Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
  • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• beta blocker propranolol approved by the FDA in 1967, remains the only approved therapy for ET in the United States.
• a non-selective beta blocker, propranolol is contraindicated for individuals with certain respiratory or cardiac issues, which are common comorbidities in the age group frequently affected by ET.
• Primidone an anticonvulsant, may be used to control ET, but it requires slow titration over six to eight weeks and can cause sedation and balance issues while accelerating osteoporosis with long-term use.
• Topiramate is another example of an anticonvulsant that may be used to treat ET, but patients often report undesirable side effects, including visual problems, cognitive problems, loss of appetite, and tingling sensations.
• Described herein are methods 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 administering to the subject a compound of Formula (I): or a pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or pharmaceutically acceptable salts thereof.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with propranolol or a pharmaceutically acceptable salt thereof.
• the disease or condition relating to aberrant function or activity of a T-type calcium channel is essential tremor (ET). Therefore, also disclosed herein are methods of treating ET in a subject in need thereof, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or pharmaceutically acceptable salts thereof.
• the compound used for treating the disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET is the hydrochloride (HC1) salt of the compound of Formula (I), depicted below:
• the compound used for treating the disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET is a crystalline form of the compound of Formula (I), e.g., crystalline HC1 salt of the compound of Formula (I).
• the compound used for treating the disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET is a polymorph of a crystalline salt of the compound of Formula (I), e.g., a polymorph of a crystalline HC1 salt of the compound of Formula (I), e.g., as described in WO 2021007487A1, the entire contents of which are hereby incorporated herein by reference.
• propranolol is administered as an HC1 salt.
• propranolol or a pharmaceutically acceptable salt thereof is administered as an (S)-enantiomer.
• (S)-propranolol hydrochloride is administered in combination with the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt).
• (R) -propranolol hydrochloride is administered in combination with the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt).
• compound of Formula (I) or a pharmaceutically acceptable salt thereof, e.g., the HC1 salt of compound of Formula (I) may be referred to herein in the examples as the “study drug”.
• a subject who had previously been on a dosing regimen of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof had an active prescription for propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, and was directed by a physician to take propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof.
• the method of treating the disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET, in a subject in need thereof comprises administering at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof (e.g., propranolol HC1) and administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) on a schedule that involves titrating the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof up to a desired dosing level.
• a pharmaceutically acceptable salt thereof e.g., propranol HC1
• the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be titrated from a dose starting at about 20 mg daily up to a dose of about 120 mg daily (e.g., about 40 mg daily, about 60 mg daily, about 80 mg daily, or about 100 mg daily).
• each dose is administered in a modified or extended release composition, as set forth herein.
• FIG. 1 is a graph showing the percent change in modified activities of daily living (ADL) scores as compared to baseline combined upper limb (CUL) scores from Part B participants, as discussed in Example 1.
• FIG. 3 is a graph showing the percent change in tremor amplitude as compared to baseline CUL scores from Part A participants (left) and Part B participants (right), as discussed in Example 1.
• FIG. 6 is a graph showing sLMA as total distance travelled (in mm) over time measured in rats treated with the compound of Formula (I) (the “study drug”) and propranolol alone or in combination.
• FIG. 7 is a bar graph showing the tremor score measured in rats that were administered 30 mg/kg harmaline and also administered 10 mg/kg propranolol or 1 mg/kg, 3 mg/kg or 10 mg/kg study drug, z.e., compound of Formula (I).
• FIG. 9 is a bar graph showing the mean of fall latency measured in rats that were administered 30 mg/kg harmaline and also administered 10 mg/kg propranolol or 1 mg/kg, 3 mg/kg or 10 mg/kg study drug, z.e., compound of Formula (I).
• FIG. 11 is a bar graph showing traveling distance in 0-30 minutes (mm) of rats treated with harmaline (30 mg/kg) and also treated with 3 mg/kg propranolol and 1 mg/kg and 3 mg/kg of the study drug, z.e., compound of Formula (I).
• FIG. 13 is a bar graph showing the same data as in FIGs. 11 and 12, and also showing the results of statistical comparison between different groups of rats. DETAILED DESCRIPTION
• 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.
• a modified-release polymer is used to dissolve a drug over time in order to be released more slowly and/or more steadily into the bloodstream.
• a modified-release polymer is a controlled-release polymer.
• a modified- release polymer or a controlled-release polymer is a hydroxy-propyl methylcellulose (HPMC) polymer.
