum titrated dosage is reached 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 embodiments, the maximum titrated dosage is reached in about 10 to about 42 days, such as, for example, about 36-42 days, about 22-28 days, about 16-18 days, or about 10-12 days. Dosage forms and compositions

[0105] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, e.g., the compound of formula (II) may be in a dosage form or in a pharmaceutical composition.

[0106] In some embodiments, a composition that can be used in a method described herein 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 some embodiments, the pharmaceutical composition may be a swellable core technology formulations.

[0107] In certain embodiments, a dosage form that can be used in a method described herein 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., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS 100)).

[0108] In other embodiments, a dosage form that can be used in a method described herein 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., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS 100)), for example, in an amount sufficient to modify the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) upon an administration to the subject.

[0109] In some embodiments, the dosage form may comprise from about 0.9% by weight to about 40% by weight (e.g., 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, 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 (e.g., 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 (e.g., the compound of formula (II)).

[0110] In some embodiments, the dosage form may comprises from about 14% by weight to about 25% by weight 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 19% by weight to about 20% by weight 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 21% by weight to about 22% by weight 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 4% by weight to about 15% by weight 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 4% by weight to about 10% by weight 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 form about 4% by weight to about 5% by weight 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% by weight to about 6% by weight 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 9% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0111] In other embodiments, a dosage form that can be used in a method described herein may be a dosage form or composition comprising from about 1 mg to about 120 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg) of 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., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS 100)), for example, in an amount sufficient to modify the release rate of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) upon an administration to the subject.

[0112] 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)). In 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)).

[0113] 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 60% by weight of the modified-release polymer (e.g., an HPMC polymer).

[0114] 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 (e.g., 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) microcrystalline cellulose. In some embodiments, the dosage form comprises from about 15 mg to about 25 mg microcrystalline cellulose. In some embodiments, the dosage form comprises from about 30 mg to about 40 mg microcrystalline cellulose. In some embodiments, the dosage form comprises from about 15% to about 35% by weight (e.g., from about 15% to about 20%, from about 20% to about 25%, from 25% to about 30%, from 30% to about 35% by weight) microcrystalline cellulose.

[0115] In some embodiments, the dosage form further comprises a glidant. In some embodiments, the glidant comprises colloidal silicon dioxide. In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the dosage form further comprises a coating.

[0116] In some embodiments, about 80% of the compound of formula (I) or a pharmaceutically acceptable salt is released within 7 hours upon administration to a subject. In certain embodiments, about 80% of the compound of formula (I) or a pharmaceutically acceptable salt thereof is released in 7 hours using USP apparatus type-I, media containing 900 mL 0.1 M HC1, and a paddle speed of 100 rpm.

[0117] In some embodiments, the dosage form, upon administration to a subject, has a reduced 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, a dosage form that does not have a modified-release polymer, e.g., an HPMC polymer). In some embodiments, the dosage form, upon administration to a subject, has a greater 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, a dosage form that does not have a modified-release polymer, e.g., an HPMC polymer).

[0118] In other embodiments, the dosage form is administered to a patient once 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.

[0119] In some embodiments, a dosage form that can be used in a method described herein may be an oral dosage form (e.g., particulate) comprising: from about 15 mg to 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.

[0120] In other embodiments, a dosage form that can be used in a method described herein may be an oral dosage form (e.g., particulate) comprising from about 14% by weight to about 25% 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.

[0121] In certain embodiments, a dosage form that can be used in a method described herein may be an oral dosage form (e.g., particulate) comprising from about 3 mg to 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.

[0122] In some embodiments, a dosage form that can be used in a method described herein 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.

[0123] In other embodiments, a dosage form that can be used in a method described herein may be an oral (e.g., particulate) 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, e.g., an HPMC polymer as a hydrophilic matrix polymer). 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., the compound of formula (II)). In some embodiments, the composition comprises from about 14% by weight to about 25% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises about 19% by weight to about 20% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises about 21% by weight to about 22% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises from about 4% by weight to about 15% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises from about 4% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises about 4% by weight to about 5% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises about 5% by weight to about 6% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In some embodiments, the composition comprises about 9% by weight to about 10% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)).

[0124] In some embodiments, the composition comprises from about 1 mg to about 120 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about

[0125] 105 mg, about 110 mg, about 115 mg, or about 120 mg) of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)). In certain embodiments, the composition comprises 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 other embodiments, the composition 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 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., the 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., the 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., the 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., the compound of formula (II)). In other embodiments, the composition 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 composition 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 composition 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 composition 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 composition 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 composition 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)).

[0126] 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 (e.g., 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), microcrystalline cellulose. In some embodiments, the composition comprises from about 15% to about 35% by weight (e.g., from about 15% to about 20%, from about 20% to about 25 %, from 25% to about 30%, from 30% to about 35% by weight) microcrystalline cellulose.

[0127] In some embodiments, the composition comprises from about 15 mg to about 25 mg microcrystalline cellulose. In some embodiments, the composition comprises from about 30 mg to about 40 mg microcrystalline cellulose. In some embodiments, the composition further comprises a glidant. In some embodiments, the glidant comprises colloidal silicon dioxide. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the composition further comprises a coating. In some embodiments, the compound of formula (I) or (II), including, for example, 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 about 25 °C at 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at about 25 °C at 60% relative humidity for at least 60 months. In some embodiments, the compound is stable at about 40 °C at 75% relative humidity for at least 6 months.

[0128] In some embodiments, the composition may include a single-unit dosage form comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of Formula (II)). In certain embodiments, single-unit dosage form comprises up to 200 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the single-unit dosage form comprises a length of up to 16 mm, e.g., about 14 mm to about 16 mm, and / or a width of up to 7 mm, e.g., about 5 mm to about 7 mm. In some embodiments, the single-unit dosage form is bioequivalent to a reference composition of the same dosage strength administered as multiple dosage forms, such as the a modified release (MR) formulation comprising the compound of Formula (I) available as 5 mg and 20 mg tablets that are round and small in size (e.g., about 6 mm in diameter). In some embodiments, bioequivalency may be established by: (a) a 90% Confidence Interval for AUC which is between about 80% and about 125%, and (b) a 90% Confidence Interval for Cmax, which is between about 80% and about 125%.

[0129] In other embodiments of the oral dosage forms or compositions described herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is a crystalline form. In certain embodiments, the crystalline form is a crystalline form previously or contemporaneously described, such as crystalline Pattern B, crystalline Pattern C or crystalline Pattern D. Crystalline Pattern B and crystalline Pattern C are described, e.g., in WO 2021 / 007487, the entire contents of which are hereby incorporated herein by reference. Crystalline Pattern D is characterized by an x-ray powder diffraction (XRPD) pattern comprising at least one peak at the diffraction angle (° 29) 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°.

[0130] Immediate-release formulations

[0131] In some embodiments, a dosage form or composition that can be used in a method described herein 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)), where the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is released immediately upon an administration to the subject.

[0132] In other embodiments, a dosage form that can be used in a method described herein may be an oral capsule for immediate release 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)); and from about 75 mg to 85 mg diluent; from about 2 mg to 10 mg binder; from about 1 % to about 5 % disintegrant; and from about 0.1 mg to 5 mg lubricant.

[0133] Administrations

[0134] In some embodiments, the dosage form is administered to the subject once a day (e.g., one 5 mg tablet once a day, two 5 mg tablets once a day, one 20 mg tablet once a day, two 20 mg tablets once a day, three 20 mg tablets once a day, four 20 mg tablets once a day, or five 20 mg tablets once a day). In certain embodiments, about 5 mg to 100 mg, such as 5 mg, 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg, of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the compound of formula (II)) is administered to the subject daily.

[0135] Parkinson’s Disease

[0136] The compositions described herein are useful in the treatment of Parkinson’s disease (PD). PD may be characterized by one or more of tremor, bradykinesia, rigidity, posture and gait disorder. Without wishing to be bound by any particular theory, it is believed that delivery of a T-type calcium channel modulator minimizes these symptoms. Accordingly, in some embodiments, the present invention provides methods for treating a subject with PD comprising administering to said subject a TTCC blocker, e.g., compound of formula (I): or a pharmaceutically acceptable salt thereof, such that at least one symptoms of PD is treated, prevented or alleviated in said subject.