• HPMC hydroxy-propyl methylcellulose
• a modified-release polymer may include hydrophilic matrix polymers (e.g., hypromellose, HPMC), hydrophobic matrix polymers (e.g., ethyl cellulose, ethocel), or polyacrylate polymers (e.g., Eudragit RL100, Eudragit RS 100).
• hydrophilic matrix polymers e.g., hypromellose, HPMC
• hydrophobic matrix polymers e.g., ethyl cellulose, ethocel
• polyacrylate polymers e.g., Eudragit RL100, Eudragit RS 100.
• pharmaceutically acceptable salt refers to those salts that 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 al., 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.
• salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
• 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.
• 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.
• a disease, disorder, or condition described herein is refractory (e.g., refractory epilepsy or refractory absence seizures) and does not respond to standard therapy or treatment.
• the patients who are taking propranolol no longer respond to propranolol.
• a “subject” to which administration is contemplated includes, but is not limited to, humans (/'. ⁇ ?., 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.
• the subject is a human.
• the subject is a non-human animal.
• the terms “human” and “patient” are used interchangeably herein, while the term “subject” may refer to human or non-human animals.
• a “subject in need thereof’ is a subject who has a disease, disorder or condition relating to aberrant function or activity of a T-type calcium channel.
• a “subject in need thereof’ is a subject who has essential tremor (ET).
• a “subject in need thereof’ is a subject who has ET that is or has become refractory to treatment with propranolol, primidone, topiramate or a pharmaceutically acceptable salt thereof.
• terapéuticaally 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.
• therapeutically effective amount can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
• treat 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, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment” or “prevention” of the specified disease, disorder or condition).
• treat also refer to reversing, alleviating, arresting or ameliorating a disease, e.g., ET, or at least one of the clinical symptoms of a disease, e.g., ET, or inhibiting the progress of a disease or at least one of the clinical symptoms of the disease, e.g., ET.
• coating refers to an excipient to protect tablet ingredients from deterioration by moisture in the air and/or make large or unpleasant-tasting tablets easier to swallow.
• diluent refers to an excipient used to increase weight and improve content uniformity.
• 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), and sugar alcohols (e.g., sorbitol, xylitol and mannitol).
• glidant refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion.
• glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.
• methods provided by the present disclosure comprise administering to a subject in need thereof a compound of Formula (I): or a pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or pharmaceutically acceptable salts thereof.
• the term “in combination” refers to administration to a subject in need thereof of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and of at least one of propranolol, primidone, topiramate, or pharmaceutically acceptable salts thereof whereby the subject has an active prescription for the compound of Formula (I) or a pharmaceutically acceptable salt thereof and an active prescription for at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, and is being directed by a physician to take the compound of Formula (I) of a pharmaceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) of a pharmaceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof may be each be administered to a subject in need thereof over the same period of time once daily, e.g., in the morning.
• the compound of Formula (I) of a pharmaceutically acceptable salt thereof may be administered to a subject once daily, e.g., in the morning, and at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof two or three times daily over the same period of time.
• a disease or condition relating to aberrant function or activity of a T-type calcium channel in a subject in need thereof comprising administering a compound of Formula (I): or a pharmaceutically acceptable salt thereof in combination with at least one of propranolol, primidone, topiramate, or pharmaceutically acceptable salts thereof.
• the deuterium-enriched compound has a Formula (II-B), or a pharmaceutically acceptable salt thereof, wherein: each of Ri a , Rib, R2 a , R2b, and R7 is independently hydrogen or deuterium; each of each of R3, R4, and R5 is -C(R a )3, wherein each R a is independently hydrogen or deuterium; m is an integer selected from 0 to 3; at least one of Re a , Reb, Rec, and Re is deuterium; and each of Re e , Ref, Reg, Reh is independently hydrogen or deuterium.
• Formula (II-B) Formula (II-B), or a pharmaceutically acceptable salt thereof, wherein: each of Ri a , Rib, R2 a , R2b, and R7 is independently hydrogen or deuterium; each of each of R3, R4, and R5 is -C(R a )3, wherein each R a is independently hydrogen or deuterium; m is an integer selected from
• the present disclosure provides a method of treating the disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET, in a subject in need thereof, the method comprising administering (e.g., once, twice, or 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 20 mg to about 100 mg, or from about 20 mg to about 80 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt), wherein the subject is concurrently taking at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof (e.g., propranolol HC1), i.e., the subject is being administered the compound of Formula (I) in combination with at least one of propranolol, primidone
• the subject had been taking a dose of from about 10 mg to about 1000 mg/daily of primidone, prior, e.g., at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks or at least 1 week prior to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject had been taking a dose of from about 12.5 mg to about 750 mg/daily of primidone, prior, e.g., at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks or at least 1 week prior to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject had been taking a dose of from about 50 mg to about 250 mg/daily primidone, prior, e.g., at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks or at least 1 week prior to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject had been taking a dose of from about 10 mg to about 400 mg/daily of topiramate, prior, e.g., at least 1 year, at least 6 months, at least 3 months, at least 2 months, at least 1 month, at least 2 weeks or at least 1 week prior to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject can remain on the same dosing regimen of the propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof that the subject was on prior to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject can be administered a lower dose of the propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof than the subject was on prior to the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject can be administered a dose of 10 mg propranolol HC1 once daily after the subject begins administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the subject is administered a dose of propranolol, primidone, topiramate in combination with the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the dose of propranolol, primidone, topiramate is about 5% to about 90% lower than the dose of propranolol, primidone, topiramate that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the dose of propranolol, primidone, topiramate is about 10% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, or about 40% to about 50%, lower than the dose of propranolol, primidone, topiramate that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the dose of propranolol, primidone, topiramate is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% lower than the dose of propranolol, primidone, topiramate that the subject received prior to administration the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can be administered to the subject PRN (as needed).
• the propranolol or a pharmaceutically acceptable salt thereof can be administered to the subject PRN.
• the subject suffering from a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET, who is taking at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof (e.g., propranolol HC1) is administered a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) on a schedule that involves titrating the dose of the compound of Formula (I) or pharmaceutically acceptable salt thereof up to a desired dosing level.
• a T-type calcium channel such as ET
• the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is titrated from a dose starting at about 5 mg daily up to a dose of about 120 mg daily.
• the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is titrated from a dose starting at about 10 mg daily up to a dose of about 120 mg daily (e.g., about 20 mg daily, about 60 mg daily, about 80 mg daily, or about 100 mg daily).
• the dose of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is titrated from a dose starting at about 20 mg daily up to a dose of about 120 mg daily (e.g., titrating from about 20 mg daily in 20 mg increments to about 40 mg daily, to about 60 mg daily, to about 80 mg daily, to about 100 mg daily, or to about 120 mg daily).
• the subject suffering from a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET, who is taking at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof is administered the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) according to a dosing regimen comprising:
• the method further comprises (d) administering to the subject for a fourth period (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more), about 80 mg daily of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt).
• a fourth period e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more
• a pharmaceutically acceptable salt thereof e.g., the HC1 salt
• the method further comprises (e) administering to the subject for a fifth period (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 days or more), about 100 mg daily of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt).
• the method further comprises (f) administering to the subject for a sixth period (e.g., 2, 3, 4, 5, 6, 7, 8 or 9 days or more), about 120 mg daily of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt).
• the subject is a human.
• the subject is a human and is 10 to 100 years old, e.g., 10 to 30 years old, 15 to 45 years old, 18 to 55 years old, 10 to 80 years old, 15 to 75 years old, 40 to 90 years old, 50 to 80 years old, 60 to 75 years old or 25 to 65 years old.
• the subject is a human and is 18 to 55 years old.
• the subject has ET with onset at the age of 30 years old or less, 40 years old or less, 50 years old or less, 60 years old or less, 70 years old or less or 80 years old or less. In some embodiments, the subject has ET with onset at the age of from 10 to 90 years old, from 30 to 60 years old, from 40 to 80 years old, or from 50 to 75 years old.
• the subject suffering from a disease or condition relating to aberrant function or activity of a T-type calcium channel also suffers from another disorder, including another disease or condition relating to aberrant function or activity of a T-type calcium channel.
• the other disorder is selected from the group consisting of psychiatric disorders (e.g., mood disorder (e.g., major depressive disorder)), pain, tremor, seizures (e.g., absence seizures), and epilepsy or an epilepsy syndrome (e.g., juvenile myoclonic epilepsy).
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered to the subject suffering from a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET, that has become refractory to treatment with propranolol or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be administered to the subject suffering from a disease or condition relating to aberrant function or activity of a T-type calcium channel, such as ET, that has become refractory to other first-line therapies such as primidone and/or topiramate.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor severity by at least about 20% when measured by The Essential Tremor Rating Assessment Scale (TETRAS).