[0137] The methods described herein can be used to treat tremor, for example a dosage or composition disclosed herein can be used to treat Parkinsonian 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 Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced (neuroleptics tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be a neuropathic tremor, and can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor), primary orthostatic tremor, task- and position-specific tremor, dystonic tremor, Parkinsonian tremor, cerebellar tremor, Holmes’ tremor (i.e., rubral tremor), palatal tremor, toxic or drug-induced tremor, and psychogenic tremor. The tremor may be familial tremor. Tremor is an involuntary, rhythmic, oscillation of one or more body parts e.g., hands, arms, eyes, face, head, vocal folds, trunk, and / or legs).

[0138] In some embodiments, the subjects are selected for treatment with a TTCC blocker, e.g., compound of formula (I), (II) or (III), due to a clinical diagnosis of essential tremor. In some embodiments, the subjects selected for treatment with a TTCC blocker, e.g., compound of formula (I), (II) or (III), have essential tremor, but do not have intention tremor.

[0139] Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.

[0140] In some embodiments, the subjects selected for treatment with a TTCC blocker, e.g., compound of formula (I), (II) or (III) in the context of the present disclosure do not have intention tremor.

[0141] The methods herein can be used to treat bradykinesia, rigidity, posture, and gait disorders. Bradykinesia refers to slow movement, and in PD, is usually characterized in combination with at least one of rest tremor (4-6 Hz) or rigidity. Rigidity is characterized by stiff or inflexible muscles. Posture disorders in PD are generally characterized by one or more of stooped or rounded shoulders, decreased low-back curve, or forward lean of the head and whole body. Gait disorders in PD patients, also referred to as Parkinsonian gait, is generally characterized by small, shuffling steps due to difficulty picking up feet.

[0142] Accordingly, in certain embodiments, the present invention provides methods for alleviating at least one symptom of PD in a subject indicated by a lack of an increase in the total score as measured according to the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS total score), as compared to the baseline MDS-UPDRS total score. The phrase “lack of an increase” as used herein refers to a score staying the same or decreasing following treatment. The phrase “baseline MDS-UPDRS total score” as used herein refers to the MDS-UPDRS total score measured prior to treatment with compound of formula (I). The UPDRS has been one of the most widely used clinical rating scales used for PD since it was introduced in the 1980s. A revised version of the UPDRS developed by the MDS, the MDS-UPDRS, is now one of the most common scales for evaluating the severity of PD across behaviors and complications associated with the disease (Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Movement Disord. 2008;23:2129-70. doi: 10.1002 / mds.22340). The scale consists of 4 parts that capture different dimensions of the disease across 65 scores, which are as follows:

[0143] • Part 1 is the Non-Motor Aspects of Experiences of Daily Living section, assessing the non-motor impact of PD on experiences of daily living (13 items, 6 of which are clinician-rated and 7 of which are patient- or caregiver-rated);

[0144] • Part 2 is the Motor Aspects of Experiences of Daily Living section, assessing the motor impact of PD on experiences of daily living (13 items, all of which are patient- or caregiver-rated);

[0145] • Part 3 is the clinician-rated Motor Examination, assessing the motor signs of PD in the ON and OFF state (33 scores based on 18 items, some with right, left, or other body distribution scores; all of which are clinician-rated);

[0146] • Part 4 is the Motor Complications section, assessing dyskinesia, motor fluctuations, and OFF-state dystonia (6 items, all of which are clinician-rated).

[0147] The scale takes approximately 30 minutes to complete. It can be completed by a qualified rater with input from the patient, caregiver, or both, as directed by the scale instructions. Each question presents a clinical descriptor with a prompt to rate the severity of the participant’s symptom on a 5-point Likert scale (range of scores is 0 through 4). Higher scores indicate greater severity (greater frequency or greater intensity) as follows:

[0148] • “Normal” (0) indicates the clinical sign or symptom is not present;

[0149] • “Slight” (1) indicates frequency or intensity causing no impact on function;

[0150] • “Mild” (2) indicates frequency or intensity causing a modest impact on function; • “Moderate” (3) indicates frequency or intensity causing considerable impact on function, but not preventing it;

[0151] • “Severe” (4) indicates frequency or intensity preventing function.

[0152] Part I, II, and IV ratings are based on the average or usual function of the participant over the past week, including the day the scale is completed.

[0153] Total scores are calculated for each part of the MDS-UPDRS. In addition, the MDS- UPDRS tremor score is calculated as the sum of item 10 from Part 2 and items 15 (a and b), 16 (a and b), 17 (a through e), and 18 from Part 3.

[0154] Accordingly, in some embodiments, the MDS-UPDRS total score is measured in the OFF state. The term “OFF state” as used herein refers to a state in a subject with PD that results when the subject has not been dosed with an anti -Parkinsonian medication for at least 8 hours. In yet further embodiments, the MDS-UPDRS total score is measured in the ON state. The term “ON state” as used herein refers to a state in a subject with PD that results 1 hour after the subject has been dosed with an anti-Parkinsonian medication.

[0155] In certain embodiments, the present invention provides methods for alleviating at least one symptom of PD in a subject indicated by a lack of an increase in one or more of MDS- UPDRS Part 1 score, MDS-UPDRS Part 2 score, MDS-UPDRS Part 3 score, and MDS-UPDRS Part 4 score. In further embodiments, the lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS-UPDRS subscale score for one or more of the following symptoms: tremor, bradykinesia, rigidity, posture, and gait disorder.

[0156] In certain embodiments, a lack of increase in the MDS-UPDRS total score comprises the decrease in the MDS-UPDRS total score of at least 5 points, at least at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, at least 40 points, at least 45 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 75 points, at least 80 points, at least 85 points, at least 90 points, at least 95 points, at least 100 points, at least 105 points, at least 110 points, at least 115 points, at least 120 points, at least 125 points, at least 130 points, at least 135 points, at least 140 points, at least 145 points or at least 150 or more points. In certain embodiments, a lack of increase in the MDS-UPDRS Part 1 score comprises a decrease in the MDS-UPDRS Part 1 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0157] In certain embodiments, a lack of increase in the MDS-UPDRS Part 2 score comprises a decrease in the MDS-UPDRS Part 2 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0158] In certain embodiments, a lack of increase in the MDS-UPDRS Part 3 score comprises a decrease in the MDS-UPDRS Part 3 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0159] In certain embodiments, a lack of increase in the MDS-UPDRS Part 3 subscale score for tremor comprises a decrease in the MDS-UPDRS Part 3 subscale score for tremor of at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

[0160] In certain embodiments, a lack of increase in the MDS-UPDRS Part 3 subscale score for bradykinesia comprises a decrease in the MDS-UPDRS Part 3 subscale score for bradykinesia of at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

[0161] In certain embodiments, a lack of increase in the MDS-UPDRS Part 3 subscale score for rigidity comprises a decrease in the MDS-UPDRS Part 3 subscale score for rigidity of at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

[0162] In certain embodiments, a lack of increase in the MDS-UPDRS Part 3 subscale score for posture comprises a decrease in the MDS-UPDRS Part 3 subscale score for posture of at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

[0163] In certain embodiments, a lack of increase in the MDS-UPDRS Part 3 subscale score for gait disorder comprises a decrease in the MDS-UPDRS Part 3 subscale score for gait disorder of at least 1 point, at least 2 points, at least 3 points, at least 4 points, or at least 5 points.

[0164] In certain embodiments, a lack of increase in the MDS-UPDRS Part 4 score comprises a decrease in the MDS-UPDRS Part 4 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

[0165] The Beck Depression Inventory (BDI-II) is a list of 21 common symptoms of depression (Beck AT, Steer RA, Ball R, Ranieri WF. Comparison of Beck Depression Inventories-IA and-II in psychiatric outpatients. J Pers Assess. 1996;67:588-97. doi : 10.1207 / sl5327752jpa6703_13). Each item is scored on a 4-point Likert scale (range of scores is 0 through 3). The time frame for assessment is the preceding month or since the last assessment. The BDI-II is divided into 2 subscales: Affective and Somatic. The subscale scores are calculated as the sum of the items comprising each subscale. The total score is calculated as the sum of all 21 items and ranges from 0 to 63. A total score of 0 to 13 indicates minimal depressive symptoms. A total score of 14 to 19 indicates mild depressive symptoms. A total score of 20 to 28 indicates moderate depressive symptoms. A total score of 29 to 63 indicates severe depressive symptoms. The BDI- II is assessed at screening to exclude participants with moderate to severe depressive symptoms.

[0166] Accordingly, in some embodiments, the method does not result in moderate depressive symptoms or severe depressive symptoms in the subject as measured by BDI-II.