• TTRAS refers to a scale developed to quantify severity of ET and its impact on daily activities. It has an activities of daily living (ADL) section and a performance section. The ADL section has 12 items rated between 0 to 4, and the performance section has 9 items rated between 0 to 4. See, e.g., Elble, R.R., The Essential Tremor Rating Assessment Scale, J. Neurology Neuromed. 2016, l(4):34-38.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor severity by at least about 30% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor severity by at least about 40% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce upper limb tremor amplitude by at least about 20% when measured by The Essential Tremor Rating Assessment Scale (TETRAS).
• TETRAS The Essential Tremor Rating Assessment Scale
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce upper limb tremor amplitude by at least about 30% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce upper limb tremor amplitude by at least about 40% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, can reduce upper limb tremor amplitude by at least about 50% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof, can reduce upper limb tremor amplitude by at least about 60% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce upper limb tremor amplitude by from about 20% to about 70% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce upper limb tremor amplitude by from about 30% to about 50% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor amplitude when drawing Archimedes spirals with the right or left hands by at least about 20% when measured by The Essential Tremor Rating Assessment Scale (TETRAS).
• TTRAS Essential Tremor Rating Assessment Scale
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor amplitude when drawing Archimedes spirals with the right or left hands by at least about 30% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor amplitude when drawing Archimedes spirals with the right or left hands by at least about 40% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor amplitude when drawing Archimedes spirals with the right or left hands by at least about 60% when measured by TETRAS.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered in combination with at least one of propranolol, primidone, topiramate, or a pharmaceutically acceptable salt thereof can reduce tremor amplitude when drawing Archimedes spirals with the right or left hands by from about 30% to about 50% when measured by TETRAS.
• the at least one modified-release polymer includes, but is not limited to, controlled- release polymers, hydrophilic matrix polymers such as an HPMC polymer, hydrophobic matrix polymers such as ethyl cellulose and ethocel, and polyacrylate polymers such as Eudragit RL100 and Eudragit RS 100.
• the at least one modified-release polymer is typically present in an amount sufficient to modify the release rate of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) upon administration to the subject.
• 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 pharmaceutical
• composition or dosage form may comprise from about
• the composition or 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 HC1 salt). In some embodiments, the composition or 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 HC1 salt). In some embodiments, the composition or 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 HC1 salt).
• the composition or 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 HC1 salt). In some embodiments, the composition or dosage form comprises from about 4% by weight to about 5% by weight of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt). In some embodiments, the composition or 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 HC1 salt). In some embodiments, the composition or 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 HC1 salt).
• the composition or dosage form that can be used in the methods described herein may be a dosage form or composition comprising from about 1 mg to about 40 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg) of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt), and in some embodiments, the composition or dosage form may further comprise at least one modified-release polymer (e.g., controlled-release polymers, hydrophilic matrix polymers such as an HPMC polymer, hydrophobic matrix polymers such as ethyl cellulose and ethocel, and polyacrylate polymers such as Eudragit RL100 and Eudragit RS 100). Typically, the at least one modified-release polymer is present in an amount sufficient to modify the release rate of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) upon administration to the
• the composition or 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 HC1 salt). In certain embodiments, the composition or 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 HC1 salt). In some embodiments, the composition or 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 HC1 salt).
• the composition or 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 HC1 salt). In certain embodiments, the composition or 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 HC1 salt).
• the composition or dosage form comprises from about 55 mg to about 65 mg of a modified-release polymer (e.g., an HPMC polymer). In some embodiments, the composition or 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 composition or dosage form comprises from about 50% by weight to about 60% by weight of the modified-release polymer (e.g., an HPMC polymer).
• a modified-release polymer e.g., an HPMC polymer
• the composition or dosage form comprises from about 50% by weight to about 60% by weight of the modified-release polymer (e.g., an HPMC polymer).
• the composition or 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 about 25% to about 30%, or from about30% to about 35% by weight) microcrystalline cellulose.
• the composition or dosage form further comprises at least one glidant.
• the glidant comprises colloidal silicon dioxide.
• the composition or dosage form further comprises at least one lubricant.
• the lubricant comprises magnesium stearate.
• the composition or dosage form further comprises at least one coating.
• about 80% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof is released within 7 hours upon administration to a subject. In certain embodiments, about 80% of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) is released within 7 hours, as measured by using USP apparatus type-I, media containing 900 mL 0.1 M HC1, and a paddle speed of 100 rpm.