[0167] The Beck Anxiety Index (BAI) is a brief measure of anxiety with a specific attention on somatic symptoms of anxiety that was developed as a measure aimed at discriminating between anxiety and depression (Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psych. 1988;56:893-7. doi : 10.1037 / / 0022-006x.56.6.893). The BAI contains 21 questions about the common symptoms of anxiety that the subject could have experienced during the past week (including the day the BAI is administered). The common symptoms of anxiety include numbness and tingling, sweating not due to heat, and fear of the worst happening. It is designed for individuals who are of 17 years of age or older and takes 5 to 10 minutes to complete. Each answer is scored on a scale value of 0 (not at all) to 3 (severely). Higher total scores indicate more severe anxiety symptoms. The standardized cutoffs are the following: 0-7: minimal, 8-15: mild, 16-25: moderate, 26-63: severe.

[0168] Accordingly, in some embodiments, the method does not result in moderate anxiety symptoms or severe anxiety symptoms as measured by BAI.

[0169] The Clinical Global Impression-Severity (CGI-S) (Guy 1976) assesses the clinician’s impression of the participant’s functioning prior to and after initiating study medication. The clinician should use his / her total clinical experience with this patient population and rate the current severity of the participant’s parkinsonian symptoms on a 7-point scale from 1 (Normal, not at all ill) to 7 (Among the most extremely ill patients).

[0170] Accordingly, in some embodiments, the method results in a decrease in CGI-S score compared to baseline, e.g., a decrease in the CGI-S score as compared to the CGI-S score measured prior to treatment with compound of formula (I).

[0171] The Patient Global Impression-Severity (PGI-S) (Viktrup L, Hayes RP, Wang P, Shen W. Construct validation of patient global impression of severity (PGI-S) and improvement (PGI- I) questionnaires in the treatment of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. BMC Urol. 2012 Nov 7;12:30. doi: 10.1186 / 1471-2490-12-30) is a global self-assessment of the participant’s level of functioning prior to and after initiating study medication. It was originally developed for assessment in women with stress urinary incontinence. However, due to its lack of specificity for medical conditions and its sensitivity to change, it has also been used for participant self-assessment in other conditions. The participant rates his / her Parkinsonian symptoms on a 7-point scale from 1 (Not present) to 7 (Extremely severe).

[0172] Accordingly, in some embodiments, the method results in a decrease in PGI-S score as compared to the baseline PGI-S score, e.g., a decrease in the PGI-S score as compared to the PGI-S score measured prior to treatment with compound of formula (I).

[0173] The Motor Complications Assessment is an assessment of ON / OFF state and dyskinesia conducted every 30 minutes for the 4 hours following administration of study drug. For each assessment, clinicians indicate whether participants are asleep, in the OFF state, or in the ON state. For participants in the ON state, the clinician also assesses whether dyskinesia is absent, mild, moderate, or severe. The motor complications assessment is adapted from Hauser et al 2000 (Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O’Brien CF, et al. A home diary to assess functional status in patients with PD with motor fluctuations and dyskinesia. Clin Neuropharmacol. 2000;23:75. doi: 10.1097 / 00002826-200003000-00003).

[0174] Accordingly, in some embodiments, the method results in a decrease in dyskinesia as measured by the Motor Complications Assessment in the ON state, as compared to dyskinesia measured in the ON state prior to treatment with compound of formula (I). In some embodiments, the method results in a decrease in dyskinesia as measured by the Motor Complications Assessment in the OFF state, as compared to dyskinesia measured in the OFF state prior to treatment with compound of formula (I). In some embodiments, the method results in a decrease dyskinesia as measured by the Motor Complications Assessment every 30 minutes for 4 hours on Days 21, 49, 77, and 91 compared to baseline when a subject is in the ON state.

[0175] The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease - Rating Scale (QUIP -RS) is a brief, rater-administered scale to assess the severity of ICDs in participants with PD (Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in Parkinson’s Disease-Rating Scale. Movement Disord. 2012;27:242-7. doi: 10.1002 / mds.24023). The QUIP -RS consists of 4 questions that each ask about 7 behaviors / activities that each use a 5-point Likert scale (range of scores is 0 through 4) to measure the frequency of behaviors occurring in the preceding 4 weeks. Higher scores indicate greater frequency of behaviors. Total scores on the QUIP -RS range from 0 to 112.

[0176] Accordingly, in some embodiments, the method results in a decrease in QUIP -RS score as compared to the QUIP -RS score prior to treatment with compound of formula (I). In some embodiments, the method results in a decrease in QUIP -RS score at Day 77 compared to baseline.

[0177] The Montreal Cognitive Assessment (MoCA) is a 10-minute cognitive screening tool for detecting mild cognitive impairment (Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695-9. doi: 10.1111 / j .1532- 5415.2005.53221.x). Cognitive domains assessed include short-term memory, visuospatial abilities, executive function, attention, working memory, and language. Orientation to time and place is also evaluated. Scores on the MoCA range from 0 to 30 with lower scores indicating greater cognitive impairment. A score of 26 or less is considered mild cognitive impairment.

[0178] Accordingly, in some embodiments, the method results in a decrease in MoCA score as compared to MoCA score prior to treatment with compound of formula (I). In some embodiments, the method results in a decrease in MOCA score at Day 77 compared to baseline.

[0179] The Epworth Sleepiness Scale (ESS) is a scale that captures the participant’s report of sleep propensity throughout the day by asking how likely they are to fall asleep in 8 specific situations (Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1990;14:540-5. doi: 10.1093 / sleep / 14.6.540). Participants will rate their likeliness of sleep on a 4-point Likert scale (range of scores is 0 to 3) with higher scores indicating a greater chance of falling asleep. Participants are asked to rate the likelihood of sleep on a usual day in recent times. The total score on the scale ranges from 0 to 24.

[0180] Accordingly, in some embodiments, the method results in a decrease in ESS score as compared to ESS socre prior to treatment with compound of formula (I). In some embodiments, the method results in a decrease in ESS score at Days 21, 49, and 77 compared to baseline.

[0181] Combination Therapy

[0182] A dosage form or composition described herein (e.g., for use in modulating a T-type calcium ion channel) may be administered in combination with at least one other agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. In certain embodiments, these diseases or conditions can relate to epilepsy or an epilepsy syndrome (e.g., absence seizures, juvenile myoclonic epilepsy, or a genetic epilepsy) or tremor (e.g., essential tremor or Parkinsonian tremor).

[0183] Tremor Medications

[0184] By way of non-limiting example, essential tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, zonisamide, and combinations thereof. By way of non-limiting example, Parkinsonian tremor medications include levodopa, carbidopa, zonisamide, scopolamine, nadolol, hyoscyamine, foscarbidopa, foslevodopa, amantadine, pramipexole, rotigotine, ropinirole, istradefylline, apomorphine, trinexyphenidyl, benztropine, safinamide, selegiline, rasagiline, entacapone, opicapone, tolcapone, and combinations thereof. In an embodiment, a medication for Parkinson’s disease is levodopa. In an embodiment, Parkinson’s disease medications include any of levodopa, carbidopa, dopamine agonists, anticholinergics, monoamine oxidase inhibitors (including MAO-B inhibitors), chatechol-O- methyltransferase inhibitors (COMT inhibitors), or combinations thereof. EXAMPLES

[0185] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0186] Example 1: A Phase 2 / 3, Randomized, Double-Blind, Flexible Dose, Placebo Controlled, Parallel Design, Randomized Withdrawal Study Evaluating Efficacy, Safety, Tolerability, and Pharmacokinetics of Ulixacaltamide in Adults with Parkinson’s Disease

[0187] Introduction

[0188] There is an urgent need for non-dopaminergic therapeutic options in Parkinson’s disease (PD) given dopaminergic treatment often poorly controls tremor and / or is associated with motor complications in advanced disease. Notably, degeneration of nigral dopaminergic neurons in PD is associated with aberrant burst firing in key regions of the basal ganglia circuit that correlates with akinesia and rigidity (AR), while inducing tremor-coherent thalamic oscillatory activity in the VIM thalamic nucleus of the cerebello-thalamo-cortical circuit. Ulixacaltamide (compound 1) has the potential to improve PD motor symptoms by suppressing these neuronal circuit aberrancies. This is a Phase 2 / 3 trial that aims to evaluate the efficacy, safety, and tolerability of ulixacaltamide in PD.

[0189] This is a double-blind, randomized, placebo-controlled, parallel-design / randomized withdrawal trial in adults (aged 50-80 years) with a PD diagnosis consistent with UK Brain Bank and Movement Disorder Society (MDS) criteria. Eligible participants must have disabling tremor, Hoehn and Yahr stage 2-3 (motor on state), and be without motor complications (early morning motor off periods allowed). Participants will be randomized 2: 1 to ulixacaltamide or placebo for 12 weeks. Responders meeting the predefined threshold at Week 12 will be further randomized 1 : 1 to ulixacaltamide or placebo for 4 weeks (RW period).

[0190] The primary endpoint is the proportion of participants that maintain tremor response at Week 16 in the RW period as measured by a novel Upper Extremity tremor ADL scale. Key secondary endpoints will include the MDS-Unified Parkinson’s Disease Rating Scale Part III score, Part II score and individual tremor sub-items, as well as Patient Global Impression of Severity / Change and Clinician Global Impression of Severity / Improvement. This is an innovative trial designed to provide evidence of efficacy, safety and tolerability of ulixacaltamide for the treatment of PD motor symptoms.

[0191] Overview

[0192] This is a decentralized, double-blind, Phase 2 / 3 clinical trial evaluating the efficacy, safety, and tolerability of ulixacaltamide for the treatment of tremor and other motor symptoms in adults with Parkinson’s disease (PD). This trial includes 2 parts:

[0193] Part A: The initial 12-week parallel design portion of the trial that includes a 4-week flexible titration period, where eligible adult participants with PD are randomized 2: 1 to receive either ulixacaltamide or placebo.

[0194] Part B: The 4-week randomized withdrawal portion of the trial for participants who meet pre-defined responder criteria at Week 12. These participants will be randomized 1 : 1 to either continue receiving ulixacaltamide or transition to receiving placebo until Week 16.

[0195] During Part B, non-responders from Part A will continue to receive their assigned treatment of ulixacaltamide or placebo, thereby extending the parallel design portion of the trial to run in parallel with the randomized withdrawal (Figure 1).

[0196] For those randomized to ulixacaltamide, the dose of study drug will be titrated from 10 mg up to a range between 40 mg and 80 mg, based on each participant’s tolerability. Those who cannot tolerate a dose of >40 mg by the end of the Titration Period will discontinue the study following an Early Discontinuation (ED) Visit and completion of the Safety Follow-up (SFU) Visit.

[0197] This trial assesses a broad array of PD motor symptoms but is also tailored to assess the unique clinical features and issues associated with PD tremor. As such the primary efficacy endpoint is focused on tremor, with the upper extremity tremor-activities of daily living (UE Tremor- ADL) derived from The Essential Tremor Rating Assessment Scale Activities of Daily Living (TETRAS-ADL).

[0198] Objectives and Endpoints

[0199] The objectives and endpoints for the trial are summarized in Table 1. Table 1. Objectives and Endpoints

[0200] ADL=activities of daily living; AR=akinetic rigid; BAI=Beck Anxiety Index; BDI-II=Beck

[0201] Depression Inventory-Second Edition; CGI-I=Clinician Global Impression of Improvement; CGI- S=Clinician Global Impression of Severity; C-SSRS=Columbia-Suicide Severity Rating Scales; ECG=electrocardiogram; EOM=extraocular muscles; FDG-PET=fluorodeoxyglucose positron emission tomography; MDS-UPDRS=Intemational Parkinson and Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; MoCA=Montreal Cognitive Assessment; PD=Parkinson’s disease; PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; RW=randomized withdrawal; SAE=serious adverse event; TD=tremor-dominant; TEAE=treatment- emergent adverse event; TETRAS-ADL=The Essential Tremor Rating Assessment Scale Activities of Daily Living UE=upper extremity. Overall Design

[0202] This is a phase 2 / 3 multi -center, randomized, double-blind, flexible dose, placebo- controlled, trial to assess the efficacy, safety, and tolerability of ulixicaltamide for the treatment of tremor and other motor symptoms in adults with PD.

[0203] This clinical trial will enroll participants who have a diagnosis of PD consistent with United Kingdom (UK) Brain Bank criteria and International Parkinson and Movement Disorder Society (MDS) PD research criteria (APPENDIX ) and have functionally detectable tremor based on assessment scores at screening. Participants must be on a stable daily regimen of antiparkinsonian oral medications for at least 4 weeks prior to Screening and will be required to remain on a stable regimen throughout the study to be eligible for the trial.

[0204] The trial consists of the following periods:

[0205] Screening Period: a 4-week period where participants may complete designated screening assessments at the first screening visit (VI, at the beginning of the Screening Period) and / or second screening visit (V2, approximately 2 weeks after VI).

[0206] Part A Intervention Period: a 4-week flexible Titration Phase and an 8-week Part A Maintenance Phase, where participants who can tolerate doses >40 mg will continue to receive stable daily doses of study drug through Week 12.

[0207] Part B Intervention Period: a 4-week continuation of the Maintenance Phase for those who were either non-responders or randomized to placebo in Part A or a 4-week Randomized Withdrawal Phase for participants who meet the responder criteria based on the UE Tremor- ADL Tremor Score in at the end of Part A (Week 12).

[0208] Safety Follow-Up Period: Participants who complete the Intervention Period (Parts A and B) will directly enter the 2-week Safety Follow-up (SFU) Period. Those who discontinue early from the study for anyreason will have an early discontinuation (ED) Visit scheduled as soon as possible and an SFU Visit 14 days following the last dose of study drug.

[0209] The schedule of on-site and telehealth visits is outlined in the Trial Schema shown in Figure 1.

[0210] Eligible participants will be randomized in a 2: 1 ratio to ulixacaltamide or placebo, and the blinded flexible dose Titration Period will begin. Participants will begin study drug at a 10 mg dose that will be incrementally increased every 5 days to 80 mg or the highest tolerated dose. Participants who do not tolerate a dose of >40 mg during the Titration Period will be withdrawn from the study without tapering down and without being replaced. Participants who discontinue study drug after randomization will complete an ED Visit and then continue into the Safety Follow-Up (SFU) Period.

[0211] Duration and Study Periods of Clinical Trial

[0212] The duration of the trial can be as long as 22 weeks (154 days), including the Screening, Intervention, and Safety Follow-up Periods. An additional week may be granted to extend the Screening Period as per Sponsor approval.

[0213] Table 2. Study Periods

[0214] The Screening Period may be extended up to 1 week, at the discretion of the Sponsor.

[0215] Overall Design

[0216] This clinical trial will enroll participants who have a diagnosis of PD consistent with United Kingdom (UK) Brain Bank criteria and International Parkinson and Movement Disorder Society (MDS) PD research criteria (link to appendix with criteria) and detectable tremor. Participants must have functionally detectable tremor, as defined by UE Tremor-ADL Tremor Score >X, a MDS-Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 total score of >12 and <59, and a Hoehn and Yahr stage 2 or 3 in the medication on state. Participants must be on a stable daily regimen of antiparkinsonian oral medications for at least 4 weeks prior to Screening and will be required to remain on a stable regimen throughout the study period to be eligible for the trial.

[0217] Participants will be excluded if they have a diagnosis of secondary or atypical parkinsonism, have a Montreal Cognitive Assessment (MoCA) score of <24 at Screening, orthostatic hypotension, psychosis, dopamine dysregulation or impulsivity control symptoms as defined in the exclusion criteria. Patients that received magnetic resonance-guided focused ultrasound, surgical intervention for PD or tremor such as DBS, currently treated with continuous intestinal levodopa, other continuous dopamine treatment or botulinum toxin injection within 6 months for any reason prior to Screening will be excluded..

[0218] The trial consists of the following periods:

[0219] Screening Period: a 4-week period where participants may complete designated screening assessments at the first screening visit (VI, at the beginning of the Screening Period) and / or second screening visit (V2, approximately 2 weeks after VI).

[0220] Part A Intervention Period: a 4-week flexible Titration Phase and an 8-week Part A Maintenance Phase, where participants who can tolerate >40 mg doses continue to receive stable daily doses of study drug through Week 12.

[0221] Part B Intervention Period: a 4-week continuation of the Maintenance Phase for those who were either non-responders or randomized to placebo in Part A or a 4-week Randomized Withdrawal Phase for participants who meet the responder criteria based on the UE Tremor- ADL Tremor Score in at the end of Part A (Week 12).