• the composition or dosage form upon administration to a subject, has a reduced Cmax value as compared to a reference oral dosage form (e.g., a composition or dosage form with any intended release rate profile, including, for example, a modified release rate profile, a composition or dosage form that does not have a modified release rate profile, or a composition or dosage form that does not have a modified-release polymer, e.g., an HPMC polymer).
• a reference oral dosage form e.g., a composition or dosage form with any intended release rate profile, including, for example, a modified release rate profile, a composition or dosage form that does not have a modified release rate profile, or a composition or dosage form that does not have a modified-release polymer, e.g., an HPMC polymer.
• the composition or dosage form is administered to a patient once daily. In certain embodiments, the composition or dosage form is administered to a patient twice daily. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.
• a dosage form that can be used in the methods described herein may be an oral dosage form comprising: from about 15 mg to 25 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt); and from about 55 mg to 65 mg of an HPMC polymer.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof is stable within the composition at about 25 °C at 60 % relative humidity for at least 24 months. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) is stable within the composition at about 25 °C at 60 % relative humidity for at least 36 months. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) is stable with the composition at about 25 °C at 60 % relative humidity for at least 48 months.
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof is stable within the composition at about 25 °C at 60 % relative humidity for at least 60 months. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) is stable within the composition at about 40 °C at 75 % relative humidity for at least 6 months.
• a composition that can be used in the methods described herein may be an oral (e.g., particulate) composition 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 HC1 salt); and from about 53% to about 64% by weight of an HPMC polymer.
• an oral (e.g., particulate) composition 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 HC1 salt); and from about 53% to about 64% by weight of an HPMC polymer.
• a composition that can be used in the methods described herein may be an oral (e.g., particulate) composition 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 HC1 salt); and from about 53% to about 64% by weight of an HPMC polymer.
• an oral (e.g., particulate) composition 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 HC1 salt); and from about 53% to about 64% by weight of an HPMC polymer.
• a dosage form or composition that can be used in the methods described herein may be a dosage form or composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt), where the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., the HC1 salt) is released immediately upon an administration to the subject.
• a pharmaceutically acceptable salt thereof e.g., the HC1 salt
• a dosage form that can be used in the methods 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 HC1 salt); and from about 75 mg to about 85 mg of at least one diluent; from about 2 mg to about 10 mg of at least one binder; from about 1 % to about 5 % of at least one disintegrant; and from about 0.1 mg to about 5 mg of at least one lubricant.
• a pharmaceutically acceptable salt thereof e.g., the HC1 salt
• the dosage form or composition is administered to the subject more than once a day (e.g., twice a day, three times a day, or four times a day).
• the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one of propranolol, primidone, topiramate or a pharmaceutically acceptable salt thereof are administered in separate pharmaceutical compositions.
• each composition is administered orally once daily to the subject in need thereof.
• This multi-center clinical trial assessed the efficacy, safety, tolerability, and PK of the HC1 salt compound of Formula (I) in participants aged 18 years of age or older who have had signs and symptoms consistent with ET for at least 3 years, with an onset before age 65.
• the clinical trial was conducted in 2 parts (Part A and Part B). Both parts consisted of 3 periods: Screening/Baseline, Intervention, and Safety Follow-up Periods.
• Part B of the clinical trial consisted of both an open-label titration phase and a randomized, double-blind, placebo-controlled withdrawal phase. Part B assessed the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity and the duration of that effect.
• the daily dose levels of the HC1 salt compound of Formula (I) were titrated from 20 mg (Days 1 to 3) to 40 mg (Days 4 to 7) to 60 mg (Days 8 to 14) to 80 mg (Days 15 to 21) to 100 mg (Days 22 to 28) to 120 mg (Days 29 to 42) or the highest tolerated dose.
• participants were either maintained on their final open-label dose or switched to placebo for an additional 14 days (Days 43 to 56).
• the Screening period for Part A and Part B lasted up to 28 days (Day -28 to Day - 1). Fourteen additional days (/'. ⁇ ?., 42 days total) were allowed in the Screening period for participants who discontinued primidone.
• Key Screening assessments included medical history, demographics, physical examination, drug screen, clinical laboratory evaluations and serum pregnancy for women of childbearing potential, 12-lead ECG, vital signs, C-SSRS, assessment of ET severity using the TETRAS Performance subscale (including a video for independent review of eligibility), and a review of concomitant medications.
• potential participants who were taking prohibited medications needed to successfully discontinue those medications for at least 5 halflives or 14 days prior (whichever was the longer period of time) before the first dose of study drug.