[0222] Safety Follow-Up Period: Participants who complete the Intervention Period (Parts A and B) will directly enter the 2-week Safety Follow-up (SFU) Period. Those who discontinue early from the study for any reason will have an early discontinuation (ED) Visit scheduled as soon as possible and an SFU Visit 14 days following the last dose of study drug.

[0223] The schedule of in-person and telehealth visits is outlined in Figure 1.

[0224] After Eligibility Review and Assessment Committee (ERAC) approval, eligible participants will be randomized in a 2: 1 ratio to ulixacaltamide or placebo, and the blinded flexible dose Titration Period will begin. Participants will begin study drug at a 10 mg dose that will be incrementally increased every 5 days to 80 mg or the highest tolerated dose (refer to Table 5).

[0225] Participants who do not tolerate a dose of >40 mg during the Titration Period will be withdrawn from the study without tapering down and without being replaced. Participants who discontinue study drug after randomization will complete an ED Visit and then continue into the Safety Follow-Up (SFU) Period.

[0226] Screening Period

[0227] The Screening Period is 28 days (Days -28 to -1) but can be extended an additional 7 days with sponsor approval and will include 2 visits (VI and V2). Key screening assessments during VI will include review of medical history (including familial history of PD and / or ET), demographics, body weight and height, body mass index (BMI), and drug / alcohol, hepatitis, and human immunodeficiency virus (HIV) screens. Safety assessments during VI include complete physical examinations, clinical laboratory evaluations (including serum pregnancy test for women of childbearing potential), ECG, vital signs, C-SSRS, and review of any AEs and concomitant medications (including anti-Parkinsonian medications). The following assessments will be administered to ascertain participant eligibility: International Parkinson and Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), TETRAS-ADL, Hoehn and Yahr staging, MoCA, Beck Depression Inventory, second edition (BDI-II), Beck Anxiety Inventory (BAI).

[0228] Participants will complete a second screening visit (V2, telehealth visit) for review of screening data and to determine eligibility. This visit may be conducted as an on-site if needed, at the discretion of the sponsor.

[0229] Eligibility will be determined by an ERAC. Participants who are confirmed to be eligible by the ERAC may proceed to Baseline V3 (Day 1).

[0230] Intervention Period

[0231] Eligible participants will be randomized 2: 1 to receive either ulixacaltamide or placebo and will receive their first dose of study drug at the on-site Baseline Visit (V3). The Intervention Period is 16 weeks in duration and encompasses the Part A Titration and Maintenance Phases (12 weeks) and the Part B Randomzaed Withdrawal and Maintenance Phases (4 weeks).

[0232] If participants need to discontinue the study drug for any reason during the Intervention Period (including the Titration, Maintenance, and Randomized Withdrawal Phases), they will have an ED Visit as soon as possible. The SFU Visit will occur 2 weeks (±2 days) after the last dose of study drug.

[0233] Titration Phase

[0234] At the Baseline Visit (V3), participants will arrive at the clinic and complete a baseline pre-dose assessments. Following randomization, they will receive ulixacaltamide or matching placebo at the clinic before completing all post-dose assessments. Participants will be instructed to take study drug at home every morning (QAM) with or without food.

[0235] During the Titration Phase participants will have scheduled telehealth visits at the end of each dosing interval to determine whether their dose level should be increased. Participants who are not escalated to the next dose of study drug may be increased to the next dose level at any subsequent dosing interval. All participants will be instructed to titrate to the highest tolerated dose. Those who cannot tolerate a dose of >40 mg study drug by the end of the Titration Phase will have an ED Visit scheduled as soon as possible and an SFU Visit approximately 14 days after the last dose of study drug.

[0236] After the Baseline Visit (V3), all Titration Phase visits will be telehealth visits and will assess the suitability of escalating to the next highest dose level, adverse events (AEs), concomitant medications and procedures, and Columbia-Suicide Severity Rating Scale (C- SSRS). However, any visit may be on site, if required for safety assessments or at the discretion of the investigator or sponsor.

[0237] Maintenance Phase (Parts A and B)

[0238] The 8-week Part A Maintenance Phase will last from Week 5 to Week 12. During this parallel design portion of the study, all participants will remain on stable doses of study drug (>40 mg of ulixacaltamide or matching placebo).

[0239] At the start of the Maintenance Phase (on Day 28), participants will take their morning dose of study drug at home before arriving at the clinic for an on-site visit (V9). Key assessments during V9 will include standard safety assessments in addition to efficacy assessments (TETRAS-ADL, MDS-UPDRS, PGI-S, CGI-S, CGI-I, and PGI-C). Serum samples to ascertain study drug concentration will also be collected at this visit and should be obtained at the same time as the clinical laboratory assessments. All other visits scheduled during the Part A Maintenance Phase will be telehealth visits, unless an on-site visit is required for safety assessments or at the discretion of the investigator or sponsor.

[0240] On Day 81 or Day 82 of the Part A Maintenance Phase, a telehealth visit will be scheduled and the efficacy assessments performed at this visit will determine whether participants are categorized as a Responders or Non-responders. If a participant is deemed a Responder, they will be randomized 1 : 1 to receive either ulixacaltamide or placebo in the Part B randomized withdrawal portion of the trial. If the participant is deemed a Non-responder, they will continue into the Part B Maintenance Phase for another 4 weeks continuing to receive the same dose of study drug. Investigators and participants will be blind to responder status and selection for either the Part B randomized withdrawal or continued parallel design portion of the study.

[0241] Randomized Withdrawal Phase (Part B) The 4-week Randomized Withdrawal Phase will last from Week 13 to Week 16. During this phase of the study, Responders from Part A will be randomized 1 : 1 to receive either ulixacaltamide or placebo. Those randomized to ulixacaltamide will remain on the same stable dose established in Part A.

[0242] At the start of the Randomized Withdrawal Phase (on Day 85) participants will not take their morning dose of study drug at home, as it will be administered onsite at the VI 3 visit. Key assessments during VI 3 will include standard safety assessments in addition to serum samples to ascertain study drug concentration that should be collected at the same time as the clinical laboratory assessments.

[0243] Telehealth visits will be conducted over the first 3 weeks of the Randomized Withdrawal Phase (V14, V15, and V16) to collect standard safety assessments. Efficacy assessments TETRAS-ADL and MDS-UPDRS will be collected at V14 and V15. On Day 112 (V17), the last day of the Intervention Period, all standard safety and efficacy assessments will be performed.

[0244] Taper-Down Phase

[0245] After completion of Part B, participants will enter a blinded 2-week Taper-Down Phase. In the first week of taper down, participants will receive a dose of 50 mg of study drug. In the second week of taper down, the study drug dose will be reduced to 25 mg. Study drug administration will stop after Day 91. Participants will then proceed into the Safety Follow-Up Period.

[0246] Safety Follow-Up Period

[0247] The SFU Period lasts for 2 weeks following the last dose of study drug. A telehealth visit will be conducted on the last day of the SFU Period (±3 days) to assess TEAEs and concomitant medications.

[0248] Early Discontinuation of Study Treatment

[0249] If study drug is discontinued before the end of the trial for any reason, an on-site ED Visit will occur as soon as possible after the last dose of study drug. Assessments to be completed during the ET Visit include all standard safety assessments, all efficacy assessments, and serum samples to ascertain study drug concentration. All participants who discontinue the trial must also enter the SFU Period, attending a telehealth visit 14 days after the last dose of study drug. Study Drug(s) Administered

[0250] Ulixacaltamide will be supplied as 10 mg, 20 mg, 40 mg, and 60 mg modified release tablets. Matching placebo will also be supplied. Participants receiving ulixacaltamide will receive a certain number of tablets of study drug per day, depending on the titration or maintenance dose being administered. Participants receiving placebo will receive the same number of tablets as those receiving ulixacaltamide. Following the flexible Titration Period, participants will not be allowed to adjust the number of tablets per day without instruction from the study site. Participants will have scheduled telehealth visits on the last day of each dosing interval to determine the most suitable dose for the subsequent dosing interval.

[0251] Efficacy Assessments

[0252] All efficacy assessments will be collected in the PD medication on state.

[0253] TETRAS Activity of Daily Living

[0254] The TETRAS was developed to quantify ET severity and its impact on ADLs. This scale can be completed in less than 10 minutes. This study will collect only the TETRAS-ADL which is a 12-item assessment of typical daily activities that are impacted by tremor. Activities are assessed in the following functional domains: speaking, feeding, drinking, personal hygiene, dressing, pouring, carrying, using keys, writing, working, overall disability and social activity. The impact to 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.

[0255] The mADLl l score is a composite sum of items 1 to 11 (omission of item 12 social impact score) of the TETRAS-ADL subscale. Scoring of each item is transformed to a 4-point scale from 0 to 3 with total score range from 0 to 33. The TETRAS ADL will be collected and the mADLl 1 will be used for data analysis purposes.

[0256] Upper Extremity Tremor-ADL Score

[0257] The UE Tremor-ADL Score is the sum of items 2 to 9 and 11 (omission of item 1 [voice], item 10 [work], and item 12 [social impact score]) of the TETRAS-ADL subscale. Scoring of each item is transformed to a 4-point scale from 0 to 3 with total score range from 0 to 30). The TETRAS-ADL will be collected, and the UE Tremor-ADL Score will be used for the analysis of tremor in this PD patient population.

[0258] MDS-UPDRS The MDS-UPDRS has been one of the most widely used clinical rating scales used for PD since it was introduced in the 1980s. A revised version of the MDS-UPDRS developed by the MDS is now one of the most common scales for evaluating the severity of PD across behaviors and complications associated with the disease. The scale consists of 4 parts that capture different dimensions of the disease across 65 scores.

[0259] Part I is the Non-Motor Aspects of Experiences of Daily Living section, assessing the non-motor impact of PD on experiences of daily living (13 items, 6 of which are clinician-rated, and 7 of which are patient- or caregiver-rated)

[0260] • Part II is the Motor Aspects of Experiences of Daily Living section, assessing the motor impact of PD on experiences of daily living (13 items, all of which are patient- or caregiver-rated)

[0261] • Part III is the clinician-rated Motor Examination, assessing the motor signs of PD in the ON and OFF state (33 scores based on 18 items, some with right, left, or other body distribution scores; all of which are clinician-rated)

[0262] • Part IV is the Motor Complications section, assessing dyskinesia, motor fluctuations, and OFF-state dystonia (6 items, all of which are clinician -rated)

[0263] The scale takes approximately 30 minutes to complete. It will be completed by a qualified rater with input from the patient, caregiver, or both, as directed by the scale instructions. Each question presents a clinical descriptor with a prompt to rate the severity of the participant’s symptom on a 5-point Likert scale (range of scores is 0 through 4). Higher scores indicate greater severity (greater frequency or greater intensity) as follows:

[0264] “Normal” (0) indicates the clinical sign or symptom is not present

[0265] “Slight” (1) indicates frequency or intensity causing no impact on function

[0266] “Mild” (2) indicates frequency or intensity causing a modest impact on function

[0267] “Moderate” (3) indicates frequency or intensity causing considerable impact on function, but not preventing it

[0268] “Severe” (4) indicates frequency or intensity preventing function

[0269] Parts I and II, and IV ratings are based on the average or usual function of the participant over the past week, including the day the scale is completed. Total scores are calculated for each part of the MDS-UPDRS. In addition, the MDS- UPDRS tremor score is calculated as the sum of item 10 from Part II and items 15 (a and b), 16 (a and b), 17 (a through e), and 18 from Part 3.

[0270] Clinical Global Impression-Severity (CGI-S)and Clinical Global Impression of Improvement (CGI-I)

[0271] The CGI-S assesses the clinician’s impression of the participant’s functioning prior to and after initiating study drug. The clinician should use his / her total clinical experience with this patient population and rate the current severity of the participant’s Parkinsonian symptoms on a 7-point scale from 1 (Normal, not at all ill) to 7 (Among the most extremely ill patients). The CGI-I assesses the clinician’s improvement (or worsening). The clinician is required to assess their condition relative to Baseline (Pre-dose on Day 1) on a 7-point scale from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the clinician believes the improvement / worsening is drug-related or not.

[0272] A modified version of the CGI-I motor fluctuations will also be administered to assess the presence of motor fluctuation and the clinician’s impression of improvement (of worsening) of motor fluctuation.

[0273] Patient Global Impression-Severity (PGI-S) and Clinical Global Impression of Change (CGI-C)

[0274] The PGI-S is a global self-assessment of the participant’s level of functioning prior to and after initiating study drug. It was originally developed for assessment in women with stress urinary incontinence. However, due to its lack of specificity for medical conditions and its sensitivity to change, it has also been used for participant self-assessment in other conditions. The participant rates his / her Parkinsonian symptoms on a 7-point scale from 1 (Not present) to 7 (Extremely severe). The PGI-C assesses the participant’s improvement (or worsening). The participant is required to assess their condition relative to Baseline (Pre-dose on Day 1) on a 7- point scale from 1 (very much improved) to 7 (very much worse). In all cases, the assessment should be made independent of whether the participant believes the improvement / worsening is drug-related or not.

[0275] Physical Examinations

[0276] A complete physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, dermatologic, and neurological systems. ECG

[0277] Twelve-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT intervals.

[0278] Triplicate measurement will be taken at Screening only; for all other timepoints, single measurement is acceptable. When triplicate ECGs are required, 3 individual ECG tracings should be obtained as closely as possible in succession, but no more than 2 minutes apart.

[0279] Columbia-Suicide Severity Rating Scale (C-SSRS)

[0280] The C-SSRS was developed by researchers at Columbia University as a tool to help systematically assess suicidal ideation and behavior in participants during participation in a clinical trial of centrally acting drugs. The C-SSRS is composed of 5 questions addressing suicidal behavior and 5 questions addressing suicidal ideation, with sub-questions assessing the severity. Two versions of the C-SSRS will be used in this clinical trial: the Baseline / Screening Version (at the Screening Visit) and the Since Last Visit Version (at all other visits). It takes approximately 5 to 10 minutes to administer the C-SSRS. The tool should be administered via interview with the participant (by a trained operator / interviewer).

[0281] Pharmacokinetic Assessments

[0282] Blood samples will be collected for measurement of plasma concentrations of study drug. Samples collected may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the clinical trial. Samples may also be used for additional exploratory method development and / or metabolite characterization purposes.

[0283] Study drug concentration information that may unblind the clinical trial will not be reported to investigative sites or blinded personnel until the clinical trial has been unblinded.

[0284] Example 2: Evaluation of the Compound of Formula (III) with or without L-DOPA on Motor Performance in a 6-OHDA Model

[0285] In preclinical PD models, aberrant bursting activity in the basal ganglia circuit has been associated with motor dysfunction. Additionally, preclinical data suggest that TTCCs in the basal ganglia may contribute to the abnormal burst firing observed in patients and animal models of PD. Thus, it was hypothesized that TTCC blockade can improve motor symptoms in PD. In line with this, local infusion of TTCC blockers into the subthalamic nucleus of 6-0HDA- lesioned rats has been shown to reduce subthalamic burst firing and improve motor performance. However, motor performance after systemic delivery of TTCC blockers had not been previously tested.

[0286] To this end, motor performance in a rat model of unilateral 6-OHDA lesion (of the medial forebrain bundle) after acute oral administration of an exemplary TTCC blocker, compound of formula (III), (3 or lOmg / kg; n=12 / group) was evaluated using the cylinder test. The effect of orally administered compound of formula (III) at the dose of 3 mg / kg or lOmg / kg (n=12 / group) on abnormal involuntary movement (AIMs) and rotation behavior elicited by L- DOPA (1 mg / kg) treatment was tested. To control for potential effects on gross motor behavior, spontaneous locomotor activity in healthy rats was tested after acute administration of the compound of formula (III).

[0287] Experiment 1

[0288] Rats with 6-OHDA lesion in the right medial forebrain bundle (MFB) have very low level of dopamine in the right basal ganglia which leads to reduced use of the paw contralateral to the lesion site (left paw). Therefore, when rats rear, they will mostly use the paw ipsilateral to the lesion side (right paw) for balance and display large asymmetry of paw use as illustrated in Figure 2. In the cylinder test, rats are placed in a glass cylinder and observed for 10 minutes or until 10 rears occur. During this time, the number of rears supported by the right, left or both paws is recorded and used to calculate a % asymmetry of paw use.

[0289] The goal of Experiment 1 was to determine the ability of the compound of formula (III) to reduce % paw asymmetry and abnormal involuntary movements (AIMs) in a 6-OHDA rat model. The testing conditions used for Experiment 1 are shown in Table 3 below.