• Baseline assessments Day 0
• Day 1 activities were combined with Day 1 activities, provided that Baseline activities were completed before dosing and that dosing occurred in the morning of Day 1.
• Baseline efficacy assessments were either conducted on Day 0 or Day 1 pre-dose, but not both to avoid learning effects.
• TETRAS Upper Limb items were also completed with accelerometry at Screening and via telehealth on Day -2 of the Screening period.
• the Screening telehealth visit was needed to ensure participants could complete the TETRAS Upper Limb assessment successfully via telehealth and to provide a pre-dose measure.
• Additional assessments added to Part B screening included TETRAS ADL and a Clinical Global Impressions scale measuring severity of illness (CGLS).
• Key safety measures included clinical laboratory evaluations, 12-lead ECG, C- SSRS, and vital signs.
• participant groups escalated to 60 mg QAM through Day 14.
• participants received a telephone call from site staff to inquire about AEs and concomitant medications, confirm dose escalation, and remind the participant about the number of study drug tablets to take on Day 15 through Day 21.
• participants escalated to 80 mg QAM through Day 21, when they returned to the clinic for safety assessments and efficacy testing.
• participants escalated to 100 mg QAM through Day 28.
• participants received a telephone call from site staff to inquire about AEs and concomitant medications, confirm dose escalation, and remind the participant about the number of study drug tablets to take on Day 29 through Day 42.
• participants escalated to 120 mg QAM through Day 42, when they returned to the clinic for safety assessments and efficacy testing.
• Part A The Safety Follow-up period took place from Day 15 to Day 21. At the end of the Safety Follow-up period, participants returned to the clinic on Day 21 ( ⁇ 1 day) for the final clinical trial assessments.
• Part B The Safety Follow-up period took place from Day 57 to Day 70. At the end of the Safety Follow-up period, participants returned to the clinic on Day 70 for the final clinical trial assessments.
• Part A In Part A of the study, 7 participants were administered study drug.
• Part B In Part B of the study, 17 participants were administered study drug for the first 42 days followed by randomization (1:1) for 2 additional weeks on either the highest tolerated dose of study drug or placebo.
• CGI-I Clinical Global Impression-Improvement
• FAS full analysis set
• OLT open-label titration
• PGI-C Patient Global Impression of Change
• RWAS randomized withdrawal analysis set
• RWD randomized withdrawal, a Change from pre-dose baseline.
• BAI Beck Anxiety Inventory
• BDI-II Beck Depression Inventory-Second Edition
• FAS full analysis set
• Preliminary Part B data showing modified activities of daily living (ADL) scores as compared to baseline combined upper limb (CUL) score is provided in FIG. 1.
• TETRA CUL and TETRAS ADL are provided in FIG. 2.
• TETRAS CUL is provided in FIG. 3.
• Part A was open-label and assessed the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity.
• Daily dose levels were titrated from 20 mg to 40 mg.
• Part B consisted of both an open-label titration phase and a randomized, double-blind, placebo-controlled withdrawal phase.
• Part B assessed the safety and tolerability of the study drug, as well as the overall magnitude and pattern of change in ET severity and the duration of that effect.
• Daily dose levels were titrated from 20 mg to up to 120 mg during the open-label phase.
• participants were either maintained on their final open-label dose or switched to placebo.
• the primary objective of this study was to evaluate the efficacy of the study drug on upper limb tremor in participants with ET.
• TETRAS PS TETRAS ADL
• the Essential Tremor Performance Based Test ET Performance Based Test
• CGI-S CGI-S
• QUEST CGI-S
• BDI-II BDI-II
• BAI Mobile Phone-Based Video Tremor Tasks
• Additional assessments were performed pre-dose including pharmacokinetic (PK) sampling.
• PK pharmacokinetic
• the Safety follow-up Period was from Day 57 to Day 70. At the end of the Safety Follow-up Period, participants returned to the study site on Day 70 ( ⁇ 1 day) for the final clinical trial assessments.
• sLMA rat spontaneous locomotor activity
• FIG. 12 is a bar graph showing traveling distance in 0-30 minutes (mm) of rats treated with harmaline (30 mg/kg) and also treated with 10 mg/kg propranolol and 1 mg/kg and 3 mg/kg of the study drug.
• FIG. 13 is a bar graph showing the same data as in FIGs. 11 and 12, and also showing the results of statistical comparison between different groups of rats, including data from an identical study from 30 mg/kg harmaline and 1 and 3 mg/kg of the study drug alone (without propranolol). As shown in FIG.

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