[0290] Table 3. Experiment 1 : Assessment of asymmetry paw use and AIMs in the cylinder task after acute treatment testing conditions

[0291] The cylinder test was performed on the 6-OHDA rats 30 minutes after administration of the PO dose for different groups listed in Table 3, and the results are presented in Figure 3. Specifically, Figure 3, panel A is a bar graph showing % paw asymmetry measured in 6-OHDA rats after administration of vehicle or compound of formula (III) at 3 mg / kg and 10 mg / kg. Figure 3, panel B is a bar graph showing % paw asymmetry measured in 6-OHDA rats after administration of L-DOPA alone or in combination with compound of formula (III) at 3 mg / kg and 10 mg / kg. The results presented in Figure 3 demonstrate that compound of formula (III), when administered alone or in combination with L DOPA, can reduce % paw asymmetry in a 6- OHDA rate model.

[0292] Administration of L-DOPA leads to abnormal involuntary movements (AIMs) in rats. Experiment 1 was conducted with a low, suboptimal dose of L-DOPA which induces a low level of AIMs and allows to probe increase and decreases of L-DOPA induced AIMs. The number of AIMs was assessed for different groups listed in Table 3, and the results are presented in Figure 4. Specifically, Figure 4, panel A is a bar graph showing the number of abnormal involuntary movements (AIMs) measured in 6-OHDA rats after administration of vehicle or compound of formula (III) at 3 mg / kg and 10 mg / kg. Figure 4, panel B is a bar graph showing the number of AIMs measured in 6-OHDA rats after administration of L-DOPA alone or in combination with compound of formula (III) at 3 mg / kg and 10 mg / kg. The results presented in Figure 4 demonstrate that compound of formula (III), when administered alone or in combination with L DOPA, does not induce AIMs or alter L-DOPA AIMs.

[0293] Experiment 2

[0294] The goal of this experiment was to assess the ability of the compound of formula (III) to alter AIMs and contraversive rotations induced by L-DOPA when L-DOPA is administered at a medium dose that induces a moderate level of AIMS. The testing conditions used for Experiment 2 are shown in Table 4 below.

[0295] Table 4. Experiment 2: Assessment of rotations and AIMs after acute treatment

[0296] The number of AIMs was assessed for different groups listed in Table 4, and the results are presented in Figures 5 and 6. Specifically, Figure 5 is a graph showing total AIMs measured over 180 minutes in 6-OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone. Figure 6, panel A is a bar graph showing total AIMs measured over 0-90 minutes post-dose in 6-OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone. Figure 6, panel B is a bar graph showing total AIMs measured over 90-180 minutes post-dose in 6-OHDA rats treated with 3 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone. The results presented in Figures 5 and 6 indicate that there is a small decrease in AIMs after dosing compound of formula (III) at 10 mg / kg observed during peak L-DOPA- induced AIMs. In contrast to administration of entacapone, administration of the compound of formula (III) did not have an effect on the duration of total AIMs.

[0297] Administration of L-DOPA to 6-OHDA rats leads to contraversive rotations in relation to lesion site, with the peak effect observed at ~60 mins post-dose). The number of contraversive rotations over 180 minutes was measured for all groups listed in Table 4, and net contraversive rotations were calculated as the difference between the total number of contraversive rotations and the total number of ipsiversive rotations.

[0298] The results are presented in Figure 7. Specifically, Figure 7 is a graph showing net contraversive rotations measured over 180 minutes in 6-OHDA rats treated with 3 mg / kg L- DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 10 mg / kg entacapone. The results presented in Figure 7 indicate that administration of the compound of formula (III) at 3 mg / kg and 10 mg / kg during peak tended to reduce the net contraversive rotations. In contrast to administration of entacapone, administration of the compound of formula (III) did not have an effect on the duration of the net contraversive rotations.

[0299] Experiment 3

[0300] The goal of this experiment was to assess the ability of the compound of formula (III) to alter AIMs and contraversive rotations induced by L-DOPA when L-DOPA is administered at a high dose that induces a severe level of AIMS. The testing conditions used for Experiment 3 are shown in Table 5 below.

[0301] Table 5. Experiment 3: Assessment of rotations and AIMs after acute treatment

[0302] The number of AIMs was assessed for different groups listed in Table 5, and the results are presented in Figures 8 and 9. Specifically, Figure 8 is a graph showing total AIMs measured over 180 minutes in 6-OHDA rats treated with 6 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine. Figure 9, panel A is a bar graph showing total AIMs measured over 0-180 minutes post-dose in 6-OHDA rats treated with 6 mg / kg L-DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine. Figure 9, panel B is a bar graph showing total AIMs measured over 0-90 minutes post-dose in 6-OHDA rats treated with 6 mg / kg L- DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine. The results presented in Figures 8 and 9 indicate that there is a small decrease in AIMs after dosing compound of formula (III) at 10 mg / kg observed during peak L- DOPA-induced AIMs. Administration of L-DOPA to 6-OHDA rats leads to contraversive rotations in relation to lesion site, with the peak effect observed at ~60 mins post-dose). The number of contraversive rotations over 180 minutes was measured for all groups listed in Table 5, and net contraversive rotations were calculated as the difference between the total number of contraversive rotations and the total number of ipsiversive rotations.

[0303] The results are presented in Figure 10. Specifically, Figure 10 is a graph showing net contraversive rotations measured over 180 minutes in 6-OHDA rats treated with 6 mg / kg L- DOPA and also treated with the compound of formula (III) at 3 mg / kg or 10 mg / kg, or with 30 mg / kg amantadine. The results presented in Figure 9 indicate that administration of the compound of formula (III) at 3 mg / kg and 10 mg / kg during peak did not have an effect on net contraversive rotations.

[0304] Overall, the results of Experiments 1, 2 and 3 demonstrate that compound of formula (III) administered at the doses of 3 mg / kg and 10 mg / kg reduced paw use asymmetry in rats in the cylinder test by 20% (p<0.01) to 28% (p<0.05), as compared to vehicle. Importantly, acute delivery of both doses did not elicit significant changes in locomotor activity in rats. At doses that reduced paw asymmetry, compound of formula (III) did not increase the number or duration of AIMs or rotations when combined with L-DOPA.

[0305] These data demonstrate that compound of formula (III), an exemplary TTCC blocker, improves motor performance in a preclinical PD model. These data further indicates that TTCC blockade offers a non-dopaminergic treatment option for treating motor symptoms in patients with PD.

[0306] Equivalents and Scope

[0307] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0308] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it 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, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0309] 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 instant specification, the specification shall control. In addition, 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. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0310] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes 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.

Claims

CLAIMS1. A method of treating or preventing at least one symptom of Parkinson’s disease in a subject in need thereof, said method comprising administering to said subject a T-type calcium channel (TTCC) blocker, such that at least one symptom of Parkinson’s disease is treated or prevented in said subject.

2. The method of claim 1, wherein the TTCC blocker is compound of formula (I) represented by the following structure:or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the TTCC blocker is a compound of formula (II) represented by the following structure:

4. The method of claim 1, wherein the TTCC blocker is compound of formula (III) represented by the following structure:or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1-4, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is indicated by lack of an increase in the total score as measured according to the Movement Disorder Society-Sponsored Revision of theUnified Parkinson's Disease Rating Scale (MDS-UPDRS total score), as compared to the MDS- UPDRS total score measured prior to administration of the TTCC blocker to the subject.

6. The method of claim 5, wherein the MDS-UPDRS total score is measured in the OFF state.

7. The method of claim 5, wherein the MDS-UPDRS total score is measured in the ON state.

8. The method of any one of claims 5-7, wherein lack of an increase in the MDS-UPDRS total score comprises a lack of an increase in one or more of the following: a) MDS-UPDRS Part 1 score; b) MDS-UPDRS Part 2 score; c) MDS-UPDRS Part 3 score; and d) MDS-UPDRS Part 4 score.

9. The method of claim 8, wherein lack of an increase in the MDS-UPDRS total score comprises lack of an increase in the MDS-UPDRS Part 1 score.

10. The method of claim 8, wherein lack of an increase in the MDS-UPDRS total score comprises lack of an increase in the MDS-UPDRS Part 2 score.

11. The method of claim 8, wherein lack of an increase in the MDS-UPDRS total score comprises lack of an increase in the MDS-UPDRS Part 3 score.

12. The method of claim 8, wherein lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS-UPDRS subscale score for one or more of the following: tremor, bradykinesia, rigidity, posture and gait disorder.

13. The method of claim 12, wherein lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS-UPDRS subscale score for tremor.

14. The method of claim 12, wherein lack of an increase in the MDS-UPDRS Part 3 score comprises lack of an increase in the MDS-UPDRS subscale score for bradykinesia, rigidity, posture and gait disorder.

15. The method of claim 8, wherein lack of an increase in the MDS-UPDRS total score comprises lack of an increase in MDS-UPDRS Part 4 score.

16. The method of any one of claims 2-3 and 5-15, wherein compound of formula (I) is administered at the dose of at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg or at least about 100 mg.

17. The method of any one of claims 2-3 and 5-16, wherein compound of formula (I) is administered once daily.

18. The method of any one of claims 2-3 and 5-17, wherein compound of formula (I) is administered for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, or at least 7 or more weeks.

19. The method of any one of claims 5-18, wherein lack of an increase in the MDS-UPDRS total score or UPDRS total score comprises the decrease in the MDS-UPDRS total score of at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, at least 40 points, at least 45 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 75 points, at least 80 points, at least 85 points, at least 90 points, at least 95 points, at least 100 points, at least 105 points, at least 110 points, at least 115 points, at least 120 points, at least 125 points, at least 130 points, at least 135 points, at least 140 points, at least 145 points, at least 150, at least 155, at least 160, at least 165, at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 205, at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, or at least 255 or more points.

20. The method of any one of claims 8-9 and 16-18, wherein lack of an increase in the MDS- UPDRS Part 1 score comprises a decrease in the MDS-UPDRS Part 1 score 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 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

21. The method of any one of claims 8, 10 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 2 score comprises a decrease in the MDS-UPDRS Part 2 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

22. The method of any one of claims 8, 11 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 score comprises a decrease in the MDS-UPDRS Part 3 score of at least 1 point, at least 2 points, at least 4 points, at least 5 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, at least 40 points, at least 45 points, at least 50 points, at least 55 points, at least 60 points, at least 65 points, at least 70 points, at least 75 points, at least 80 points, at least 85 points, at least 90 points, at least 95 points, at least 100 points, at least 105 points, at least 110 points, at least 115 points, at least 120 points, or at least 125 or more points.

23. The method of any one of claims 12-13 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale score for tremor comprises a decrease in the MDS-UPDRS Part 3 subscale score for tremor of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, or at least 30 points.

24. The method of any one of claims 12, 14 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale score for bradykinesia comprises a decrease in the MDS-UPDRS Part 3 subscale score for bradykinesia of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points.

25. The method of any one of claims 12, 14 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale score for bradykinesia comprises a decrease in the MDS-UPDRS Part 3 subscale score for bradykinesia of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 10 points, at least 15 points, at least 20 points, at least 25 points, at least 30 points, at least 35 points, or at least 40 points.

26. The method of any one of claims 12, 14 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale score for rigidity comprises a decrease in the MDS-UPDRS Part 3 subscale score for rigidity 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 8 points, at least 10 points, at least 12 points, at least 14 points, or at least 16 points.

27. The method of any one of claims 12, 14 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale score for posture comprises a decrease in the MDS-UPDRS Part 3 subscale score for posture 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 8 points, at least 10 points, at least 12 points, at least 14 points, or at least 16 points.

28. The method of any one of claims 12, 14 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale score for gait postural instability comprises a decrease in the MDS-UPDRS Part 3 subscale score for gait postural instability of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 7 points, at least 10 points, or at least 15 points.

29. The method of any one of claims 12, 14 and 16-18, wherein lack of an increase in the MDS-UPDRS Part 3 subscale for axial score comprises a decrease in the MDS-UPDRS Part 3 subscale axial score of at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 7 points, at least 10 points, or at least 15 points.

30. The method of any one of claims 8 and 15-18, wherein lack of an increase in the MDS- UPDRS Part 4 score comprises a decrease in the MDS-UPDRS Part 4 score of at least 1 point, at least 2 points, at least 4 points, at least 6 points, at least 8 points, at least 10 points, at least 15 points, at least 20 points or at least 25 or more points.

31. The method of any one of claims 1 -30, wherein the method does not result in moderate depressive symptoms or severe depressive symptoms in the subject as measured by Beck Depression Inventory - Second Edition (BDI-II).

32. The method of any one of claims 1-31, wherein the method does not result in adverse events.

33. The method of claim 32, wherein the method does not result in serious adverse events.

34. The method of any one of claims 1-33, wherein the method does not result in moderate anxiety symptoms or severe anxiety symptoms as measured by Beck Anxiety Inventory (BAI).

35. The method of any one of claims 1-34, wherein the method results in a decrease in MDS- UPDRS Part 1 total scoreas compared to MDS-UPDRS Part 1 total score prior to administration of the TTCC blocker to the subject as assessed in the off state.

36. The method of any one of claims 1-35, wherein the method results in a decrease in MDS- UPDRS Part 2 total score as compared to MDS-UPDRS Part 2 total score prior to administration of the TTCC blocker to the subject as assessed in the off state.

37. The method of any one of claims 1-36, wherein the method results in a decrease in MDS- UPDRS Part 3 total score as compared to MDS-UPDRS Part 3 total score prior to administration of the TTCC blocker to the subj ectas assessed in the off state.

38. The method of any one claims 1-37, wherein the method results in a decrease in MDS- UPDRS Part 1 total score as compared to MDS-UPDRS Part 1 total score prior to administration of the TTCC blocker to the subject as assessed in the on state.

39. The method of any one of claims 1-38 wherein the method results in a decrease in MDS- UPDRS Part 2 total score as compared to MDS-UPDRS Part 2 total score prior to administration of the TTCC blocker to the subject as assessed in the on state.

40. The method of any one claims 1-39, wherein the method results in a decrease in MDS- UPDRS Part 3 total score as compared to MDS-UPDRS Part 3 total score prior to administration of the TTCC blocker to the subject as assessed in the on state in the subject.

41. The method of any one of claims 1-40, wherein the method results in a decrease in MDS- UPDRS Part 4 score as compared to MDS-UPDRS Part 4 score prior to administration of the TTCC blocker to the subject.

42. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to the Beck Anxiety Inventory (BAI).

43. The method of claim 42, wherein the method results in a decrease in BAI score as compared to BAI score prior to administration of the TTCC blocker to the subject.

44. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to the Beck Depression Inventory, second edition (BDI-II).

45. The method of claim 44, wherein the method results in a decrease in BDI-II score as compared to BDI-II score prior to administration of the TTCC blocker to the subject.

46. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to to the Questionnaire for Impulsive Control Disorders in Parkinson’s Disease - Rating Scale (QUIP -RS).

47. The method of claim 46, wherein the method results in a decrease in QUIP -RS score as compared to QUIP -RS score prior to administration of the TTCC blocker to the subject.

48. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to the Montreal Cognitive Assessment (MoCA).

49. The method of claim 48, wherein the method results in a decrease in MoCA score as compared to MoCA score prior to administration of the TTCC blocker to the subject.

50. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to the Patient Global Impression of Severity (PGI-S).

51. The method of claim 50, wherein the method results in a decrease in PGI-S score as compared to PGI-S score prior to administration of the TTCC blocker to the subject.

52. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according the Motor Complications Assessment.

53. The method of claim 52, wherein the method results in a decrease dyskinesia as measured by the Motor Complications Assessment in the on state in the subject as compared to dyskinesia prior to administration of the TTCC blocker to the subject.

54. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to the Epworth Sleepiness Scale (ESS).

55. The method of claim 54, wherein the method results in a decrease in ESS score in the subject as compared to ESS score prior to administration of the TTCC blocker to the subject.

56. The method of claim 1, wherein treatment or prevention of the at least one symptom of Parkinson’s disease in the subject is measured according to the Clinician Global Impression of Severity (CGI-S).

57. The method of claim 56, wherein the method results in a decrease in CGI-S score in the subject as compared to CGI-S score prior to administration of the TTCC blocker to the subject.

58. The method of any one of claims 1-57, wherein the TTCC blocker is administered to the subject for at least 21 days, at least 49 days, at least 77 days or at least 91 days.

59. The method of any one of claims 1-57, wherein the TTCC blocker is administered to the subject for at least 3 months, at least 6 months, at least 9 months or at least 12 months.

60. The method of any one of claims 1-57, wherein the TTCC blocker is administered to the subject for at least 3 years, at least 5 years or at least 10 years.

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